VI-RADS followed by Photodynamic Transurethral Resection of Non-Muscle-Invasive Bladder Cancer vs White-Light Conventional and Second-resection: the 'CUT-less' Randomised Trial Protocol.

BACKGROUND: A second transurethral resection of bladder tumour (Re-TURBT) is recommended by European Association of Urology (EAU) Guidelines on non-muscle-invasive bladder cancers (NMIBCs) due to the risk of understaging and/or persistent disease following the primary resection. However, in many cases this may be unnecessary, potentially harmful, and significantly expensive constituting overtreatment. The CUT-less trial aims to combine the preoperative staging accuracy of Vesical Imaging-Reporting and Data System (VI-RADS) and the intraoperative enhanced ability of photodynamic diagnosis (PDD) to overcome the primary TURBT pitfalls thus potentially re-defining criteria for Re-TURBT indications. STUDY DESIGN: Single-centre, non-inferiority, phase IV, open-label, randomised controlled trial with 1:1 ratio. ENDPOINTS: The primary endpoint is short-term BC recurrence between the study arms to assess whether patients preoperatively categorised as VI-RADS Score 1 and/or Score 2 (i.e., very-low and low likelihood of MIBC) could safely avoid Re-TURBT by undergoing primary PDD-TURBT. Secondary endpoints include mid- and long-term BC recurrences and progression (i-ii). Also, health-related quality of life (HRQoL) outcomes (iii) and health-economic cost-benefit analysis (iv) will be performed. PATIENTS AND METHODS: All patients will undergo preoperative Multiparametric Magnetic Resonance Imaging of the bladder with VI-RADS score determination. A total of 327 patients with intermediate-/high-risk NMIBCs, candidate for Re-TURBT according to EAU Guidelines, will be enrolled over a 3-year period. Participants will be randomised (1:1 ratio) to either standard of care (SoC), comprising primary white-light (WL) TURBT followed by second WL Re-TURBT; or the Experimental arm, comprising primary PDD-TURBT and omitting Re-TURBT. Both groups will receive adjuvant intravesical therapy and surveillance according to risk-adjusted schedules. Measure of the primary outcome will be the relative proportion of BC recurrences between the SoC and Experimental arms within 4.5 months (i.e., any 'early' recurrence detected at first follow-up cystoscopy). Secondary outcomes measures will be the relative proportion of late BC recurrences and/or BC progression detected after 4.5 months follow-up. Additionally, we will compute the HRQoL variation from NMIBC questionnaires modelled over a patient lifetime horizon and the health-economic analyses including a short-term cost-benefit assessment of incremental costs per Re-TURBT avoided and a longer-term cost-utility per quality-adjusted life year gained using 2-year clinical outcomes to drive a lifetime model across the two arms of treatment. TRIAL REGISTRATION: ClinicalTrial.gov identifier (ID): NCT05962541; European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) ID: 2023-507307-64-00.

Tear levels of apoptotic, matrix-degrading and antioxidant biomarkers in patients with and without keratoconus: A cross sectional study.

PURPOSE: To assess the tear levels of a set of apoptotic, matrix-degrading and antioxidant biomarkers, including Metalloproteinase 9 (MMP9), High Mobility Group Box 1 (HMGB1) and Superoxide Dismutase 3-Extracellular (SOD3). METHODS: Sandwich-ELISA commercial kits were used to test the expression of the three tear biomarkers in the lacrimal fluid of eligible participants. Linear logistic regression analysis was performed todetermine whether the set of tear biomarkers could be associated with clinically manifest keratoconus. ROC curve analysis using 10-fold cross-validation was performedto evaluate the prediction accuracy of the model. RESULTS: Eighty-one participants aged 30-48 years old were enrolled in this study; 48 were patients with keratoconus and 33 were age-matched healthy subjects. The linear combination of the three tear biomarkers levels (AUC = 0.811; CI 95 %: 0.712-0.911) accurately indicated the existence of keratoconus; higher levels of MMP9 (Odd Ratio: 1.069; CI 95 %: 1.029-1.130) and HMGB1 (OR: 1.011; CI 95 %: 1.003-1.022) and lower levels of SOD3 (OR: 0.994; CI 95 %: 0.989-0.997) were significantly associated with a higher probability of keratoconus. CONCLUSION: Multivariable analysis of the set of tear levels of MMP9, HMGB1 and SOD3 biomarkers confirmed a chronic state of inflammation in the ocular surface of patients with keratoconus.

Prevalence of delivery mode in an Italian nationwide cohort with celiac disease: a SIGENP multicenter retrospective study (the CD-deliver-IT).

BACKGROUND: Studies have indicated an association between cesarean section (CS), especially elective CS, and an increased risk of celiac disease (CD), but the conclusions of other studies are contradictory. The primary aim of this study (CD-deliver-IT) was to evaluate the rate of CS in a large population of CD patients throughout Italy.  METHODS: This national multicenter retrospective study was conducted between December 2020 and November 2021. The coordinating center was the Pediatric Gastroenterology and Liver Unit of Policlinico Umberto I, Sapienza, University of Rome, Lazio, Italy. Eleven other referral centers for CD have participated to the study. Each center has collected data on mode of delivery and perinatal period of all CD patients referring to the center in the last 40 years. RESULTS: Out of 3,259 CD patients recruited in different Italian regions, data on the mode of delivery were obtained from 3,234. One thousand nine hundred forty-one (1,941) patients (60%) were born vaginally and 1,293 (40%) by CS (8.3% emergency CS, 30.1% planned CS, 1.5% undefined CS). A statistically significant difference was found comparing median age at time of CD diagnosis of patients who were born by emergency CS (4 years, CI 95% 3.40-4.59), planned CS (7 years, CI 95% 6.02-7.97) and vaginal delivery (6 years, CI 95% 5.62-6.37) (log rank p < 0.0001). CONCLUSIONS: This is the first Italian multicenter study aiming at evaluating the rate of CS in a large population of CD patients through Italy. The CS rate found in our CD patients is higher than rates reported in the general population over the last 40 years and emergency CS seems to be associated with an earlier onset of CD compared to vaginal delivery or elective CS in our large nationwide retrospective cohort. This suggests a potential role of the mode of delivery on the risk of developing CD and on its age of onset, but it is more likely that it works in concert with other perinatal factors. Further prospective studies on other perinatal factors potentially influencing gut microbiota are awaited in order to address heavy conflicting evidence reaming in this research field.

Pancreatic Stone Protein in the Diagnosis of Sepsis in Children Admitted to High-Dependency Care: A Single-Center Prospective Cohort Study.

OBJECTIVES: Blood level of pancreatic stone protein (PSP) is a promising biomarker of sepsis both in adults and children. The aim of our study was to investigate the diagnostic accuracy of PSP in children with suspected sepsis and to compare diagnostic performance with other sepsis biomarkers approved for clinical use, that is, procalcitonin (PCT) and C-reactive protein (CRP). DESIGN: Prospective study. SETTING: PICU and pediatric emergency department. INTERVENTION: Blood levels of PSP were measured using a nanofluidic point-of-care immunoassay (abioSCOPE, Abionic SA, Switzerland) within 24 hours of admission. MEASUREMENTS AND MAIN RESULTS: We studied 99 children aged between older than 1 month and younger than 18 years with signs and symptoms of systemic inflammatory response syndrome (irrespective of associated organ dysfunction). The prevalence of sepsis was 35 of 99 (35.4%). Patients with sepsis had higher PSP levels ( p < 0.001) than patients with systemic inflammation of noninfectious cause. In this analysis, the optimal cutoff for the diagnosis of sepsis using PSP was 123 ng/mL, which resulted in a sensitivity of 0.63 (95% CI, 0.43-0.80), specificity of 0.89 (95% CI, 0.77-0.95). The PSP test area under the receiver operating characteristic curve (AUROC) was 0.82 (95% CI, 0.73-0.91) and, by comparison, procalcitonin and CRP AUROC were 0.70 (95% CI, 0.58-0.82) and 0.72 (95% CI, 0.60-0.84), respectively. Overall, the pretest to posttest probability of sepsis with a positive test changed from 0.35 to 0.73. CONCLUSIONS: In this single-center prospective pediatric cohort, admitted to the high intensive care and to the PICU, our findings suggested the potential use of PSP as a sepsis biomarker. However, because of the clinical diagnostic uncertainty with a positive result, further investigation is needed particularly in combination with other biomarkers.

Assessment of the Predictive Ability of Theranostics for Corneal Cross-linking in Treating Keratoconus: A Randomized Clinical Trial.

PURPOSE: To validate the ability of theranostic imaging biomarkers in assessing corneal cross-linking (CXL) efficacy in flattening the maximum keratometry (Kmax) index. DESIGN: Prospective, randomized, multicenter, masked clinical trial (ClinicalTrails.gov identifier, NCT05457647). PARTICIPANTS: Fifty patients with progressive keratoconus. INTERVENTION: Participants were stratified to undergo epithelium-off (25 eyes) and epithelium-on (25 eyes) CXL protocols using an ultraviolet A (UV-A) medical device with theranostic software. The device controlled UV-A light both for performing CXL and assessing the corneal riboflavin concentration (riboflavin score) and treatment effect (theranostic score). A 0.22% riboflavin formulation was applied onto the cornea for 15 minutes and 20 minutes in epithelium-off and epithelium-on protocols, respectively. All eyes underwent 9 minutes of UV-A irradiance at 10 mW/cm2. MAIN OUTCOME MEASURES: The primary outcome measure was validation of the combined use of theranostic imaging biomarkers through measurement of their accuracy (proportion of correctly classified eyes) and precision (positive predictive value) to classify eyes correctly and predict a Kmax flattening at 1 year after CXL. Other outcome measures included change in Kmax, endothelial cell density, uncorrected and corrected distance visual acuity, manifest spherical equivalent refraction and central corneal thickness 1 year after CXL. RESULTS: Accuracy and precision of the theranostic imaging biomarkers in predicting eyes that had >0.1 diopter (D) of Kmax flattening at 1 year were 91% and 95%, respectively. The Kmax value significantly flattened by a median of -1.3 D (IQR, -2.11 to -0.49 D; P < 0.001); both the uncorrected and corrected distance visual acuity improved by a median of -0.1 logarithm of the minimum angle of resolution (logMAR; IQR, -0.3 to 0.0 logMAR [P < 0.001] and -0.2 to 0.0 logMAR [P < 0.001], respectively). No significant changes in endothelial cell density (P = 0.33) or central corneal thickness (P = 0.07) were noted 1 year after surgery. CONCLUSIONS: The study demonstrated the efficacy of integrating theranostics in a UV-A medical device for the precise and predictive treatment of keratoconus with epithelium-off and epithelium-on CXL protocols. Concentration of riboflavin and its UV-A light mediated photoactivation in the cornea are the primary factors determining CXL efficacy. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Psychophysical, electrofunctional, and morphological evaluation in naïve neovascular AMD patients treated with intravitreal anti-VEGF.

Objectives: The aim of this study was to investigate the retinal morpho-functional characteristics of patients with neovascular wet age-related macular degeneration (nAMD) treated with intravitreal injection (IV) of aflibercept (AFL). Methods: The study was conducted on 35 patients previously diagnosed with type 1 nAMD who received a fixed-dosing regimen of aflibercept injections over 12 months. The goal was to assess trends in visual abilities over time by measuring visual acuity (VA), contrast sensitivity (CS), visual evoked potentials (VEPs), and spectral domain-optical coherence tomography (SD-OCT). The same psychophysical, electro-functional, and morphological tests administered at baseline (T0) were repeated 4 to 8 weeks after the last aflibercept injection (Tn), resulting in a total of six examinations. Results: At Tn, all subjects exhibited improved VA for both far and near distances compared to values detected at T0. Similarly, VEP amplitude and latency values at Tn showed a greater P100 improvement than those observed at T0. Additionally, the CS examination at Tn demonstrated improvement, particularly at high spatial stimulation frequencies. The Tn SD-OCT results highlighted a reduction in macular thickness compared to T0 values. Conclusions: This exploratory research indicates that intravitreal injections of AFL, following a fixed-dosing regimen, represent a valuable therapeutic approach for enhancing visual performance. This conclusion is supported by comprehensive statistical analysis of psychophysical, electro-functional, and morphological examinations within the same group of patients with nAMD, as demonstrated for the first time.

Targeted next-generation sequencing analysis in Italian patients with keratoconus.

OBJECTIVE: To report variants in 26 candidate genes and describe the clinical features of Italian patients with keratoconus (KC). SUBJECTS/METHODS: Sixty-four patients with a confirmed diagnosis of KC were enrolled in this genetic association study. Patients were classified into two study groups according to whether they had a confirmed diagnosis of progressive or stable KC. A purpose-developed Next Generation Sequencing (NGS) panel was used to identify and analyse the coding exons and flanking exon/intron boundaries of 26 genes known to be associated with KC and corneal dystrophies. Interpretation of the pathogenic significance of variants was performed using in silico predictive algorithms. RESULT: The targeted NGS research identified a total of 167 allelic variants of 22 genes in the study population; twenty-four patients had stable keratoconus (n. 54 variants) and forty patients had progressive disease (n. 113 variants). We identified genetic variants of certain pathogenic significance in five patients with progressive KC; in addition, eight novel genetic variants were found in eight patients with progressive KC. Mutations of FLG, LOXHD1, ZNF469, and DOCK9 genes were twice more frequently identified in patients with progressive than stable disease. Filaggrin gene variants were found in 49 patients (76% of total), of whom 32 patients (80% of progressive KC group) had progressive disease. CONCLUSIONS: Targeted NGS research provided new insights into the causative effect of candidate genes in the clinical phenotype of keratoconus. Filaggrin mutations were found to represent a genetic risk factor for development of progressive disease in Italy.

Estimated prevalence of keratoconus in the largest metropolitan area of Italy.

PURPOSE: To estimate the prevalence of keratoconus in a population of subjects undergoing first eye examination in an eye clinic in Italy. METHODS: A single-center, cross-sectional, study was conducted involving patients who underwent first eye examination at an eye clinic in Rome between September 2021 and June 2022. The prevalence of keratoconus was determined by Placido-disk corneal topography using the maximum keratometry (Kmax) value and the Cone Magnitude and Location Index (CLMI) for keratoconus screening. Subjective analysis was performed by two experienced corneal specialists, who classified the outcome into two groups: normal and keratoconus. Risk factors, including family history of keratoconus, allergy or atopy, thyroid disease, eye rubbing habit and gender were also examined. RESULTS: A total of 512 subjects between 7 and 81 years old were evaluated. The inter-observer agreement to classify subjects in normal or keratoconus group was excellent (k = 1.0); the estimated prevalence in the specific population was 2.1%. Presence of positive family history (9% of keratoconus vs 5% normal), concomitant allergy or atopy (27% vs 9%) and eye rubbing habit (18% vs 4%) were associated with a higher risk of disease. CONCLUSION: This study reported a high estimated prevalence of keratoconus in a metropolitan area of Italy, as found in recent studies in the Mediterranean and Middle East countries. Screening for keratoconus is highly recommendable and easily feasible with corneal topography under expert supervision and may be indicated primarily in young population to improve early detection and prompt therapeutic management for halting disease progression.

Screening for colorectal cancer by full colonoscopy in first-degree relatives of colorectal cancer patients: a multicentric study by the Italian League for the Fight against Cancer.

Background: Colorectal cancer currently presents the third-highest incidence of cancers worldwide, making secondary prevention through screening programs for colorectal cancer, usually by Fecal Occult Blood Testing, an essential preventive medicine intervention. First-degree relatives of colorectal cancer patients are a particularly at-risk group, with indications to consider direct screening by full colonoscopy. Colonoscopy is considered the gold standard for diagnosing colorectal cancer, as it has high sensitivity and specificity, and is both a diagnostic and therapeutic tool. However, it requires significant organizational and financial resources, and has a small but relatively higher risk of complications as opposed to fecal occult blood testing. The present study aimed to assess the appropriateness of a screening program without age restrictions of CRC by full colonoscopy in asymptomatic, first-degree adult relatives of patients with colorectal cancer, aiming both to actively increase screening coverage and to determine the detection rate of precancerous lesions and colorectal cancer in this population. Study Design: Uncontrolled interventional study - colorectal cancer screening by full colonoscopy for at-risk population. Methods: The Italian League for the Fight against Cancer started a colorectal cancer screening program by full colonoscopy for first-degree relatives of colorectal cancer patients in 1998 in the province of Latina, Lazio Region, Italy. The program was expanded to the provinces of Rieti, Lazio Region, and Sassari, Sardinia Region, in 2014 and 2016 respectively, and was concluded in 2018. Subjects were actively and voluntarily recruited by the study's working group. Subjects that had already been subjected to a full colonoscopy in the preceding 5 years were excluded from this study. Identified neoplastic lesions were treated either directly or referred to the Day Hospital setting, and histologically diagnosed following World Health Organization guidelines. Results: In total, 2,288 subjects (age range 15-88, mean 52.3 yrs, M/F = 946/1,204) were screened by colonoscopy, of which 103 (4.5%) were incomplete and 2,173 (95.0%) complete, with data on colonoscopy performance missing for 12 participants. Out of 468 positive outcomes on colonoscopy, diagnosis for 422 (204M/173F), 19.4% of total subjects, was adenomatous polyps and 46 (20M/20F), 2.1% of total subjects, was colorectal cancer. Female sex was a protective factor against a positive test outcome, with a 35% reduction compared to male sex, with OR=0.64 95%CI (0.52-0.80). On the other hand, being over 50 years of age was found to be a risk factor, making a positive outcome more than twice as likely, with OR=2.3 95%CI (1.8-2.9). Subjects over 50 also had significantly more instances of multiple adenomas being found, however the size distribution of found adenomas was not significantly different between subjects under and over 50, despite size being a predictor of risk of neoplastic progression. Conclusions: Given the high detection rate of precancerous lesions and colorectal cancer in the studied population, it is our opinion that guidelines should continue to recommend earlier and more frequent screening in first-degree relatives of patients with colorectal cancer, and, barring the introduction of more cost-effective and/or lower risk procedures with a similar efficacy profile, maintain the use of colonoscopy as the main screening option.

Emotional abilities in preadolescents and adolescents with long-term cochlear implant use.

OBJECTIVES: Emotional abilities (EAs) are particularly important during preadolescence/adolescence, two challenging periods characterized by significant biological, physical, and cognitive changes. The present study attempted to a holistic EA approach in preadolescents/adolescents with cochlear implants (CI) and typical hearing (TH), considering various aspects such as perception, cognitive facilitation, comprehension, and management of emotions. A secondary aim was to identify significant demographic and audiological factors of EA development. METHODS: CI/TH groups were matched for chronological age, nonverbal IQ, gender, economic income, and maternal level of education. Each group consisted of 43 participants (age range 10-18 years). EAs were evaluated by using the multi-trait/method IE-ACCME test. Auditory-linguistic assessments included participants' lexical skills and Matrix performance as well. RESULTS: EA performance for perception and cognitive facilitation did not show any statistically significant CI/TH group differences (p > 0.05). Significant CI/TH differences emerged for emotion comprehension and management: CI group performed significantly worse in understanding emotional blends (t = 2.56, p = 0.014) but better in personal emotion management (t = -2.01, p = 0.048). For the CI group, gender showed statistically significant effects on cognitive facilitation in sensations, with males performing better than females (U = 129, p = 0.018). TH preadolescents showed significantly lower scores in understanding emotional changes in comparison to TH adolescents (U = 125.5, p = 0.01). Emotional blends understanding showed a weak negative correlation with Matrix performance (r = - 0.38, p = 0.013) and a moderate positive correlation with lexical skills (r = 0.40, p = 0.008). Relationships management showed various significant correlations: weak negative correlations with age at CI (r = - 0.38, p = 0.011) and Matrix performance (r = - 0.36, p = 0.016) as well as weak positive correlations with nonverbal-IQ (r = 0.38, p = 0.013) and positive moderate correlations with lexical skills (r = 0.49, p < 0.001). CONCLUSION: Cochlear implantation seems to show significant positive effects on emotional development in children, allowing them to achieve age appropriate EAs as they grow up and become preadolescents/adolescents. EA assessment in CI users may not only support monitorization of EA trajectory, but also early identification of any EA disorders, so that subjects with low EA profiles could be timely and properly intervened.

Supermicrosurgery with perforator-to-perforator anastomoses for lower limb reconstructions - A systematic review and meta-analysis.

BACKGROUND: Supermicrosurgical flaps based on perforator-to-perforator microanastomoses have been described for lower limb reconstruction. This approach offers the benefit of raising short pedicles while sparing axial vessels, which effectively enables complex reconstructive techniques in comorbid patients at high risk of reconstructive failure. The aim of our study is to assess the surgical outcomes of perforator-to-perforator based flaps in comparison to conventional free flaps for reconstructions of the lower limb district, through a systematic review of literature and meta-analysis. METHODS: A search on PubMed, Embase, Cohrane, and Web of Science was performed between March-July 2022. No restrictions were placed on study date. Only English manuscripts were assessed. Reviews, short communications, letters, correspondence were excluded after reviewing their references for potentially relevant studies. A Bayesian approach was used to conduct the meta-analysis comparing flap-related outcomes. RESULTS: From 483 starting citations, 16 manuscripts were included for full-text analysis in the review, and three were included in the meta-analysis. Out of 1556 patients, 1047 received a perforator-to-perforator flap. Complications were reported in 119 flaps (11.4%), which included total flap failure in 71 cases (6.8%), partial flap failure in 47 cases (4.5%). Overall flap complications had a HR of 1.41 (0.94-2.11; 95% C.I.). Supermicrosurgical and conventional microsurgical reconstructions were not associated with statistically significant differences (p = .89). CONCLUSION: Our evidence supports the safety of surgical outcomes, with acceptable flap complication rates. Nevertheless, these findings are limited by poor overall quality which must be addressed and used to encourage higher-level evidence in the field.

Heart failure 'the cancer of the heart': the prognostic role of the HLM score.

AIMS: The multi-systemic effects of heart failure (HF) resemble the spread observed during cancer. We propose a new score, named HLM, analogous to the TNM classification used in oncology, to assess the prognosis of HF. HLM refers to H: heart damage, L: lung involvement, and M: systemic multiorgan involvement. The aim was to compare the HLM score to the conventional New York Heart Association (NYHA) classification, American College of Cardiology/American Heart Association (ACC/AHA) stages, and left ventricular ejection fraction (LVEF), to assess the most accurate prognostic tool for HF patients. METHODS AND RESULTS: We performed a multicentre, observational, prospective study of consecutive patients admitted for HF. Heart, lung, and other organ function parameters were collected. Each patient was classified according to the HLM score, NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography. The follow-up period was 12 months. The primary endpoint was a composite of all-cause death and rehospitalization due to HF. A total of 1720 patients who completed the 12 month follow-up period have been enrolled in the study. 520 (30.2%) patients experienced the composite endpoint of all-cause death and rehospitalization due to HF. 540 (31.4%) patients were female. The mean age of the study population was 70.5 ± 12.9. The mean LVEF at admission was 42.5 ± 13%. Regarding the population distribution across the spectrum of HLM score stages, 373 (21.7%) patients were included in the HLM-1, 507 (29.5%) in the HLM-2, 587 (34.1%) in the HLM-3, and 253 (14.7%) in the HLM-4. HLM was the most accurate score to predict the primary endpoint at 12 months. The area under the receiver operating characteristic curve (AUC) was greater for the HLM score compared with the NYHA classification, ACC/AHA stages, or LVEF, regarding the composite endpoint (HLM = 0.645; NYHA = 0.580; ACC/AHA = 0.589; LVEF = 0.572). The AUC of the HLM score was significantly better compared with the LVEF (P = 0.002), ACC/AHA (P = 0.029), and NYHA (P = 0.009) AUC. CONCLUSIONS: The HLM score has a greater prognostic power compared with the NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography in terms of the composite endpoint of all-cause death and rehospitalization due to HF at 12 months of follow-up.

Accuracy of an Air-Puff Dynamic Tonometry Biomarker to Discriminate the Corneal Biomechanical Response in Patients With Keratoconus.

PURPOSE: The aim of this study was to assess accuracy of the mean corneal stiffness ( kc , N/m) parameter to discriminate between patients with keratoconus and age-matched healthy subjects. METHODS: Dynamic Scheimpflug imaging tonometry was performed with Corvis ST (Oculus Optikgeräte GmbH, Germany) in patients with keratoconus (n = 24; study group) and age-matched healthy subjects (n = 32; control). An image processing algorithm was developed to analyze the video sequence of the Corvis ST air-puff event and to determine the geometric and temporal parameters that correlated with the corneal tissue biomechanical properties. A modified 3-element viscoelastic model was used to derive the kc parameter, which represented the corneal tissue resistance to deformation under load. Receiver operating characteristic curves were used to assess the overall diagnostic performance for determining the area under the curve, sensitivity, and specificity of the kc in assessing the corneal tissue deformation to the Corvis ST air-puff event in keratoconus and control eyes. The Corvis Biomechanical Index ( CBI ) was analyzed for external validation. RESULTS: The kc parameter was significantly different between keratoconus and controls ( P < 0.001), ranging from 24.9 ±3.0 to 34.2 ±3.5 N/m, respectively. It was highly correlated with CBI (r = -0.69; P < 0.001); however, the kc parameter had greater specificity (94%) than CBI (75%), whereas the 2 biomarkers had similar area under the curve (0.98 vs. 0.94) and sensitivity (96% vs. 92%) in predicting the occurrence of keratoconus. CONCLUSIONS: The kc parameter extracted by video processing analysis of dynamic Scheimpflug tonometry data was highly accurate in discriminating patients with clinically manifest keratoconus compared with controls.

Accuracy of Pancreatic Stone Protein for diagnosis of sepsis in children admitted to pediatric intensive care or high-dependency care: a pilot study.

BACKGROUND: Pancreatic Stone Protein (PSP) is one of the most promising diagnostic and prognostic markers. The aim of the study was to assess the accuracy of PSP, compared to C-Reactive Protein (CRP), and Procalcitonin (PCT) for sepsis diagnosis in pediatric patients. Furthermore, we explored the correlation of PSP levels with sepsis severity and organ failure measured with PELOD-2 score. METHODS: Forty pediatric patients were enrolled following admission to pediatric intensive care, high dependency care or pediatric ward. PSP blood levels were measured in Emergency Department (nanofluidic point-of-care immunoassay; abioSCOPE, Abionic SA, Switzerland) on day 1, 2, 3, 5 and 7 from the onset of the clinical signs and symptoms of sepsis or SIRS. Inclusion criteria were: 1) patient age (1 month to 18 years old), 2) signs and symptoms of SIRS, irrespective of association with organ dysfunction. Exclusion criteria were: 1) hemato-oncological diseases and/or immunodeficiencies, 2) pancreatic diseases. RESULTS: Septic patients showed higher PSP levels than those with non-infectious systemic inflammation. The optimal cut-off in diagnosis of sepsis for PSP at day 1 was 167 ng/ml resulted in a sensitivity of 59% (95% IC 36%-79%) and a specificity of 83% (95% IC 58%-96%) with an AUC of 0.636 for PSP in comparison to AUC of 0.722 for PCT and 0.503 for C-RP. ROC analysis for outcome (survival versus no survival) has showed AUC 0.814 for PSP; AUC 0.814 for PCT; AUC of 0.657 for C-RP. CONCLUSIONS: PSP could distinguish sepsis from non-infectious systemic inflammation; however, our results need to be confirmed in larger pediatric population.

Real-life comparison of mortality in patients with SARS-CoV-2 infection at risk for clinical progression treated with molnupiravir or nirmatrelvir plus ritonavir during the Omicron era in Italy: a nationwide, cohort study.

Background: Comparative data on mortality in COVID-19 patients treated with molnupiravir or with nirmatrelvir plus ritonavir are inconclusive. We therefore compared all-cause mortality in community-dwelling COVID-19 patients treated with these drugs during the Omicron era. Methods: Data collected in the nationwide, population-based, cohort of patients registered in the database of the Italian Medicines Agency (AIFA) were used. To increase completeness of the recorded deaths and date correctness, a cross-check with the National Death Registry provided by the Ministry of the Interior was performed. We included in this study all patients infected by SARS-CoV-2 treated within 5 days after the test date and symptom onset between February 8 and April 30, 2022. All-cause mortalities by day 28 were compared between the two treatment groups after balancing for baseline characteristics using weights obtained from a gradient boosting machine algorithm. Findings: In the considered timeframe, 17,977 patients treated with molnupiravir and 11,576 patients with nirmatrelvir plus ritonavir were included in the analysis. Most patients (25,617/29,553 = 86.7%) received a full vaccine course including the booster dose. A higher crude incidence rate of all-cause mortality was found among molnupiravir users (51.83 per 100,000 person-days), compared to nirmatrelvir plus ritonavir users (22.29 per 100,000 person-days). However, molnupiravir-treated patients were older than those treated with nirmatrelvir plus ritonavir and differences between the two populations were found as far as types of co-morbidities were concerned. For this reason, we compared the weight-adjusted cumulative incidences using the Aalen estimator and found that the adjusted cumulative incidence rates were 1.23% (95% CI 1.07%-1.38%) for molnupiravir-treated and 0.78% (95% CI 0.58%-0.98%) for nirmatrelvir plus ritonavir-treated patients (adjusted log rank p = 0.0002). Moreover, the weight-adjusted mixed-effect Cox model including Italian regions and NHS centers as random effects and treatment as the only covariate confirmed a significant reduced risk of death in patients treated with nirmatrelvir plus ritonavir. Lastly, a significant reduction in the risk of death associated with nirmatrelvir plus ritonavir was confirmed in patient subgroups, such as in females, fully vaccinated patients, those treated within day 2 since symptom onset and patients without (haemato)-oncological diseases. Interpretation: Early initiation of nirmatrelvir plus ritonavir was associated for the first time with a significantly reduced risk of all-cause mortality by day 28 compared to molnupiravir, both in the overall population and in patient subgroups, including those fully vaccinated with the booster dose. Funding: This study did not receive funding.

The efficacy of preoperative low-residue diet on postoperative ileus following cesarean section.

OBJECTIVE: To evaluate the efficacy of preoperative low-residue diet on postoperative ileus in women undergoing elective cesarean section (CS). METHODS: This is a surgeon-blind, randomized controlled trial enrolling pregnant women at ≥39 weeks of gestation undergoing elective CS. Patients were preoperatively randomized to receive either low-residue diet (arm A) or free diet (arm B) starting from three days before surgery. The primary outcome was the postoperative ileus. The secondary outcomes were the postoperative pain (assessed through VAS scale), the quality of the surgical field (scored using a 5-point scale, from poor to excellent), postoperative complications, and the length of hospital stay. Perioperative data were collected and compared between groups. RESULTS: A total of 166 patients were enrolled and randomized in arm A (n = 83) and arm B (n = 83). Postoperative ileus over 24 h was significantly shorter in arm A, compared to arm B (19.3% vs 36.2%). The surgical evaluation of small intestine was scored ≥3 in 96.4% of arm A patients versus 80.7% in arm B, while evaluation of large intestine, respectively, in 97.7% and 81.9%. Postoperative pain after 12 h from CS was significantly lower in arm A (VAS, 3.4 ± 1.7) compared to arm B (VAS, 4.1 ± 1.8). There were no significant differences as regards postoperative pain at 24 and 48 h, nausea/vomit, surgical complications, and hospital stay. CONCLUSIONS: Implementation of a preoperative low-residue diet for women scheduled for elective CS would reduce postoperative ileus and pain. Further large-scale studies are required before translating these research findings into routine obstetrical practice.

External validation of the ADA score for predicting thrombosis among acutely ill hospitalized medical patients from the APEX Trial.

The ADA (Age-D-dimer-Albumin) score was developed to identify hospitalized patients at an increased risk for thrombosis in the coronavirus infectious disease-19 (COVID-19) setting. The study aimed to validate the ADA score for predicting thrombosis in a non-COVID-19 medically ill population from the APEX trial. The APEX trial was a multinational, randomized trial that evaluated the efficacy and safety of betrixaban vs. enoxaparin among acutely ill hospitalized patients at risk for venous thromboembolism. The study endpoints included the composite of arterial or venous thrombosis and its components. Metrics of model calibration and discrimination were computed for assessing the performance of the ADA score as compared to the IMPROVE score, a well-validated VTE risk assessment model. Among 7,119 medical inpatients, 209 (2.9%) had a thrombosis event up to 77 days of follow-up. The ADA score demonstrated good calibration for both arterial and venous thrombosis, whereas the IMPROVE score had adequate calibration for venous thrombosis (p > 0.05 from the Hosmer-Lemeshow test). For discriminating arterial and venous thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.620 [95% CI: 0.582 to 0.657] vs. 0.590 [95% CI: 0.556 to 0.624]; ∆ c statistic = 0.030 [95% CI: -0.022 to 0.081]; p = 0.255). Similarly, for discriminating arterial thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.582 [95% CI: 0.534 to 0.629] vs. 0.609 [95% CI: 0.564 to 0.653]; ∆ c statistic = -0.027 [95% CI: -0.091 to 0.036]; p = 0.397). For discriminating venous thrombosis, the ADA score was modestly superior to the IMPROVE score (c statistic = 0.664 [95% CI: 0.607 to 0.722] vs. 0.573 [95% CI: 0.521 to 0.624]; ∆ c statistic = 0.091 [95% CI: 0.011 to 0.172]; p = 0.026). The ADA score had a higher sensitivity (0.579 [95% CI: 0.512 to 0.646]; vs. 0.440 [95% CI: 0.373 to 0.507]) but lower specificity (0.625 [95% CI: 0.614 to 0.637] vs. 0.747 [95% CI: 0.737 to 0.758]) than the IMPROVE score for predicting thrombosis. Among acutely ill hospitalized medical patients enrolled in the APEX trial, the ADA score demonstrated good calibration but suboptimal discrimination for predicting thrombosis. The findings support the use of either the ADA or IMPROVE score for thrombosis risk assessment. The applicability of the ADA score to non-COVID-19 populations warrants further research.Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

A randomized clinical trial assessing theranostic-guided corneal cross-linking for treating keratoconus: the ARGO protocol.

The Assessment of theranostic guided riboflavin/UV-A corneal cross-linking for treatment of keratoconus (ARGO; registration number NCT05457647) clinical trial tests the hypothesis that theranostic-guided riboflavin/UV-A corneal cross-linking (CXL) can provide predictable clinical efficacy for halting keratoconus progression, regardless of treatment protocol, i.e., either with or without epithelial removal. Theranostics is an emerging therapeutic paradigm of personalized and precision medicine that enables real-time monitoring of image-guided therapy. In this trial, the theranostic software module of a novel UV-A medical device will be validated in order to confirm its accuracy in estimating corneal cross-linking efficacy in real time. During CXL procedure, the theranostic UV-A medical device will provide the operator with an imaging biomarker, i.e., the theranostic score, which is calculated by non-invasive measurement of corneal riboflavin concentration and its UV-A light mediated photo-degradation. ARGO is a randomized multicenter clinical trial in patients aged between 18 and 40 years with progressive keratoconus aiming to validate the theranostic score by assessing the change of the maximum keratometry point value at 1-year postoperatively. A total of 50 participants will be stratified with allocation ratio 1:1 using a computer-generated stratification plan with blocks in two treatment protocols, such as epithelium-off or epithelium-on CXL. Following treatment, participants will be monitored for 12 months. Assessment of safety and performance of theranostic-guided corneal cross-linking treatment modality will be determined objectively by corneal tomography, corneal endothelial microscopy, visual acuity testing and slit-lamp eye examination.

A Survey on Methodological Issues of Clinical Research Studies Reviewed by Independent Ethic Committees during the COVID-19 Pandemic in Italy.

The struggle for information and the hasty search for answers caused by the COVID-19 pandemic threatened the possibility of lowering study quality, as well as ethical committees' review standards during the outbreak. Our investigation aimed to assess the impact of COVID-19 on the quality of clinical research studies submitted to Italian Ethics Committees in the period between April and July 2020. All 91 Italian ethics committees were contacted via email in order to collect anonymized information on the type and quality of COVID-19-related studies submitted to each committee during the study period. The present study summarizes the characteristics of the 184 study applications collected, pointing out, especially, how the quality of the study population and statistical analysis are crucial variables in determining the study approval. Nevertheless, despite the need for high-quality and open scientific information, especially exacerbated by this particular historical period, only a minority of the ethics committees (20.9%) agreed to share their data; such scarce participation, beyond biasing the representativeness of the results obtained by the present study, more importantly, hinders the broader goal of creating trust between researchers and the general public.

Thoracodorsal artery perforator flap, muscle-sparing latissimus dorsi, and descending branch latissimus dorsi: A multicenter retrospective study on early complications and meta-analysis of the literature.

The thoracodorsal (TD) vessels represent a complex vascular system that offers a variety of pedicled and free flaps. Variations of the classical latissimus dorsi (LD) flap have been developed to overcome its major drawbacks. The thoracodorsal artery perforator (TDAP) flap described by Angrigiani represents one of these options. Other techniques have been defined as "muscle-sparing" latissimus dorsi (MSLD) due to the preservation of the LD muscle and the TD nerve, in whole or in part. Nevertheless, the term "muscle sparing" has also been applied to the descending branch LD (DB-LD) flap which requires the denervation of the LD muscle. According to our knowledge, there are no articles in the literature reviewing and comparing the reconstructive options based on the TD vessels. We performed a systematic search in PubMed, Web of Science, and Cochrane databases to perform a literature review and meta-analysis about the reconstructive options based on the TD vessels. The primary outcome of interest was the percentage of flaps developing a specific early complication, i.e., hematoma of the donor site, seroma of the donor site, partial flap loss, total flap loss, wound dehiscence, and wound infection. Moreover, we analyzed the outcomes and complications of our cases, comparing the MSLD flaps, the DB-LD flaps, and the TDAP flaps. According to both our casuistry and the literature, the three techniques can be considered safe in terms of early donor site complications. According to the literature, MSLD has been shown to develop partial flap necrosis more frequently than the TDAP flap.