De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling.

Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants.

Regulation of autophagosome biogenesis by OFD1-mediated selective autophagy.

Autophagy is a lysosome-dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy-mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral-Facial-Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self-regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals.

Dental age estimation in children affected by juvenile rheumatoid arthritis.

Dental root calcification has proven to be a reliable biological evidence to estimate chronological age of children. The development of structures usually examined in the age estimation forensic practice (e.g. skeleton, teeth) is supposed to be influenced by diseases and nutritional, environmental, ethnic, and ultimately even socioeconomic factors. This research aims to study the age estimation in children affected by juvenile rheumatoid arthritis (JRA) with and without steroids treatment and compared with healthy subjects. MATERIAL AND METHODS: Dental age estimations based on 752 OPGs, 420 girls and 332 boys, aged from 3.3 to 15.99 years, were provided by applying Demirjian and Willems' original methods. Of the whole sample, 103 individuals were affected by JRA and 40 received a continuous corticosteroid therapy, over 1 year long. CONCLUSIONS: Willems' and Demirjian's original methods, as methods commonly applied to estimate age for sub-adults with unremarkable medical history, can be used for medico-legal purposes to children affected by JRA. Willems' method tended to underestimate age while Demirjian's method resulted to be prone to overestimation for both healthy and JRA-affected children. JRA showed to have no influence on root calcification process even in children that received steroid treatment for 1 year or longer.

Comparison of Frontal Sinuses for Personal Identification in 3 Populations Using Cameriere's Code Number.

ABSTRACT: The identification of unknown individuals is of crucial importance to society, especially in the context of mass disasters involving individuals of different nationalities. The comparison of frontal sinus patterns is an important tool for personal identification. In Cameriere's method, a new personal code number (codC) containing 8 digits was elaborated, based on the measurements of frontal sinus patterns. The present study is an update of this previous work. Digital radiographic images of the skulls of 299 individuals of different nationalities (100 Italians, 99 Kosovars, and 100 Turks) were analyzed, adopting the same maximum-weight dependence tree used in the original work. For comparisons between groups, Fisher exact test and the χ2 test were carried out. The method, applied to different population groups, significantly increases the likelihood of identifying a person by comparison of antemortem and postmortem frontal sinus radiographs. Results demonstrated that the model is more discriminative in identifying individuals of different nationalities.

Age estimation in Turkish children and young adolescents using fourth cervical vertebra.

This study aimed to test radiographic projections of the posterior and anterior sides of the C4 vertebral body for age estimation in a cross-sectional sample of Turkish children and adolescents from the Baskent University Faculty of Dentistry. A sample of 232 x-rays from individuals aged between 5 and 15 years (101 boys and 131 girls) was analysed to investigate the correlation of age and changes in the projection ratio of the anterior and posterior sides of the body of the fourth cervical vertebra (Vba) in lateral cephalograms. The Normal Bayesian Calibration (NBC) model for age estimation was used to assess the relationship between Vba and age. The intra-observer repeatability and inter-observer agreement were 0.95 and 0.94, respectively. Age distribution gradually increased as Vba increased up to 14 years in both sexes. The difference between chronological and estimated ages did not increase with the increase in age. Calibration distributions of the dataset by the evaluation of Vba suggested mean absolute errors (MAEs) of 0.879 years and 0.906 years (mean interquartile ranges (MIQRs) 1.290 and 1.435 years)) in boys and girls, respectively. The biases of the estimates (ßERR) were 0.013 and 0.027 for boys and girls, respectively. In conclusion, the NBC method on Vba variable appears to be suitable for age estimation in Turkish children and adolescents.

Low incidence of nephrotoxicity following intravenous administration of iodinated contrast media: a prospective study.

OBJECTIVES: To estimate the incidence of contrast-induced acute kidney injury (CI-AKI) after intravenous (iv) iodinated contrast material (ICM) exposure. METHODS: This prospective cohort study included all consecutive patients who underwent radiological investigations using low-osmolar iopamidol 370 mg/ml in a regional hospital over a period of 36 months, without any exclusion criteria. The estimated glomerular filtration rate (eGFR) was evaluated using the MRDR equation before (2-10 days) and after (24-36 h) radiological investigations. CI-AKI was defined as a ≥ 25% decrease in eGFR from baseline. CI-AKI incidence was estimated using a binomial distribution. The association between CI-AKI and demographic and clinical characteristics was modeled using logistic regression. RESULTS: The study included 1541 patients with a median age of 68 (1st-3rd quartiles 58-76) years with various comorbidities, 30% of whom had pre-existing CKD. Patients affected by stage III or IV chronic kidney disease (CKD) received an infusion of 0.9% normal saline (1.0-1.5 ml/kg/h) before and after iso-osmolar iodixanol administration. CI-AKI was observed in 33 patients (2.1%, 95% CI 1.5-3.0). The logistic regression analysis showed that antibiotic and statin therapies were significantly associated with CI-AKI. The probability of developing CI-AKI decreased by 80% in patients taking statins (OR = 0.20, 95% CI 0.03; 0.68) and increased approximately three times in patients with antibiotic therapy compared with those who did not take statins and antibiotics (OR = 2.92, 95% CI 1.21; 6.36). CONCLUSIONS: Our data suggest that low-osmolar iopamidol carries a low incidence of nephrotoxicity, even in subjects with various comorbid conditions or reduced renal function. KEY POINTS: • IV administration of ICM carries a low incidence of nephrotoxicity, which was transient in observed patients. • Statin therapy is negatively associated with AKI in patients exposed to ICM. • Pre-existing impairment of renal function is not associated with AKI in patients exposed to ICM.

Carpals and epiphyses of radius and ulna as age indicators using longitudinal data: a Bayesian approach.

The aim of this study is to develop a new formula for age estimation in a longitudinal study of a sample from the radiological collection of wrist bones of growing infants, children, and adolescents recorded at the Burlington Growth Centre. A sample of 82 individuals (43 boys and 39 girls), aged between 3 and 16 years, were analyzed with a total of 623 X-rays of left hand-wrist bones by measuring the area of carpal bones and epiphyses of the ulna and radius (Bo) and carpal area (Ca). The intra-class correlation coefficient (ICC) and its 95% confidence interval were used to evaluate intra-observer agreement. Hierarchical Bayesian calibration has been adopted to exceed the bias deriving from the classical regression approach used for age estimation in forensic disciplines, since it tends to overestimate or underestimate the age of the individuals. Calibration distributions of the dataset obtained by the evaluation of BoCa (the ratio of Bo and Ca) suggested mean absolute errors (MAE) of 1.07 and 1.34 years in boys and girls, respectively. The mean interquartile range (MIQR) was 1.7 and 2.42 years in boys and girls, respectively. The respective bias of the estimates was ßERR = - 0.025 and - 0.074. Furthermore, a correspondence between different BoCa values and estimated age with its standard deviation (SD) was calculated for boys and girls, respectively. In conclusion, the Bayesian calibration method appears to be suitable for assessing both age and its distribution in subadults, according to hand-wrist maturity. Furthermore, it can easily incorporate other age predictors, obtaining a distribution of the subjects with multivariate predictors.

Segmented Bayesian calibration approach for estimating age in forensic science.

Forensic age estimation is receiving growing attention from researchers in the last few years. Accurate estimates of age are needed both for identifying real age in individuals without any identity document and assessing it for human remains. The methods applied in such context are mostly based on radiological analysis of some anatomical districts and entail the use of a regression model. However, estimating chronological age by regression models leads to overestimated ages in younger subjects and underestimated ages in older ones. We introduced a full Bayesian calibration method combined with a segmented function for age estimation that relied on a Normal distribution as a density model to mitigate this bias. In this way, we were also able to model the decreasing growth rate in juveniles. We compared our new Bayesian-segmented model with other existing approaches. The proposed method helped producing more robust and precise forecasts of age than compared models while exhibited comparable accuracy in terms of forecasting measures. Our method seemed to overcome the estimation bias also when applied to a real data set of South-African juvenile subjects.

A biochemical approach for assessing cutoffs at the age thresholds of 14 and 18 years: a pilot study on the applicability of bone specific alkaline phosphatase on an Italian sample.

BACKGROUND: The majority of age estimation methods analyze morphological changes of specific skeletal (or dental) structures reflecting global bone development (biological parameter) in order to estimate a chronological value. This morphological and structural development is the consequence of a very active tissue metabolism and intensive modeling process which involve both bone formation and bone resorption. Several biochemical markers of bone formation and bone resorption are available, and specific biochemical tests can be performed on blood or urine samples, but such markers of bone turnover have never been employed for age estimation in living individuals for forensic purposes. The aim of this study was to ascertain the applicability of serum bone alkaline phosphatase (BALP) concentration in the age estimation for forensic purposes. We focused on the legal age thresholds of 14 and 18 years (LAT) because, in Italy, the former is considered the minimum age for criminal responsibility and the latter defines adult age and the possibility of applying general criminal laws. MATERIALS AND METHODS: This study analyzed, from a forensic point of view, BALP and Tanner stages of 202 healthy white individuals (116 females and 86 males) between the ages of 10 and 30 years. We derived a linear logistic model to estimate the probability that an individual was older or younger than LAT using two variables: BALP concentration and Tanner stages. The predictive accuracy of the test was assessed by the determination of the receiver-operating characteristic curve (ROC curve). The test was performed to identify a threshold (cutoff) that could be used to assign an individual to the population of those younger or older than LAT. RESULTS: ROC curve showed that the use of both serum BALP concentration and Tanner stages has a very good level of reliability in age assessment (the area under the ROC curve, AUC, ranged from 0.918 to 0.962). Best results were obtained in the assessment of male over 18 years of age (sensibility and specificity respectively of 0.90 and 0.93 with an accuracy of 0.92). Worst results were obtained in the assessment of female over 18 years of age (sensibility and specificity respectively of 0.87 and 0.82 with an accuracy of 0.84). We also calculated the probability of the correctness in the age estimation. CONCLUSION: The results showed that the use of serum BALP concentration in the age assessment could be a promising and integrative method to established ones, but more research has to be done to validate the value of the proposed method in the forensic practice.

Bayesian calibration for forensic age estimation.

Forensic medicine is increasingly called upon to assess the age of individuals. Forensic age estimation is mostly required in relation to illegal immigration and identification of bodies or skeletal remains. A variety of age estimation methods are based on dental samples and use of regression models, where the age of an individual is predicted by morphological tooth changes that take place over time. From the medico-legal point of view, regression models, with age as the dependent random variable entail that age tends to be overestimated in the young and underestimated in the old. To overcome this bias, we describe a new full Bayesian calibration method (asymmetric Laplace Bayesian calibration) for forensic age estimation that uses asymmetric Laplace distribution as the probability model. The method was compared with three existing approaches (two Bayesian and a classical method) using simulated data. Although its accuracy was comparable with that of the other methods, the asymmetric Laplace Bayesian calibration appears to be significantly more reliable and robust in case of misspecification of the probability model. The proposed method was also applied to a real dataset of values of the pulp chamber of the right lower premolar measured on x-ray scans of individuals of known age.

Radiological tooth/pulp ratio in canines and individual age estimation in a sample of adult neolithic skeletons from Italy.

OBJECTIVES: The estimation of an individual's age at the time of death is one of the most important components in anthropological studies and is the basis for demographic studies on ancients. However, the different methods commonly used in anthropology for adult age estimation at death provide results with a high level of uncertainty. The consequence is the inability to develop demographic studies with a good degree of reliability. A non-destructive method currently available is the analysis of the apposition of secondary dentine on which Cameriere's method is based. MATERIALS AND METHODS: The purpose of this work was age estimation using Cameriere's method on a sample of 18 adult Neolithic skeletons from four sites in Southern Italy (Apulia): Carpignano, Masseria della Marina, Samari and Serra Cicora. The estimates derived from the study of mandibular and maxillary canines were compared with the age ranges obtained with commonly used anthropological indicators: fusion of cranial sutures, degree of tooth wear, remodelling of the pubic symphysis and the auricular surface of the ilium. The latter two provide intervals which encompass the ages estimated with Cameriere's method. RESULTS: The results show that the population was composed of individuals of advanced age, even beyond the age of 50, hardly distinguishable by other methods. DISCUSSION: This finding may support the hypothesis that individuals aged 50+ are rare in prehistoric skeletal samples due to the unreliability of classical anthropological methods, not only because they were actually rare in prehistoric populations, or absent for taphonomical reasons.

Reliability of frontal sinus by cone beam-computed tomography (CBCT) for individual identification.

Analysis of the frontal sinus is an important tool in personal identification. Cone beam-computed tomography (CBCT) is also progressively replacing conventional radiography and multi-slice computed tomography (MSCT) in human identification. The aim of this study is to develop a reproducible technique and measurements from 3D reconstructions obtained with CBCT, for use in human identification. CBCT from 150 patients (91 female, 59 male), aged between 15 and 78 years, was analysed with the specific software program MIMICS 11.11 (Materialise N.V., Leuven, Belgium). Corresponding 3D volumes were generated and maximal dimensions along 3 directions (x, y, z), X M, Y M, Z M (in mm), total volume area (in mm(3)), V t, and total surface (in mm(2)), S t, were calculated. Correlation analysis showed that sinus surfaces were strongly correlated with their volume (r = 0.976). Frontal sinuses were separate in 21 subjects (14 %), fused in 67 (44.6 %) and found on only one side (unilateral) in 9 (6 %). A Prominent Middle of Fused Sinus (PMS) was found in 53 subjects (35.3 %). The intra- (0.963-0.999) and inter-observer variability (0.973-0.999) showed a great agreement and a substantial homogeneity of evaluation.

Role of viable but non culturable cells in patients with cystic fibrosis in the era of highly effective modulator therapy.

BACKGROUND: Lung infections antibiotic treatment in Cystic Fibrosis patients (pwCF) is often complicated by bacterial persisters, including the so-called Viable but Non Culturable (VBNC) forms, live cells undetected by the routine cultural microbiological methods. This study investigated the occurrence of VBNC cells of five CF bacterial pathogens in 94 pwCF over one year and the possible associations with the patients' clinical features. METHODS: Sputum samples, recovered at routine visits and during exacerbation episodes, were analyzed for the presence of the five pathogens by both routine culture-based assays and species-specific qPCR. VBNC cells were estimated as the difference between molecular and cultural counts and their presence was matched with the clinical data in particular the therapeutic regimens. RESULTS: All but ten pwCF showed the presence of VBNC cells at least once during the study. Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus aureus were the species most frequently found in the VBNC state. Only the former showed a significant association between chronic infection and VBNC cells presence; VBNC-MSSA positive patients significantly increased overtime. The presence of non culturable bacteria was generally concurrent with poor lung functionality and more frequent pulmonary exacerbations. No significant association with modulator treatment was evidenced. CONCLUSIONS: The obtained data demonstrated the overwhelming occurrence of bacterial VBNC cells in CF lung infections, warranting a constant monitoring of pwCF and underlining the need of implementing the routine culture-based assays with culture-independent techniques. This is pivotal to understand the CF bacterial population dynamics and to efficiently contrast the lung infection progression and worsening.

A MiR181/Sirtuin1 regulatory circuit modulates drug response in biliary cancers.

Despite recent advances, biliary tract cancer (BTC) remains one of the most lethal tumor worldwide due to late diagnosis, limited therapeutic strategies and resistance to conventional therapies. In recent years, high-throughput technologies have enabled extensive genome, and transcriptome sequencing unveiling, among others, the regulatory potential of microRNAs (miRNAs). Compelling evidence shown that miRNA are attractive therapeutic targets and promising candidates as biomarkers for various therapy-resistant tumors. The analysis of miRNA profile successfully identified miR-181c and -181d as significantly downregulated in BTC patients. Low miR-181c and -181d expression levels were correlated with worse prognosis and poor treatment efficacy. In fact, progression-free survival analysis indicated poor survival rates in miR-181c and -181d low expressing patients. The expression profile of miR-181c and -181d in BTC cell lines revealed that both miRNAs were dysregulated. Functional in vitro experiments in BTC cell lines showed that overexpression of miR-181c and -181d affected cell viability and increased sensitivity to chemotherapy compared to controls. In addition, by using bioinformatic tools we showed that the miR-181c/d functional role is determined by binding to their target SIRT1 (Sirtuin 1). Moreover, BTC patients expressing high levels of miR-181 and low SIRT1 shown an improved survival and treatment response. An integrative network analysis demonstrated that, miR-181/SIRT1 circuit had a regulatory effect on several important metabolic tumor-related processes. Our study demonstrated that miR-181c and -181d act as tumor suppressor miRNA in BTC, suggesting the potential use as therapeutic strategy in resistant cancers and as predictive biomarker in the precision medicine of BTC.

An Effective Model for Estimating Age in Unaccompanied Minors under the Italian Legal System.

This article presents an effective model for estimating the age of subjects without identification documents, in accordance with Italian legislation covering unaccompanied minors, using instrumental methods recognized by the scientific community for age estimation. A decision-making tree has been developed, in which the first step is a physical examination. If secondary sexual characteristics are fully developed and there are no obvious signs of abnormal growth, dental X-rays are the next step. If the roots of the seven left mandibular teeth between the central incisor and the second molar are completely developed, the focus then moves to the third molar. If the index of the third molar (I3M) value is less than 0.08, or if third molars are not assessable, the following step is to study the clavicle which, if fully formed, indicates that the subject is an adult with 99.9% probability; otherwise, the probability is 96%. In all other cases (where the I3M is over 0.08), the probability that the subject has reached 18 years is less than 60%. The research, carried out initially on x-rays of the wrist, teeth and clavicle, highlighted the uselessness of the x-ray of the wrist for determining the age of majority, because in our sample, all subjects with incomplete maturity of hand/wrist bones were under 16 years of age; thus, OPT was necessary anyway. What we propose is a practical, easily feasible, fast, economical, and extremely reliable method, which can be used on Caucasian populations and beyond for multiple forensic purposes.

Combining Bayesian Calibration and Copula Models for Age Estimation.

Accurately estimating and predicting chronological age from some anthropometric characteristics of an individual without an identity document can be crucial in the context of a growing number of forced migrants. In the related literature, the prediction of chronological age mostly relies upon the use of a single predictor, which is usually represented by a dental/skeletal maturity index, or multiple independent ordinal predictor (stage of maturation). This paper is the first attempt to combine a robust method to predict chronological age, such as Bayesian calibration, and the use of multiple continuous indices as predictors. The combination of these two aspects becomes possible due to the implementation of a complex statistical tool as the copula. Comparing the forecasts from our copula-based method with predictions from an independent model and two single predictor models, we showed that the accuracy increased.

One-lung ventilation in obese patients undergoing thoracoscopic lobectomy for lung cancer.

BACKGROUND: We evaluated the safety and feasibility of one-lung ventilation in obese patients undergoing thoracoscopic lobectomy and whether obesity affected peri- and postoperative outcomes. METHODS: This was a retrospective single center study including consecutive patients undergoing thoracoscopic lobectomy between October 2019 and February 2022. Obese patients were statistically compared to a control group to evaluate any differences in relation to one-lung ventilation and peri- and postoperative outcomes. RESULTS: Our study population included 111 patients; of these, 26 (23%) were included in the obese group, while 85 (77%) were included within the nonobese group. To obtain one-lung ventilation in nonobese patients, a double-lumen tube was more frequently used than a single-lumen tube with bronchial blocker (61% vs. 39%; p = 0.02), while in obese patients a single-lumen tube with bronchial blocker was used more than a double-lumen tube (81% vs. 19%, p = 0.001). Intergroup comparison showed that a double-lumen tube was the preferred method in nonobese patients, while a single-lumen tube with bronchial blockers was the strategy of choice in obese patients (p = 0.0002). Intubation time was longer in the obese group than in the nonobese group (94.0 ± 6.1 vs. 85.0 ± 7.0 s; p = 0.0004) and failure rate of first attempt at intubation was higher in the obese group (23% vs. 5%; p = 0.01). Obesity was not associated with increased intra-, peri- and postoperative complications and/or mortality. CONCLUSIONS: One-lung ventilation is a feasible and safe procedure also in obese patients and obesity did not negatively affect peri- and postoperative outcomes after lung resection.

Intraoperative DTI and brain mapping for surgery of neoplasm of the motor cortex and the corticospinal tract: our protocol and series in BrainSUITE.

We report our preliminary series of patients treated for lesions involving the motor cortex and the corticospinal tract in BrainSuite, with intraoperative MRI, tractography and "neuronavigated" electrophysiological cortical and subcortical mapping. An exact localization of the cortical and subcortical functional areas is mandatory for executing surgery of intra-parenchymal neoplasm involving the motor cortex and the corticospinal tract. Nowadays modern technology offers a variety of tools to reduce as much as possible postoperative deficits during surgery of cerebral eloquent areas. From December 2008 and June 2010, 18 patients underwent functional surgery, for neoplasm involving the motor cortex and/or the subcortical pathway, in BrainSuite. Our preliminary series include 14 gliomas and 4 metastases; Table 1 summarizes all of the data. We included in this series patients with complete removal of lesions of eloquent areas with an average distance from the corticospinal tract of 4 mm. Six neoplasms were considered in contact and/or involving the motor cortex, while in 18 cases (100%) the tumour involved eloquent areas concerning the corticospinal tract. All of the patients underwent complete removal of the lesion as subsequently demonstrated by intraoperative postsurgical MRI. Our series highlights the good integration and the high compatibility between BrainSUITE with 1.5 T intraoperative magnetic field and neurophysiological monitoring. We strongly believe that intraoperative MRI with DTI allows us to treat complex surgery tumours that without its auxilium we would not be able to deal with.

Traditional endonasal and microscopic sinus surgery complications versus endoscopic sinus surgery complications: a meta-analysis.

The aim of this study was to compare the incidence of complications of endoscopic sinus surgery (ESS) to the incidence of complications of traditional and microscopic sinus surgery. A meta-analysis was carried out on 28 series of patients (a total of 13,405) who had undergone ESS, 8 series of patients (3,887 in total) who had undergone traditional endonasal sinus surgery and 7 series of patients (1,630 in total) who had undergone microscopic sinus surgery. The authors used the Bayesian inference package WinBUGS operating from within the statistical computer program R (version 2.7.1). Major complications had a higher incidence after traditional sinus surgery than ESS but this fact did not cause a significant statistical difference, whereas microscopic surgery had significantly more complications than ESS (p < 0.05). Carrying out our meta-analytic study, comparing major and minor complications of endonasal surgical approaches, was very difficult due to several methodological biases of data extraction and evaluation from studies concerning a broad timespan. Regarding major complications, we only found a significant statistical difference (p < 0.05) between the endoscopic (1%) and the microscopic methods (2.0%), but, if we had analyzed the data considering the natural learning curve of the latest ESS surgical approach, and if we had not considered the results produced in the first 10 years (1988-1998) concerning ESS in our meta-analysis, we would have found a statistically significant difference (p < 0.05) between the endoscopic (0.4%) and the traditional (1.1%) approach as well.

Occurrence of Idiopathic Pulmonary Fibrosis in Italy: Latest Evidence from Real-World Data.

The aim of the study was to evaluate the trend in the incidence of idiopathic pulmonary fibrosis (IPF) in a real-world setting of the Marche region, a region of Central Italy, between 2014 and 2019. This observational prospective study was based on administrative databases of hospital discharges and drug prescriptions. All adult residents in the Marche Region with a first prescription of antifibrotic drugs, or a first hospitalization with a diagnosis of IPF during the study period, were identified as incident cases of IPF. A multiple Poisson regression analysis was used to estimate the IPF incidence trend, adjusted for age, sex, and health conditions. The mean incidence rate was 9.8 cases per 100,000 person-years. A significant increasing trend of 6% per year was observed. The incidence rates were significantly higher in males than females, older subjects, and those with poorer health conditions. To our knowledge, this is the first study evaluating incidences of IPF over a 6-year period in Italy, combining hospital discharge and drug prescription databases. The study highlights that the combined use of two secondary sources is a reliable strategy to accurately identify new cases of IPF when the appropriate disease registry is lacking.