Pre-operative incisional biopsy of oral squamous cell carcinoma: high podoplanin expression is related to perineural invasion and may be a useful predictor of disease progression.

OBJECTIVE: Immunohistochemical analysis of podoplanin expression as a pre-operative molecular marker for perineural invasion (PNI) may represent an attractive strategy for surgical management of oral squamous cell cancer (OSCC). We evaluated the relationship between podoplanin expression and PNI in pre-operative incisional biopsies of OSCC. STUDY DESIGN: After performing pathological staging and histologic and immunohistochemical evaluation of 83 surgical specimens, we performed multivariable logistic regression analysis to examine the relationship between PNI and independent variables. To evaluate the utility of podoplanin immunopositivity for discrimination of PNI status pre-operatively, we calculated the sensitivity, specificity, positive predictive value, and negative predictive value. We performed receiver operating characteristic curve analysis to evaluate the diagnostic accuracy of podoplanin immunopositivity for predicting PNI alone and in combination with age, T stage, N stage, and index site. RESULTS: We observed podoplanin expression in 42 (50.6%) of all the 83 pre-operative incisional biopsies and 29 of the pre-operative biopsies of the 31 (93.5%) postoperative specimens with PNI. The rate of podoplanin expression was significantly higher in patients with pT3 to pT4 stage and pN+ stage disease. Podoplanin positivity in the pre-operative biopsy showed high sensitivity in predicting PNI in the surgical specimen. CONCLUSION: Podoplanin expression appears to be an independent pre-operative variable significantly related to PNI and a possibly valuable prognostic marker for therapeutical planning and surgical treatment of OSCC.

Lipid profile in Noonan syndrome and related disorders: trend by age, sex and genotype.

Background: RASopathies are developmental disorders caused by dysregulation of the RAS-MAPK signalling pathway, which contributes to the modulation of multiple extracellular signals, including hormones and growth factors regulating energetic metabolism, including lipid synthesis, storage, and degradation. Subjects and methods: We evaluated the body composition and lipid profiles of a single-centre cohort of 93 patients with a molecularly confirmed diagnosis of RASopathy by assessing height, BMI, and total cholesterol, HDL, triglycerides, apolipoprotein, fasting glucose, and insulin levels, in the context of a cross sectional and longitudinal study. We specifically investigated and compared anthropometric and haematochemistry data between the Noonan syndrome (NS) and Mazzanti syndrome (NS/LAH) groups. Results: At the first evaluation (9.5 ± 6.2 years), reduced growth (-1.80 ± 1.07 DS) was associated with a slightly reduced BMI (-0.34 DS ± 1.15 DS). Lipid profiling documented low total cholesterol levels (< 5th percentile) in 42.2% of the NS group; in particular, in 48.9% of PTPN11 patients and in 28.6% of NS/LAH patients compared to the general population, with a significant difference between males and females. A high proportion of patients had HDL levels lower than the 26th percentile, when compared to the age- and sex-matched general population. Triglycerides showed an increasing trend with age only in NS females. Genotype-phenotype correlations were also evident, with particularly reduced total cholesterol in about 50% of patients with PTPN11 mutations with LDL-C and HDL-C tending to decrease during puberty. Similarly, apolipoprotein A1 and apolipoprotein B deficits were documented, with differences in prevalence associated with the genotype for apolipoprotein A1. Fasting glucose levels and HOMA-IR were within the normal range. Conclusion: The present findings document an unfavourable lipid profile in subjects with NS, in particular PTPN11 mutated patients, and NS/LAH. Further studies are required to delineate the dysregulation of lipid metabolism in RASopathies more systematically and confirm the occurrence of previously unappreciated genotype-phenotype correlations involving the metabolic profile of these disorders.

Fabry Disease Nephropathy: Histological Changes With Nonclassical Mutations and Genetic Variants of Unknown Significance.

RATIONALE & OBJECTIVE: Fabry disease (FD) is an X-linked genetic disorder that causes lysosomal storage of glycosphingolipids, primarily globotriaosylceramide (Gb3) and its derivative globotriaosylsphingosine (lyso-Gb3), with multiorgan dysfunction including chronic kidney disease. Affected individuals may be carriers of gene variants that are of uncertain significance (GVUS). We describe kidney pathology at the early stages of FD-related kidney disease to gain insights into its association with GVUS and sex. STUDY DESIGN: Single-center, case series. SETTING & PARTICIPANTS: Thirty-five consecutively biopsied patients (aged 48.1±15.4 years, 22 females) from among 64 patients with genetically diagnosed FD. Biopsies were retrospectively screened using the International Study Group of Fabry Nephropathy Scoring System. OBSERVATIONS: Genetic mutation type, p.N215S and D313Y, sex, age, estimated glomerular filtration rate (eGFR), plasma lyso-Gb3 (pLyso-Gb3) levels, and histological parameters, including Gb3 deposits were recorded. Genetic analyses showed mostly missense mutations, p.N215S variant in 15, and the "benign polymorphism" D313Y in 4 of the biopsied patients. Morphological lesions were similar for men and women except for interstitial fibrosis and arteriolar hyalinosis being more common in men. Early in their clinical course, patients with normal/mild albuminuria had podocyte, tubular, and peritubular capillary vacuoles/inclusions, and evidence of chronicity, i.e., glomerulosclerosis, interstitial fibrosis, tubular atrophy. These findings appeared to be associated with pLyso-Gb3, eGFR, and age. LIMITATIONS: Retrospective design and inclusion of outpatients partially based on family pedigree. CONCLUSIONS: In early stages of kidney disease in the setting of FD, numerous histological abnormalities are present. These observations suggest that kidney biopsies early in FD may reveal activity of kidney involvement that may inform clinical management.

Insight in cognitive impairment assessed with the Cognitive Assessment Interview in a large sample of patients with schizophrenia.

The Cognitive Assessment Interview (CAI) is an interview-based scale measuring cognitive impairment and its impact on functioning in subjects with schizophrenia (SCZ). The present study aimed at assessing, in a large sample of SCZ (n = 601), the agreement between patients and their informants on CAI ratings, to explore patients' insight in their cognitive deficits and its relationships with clinical and functional indices. Agreement between patient- and informant-based ratings was assessed by the Gwet's agreement coefficient. Predictors of insight in cognitive deficits were explored by stepwise multiple regression analyses. Patients reported lower severity of cognitive impairment vs. informants. A substantial to almost perfect agreement was observed between patients' and informants' ratings. Lower insight in cognitive deficits was associated to greater severity of neurocognitive impairment and positive symptoms, lower severity of depressive symptoms, and older age. Worse real-life functioning was associated to lower insight in cognitive deficit, worse neurocognitive performance, and worse functional capacity. Our findings indicate that the CAI is a valid co-primary measure with the interview to patients providing a reliable assessment of their cognitive deficits. In the absence of informants with good knowledge of the subject, the interview to the patient may represent a valid alternative.

Describing communication profiles of low-risk preterm and full-term late talkers.

INTRODUCTION: Late talkers represent a heterogeneous population. We aimed to describe communication profiles of low-risk preterm and full-term late talkers according to their receptive and expressive vocabulary size, considering communicative, linguistic, cognitive, and motor skills, as well as biological and environmental risk factors. METHODS: Sixty-eight late talkers (33 born low-risk preterm and 35 full-term) were identified through a language screening at 30 months. Parents filled out the Italian Short Forms of the MacArthur Bates Communicative Development Inventories and the Socio Conversational Skills Rating Scales. Children were assessed with the Picture Naming Game test and the Bayley Scales of Infant and Toddler Development. RESULTS: A two-step cluster analysis identified three distinct profiles among late talkers according to their receptive and expressive vocabulary size. Severe late talkers (25%) showed less frequent use of pointing, limited verbal imitation, receptive vocabulary size, lexical and sentence production, responsiveness and assertiveness, and lower cognitive scores than mild late talkers (40%). Moderate late talkers (35%) showed less frequent verbal imitation, limited lexical and sentence production and lower cognitive scores than mild late talkers. Male gender was significantly more represented in the severe late profile, whereas other biological and environmental factors did not differ among the three profiles. CONCLUSIONS: Findings highlighted the relevance of assessing communicative, lexical, grammar, pragmatic, and cognitive skills to describe late talkers' profiles. A deeper investigation of phonological skills might also contribute to a further understanding of interindividual variability in this population.

Risk factors for Gram-negative bacterial infection of cardiovascular implantable electronic devices: multicentre observational study (CarDINe Study).

BACKGROUND: Infections of cardiovascular implantable electronic devices (CIED) are mainly due to Gram-positive bacteria (GPB). Data about Gram-negative bacteria CIED (GNB-CIED) infections are limited. This study aimed to investigate risk factors, clinical and diagnostic characteristics, and outcome of patients with GNB-CIED. METHODS: A multicentre, international, retrospective, case-control-control study was performed on patients undergoing CIED implantation from 2015 to 2019 in 17 centres across Europe. For each patient diagnosed with GNB-CIED, one matching control with GPB-CIED infection and two matching controls without infection were selected. RESULTS: A total of 236 patients were enrolled: 59 with GNB-CIED infection, 59 with GPB-CIED infection and 118 without infection. No between-group differences were found regarding clinical presentation, diagnostic and therapeutic management. A trend toward a higher rate of fluorodeoxyglucose positron emission computed tomography (FDG PET/CT) positivity was observed among patients with GNB than in those with GPB-CIED infection (85.7% vs. 66.7%; P = 0.208). Risk factors for GNB-CIED infection were Charlson Comorbidity Index Score (relative risk reduction, RRR = 1.211; P = 0.011), obesity (RRR = 5.122; P = 0.008), ventricular-pacing ventricular-sensing inhibited-response pacemaker implantation (RRR = 3.027; P = 0.006) and right subclavian vein site of implantation (RRR = 5.014; P = 0.004). At 180-day survival analysis, GNB-CIED infection was associated with increased mortality risk (HR = 1.842; P = 0.067). CONCLUSIONS: Obesity, high number of comorbidities and right subclavian vein implantation site were associated with increased risk of GNB-CIED infection. A prompt therapeutic intervention that may be guided using FDG PET/CT is suggested in patients with GNB-CIED infection, considering the poorer outcome observed in this group.

Relationship Between Immune Response to Severe Acute Respiratory Syndrome Coronavirus 2 Vaccines and Development of Breakthrough Infection in Solid Organ Transplant Recipients: The CONTRAST Cohort.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in solid organ transplant (SOT) recipients is associated with poorer antibody response (AbR) compared with non-SOT recipients. However, its impact on the risk of breakthrough infection (BI) has yet to be assessed. METHODS: Single-center prospective longitudinal cohort study enrolling adult SOT recipients who received SARS-CoV-2 vaccination during a 1-year period (February 2021 - January 2022), end of follow-up April 2022. Patients were tested for AbR at multiple time points. The primary end-point was BI (laboratory-confirmed SARS-CoV-2 infection ≥14 days after the second dose). Immunization (positive AbR) was considered an intermediate state between vaccination and BI. Probabilities of being in vaccination, immunization, and BI states were obtained for each type of graft and vaccination sequence using multistate survival analysis. Then, multivariable logistic regression was performed to analyze the risk of BI related to AbR levels. RESULTS: 614 SOT (275 kidney, 163 liver, 137 heart, 39 lung) recipients were included. Most patients (84.7%) received 3 vaccine doses. The first 2 consisted of BNT162b2 and mRNA-1273 in 73.5% and 26.5% of cases, respectively. For the third dose, mRNA-1273 was administered in 59.8% of patients. Overall, 75.4% of patients reached immunization and 18.4% developed BI. Heart transplant recipients showed the lowest probability of immunization (0.418) and the highest of BI (0.323); all mRNA-1273 vaccine sequences showed the highest probability of immunization (0.732) and the lowest of BI (0.098). Risk of BI was higher for non-high-level AbR, younger age, and shorter time from transplant. CONCLUSIONS: SOT patients with non-high-level AbR and shorter time from transplantation and heart recipients are at highest risk of BI.

Trust in science, medicine and medical providers and its relations to vaccine beliefs: A latent class analysis.

AIM: People may differ in their vaccine-related beliefs (i.e. efficacy, safety, purpose), with a host of factors influencing these differences. This can produce homogeneous groups of individuals who share certain beliefs, attitudes and opinions not only towards vaccines but science and medicine in general. This study aims to characterise distinct subgroups and identify ideal targets for tailored public health interventions to reinforce favourable vaccine beliefs. METHODS: Latent class analysis was used to derive unique profiles using the 2019 Gallup survey of 140 countries. We modelled a composite of vaccine beliefs and regressed this on class membership and relevant covariates. RESULTS: Patterns of item endorsement indicated a well-fitting five-class model, with classes distinguished based on whether individuals sought personal knowledge about science, medicine and health; trusted science and scientists; and reported confidence in the health care system. The lowest levels of vaccine beliefs were reported by a class lacking trust and confidence and the highest levels were reported by a class endorsing trust, confidence and desiring medical and scientific knowledge. Country-level income was moderately related to class membership, and vaccine beliefs were higher in lower-income countries. CONCLUSIONS: Findings suggest that public health campaigns can focus on improving trust in science and medical providers. Efforts to improve vaccination rates can only be achieved when individuals trust science, view the work of scientists as beneficial and hold favourable views towards health care providers. Individuals will then accrue the necessary wisdom to make good health care decisions that affect not only themselves but also their fellow citizens.

[Itching in dialysis, from the patient's point of view].

Itching is an annoying symptom, which afflicts patients with chronic renal failure. To assess the diffusion of itching in the dialysis population in Italy, we carried out a questionnaire, which was distributed to patients of various Italian dialysis centers. The purpose of this investigation was to bring out all those aspects, which make itching a state of chronic suffering, which daily undermines the quality of life of patients. The questionnaire had 16 questions on the intensity of itching, the timing of appearance, the report to doctors and nurses, and any suggested remedies, in addition to some other concerning age, sex, and dialysis age. The questionnaires were distributed to 153 Dialysis Centers and received 1905 responses. In 46.7% of the answered questionnaires, the patients declared the absence of itching. Instead, 53.3% of the patients interviewed reported having itching with varying degrees of intensity. We used for quantifying the intensity of itching the numerical rating scale (NRS). Among the interviewees, those (20.4%) who reported a greater intensity and severity of the symptom described it as often present always, even at night, so as to heavily condition sleep. Only 32.5% of patients solved the problem by contacting their nephrologist or dialysis nurse, and a lower percentage by contacting the dermatologist or general practitioner.

Universal Newborn Screening for Congenital Cytomegalovirus Infection - From Infant to Maternal Infection: A Prospective Multicenter Study.

Introduction: Most infants at risk for cytomegalovirus (CMV)-associated sensorineural hearing loss (SNHL) are unrecognized because of the absence of a universal neonatal CMV screening. The search of CMV-DNA by molecular methods in salivary swabs was demonstrated to be a reliable approach. This study describes the results obtained by carrying out a universal screening for congenital CMV (cCMV) infection including all live-born newborns in three Italian sites, as well as the therapeutic interventions and clinical outcome of the CMV-infected neonates. Moreover, CMV maternal infection's characteristics were evaluated. Methods: To confirm or exclude cCMV infection, a CMV-DNA-positive result on a first salivary swab was followed by repeated saliva and urine samples collected within 21 days of age. Breast milk samples were also collected. The search of CMV-DNA was performed with a single automated quantitative commercial real-time PCR assay, regardless of the type of samples used. Results: A total of 3,151 newborns were enrolled; 21 (0.66%) of them were congenitally infected (median saliva viral load at screening, 6.65 [range, 5.03-7.17] log10 IU/ml). Very low/low viral load in screening saliva samples (median value, 1.87 [range, 1.14-2.59] log10 IU/ml) was associated with false-positive results (n = 54; 1.7%). CMV-DNA was detected in almost half of the breast milk samples of mother-infant pairs with a false-positive result, suggesting that contamination from breast milk may not be the only explanation in the study population. cCMV infection confirmation with the search of CMV-DNA in a urine sample proved to be the gold standard strategy, since false-positive results were observed in 4/54 (7.5%) of the repeated saliva samples. Symptomatic cCMV infection was observed in 3/21 (14.3%) infants; notably, one (4.7%) developed moderate unilateral SNHL at 5 months after birth. Finally, two symptomatic cCMV infections were associated with primary maternal infection acquired in the first trimester of gestation; one newborn with severe cCMV symptoms was born to a mother with no CMV checkups in pregnancy. Conclusion: Without universal neonatal CMV screening, some infected infants who develop late neurological sequelae may not be recognized and, consequently, they are not able to benefit early from instrumental and therapeutic interventions to limit and/or treat CMV disease.

Presentation and outcome of chronic kidney disease in Italian and immigrant citizens: results from the Emilia-Romagna PIRP project.

INTRODUCTION: In recent decades, high income countries (HIC) have been exposed to huge human migratory flows. Consistent with this influx, there has been a dramatic increase in the number of chronic kidney disease (CKD) patients in the immigrant population. In Italy, comparisons between Italian and immigrant CKD patients are still lacking, thus we aimed to describe the baseline clinical characteristics and the main outcomes of CKD patients who immigrated to Italy and reside in the Emilia Romagna region. METHODS: This is a retrospective cohort study based on CKD patients from the Prevenzione Insufficienza Renale Progressiva (PIRP) project, which included 963 (3.1%) immigrants among the 30,702 patients seen by nephrologists between April 1st, 2004 and June 30th, 2020. We sub-divided the immigrants into seven groups based on their area of origin, and compared their baseline characteristics, CKD progression and time to end-stage kidney disease (ESKD) to those of Italian CKD patients. RESULTS: At presentation, Italian subjects were on average older (73.1 years) and had less preserved kidney function (eGFR 34.3 ml/min), while South and East Asians had the highest proportion of diabetes and obesity (approximately 45% and 30%, respectively). At 4-year follow-up, about 20% of patients from South Asia, Eastern Europe and Arab Countries were diagnosed with ESKD, compared to only 11% of Italians and Latin Americans. CONCLUSIONS: We found important differences between Italian and immigrant CKD patients, as well as among immigrant subgroups. First clinical encounters with nephrologists revealed that immigrants had varied patterns of clinical presentation and of nephropathy. During follow-up, immigrants showed faster kidney function decline which led to a higher risk of disease evolution and progression towards ESKD.

Primary synovial sarcoma of bone: a retrospective analysis of 25 patients.

AIMS: To evaluate the diagnostic accuracy of SSX and SSX::SS18 antibodies in decalcified surgical specimens and outcome of synovial sarcomas (SS) of bone. METHODS AND RESULTS: Twenty-five cases were classified as bone SS (prevalence 0.32% among malignant primary bone sarcoma). Median age was 34 years (range = 9-79). Twenty-four of 25 patients presented with non-metastatic tumours, one with lung metastases. The majority of tumours involved the long bones of extremities with metaphyseal origin. Mean size of the tumour was 7.1 cm. Twenty cases (80%) were monophasic and five (20%) were biphasic. SS18::SSX fusion-specific antibody had 92% sensitivity and 99% specificity for primary bone SS, whereas SSX C-terminus antibody had 100% sensitivity and 94% specificity. Fluorescence in-situ hybridisation (FISH) analysis was feasible in nine (36%) cases and detected SS18 rearrangement in all nine cases. All patients underwent surgical removal of their primary tumour, with adequate margins in 18 (72%) patients. Chemotherapy with metothrexate, cisplatin, doxorubicin and ifosfamide was used in the seven patients. Two patients with inadequate surgical margins received radiotherapy. With a median follow-up of 80 months (range = 6-428), 5- and 10-year overall survival (OS) was 66.6% and 47.9%, respectively, and 5 and 10 years' disease-free survival (DFS) was 36.8% [95% confidence interval (CI) = 18.0-55.7%] and 32.2% (95% CI = 14.6-51.2%), respectively. A significant improvement in 10 years' DFS in patients undergoing chemotherapy compared with patients who did not was observed (P = 0.039). CONCLUSIONS: Our series highlights the utility of SS18::SSX fusion-specific and SSX C-terminus antibodies to support the diagnosis of SS. Adjustment chemotherapy was associated with improved prognosis in this series.

COVID-19 incidence and mortality in non-dialysis chronic kidney disease patients.

Many studies reported a higher risk of COVID-19 disease among patients on dialysis or with kidney transplantation, and the poor outcome of COVID-19 in these patients. Patients in conservative management for chronic kidney disease (CKD) have received attention only recently, therefore less is known about how COVID-19 affects this population. The aim of this study was to provide evidence on COVID-19 incidence and mortality in CKD patients followed up in an integrated healthcare program and in the population living in the same catchment area. The study population included CKD patients recruited in the Emilia-Romagna Prevention of Progressive Renal Insufficiency (PIRP) project, followed up in the 4 nephrology units (Ravenna, Forlì, Cesena and Rimini) of the Romagna Local Health Authority (Italy) and alive at 1.01.2020. We estimated the incidence of COVID-19, its related mortality and the excess mortality within this PIRP cohort as of 31.07.2020. COVID-19 incidence in CKD patients was 4.09% (193/4,716 patients), while in the general population it was 0.46% (5,195/1,125,574). The crude mortality rate among CKD patients with COVID-19 was 44.6% (86/193), compared to 4.7% (215/4,523) in CKD patients without COVID-19. The excess mortality of March-April 2020 was +69.8% than the average mortality of March-April 2015-19 in the PIRP cohort. In a cohort mostly including regularly followed up CKD patients, the incidence of COVID-19 among CKD patients was strongly related to the spread of the infection in the community, while its lethality is associated with the underlying kidney condition and comorbidities. COVID-19 related mortality was about ten times higher than that of CKD patients without COVID. For this reason, it is urgent to offer a direct protection to CKD patients by prioritizing their vaccination.

Language Profiles and Their Relation to Cognitive and Motor Skills at 30 Months of Age: An Online Investigation of Low-Risk Preterm and Full-Term Children.

Purpose Wide interindividual variability characterizes language development in the general and at-risk populations of up to 3 years of age. We adopted a complex approach that considers multiple aspects of lexical and grammatical skills to identify language profiles in low-risk preterm and full-term children. We also investigated biological and environmental predictors and relations between language profiles and cognitive and motor skills. Method We enrolled 200 thirty-month-old Italian-speaking children-consisting of 100 low-risk preterm and 100 comparable full-term children. Parents filled out the Italian version of the MacArthur-Bates Communicative Development Inventories Infant and Toddler Short Forms (word comprehension, word production, and incomplete and complete sentence production), Parent Report of Children's Abilities-Revised (cognitive score), and Early Motor Questionnaire (fine motor, gross motor, perception-action, and total motor scores) questionnaires. Results A latent profile analysis identified four profiles: poor (21%), with lowest receptive and expressive vocabulary and absent or limited word combination and phonological accuracy; weak (22.5%), with average receptive but limited expressive vocabulary, incomplete sentences, and absent or limited phonological accuracy; average (25%), with average receptive and expressive vocabulary, use of incomplete and complete sentences, and partial phonological accuracy; and advanced (31.5%), with highest expressive vocabulary, complete sentence production, and phonological accuracy. Lower cognitive and motor scores characterized the poor profile, and lower cognitive and perception-action scores characterized the weak profile. Having a nonworking mother and a father with lower education increased the probability of a child's assignment to the poor profile, whereas being small for gestational age at birth increased it for the weak profile. Conclusions These findings suggest a need for a person-centered and cross-domain approach to identifying children with language weaknesses and implementing timely interventions. An online procedure for data collection and data-driven analyses based on multiple lexical and grammatical skills appear to be promising methodological innovations. Supplemental Material https://doi.org/10.23641/asha.14818179.

Hormone Receptor Expression Variations in Normal Breast Tissue: Preliminary Results of a Prospective Observational Study.

Normal breast tissue undergoes great variations during a woman's life as a consequence of the different hormonal stimulation. The purpose of the present study was to examine the hormonal receptor expression variations according to age, menstrual cycle, menopausal state and body mass index. To this purpose, 49 tissue samples of normal breast tissue, obtained during surgery performed for benign and malignant conditions, were immunostained with Estrogen (ER), Progesterone (PR) and Androgen receptors (AR). In addition, Ki67 and Gross Cystic Disease Fluid Protein were studied. The data obtained revealed a great variability of hormone receptor expression. ER and AR generally increased in older and post-menopausal women, while young women presented a higher proliferative rate, evaluated with Ki67. PR increase was observed in women with BMI higher than 25. The different hormonal receptor expression could favor the development of breast cancer.

Small-scale spatial distribution of COVID-19-related excess mortality.

Mortality due to massive events like the COVID-19 pandemic is underestimated because of several reasons, among which the impossibility to track all positive cases and the inadequacy of coding systems are presumably the most relevant. Therefore, the most affordable method to estimate COVID-19-related mortality is excess mortality (EM). Very often, though, EM is calculated on large spatial units that may entail different EM patterns and without stratifying deaths by age or sex, while, especially in the case of epidemics, it is important to identify the areas that suffered a higher death toll or that were spared. We developed the Stata COVID19_EM.ado procedure that estimates EM within municipalities in six subgroups defined by sex and age class using official data provided by ISTAT (Italian National Statistics Bureau) on deaths occurred from 2015 to 2020. Using simple linear regression models, we estimated the mortality trend in each age-and-sex subgroup and obtained the expected deaths of 2020 by extrapolating the linear trend. The results are then displayed using choropleth maps. Subsequently, local autocorrelation maps, which allow to appreciate the presence of local clusters of high or low EM, may be obtained using an R procedure that we developed.•We focused on estimating excess mortality in small-scale spatial units (municipalities) and in population strata defined by age and sex.•This method gives a deeper insight on excess mortality than summary figures at regional or national level, enabling to identify the local areas that suffered the most and the high-risk population subgroups within them.•This type of analysis could be replicated on different time frames, which might correspond to successive epidemic waves, as well as to periods in which containment measures were enforced and for different age classes; moreover, it could be applied in every instance of mortality crisis within a region or a country.

Intron 4-5 hTERT DNA Hypermethylation in Merkel Cell Carcinoma: Frequency, Association with Other Clinico-pathological Features and Prognostic Relevance.

Merkel cell carcinoma (MCC) is an aggressive skin tumor with neuroendocrine differentiation, mainly affecting elderly population or immunocompromised individuals. As methylation of the human telomerase reverse transcriptase (mhTERT) has been shown to be a prognostic factor in different tumors, we investigated its role in MCC, in particular in intron 4-5 where rs10069690 has been mapped and recognized as a cancer susceptibility locus. DNA methylation analysis of hTERT gene was assessed retrospectively in a cohort of 69 MCC patients from the University of Bologna, University of Turin and University of Insubria. Overall mortality was evaluated with Kaplan-Meier curves and multivariable Royston-Parmar models. High levels of mhTERT (mhTERThigh) (HR = 2.500, p = 0.015) and p63 (HR = 2.659, p = 0.016) were the only two clinico-pathological features significantly associated with a higher overall mortality at the multivariate analysis. We did not find different levels of mhTERT between MCPyV (+) and (-) cases (21 vs 14, p = 0.554); furthermore, mhTERThigh was strongly associated with older age (80.5 vs 72 years, p = 0.026), no angioinvasion (40.7% vs 71.0%, p = 0.015), lower Ki67 (50 vs 70%, p = 0.005), and PD-L1 expressions in both tumor (0 vs 3%, p = 0.021) and immune cells (0 vs 10%, p = 0.002). mhTERT is a frequently involved epigenetic mechanism and a relevant prognostic factor in MCC. In addition, it belongs to the shared oncogenic pathways of MCC (MCPyV and UV-radiations) and it could be crucial, together with other epigenetic and genetic mechanisms as gene amplification, in determining the final levels of hTERT mRNA and telomerase activity in these patients.

Factors Associated With Real-Life Functioning in Persons With Schizophrenia in a 4-Year Follow-up Study of the Italian Network for Research on Psychoses.

Importance: The goal of schizophrenia treatment has shifted from symptom reduction and relapse prevention to functional recovery; however, recovery rates remain low. Prospective identification of variables associated with real-life functioning domains is essential for personalized and integrated treatment programs. Objective: To assess whether baseline illness-related variables, personal resources, and context-related factors are associated with work skills, interpersonal relationships, and everyday life skills at 4-year follow-up. Design, Setting, and Participants: This multicenter prospective cohort study was conducted across 24 Italian university psychiatric clinics or mental health departments in which 921 patients enrolled in a cross-sectional study were contacted after 4 years for reassessment. Recruitment of community-dwelling, clinically stable persons with schizophrenia was conducted from March 2016 to December 2017, and data were analyzed from January to May 2020. Main Outcomes and Measures: Psychopathology, social and nonsocial cognition, functional capacity, personal resources, and context-related factors were assessed, with real-life functioning as the main outcome. Structural equation modeling, multiple regression analyses, and latent change score modeling were used to identify variables that were associated with real-life functioning domains at follow-up and with changes from baseline in these domains. Results: In total, 618 participants (427 male [69.1%]; mean [SD] age, 45.1 [10.5] years) were included. Five baseline variables were directly associated with real-life functioning at follow-up: neurocognition with everyday life (ß, 0.274; 95% CI, 0.207-0.341; P < .001) and work (ß, 0.101; 95% CI, 0.005-0.196; P = .04) skills; avolition with interpersonal relationships (ß, -0.126; 95% CI, -0.190 to -0.062; P < .001); positive symptoms with work skills (ß, -0.059; 95% CI, -0.112 to -0.006; P = .03); and social cognition with work skills (ß, 0.185; 95% CI, 0.088-0.283; P < .001) and interpersonal functioning (ß, 0.194; 95% CI, 0.121-0.268; P < .001). Multiple regression analyses indicated that these variables accounted for the variability of functioning at follow-up after controlling for baseline functioning. In the latent change score model, higher neurocognitive abilities were associated with improvement of everyday life (ß, 0.370; 95% CI, 0.253-0.486; P < .001) and work (ß, 0.102; 95% CI, 0.016-0.188; P = .02) skills, social cognition (ß, 0.133; 95% CI, 0.015-0.250; P = .03), and functional capacity (ß, 1.138; 95% CI, 0.807-1.469; P < .001); better baseline social cognition with improvement of work skills (ß, 0.168; 95% CI, 0.075-0.261; P < .001) and interpersonal functioning (ß, 0.140; 95% CI, 0.069-0.212; P < .001); and better baseline everyday life skills with improvement of work skills (ß, 0.121; 95% CI, 0.077-0.166; P < .001). Conclusions and Relevance: Findings of this large prospective study suggested that baseline variables associated with functional outcome at follow-up included domains not routinely assessed and targeted by intervention programs in community mental health services. The key roles of social and nonsocial cognition and of baseline everyday life skills support the adoption in routine mental health care of cognitive training programs combined with personalized psychosocial interventions aimed to promote independent living.