Effectiveness and safety of elexacaftor/tezacaftor/ivacaftor treatment in children aged 6-11 years with cystic fibrosis in a real-world setting.

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor (ETI) is a highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulating therapy for people with CF and at least one F508del variant. However, there is limited data about the safety and efficacy of this therapy in pediatric populations and in real-world settings. This study aimed at evaluating the effectiveness, tolerability, and safety of ETI in children with CF. METHODS: This was a prospective observational study including all children aged 6-11 years who initiated ETI therapy between October 2022 and March 2023 at the Pediatric CF Center of Milan (Italy). Study outcomes included changes in sweat chloride concentration, FEV1, LCI2.5, body mass index (BMI), tolerance, and safety. Mean changes in study outcomes from baseline through 24 weeks were estimated using mixed-effects regression models. RESULTS: The study included 34 children with CF (median age: 8.3 years). At Week 12, we observed an average decrease in LCI2.5 of 2.3 units (95% confidence interval [CI]: -3.1; -1.5). At Week 24, sweat chloride concentration decreased by 63 mEq/L (95% CI: -69; -58), FEV1 increased by 8.8 percentage point (95% CI: 3.7; 13.9) and BMI increased by 0.15 standard deviation scores (95% CI: 0.04; 0.25). Skin rashes appeared in 6 patients which spontaneously resolved within a few days. One month after treatment initiation, one patient experienced an elevation in liver function test results, which subsequently decreased during follow-up visits without necessitating discontinuation of therapy. CONCLUSIONS: Our data indicate that ETI therapy is well tolerated by children with CF and is effective in improving signs of lung function abnormalities from early childhood.

Heterogeneity in response to Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis.

BACKGROUND: Highly effective modulators of the CFTR channel have been demonstrated to dramatically impact disease progression and outcome. However, real-world data indicates that the magnitude of the clinical benefit is not equal among all patients receiving the treatment. We aimed to assess the variability in treatment response (as defined by the 6-month change in sweat chloride concentration, forced expiratory volume in one second [ppFEV1], body mass index [BMI], and CF Questionnaire-Revised [CFQ-R] respiratory domain score) and identify potential predictors in a group of patients receiving Elexacaftor-Tezacaftor-Ivacaftor (ETI) triple combination therapy. METHODS: This was a single-center, prospective cohort study enrolling adults with CF at a major center in Italy. We used linear regression models to identify a set of potential predictors (including CFTR genotype, sex, age, and baseline clinical characteristics) and estimate the variability in treatment response. RESULTS: The study included 211 patients (median age: 29 years, range: 12-58). Median changes (10-90th percentile) from baseline were: - 56 mEq/L (-76; -27) for sweat chloride concentration, +14.5 points (2.5; 32.0) for ppFEV1, +0.33 standard deviation scores (-0.13; 1.05) for BMI and +17 points (0; 39) for the CFQ-R respiratory domain score. The selected predictors explained 23 % of the variability in sweat chloride concentration changes, 18 % of the variability in ppFEV1 changes, 39 % of the variability in BMI changes, and 65 % of the variability in CFQ-R changes. CONCLUSIONS: This study highlights a high level of heterogeneity in treatment response to ETI, which can only be partially explained by the baseline characteristics of the disease.

Increased mortality in socioeconomic disadvantaged municipalities during the first phase of the COVID-19 pandemic in Lombardy region.

BACKGROUND: Lombardy was the first European region most severely affected by the coronavirus disease 2019 pandemic in the spring of 2020. During that period, a substantial increase in socioeconomic inequality in total mortality was observed. This study aims to evaluate mortality data in the region up to September 2023 to verify whether the increased disparities between the poorest and the wealthiest municipalities persisted in the subsequent phases of the pandemic. METHODS: This study analyzed mortality data from January 2019 to September 2023 in Lombardy's municipalities by month and pandemic phases characterized by the predominance of the different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Municipalities were grouped according to the average income or pension of their residents. Age-standardized mortality rates (ASMRs) and the ASMR ratio between the poorest and the wealthiest municipalities were compared throughout the study period. RESULTS: In the pre-pandemic period (January 2019 - February 2020), the ASMR ratio at all ages between the poorest and the wealthiest municipalities fluctuated between 1.12 [95% confidence interval (CI): 1.07-1.16] and 1.29 (95% CI: 1.25-1.34). In March 2020, the ASMR ratio increased to 1.49 (95% CI: 1.45-1.52 95%) and returned to values registered before the pandemic thereafter. A similar pattern was observed in the analysis of mortality ≥ 65, using the average pension for group municipalities. CONCLUSIONS: During the dramatic circumstances that the region faced in March 2020, pre-existing socioeconomic inequalities substantially widened. With the reorganization of the health system and the availability of vaccines, these disparities returned to the levels recorded before the pandemic.

Covid-19 in cystic fibrosis patients compared to the general population: Severity and virus-host cell interactions.

BACKGROUND: People with cystic fibrosis (pwCF) are considered at risk of developing severe forms of respiratory viral infections. We studied the consequences of COVID-19 and virus-host cell interactions in CF vs. non-CF individuals. METHODS: We enrolled CF and non-CF individuals, with /without COVID-like symptoms, who underwent nasopharyngeal swab for detection of SARS-CoV-2. Gene expression was evaluated by RNA sequencing on the same nasopharyngeal swabs. Criteria for COVID-19 severity were hospitalization and requirement or increased need of oxygen therapy. RESULTS: The study included 171 patients (65 pwCF and 106 non-CF individuals). Among them, 10 pwCF (15.4 %) and 43 people without CF (40.6 %) tested positive at RT-PCR. Symptomatic infections were observed in 8 pwCF (with 2 requiring hospitalization) and in 11 individuals without CF (6 requiring hospitalization). Host transcriptomic analysis revealed that genes involved in protein translation, particularly ribosomal components, were downregulated in CF samples irrespective of SARS-CoV-2 status. In SARS-CoV-2 negative individuals, we found a significant difference in genes involved with motile cilia expression and function, which were upregulated in CF samples. Pathway enrichment analysis indicated that interferon signaling in response to SARS-CoV-2 infection was upregulated in both pwCF and non-CF subjects. CONCLUSIONS: COVID-19 does not seem to be more severe in CF, possibly due to factors intrinsic to this population: the lower expression of ribosomal genes may downregulate the protein translation machinery, thus creating an unfavorable environment for viral replication.

Relationship Between Lung Volumes and Heterogeneity in the Response to Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Lung Disease.

BACKGROUND: The effects of elexacaftor/tezacaftor/ivacaftor (ETI) on respiratory outcomes for people with cystic fibrosis (CF) were demonstrated by several clinical trials, mainly based on simple spirometry. However, gains in lung function may vary greatly between patients, and predictors of FEV1 change after treatment are still missing. RESEARCH QUESTION: Which ventilatory parameters are involved in the heterogeneity of FEV1 change after 12-month ETI treatment in people with CF with advanced lung disease? STUDY DESIGN AND METHODS: This was a multicenter, observational, prospective cohort study at two major CF centers in Italy. We enrolled 47 adults with CF and advanced lung disease (FEV1 < 40% or actively listed for lung transplant) who started ETI treatment between December 2019 and December 2021. At treatment initiation and after 12 months, patients underwent body plethysmography. Values were compared at the two time points. To assess the relationship between baseline plethysmography measurements and treatment-induced changes in FEV1, we used the Spearman rank correlation coefficient (r) and median quantile regressions. RESULTS: After 12 months of ETI treatment, there was a significant increase in FEV1 % predicted from a median value of 36.0 (25th-75th percentile, 33-39) to 52 (25th-75th percentile, 43-61) (P < .001). Inspiratory capacity/total lung capacity (TLC) ratio also increased from 32.0 (25th-75th percentile, 28.6-36.9) to 36.3 (25th-75th percentile, 33.4-41.3) (P < .001). Specific airway resistance decreased from 263 (25th-75th percentile, 182-405) to 207 (25th-75th percentile, 120-258) (P < .001). Functional residual capacity/TLC ratio decreased from 68.2 (25th-75th percentile, 63.3-71.9) to 63.9 (25th-75th percentile, 58.8-67.1) (P < .001), and residual volume (RV)/TLC ratio decreased from 53.1 (25th-75th percentile, 48.3-59.4) to 45.6 (25th-75th percentile, 39.4-49.8) (P < .001). Changes in FEV1 % predicted negatively correlated with baseline functional residual capacity/TLC ratio (r = -0.38, P = .009) and RV/TLC ratio (r= -0.42, P = .004). After adjustment for age at treatment initiation and cystic fibrosis transmembrane conductance regulator genotype, we estimated that for each 10-unit increase in baseline RV/TLC ratio, the expected median change in FEV1 decreased by 2.3 (95% CI, -5.8 to -0.8). INTERPRETATION: ETI was associated with improvements in both static and dynamic volumes in people with CF and advanced lung disease. Heterogeneity in FEV1 % predicted change after 12 months of treatment may be predicted by the severity of hyperinflation at baseline.

Assessment of hepatic fibrosis with non-invasive indices in subjects with diabetes before and after liver transplantation.

Introduction: One of the most common complications of cirrhosis is diabetes, which prevalence is strictly related to severity of hepatopathy. Actually, there are no data on the persistence of post-transplant glucose abnormalities and on a potential impact of diabetes on development of fibrosis in the transplanted liver. To this aim, we evaluated liver fibrosis in cirrhotic subjects before and after being transplanted. Methods: The study included 111 individuals who had liver transplantation. The assessment was performed before and two years after surgery to investigate a potential impact of the persistence of diabetes on developing de novo fibrosis in the transplanted liver. The degree of fibrosis was assessed using the Fibrosis Index Based on 4 Factors (FIB-4) and the Aspartate to Platelet Ratio Index (APRI). Results: At pre-transplant evaluation, 63 out of 111 (56.8%) subjects were diabetic. Diabetic subjects had higher FIB-4 (Geometric mean, 95% confidence interval: 9.74, 8.32-11.41 vs 5.93, 4.71-7.46, P<0.001) and APRI (2.04, 1.69-2.47 vs 1.18, 0.90-1.55, P<0.001) compared to non-diabetic subjects. Two years after transplantation, 39 out of 111 (35.1%) subjects remained with diabetes and continued to show significantly higher FIB-4 (3.14, 2.57-3.82 vs 1.87, 1.55-2.27, P<0.001) and APRI (0.52, 0.39-0.69 vs 0.26, 0.21-0.32, P<0.001) compared to subjects without diabetes. Discussion: Thus, persistence of diabetes after surgery is a possible risk factor for an evolution to fibrosis in the transplanted liver, potentially leading to worsened long-term outcomes in this population.

Suicide After Partner's Death in the Elderly Population: Results From a Nationwide Cohort Study in Italy.

OBJECTIVE: This study aims to investigate the effect of partner loss on suicide mortality for surviving partners in the elderly Italian population and to explore differences according to sex and time elapsed since the loss. DESIGN: This was a historical cohort study. SETTING: All Italian residents registered by the 15th Italian Population Census (9 October 2011) were linked to emigration records and death certificates for 2012-2017 to track migration, vital status, and cause of death. PARTICIPANTS: 5,068,414 individuals living as a couple, as registered in the census, and aged ≥69 years on January 1, 2012. MEASUREMENTS: Mortality rate ratios (MRR) estimated through Poisson regression models were used to compare suicide mortality at age ≥75 years between subjects who experienced partner loss and those who did not. RESULTS: Among people who experienced partner loss, there were 383 suicide deaths in men and 90 in women. Suicide mortality was higher in older men and women who experienced the loss compared to those who did not, and the impact of the spouse loss on mortality was stronger in men (age-adjusted MRR=2.83) than in women (1.41). Among men the excess risk was particularly high during the first year following the loss; in women, no substantial differences in the excess risk were observed over the follow-up period. CONCLUSION: Study findings provide evidence of the sex differences in the impact of spouse loss based on data from a large national cohort and reinforce the need for monitoring suicide risk in recently widowed older people.

Legume intake and cancer risk in a network of case-control studies.

Evidence on the relationship between legume consumption and risk of specific cancer sites is inconclusive. We used data from a series of case-controls studies, conducted in Italy and in the Swiss Canton of Vaud between 1991 and 2009 to quantify the association between legume consumption and several cancer sites including oral cavity, esophagus, larynx, stomach, colorectum, breast, endometrium, ovary, prostate and kidney. Multiple logistic regression models controlled for sex, age, education, smoking, alcohol, body mass index, physical activity, comorbidities, and consumption of fruit, vegetables, processed meat and total calorie intake were used to estimate the odds ratios (OR) for different cancer sites and their corresponding 95% confidence intervals(CI). For female hormone-related cancers, the models also included adjustments for age at menarche, menopausal status and parity. Although most of the estimates were below unity, suggesting a protective effect, only colorectal cancer showed a significant association. Compared to no consumption, the OR for consuming at least one portion of legumes was 0.79 (95% CI: 0.68-0.91), the OR for consuming two or more portions was 0.68 (95% CI: 0.57-0.82) and the estimate for an increment of one portion per week was 0.87 (95% CI: 0.81-0.93). The inverse association between legume consumption and colorectal cancer suggests a possible role of legumes in preventing cancer risk.

Treatable traits and challenges in the clinical management of non-tuberculous mycobacteria lung disease in people with cystic fibrosis.

INTRODUCTION: Over the last ten years an increasing prevalence and incidence of non-tuberculous mycobacteria (NTM) has been reported among patients with cystic fibrosis (CF) Viviani (J Cyst Fibros, 15(5):619-623, 2016). NTM pulmonary disease has been associated with negative clinical outcomes and often requires pharmacological treatment. Although specific guidelines help clinicians in the process of diagnosis and clinical management, the focus on the multidimensional assessment of concomitant problems is still scarce. MAIN BODY: This review aims to identify the treatable traits of NTM pulmonary disease in people with CF and discuss the importance of a multidisciplinary approach in order to detect and manage all the clinical and behavioral aspects of the disease. The multidisciplinary complexity of NTM pulmonary disease in CF requires careful management of respiratory and extra-respiratory, including control of comorbidities, drug interactions and behavioral factors as adherence to therapies. CONCLUSIONS: The treatable trait strategy can help to optimize clinical management through systematic assessment of all the aspects of the disease, providing a holistic treatment for such a multi-systemic and complex condition.

No Excess Total Mortality in Italy in the First Semester of 2023 at All Ages and in the Working Age Population.

BACKGROUND: Italy experienced a sustained excess in total mortality between March 2020 and December 2022, resulting in approximately 226,000 excess deaths. This study extends the estimate of excess mortality in the country until June 2023, evaluating the persistence of excess mortality. METHODS: We used mortality and population data from 2011 to 2019 to establish a baseline for expected deaths during the pandemic. Over-dispersed Poisson regression models were employed, stratified by sex, to predict expected deaths. These models included calendar year, age group, and a smoothed function for the day of the year as predictors. Excess mortality was then calculated for all ages and working ages (25-64 years). RESULTS: From January to June 2023, we found a reduction in the number of deaths compared to the expected ones: 6,933 fewer deaths across all age groups and 1,768 fewer deaths in the working age category. This corresponds to a 2.1% and 5.2% decrease in mortality, respectively. CONCLUSIONS: The excess mortality observed in Italy from March to December 2022 was no longer observed in the first six months of 2023.

Cancers attributable to overweight and obesity in Italy.

BACKGROUND & AIMS: Overweight and obesity are associated with multiple cancers. We quantified the burden of cancer attributable to overweight and obesity in Italy. METHODS: We estimated sex- and cancer site-specific population attributable fractions (PAFs) combining relative risks (from recent meta-analyses) with national obesity prevalence data (from a large sample survey conducted in 2005, to account for a 15-year lag period). Using nationwide mortality statistics and cancer registries data, we estimated the number of cancer cases and deaths attributable to overweight and obesity in Italy in 2020, based on the counterfactual scenario of a body mass index < 25 kg/m2. RESULTS: 3.6% of cancers in men and 4.0% in women in Italy were attributable to overweight and obesity, corresponding, respectively, to over 6900 and 7200 diagnoses in 2020. Attributable deaths were over 3600 in men and 2700 in women. PAFs (attributable cases) of overweight and obesity in men and women were, respectively, 38.1% (215 cases) and 21.8% (49 cases) for esophageal adenocarcinoma, 19.1% (1715 cases) and 14.5% (585 cases) for liver, 18.7% (1692 cases) and 16.7% (747 cases) for kidney, 13.7% (938 cases) and 10.1% (749 cases) for pancreatic, and 10.2% (2389 cases) and 3.4% (690 cases) for colorectal cancers. In women, PAFs were 22.3% (1859 cases) for endometrial and 5.7% (2556 cases) for post-menopausal breast cancer. CONCLUSIONS: The cancer burden associated with overweight and obesity in Italy is considerable, but smaller compared to other high income countries, likely because of the lower prevalence of overweight and obesity in the Italian population.

A comprehensive analysis of all-cause and cause-specific excess deaths in 30 countries during 2020.

The impact of COVID-19 on mortality from specific causes of death remains poorly understood. This study analysed cause-of-death data provided by the World Health Organization from 2011 to 2019 to estimate excess deaths in 2020 in 30 countries. Over-dispersed Poisson regression models were used to estimate the number of deaths that would have been expected if the pandemic had not occurred, separately for men and women. The models included year and age categories to account for temporal trends and changes in size and age structure of the populations. Excess deaths were calculated by subtracting observed deaths from expected ones. Our analysis revealed significant excess deaths from ischemic heart diseases (IHD) (in 10 countries), cerebrovascular diseases (CVD) (in 10 countries), and diabetes (in 19 countries). The majority of countries experienced excess mortality greater than 10%, including Mexico (+ 38·8% for IHD, + 34·9% for diabetes), Guatemala (+ 30·0% for IHD, + 10·2% for CVD, + 39·7% for diabetes), Cuba (+ 18·8% for diabetes), Brazil (+ 12·9% for diabetes), the USA (+ 15·1% for diabetes), Slovenia (+ 33·8% for diabetes), Poland (+ 30·2% for IHD, + 19·5% for CVD, + 26 1% for diabetes), Estonia (+ 26·9% for CVD, + 34·7% for diabetes), Bulgaria (+ 22·8% for IHD, + 11·4% for diabetes), Spain (+ 19·7% for diabetes), Italy (+ 18·0% for diabetes), Lithuania (+ 17·6% for diabetes), Finland (+ 13·2% for diabetes) and Georgia (+ 10·7% for IHD, + 19·0% for diabetes). In 2020, 22 out of 30 countries had a significant increase in total mortality. Some of this excess was attributed to COVID-19, but a substantial increase was also observed in deaths attributed to cardiovascular diseases and diabetes.

Cancer mortality associated with low education in Italy.

BACKGROUND: This study provides a nationwide representative quantification of the impact of educational inequalities on cancer mortality in Italy. METHODS: The study is based on prevalence data and mortality rate ratios according to levels of education obtained from the Italian 2011 census cohort, including >35 million individuals aged 30-74. We estimated the population attributable fraction (PAF) and the number of cancer deaths associated with low education (below university degree) in Italy by sex. RESULTS: PAFs for low levels of education were 29.1% among men and 13.3% among women, corresponding to 22,271 cancer deaths associated with low education in men and 7456 in women in 2019. PAFs by cancer site in men were: 53.0% for upper aerodigestive tract (UADT), 44.6% for liver, 41.3% for stomach, 41.3% for lung, 37.0% for bladder, 18.5% for colorectal, 9.8% for prostate and 9.1% for pancreatic cancers. PAFs in women were: 44.5% for cervical, 36.1% for UADT, 34.9% for stomach and 13.9% for colorectal cancers. The cancer sites with the highest number of deaths associated with low education were lung among men (7902/22,271, 35.5%) and colorectum among women (780/7456, 10.5%). CONCLUSIONS: About a quarter of cancer deaths in 2019 in Italy may be prevented by reducing the socioeconomic determinants that contribute to educational disparities in cancer mortality.

ChatGPT: unlocking the potential of Artifical Intelligence in COVID-19 monitoring and prediction.

BACKGROUND: The COVID-19 pandemic has had an unprecedent impact of everyday life with deleterious consequences on global health, economics, and society. Thus, accurate and timely information is critical for monitoring its spread and mitigating its impact. ChatGPT is a large language model chatbot with artificial intelligence, developed by OpenAI, that can provide both textual content and R code for predictive models. It may prove to be useful in analyzing and interpreting COVID-19-related data. METHODS: This paper explores the application of ChatGPT to the monitoring of the COVID-19 pandemic, presenting R code for predictive models and demonstrating the model's capabilities in sentiment analysis, information extraction, and predictive modelling. We used the prediction models suggested by ChatGPT to predict the daily number of COVID-19 deaths in Italy. The prediction accuracy of the models was compared using the following metrics: mean squared error (MSE), mean absolute deviation (MAD) and root mean squared error (RMSE). RESULTS: ChatGPT suggested three different predictive models, including ARIMA, Random Forest and Prophet. The ARIMA model outperformed the other two models in predicting the daily number of COVID-19 deaths in Italy, with lower MSE, MAD, and RMSE values as compared to the Random Forest and Prophet. CONCLUSIONS: This paper demonstrates the potential of ChatGPT as a valuable tool in the monitoring of the pandemic. By processing large amounts of data and providing relevant information, ChatGPT has the potential to provide accurate and timely insights, and support decision-making processes to mitigate the spread and impact of pandemics. The paper highlights the importance of exploring the capabilities of artificial intelligence in the management of public emergencies and provides a starting point for future research in this area.

Effects of elexacaftor / tezacaftor / ivacaftor triple combination therapy on glycaemic control and body composition in patients with cystic fibrosis-related diabetes.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a group of new drugs for the treatment of cystic fibrosis (CF) and elexacaftor + tezacaftor + ivacaftor (ETI) triple combination therapy has been approved as first choice therapy in the treatment of patients with at least 1 copy of F508del variation. Data on the effects of CFTR modulators on glucose metabolism are limited to small studies with conflicting results. We conducted a prospective observational study on 24 CF patients with CF-related diabetes requiring insulin therapy, with the aim to evaluate the effectiveness of ETI on glucose metabolism, glucose variability and body composition. After six months of treatment, HbA1c and coefficient of variation, measured through flash or continuous glucose monitoring, significantly decreased (median changes: -0.5, P = 0.029 and -6.3, P = 0.008, respectively), despite unchanged insulin requirements. Over the treatment period, percent of fat mass increased by a median value of 3% (p = 0.029).

Unplanned pregnancies following the introduction of elexacaftor/tezacaftor/ivacaftor therapy in women with cystic fibrosis.

Cystic fibrosis (CF) causes infertility and subfertility due to various factors, including altered cervical mucus, delayed puberty, and hormonal imbalances. With the introduction of the CFTR modulator therapy elexacaftor-tezacaftor-ivacaftor, we have observed an increase in unplanned pregnancies among women undergoing ETI treatment in our CF center, despite repeated recommendations for strict fertility monitoring. It appears that these pregnancies are more likely attributed to reduced attention to the possibility of conception rather than contraceptive failure. The perception of subfertility developed by women with CF over time, before the era of modulators, can influence their long-term habits and lead to the underuse of contraceptive methods. While further research is needed to fully understand the effects of ETI on fertility, healthcare providers should be attentive to the fertility concerns of women with CF, particularly those treated with modulators in adulthood.

Heterogeneity of weight gain after initiation of Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis.

BACKGROUND: The introduction of the novel therapy, Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been effective in improving weight gain in both clinical trials and real-world studies. However, the magnitude of this effect appears to be heterogeneous across patient subgroups. This study aims to identify potential determinants of heterogeneity in weight gain following 6-month ETI therapy. METHODS: We conducted a multicenter, prospective cohort study enrolling 92 adults with CF at two major CF centers in Italy with follow-up visit at one month and six months from ETI initiation. The treatment's effect on weight changes was evaluated using mixed effect regression models that included subject-specific random intercepts and fixed effects for potential predictors of treatment response, time and a predictor-by-time interaction term. RESULTS: The mean weight gain at six months from the start of treatment was 4.6 kg (95% CI: 2.3-6.9) for the 10 patients with underweight, 3.2 kg (95% CI: 2.3-4.0) for the 72 patients with normal weight, and 0.7 kg (95% CI: -1.6-3.0) for the 10 patients with overweight. After six months of ETI treatment, 8 (80%) of the patients with underweight transitioned to the normal weight category, while 11 (15.3%) of the normal-weight patients became overweight. The major determinants of heterogeneity in weight gain were the baseline BMI and the presence of at least one CFTR residual function mutation, explaining 13% and 8% of the variability, respectively. CONCLUSIONS: Our results indicate that ETI is highly effective in improving weight gain in underweight subjects with CF. However, our data also suggests the need for close monitoring of excess weight gain to prevent potential cardiometabolic complications.

Excess Total Mortality in Italy: An Update to February 2023 with Focus on Working Ages.

BACKGROUND: Italy had a persistent excess of total mortality up to July 2022. This study provides updated estimates of excess mortality in Italy until February 2023. METHODS: Mortality and population data from 2011 to 2019 were used to estimate the number of expected deaths during the pandemic. Expected deaths were obtained using over-dispersed Poisson regression models, fitted separately for men and women, including calendar year, age group, and a smoothed function of the day of the year as predictors. The excess deaths were then obtained by calculating the difference between observed and expected deaths and were computed at all ages and working ages (25-64 years). RESULTS: We estimated 26,647 excess deaths for all ages and 1248 for working ages from August to December 2022, resulting in a percent excess mortality of 10.2% and 4.7%, respectively. No excess mortality was detected in January and February 2023. CONCLUSIONS: Our study indicates substantial excess mortality beyond those directly attributed to COVID-19 during the BA.4 and BA.5 Omicron wave in the latter half of 2022. This excess could be attributed to additional factors, such as the heatwave during the summer of 2022 and the early onset of the influenza season.

Non-sugar sweeteners and cancer: Toxicological and epidemiological evidence.

Several toxicological and epidemiological studies were published during the last five decades on non-sugar sweeteners (NSS) and cancer. Despite the large amount of research, the issue still continues to be of interest. In this review, we provided a comprehensive quantitative review of the toxicological and epidemiological evidence on the possible relation between NSS and cancer. The toxicological section includes the evaluation of genotoxicity and carcinogenicity data for acesulfame K, advantame, aspartame, cyclamates, saccharin, steviol glycosides and sucralose. The epidemiological section includes the results of a systematic search of cohort and case-control studies. The majority of the 22 cohort studies and 46 case-control studies showed no associations. Some risks for bladder, pancreas and hematopoietic cancers found in a few studies were not confirmed in other studies. Based on the review of both the experimental data on genotoxicity or carcinogenicity of the specific NSS evaluated, and the epidemiological studies it can be concluded that there is no evidence of cancer risk associated to NSS consumption.

Characterization of CFTR mutations in people with cystic fibrosis and severe liver disease who are not eligible for CFTR modulators.

Cystic-fibrosis-related liver disease (CFLD) is a variable phenotype of CF. The severe CFLD variant with cirrhosis or portal hypertension has a poor prognosis and life expectancy. CFTR modulator therapies are now available for people with CF and eligibility for such treatment is based on their CFTR genotype. We evaluated the genetic eligibility for elexacaftor, tezacaftor, ivacaftor (ETI), and ivacaftor (IVA) monotherapy in a previously reported CF cohort of 1591 people with CF of whom 171 with severe CFLD. Based on their CFTR mutations, 13% (N=184/1420) of subjects without CFLD and 11% (N=19/171) of those with severe CFLD are not eligible for either ETI or IVA therapy. The non-eligible patients without CFLD or with severe CFLD can currently not take advantage of the potential benefits of these new treatments. Although this study cannot provide any data regarding the effect of ETI or IVA on the progression of severe CFLD, the consequences for ineligibility of patients with extreme liver phenotype may be even more significant because of their poorer disease risk profile.