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 the propensity of corneal cross-linking (CXL) in flattening the maximum keratometry (Kmax) index. DESIGN: Prospective, randomized, multicenter, masked clinical trial (NCT05457647). PARTICIPANTS: Fifty patients with progressive keratoconus. INTERVENTION: Participants were stratified to undergo epithelium-off (epi-off; 25 eyes) and epithelium-on (epi-on; 25 eyes) CXL protocols using UV-A medical device incorporating theranostic software module. The device used controlled UV-A light both for performing CXL and for estimating the corneal riboflavin concentration (riboflavin score) and assessing treatment effect (theranostic score) in real time. A 0.22% riboflavin formulation was applied onto the cornea for 15 minutes and 20 minutes in epi-off and epi-on protocols respectively. All eyes underwent 9 minutes 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 correctly classify eyes and positively predict a Kmax flattening at 1 year after CXL. Other outcome measures were the change of Kmax, endothelial cell density, uncorrected and corrected distance visual acuity, manifest spherical equivalent refraction, and central corneal thickness one year after CXL. RESULTS: Accuracy and precision of the combined use of theranostic imaging biomarkers in predicting eyes that had more than 0.1 diopter (D) 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, -0.49 D; P < 0.001); both the uncorrected and corrected distance visual acuity improved by a median of -0.1 LogMAR (IQR: -0.3, 0.0 LogMAR; P < 0.001 and IQR: -0.2, 0.0 LogMAR; P < 0.001 respectively). There were no significant changes in endothelial cell density (P = 0.33) and central corneal thickness (P = 0.07) 1 year postoperatively. CONCLUSIONS: The study demonstrated the efficacy of integrating theranostics in a UV-A medical device for the precise and predictive treatment of keratoconus with epi-off and epi-on CXL protocols. The concentration of riboflavin and its UV-A light mediated photo-activation in the cornea are the primary factors determining CXL treatment efficacy.

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.

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.

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.

Association of serum Krebs von den Lungen-6 and chest CT as potential prognostic factors in severe acute respiratory syndrome SARS-CoV-2: a preliminary experience.

PURPOSE: To correlate in COVID-19 pneumonia CT-based semi-quantitative score of pulmonary involvement with high serum levels of KL-6, a biomarker of disease severity. METHODS: Between March 28 to May 21, 2020, 196 patients with strong suspicion of SARS-CoV-2 were evaluated with RT-PCR for SARS-CoV-2, chest CT scan and blood test, including KL-6 serum protein, in our Emergency Unit. The final population included only patients who underwent blood sampling for KL-6 within 5 days from CT scan (n = 63), including n = 37 COVID-19-positive patients and n = 26 with negative RT-PCR testing for SARS-CoV-2 (control group). A semi-quantitative CT score was calculated based on the extent of lobar involvement (0:0%; 1, < 5%; 2:5-25%; 3:26-50%; 4:51-75%; 5, > 75%; range 0-5; global score 0-25). RESULTS: CT score was significantly correlated with serum value of KL-6 (r = 27, p = 0.035). This correlation was also present in COVID-19 positive patients (r = 0.423, p = 0.009) and CT score median value was significantly higher in patients with high KL-6 value (> 400 U/mL; 12.00, IQR 5.00-18.00, p-value 0.027). In control group, no statistically significant correlation was found between CT score and KL-6 value and CT score was higher in patients with high KL-6, although this difference was not statistically significant (5.00, IQR:1.75-8.00 versus 3.50, IQR:2.00-6.50). "Crazy paving" at the right upper (n = 8; 61.5%) and middle lobe (n = 4; 30.8%) and "consolidation" at the middle lobe (n=5; 38.5%) were observed in COVID-19 group with a significant difference between patients with high KL-6 value. CONCLUSION: CT score is highly correlated with KL-6 value in COVID-19 patients and might be beneficial to speed-up diagnostic workflow in symptomatic cases.

Diagnostic Value of Persistently Low Positive TGA-IgA Titers in Symptomatic Children With Suspected Celiac Disease.

OBJECTIVES: While the algorithm to diagnose celiac disease (CD) in children with elevated anti-transglutaminase IgA (TGA-IgA) titers (>10 times upper limit of normal, ULN) is well defined, the management of children with low TGA-IgA values represents a clinical challenge. We aimed to identify the diagnostic value of persistently low positive TGA-IgA titers in predicting CD in children. METHODS: We retrospectively analyzed children with symptoms or signs of CD, not eligible for a no-biopsy approach. We included children with at least 2 TGA-IgA measurements, endomysial antibody (EMA) assessment and esophagogastroduodenoscopy with biopsies. TGA-IgA values were provided as multiples of ULN. Patients were classified in groups according to median TGA-IgA values: A (TGA-IgA>1 ≤ 5 × ULN; defined as "low-positive"), B (TGA-IgA > 5 < 10 × ULN; "moderate-positive"), and C (controls). RESULTS: Data of 281 children were analyzed. Of 162 children in group A, CD was diagnosed in 142 (87.7%), whereas normal duodenal mucosa was found in 20. In group B, all 62 children (100%) received a CD diagnosis. Group C included 57 controls. EMA were undetectable in 31 (15%) of mucosal atrophy cases. On the receiver-operating characteristic curve (area under the curve = 0.910), a mean value of 1.7 ULN showed a sensitivity of 81.4% and specificity of 81.8% to predict mucosal damage. CONCLUSIONS: Repeated low or moderate TGA-IgA values (<5 ULN or <10 ULN) are good predictors of a CD diagnosis. Symptomatic children with persistently low positive TGA-IgA titers should undergo esophagogastroduodenoscopy regardless of their EMA status.

Chronic inflammatory demyelinating polyneuropathy: evaluation of the vestibular system with cervical and ocular vestibular evoked myogenic potentials.

PURPOSE: To investigate the possibility of vestibular damage in a group of patients suffering from chronic inflammatory demyelinating polyneuropathy (CIDP) using a diagnostic protocol including the caloric test, C-VEMPs and O-VEMPs. METHODS: Twenty patients suffering from CIDP (mean age 58.5 years, range 33-80 years; 4 women and 16 men) were investigated. To assess any eventual audio-vestibular involvement, all patients of the study underwent pure tone audiometry, Fitzgerald-Hallpike caloric vestibular test, C-VEMPs and O-VEMPs. RESULTS: In 11 patients with CIDP values of both O-VEMPs and C-VEMPs were either absent or abnormal. An absent trace at O-VEMPs testing occurred in 36% of these pathological patients, whereas an increase of n10 latency and amplitude was present in the other 64% . CONCLUSIONS: A specific diagnostic protocol including the caloric test, C-VEMPS, O-VEMPS, could be useful when employed for identifying vestibular damage in CIDP patients.

Effect of aspirin on renal disease progression in patients with type 2 diabetes: A multicenter, double-blind, placebo-controlled, randomized trial. The renaL disEase progression by aspirin in diabetic pAtients (LEDA) trial. Rationale and study design.

Type 2 diabetes mellitus (T2DM) is one of the most common causes of chronic kidney disease and kidney failure. It has been estimated that the annual decline of estimated glomerular filtration rate (eGFR) among patients with T2DM is approximately 2.0-2.5mL min-1 y-1. Cyclooxygenase-dependent eicosanoids, such as 11-dehydro-thromboxane (Tx)B2, are increased in T2DM patients and are potentially involved in the regulation of renal blood flow. Animal models showed that cyclooxygenase inhibitors, such as aspirin, are associated with improvements in renal plasma flow and eGFR values. HYPOTHESIS: The primary end point of the LEDA trial is to evaluate the 1-year decline of eGFR in T2DM patients treated or not with low-dose aspirin (100mg/d). Secondary end points will be the rapid decline in renal function, defined as a reduction of eGFR ≥5mL/min, and change of renal function class after 1-year follow-up. Furthermore, urinary excretion 11-dehydro-TxB2 will be related to renal function modifications. STUDY DESIGN: A phase 3 no-profit, multicenter, double-blind, randomized intervention trial of aspirin 100mg/dvs placebo (ClinicalTrials.gov Identifier: NCT02895113). All patients will be monitored at 6 and 12months after randomization to assess drug adherence and eGFR changes. SUMMARY: The LEDA trial is the first double-blind, placebo-controlled, randomized clinical trial aimed at examining whether aspirin treatment may beneficially affect kidney function in patients with T2DM by reducing the annual eGFR decline. The trial will also examine whether the potential renoprotective effects of aspirin might be partly due to its inhibition of TxB2 production.

Delayed Effect of Active Pressure Treatment on Endolymphatic Hydrops.

OBJECTIVE: To identify eventual correlations between the effect of low-pressure treatment and endolymphatic hydrops in Ménière patients. MATERIAL AND METHODS: The study group consisted of subjects affected by definite Ménière disease (2015) and a severe degree of disability, who received a ventilation tube with or without a low-pressure treatment before undergoing a surgical procedure (vestibular neurectomy). After the placement of the ventilation tube, the subjects were either left alone with the tube or received 1 month of self-administered low-pressure therapy with a portable device. In all subjects, an electrocochleography (ECochG) was performed and specific questionnaires - Dizziness Handicap Inventory (DHI) and Functional Scale Level (FSL) - were completed before starting either arm of treatment, at the end of treatment, and then 3 and 6 months later. RESULTS: All selected subjects presented with an ECochG pattern that was indicative of endolymphatic hydrops before starting either treatment. At the end of pressure treatment, 80% showed symptomatic improvement while maintaining the hydropic ECochG pattern. At the 3-month control stage, the hydropic pattern resulted normalized (<0.5) in all the improved subjects. CONCLUSIONS: Although 1 month of low-pressure treatment provided a positive symptomatological outcome, normalization of the hydropic ECochG parameters occurred only at a later time. Therefore, it is possible to assume that endolymphatic hydrops could be concurrent with a non-symptomatic stage of Ménière disease, and that the anti-hydropic effect of the low-pressure treatment, if any, would present with a certain delay after its completion.

Are mast cells implicated in asphyxia?

In a previous immunohistochemical (IHC) study, we documented the reaction of lung tissue vessels to hypoxia through the immunodetection of HIF1-α protein, a key regulator of cellular response to hypoxic conditions. Findings showing that asphyxia deaths are associated with an increase in the number of mast cell (MC)-derived tryptase enzymes in the blood suggests that HIF1-α production may be correlated with MC activation in hypoxic conditions. This hypothesis prompted us to investigate the possible role of pulmonary MC in acute asphyxia deaths. Lung of 47 medico-legal autopsy cases (35 asphyxia/hypoxia deaths, 11 controls, and 1 anaphylactic death) were processed by IHC analysis using anti-CD117 (c-Kit) antibody to investigate peri-airway and peri-vascular MC together with their counts and features. Results showed a significant increase in peri-vascular c-kit(+) MC in some asphyxia deaths, such as hanging, strangulation, and aspiration deaths. A strong activation of MC in peri-airway and peri-vascular areas was also observed in lung samples from the anaphylaxis case, which was used as a positive control. Our study points to the potential role of MC in hypoxia and suggests that an evaluation of MC in the lungs may be a useful parameter when forensic pathologists are required to make a differential diagnosis between acute asphyxia deaths and other kinds of death.

Periodontal Effects of a Transposed Versus a Conventional Flap in Mandibular Third Molar Extractions.

The aim of this study was to compare a transposed with a repositioned flap by assessing the periodontal effects on the second molar and primary healing after extraction of partially impacted lower third molars. A total of 24 patients requiring partially impacted mandibular wisdom tooth removal were enrolled in the study. The test group (n = 12) underwent a transposed flap procedure, whereas the control group (n = 12) underwent a repositioned flap procedure. Plaque index, probing depth, bleeding on probing, and width of keratinized tissue were recorded the day of surgery (T1) and after 60 days (T4). Wound dehiscence was assessed on the mesio-distal and bucco-lingual directions at days 2 (T2), 7 (T3), and T4. No significant differences have been observed in the periodontal parameters between the groups at T1 and T4 (P > 0.05). Similarly, no difference was found at T2, T3, and T4 in wound dehiscence incidence (P > 0.05). To date, no data exists on the use of transposed flaps in third molar surgery; thus a comparison of results cannot be done. Further studies with larger population are needed to investigate the potential advantages of this type of flap.

Endoluminal calprotectin measurement in assessment of pouchitis and a new index of disease activity: a pilot study.

Pouchitis is the most common complication following proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis (UC). To provide a standardized definition of pouchitis clinical, endoscopic and histological markers were grouped and weighted in the pouch disease activity index (PDAI). However, the delay in the assessment of the final score due to the time requested for histological analysis remains the main obstacle to the index implementation in clinical practice so that the use of modified-PDAI (mPDAI) with exclusion of histologic subscore has been proposed. We tested the ability of calprotectin measurement in the pouch endoluminal content to mimic the histologic score as defined in the PDAI, the index that we adopted as gold standard for pouchitis diagnosis. Calprotectin was measured by ELISA in the pouch endoluminal content collected during endoscopy in 40 consecutive patients with J-pouch. In each patient PDAI and mPDAI were calculated and 15% of patients were erroneously classified by mPDAI. ROC analysis of calprotectin values vs. acute histological subscore ≥ 3 identified different calprotectin cut-off values with corresponding sensitivity and specificity allowing the definition and scoring of different range of calprotectin subscores. We incorporated the calprotectin score in the mPDAI obtaining a new score that shows the same specificity as PDAI for diagnosis of pouchitis and higher sensitivity when compared with mPDAI. The use of the proposed new score, once validated in a larger series of patients, might be useful in the early management of patients with symptoms of pouchitis.

[Cardiovascular diseases and cancer incidence in general population: results from MATISS cohort]. / Incidenza di malattie cardiovascolari maggiori e tumori nella coorte longitudinale del Progetto MATISS in persone con differente profilo di rischio cardiovascolare.

OBJECTIVES: to assess the incidence of fatal and non-fatal major cardiovascular diseases and cancers in people with different cardiovascular risk profile of a longitudinal cohort. DESIGN: longitudinal study carried out in a large sample of general population, with a median follow-up of 17.7 years. SETTING AND PARTICIPANTS: MATISS longitudinal cohort, 7,491 men and women aged 20-75 years, free of cancer or cardiovascular diseases at baseline. Two cardiovascular risk groups (low-intermediate cardiovascular risk and high cardiovascular risk) and two educational levels (low level: primary school; middle/high level: middle/high school, university) have been considered. MAIN OUTCOME MEASURES: for both cancer and cardiovascular events the standardized incidence rates have been calculated, taking into account the cardiovascular risk profile and the educational level. RESULTS: people with a high-risk profile have higher incidence of major cardiovascular diseases and cancers. Furthermore, incidence rates are higher in people with lower educational level, except for cardiovascular diseases in men. CONCLUSIONS: this study shows that, in the considered population, cancer incidence rates are higher than cardiovascular diseases rates; moreover, cancer incidence is higher in people with high-risk cardiovascular profile. The increase of prevalence of favourable risk profile in the general population could represent effective community strategies for prevention of cardiovascular diseases and cancer. Major attention should be dedicated towards people at lower socioeconomical level.

Oral bisphosphonates do not increase the risk of severe upper gastrointestinal complications: a nested case-control study.

BACKGROUND: Data on the effect of oral bisphosphonates (BPs) on risk of upper gastrointestinal complications (UGIC) are conflicting. We conducted a large population-based study from a network of Italian healthcare utilization databases aimed to assess the UGIC risk associated with use of BPs in the setting of secondary prevention of osteoporotic fractures. METHODS: A nested case-control study was carried out within a cohort of 68,970 patients aged 45 years or older, who have been hospitalized for osteoporotic fracture from 2003 until 2005. Cases were the 804 patients who experienced hospitalization for UGIC until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio (OR) associated with current and past use of BPs (i.e. for drug dispensation within 30 days and over 31 days prior the outcome onset, respectively) after adjusting for several covariates. RESULTS: Compared with patients who did not use BPs, current and past users had OR (and 95% confidence interval) of 0.86 (0.60 to 1.22) and 1.07 (0.80 to 1.44) respectively. There was no difference in the ORs estimated according with BPs type (alendronate or risedronate) and regimen (daily or weekly), nor with co-therapies and comorbidities. CONCLUSIONS: Further evidence that BPs dispensed for secondary prevention of osteoporotic fractures are not associated with increased risk of severe gastrointestinal complications is supplied from this study. Further research is required to clarify the role BPs and other drugs of co-medication in inducing UGIC.

Effectiveness of oral bisphosphonates for primary prevention of osteoporotic fractures: evidence from the AIFA-BEST observational study.

PURPOSE: Osteoporosis is a chronic disease of the bone, whose incidence increases progressively with aging. The main consequences of osteoporosis are fragility fractures, which have considerable medical, social, and economic implications. Adequate treatment of osteoporosis must be considered as a compelling public health intervention. Bisphosphonates (BPs) represent the most significant advance in this field in the past decade, and they are widely used in the treatment of osteoporosis. However, evidence for their effectiveness is limited to secondary prevention, whereas their effect in primary prevention is uncertain and needs further investigation. METHODS: Using administrative data collected in the "Biphosphonates Efficacy-Safety Tradeoff" (BEST) study, a nested case-control study was conducted by including 56,058 participants, aged 55 years who were started on oral BPs from 2003 to 2005. Cases were the 1,710 participants who were hospitalized for osteoporotic fractures until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio of fracture associated with categories of treatment duration. RESULTS: Compared with participants assuming BPs for less than 1 year, those who remained on therapy for at least 2 years had a 21% (95% confidence interval (CI) 7 to 33%) fracture risk reduction. CONCLUSION: This study provides evidence that BPs, dispensed for primary prevention of osteoporotic fractures, are associated with a reduced risk of osteoporotic fractures after at least 2 years of treatment.

User-only design to assess drug effectiveness in clinical practice: application to bisphosphonates and secondary prevention of fractures.

PURPOSE: Different strategies applicable to control for confounding by indication in observational studies were compared in a large population-based study regarding the effect of bisphosphonates (BPs) for secondary prevention of fractures. METHODS: The cohort was drawn from healthcare utilization databases of 13 Italian territorial units. Patients aged 55 years or more who were hospitalized for fracture during 2003-2005 entered into the cohort. A nested case-control design was used to compare BPs use in cohort members who did (cases) and who did not experience (controls) a new fracture until 2007 (outcome). Three designs were employed: conventional-matching (D1 ), propensity score-matching (D2 ), and user-only (D3 ) designs. They differed for (i) cohort composition, restricted to patients who received BPs straight after cohort entry (D3 ); (ii) using propensity score for case-control matching (D2 ); and (iii) compared groups of BPs users versus no users (D1 and D2 ) and long-term versus short-term users (D3 ). RESULTS: Bisphosphonate users had odds ratios (95% confidence interval) of 1.20 (1.01 to 1.44) and 0.95 (0.74 to 1.24) by applying D1 and D2 designs, respectively. Statistical evidence that long-term BPs use protects the outcome onset with respect to short-term use was observed for user-only design (D3 ) being the corresponding odds ratio (95% confidence interval) 0.64 (0.44 to 0.93). CONCLUSIONS: User-only design yielded closer results to those seen in RCTs. This approach is one possible strategy to account for confounding by indication.

Quality-of-life impairment after endoluminal locoregional resection and laparoscopic total mesorectal excision.

BACKGROUND: For selected patients with rectal cancer, endoluminal locoregional resection (ELRR) by transanal endoscopic microsurgery (TEM) may be an alternative treatment option to laparoscopic total mesorectal excision (LTME). Few data are available on quality of life (QoL) after LTME and TEM. This study aimed to compare short- and medium-term QoL for T1 rectal cancer patients undergoing LTME or ELRR by TEM. METHODS: This study investigated 35 patients with T1N0 rectal cancer who underwent TEM (n = 17) or LTME (n = 18). Quality of life was evaluated by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-C38 questionnaires preoperatively and then 1, 6, and 12 months after surgery. RESULTS: Observation 1 month after LTME showed worsening in all items of both questionnaires. After ELRR, the QLQ-CR38 showed worsening of gastrointestinal (p = 0.005) and defecation problems (p = 0.001), and the QLQ-C30 showed worsening of global health status (p = 0.014), physical functioning (p = 0.02) role functioning (p = 0.003), fatigue (p = 0.002), and pain (p = 0.001). The QLQ-CR38 6 months after LTME showed worsening of body image (p = 0.009), micturition (p = 0.035), and gastrointestinal problems (p = 0.011), and the QLQ-C30 showed worsening of physical functioning (p = 0.003), role functioning (p = 0.002), fatigue (p = 0.004), and nausea/vomiting (p = 0.030). After ELRR, neither the QLQ-CR38 nor the QLQ-C30 questionnaire showed any worsening but demonstrated improvement in global health status and physical functioning. The QLQ-CR38 12 months after LTME showed significant improvement in defecation problems (p = 0.004) and weight loss (p = 0.003), and the QLQ-C30 showed significant improvement in global health status (p = 0.001), nausea and vomiting (p = 0.003), and pain (p = 0.005). After ELRR, the QLQ-C30 showed improvement in emotional functioning (p = 0.012), whereas no significant difference was observed by the QLQ-C38. CONCLUSIONS: Functional sequelae are present up to 1 month only after ELRR by TEM and up to 6 months after LTME. At 12 months, neither procedure showed a significant difference in QoL compared with preoperative status.

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.

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.