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Antipsychotic (AP) drugs have the potential to cause prolongation of the QT interval corrected for heart rate (QTc). As this risk is dose-dependent, it may be associated with the number of AP drugs concurrently prescribed, which is known to be associated with increased cumulative equivalent AP dosage. This study analysed whether AP dose mediates the relationship between polypharmacy and QTc interval. We used data from a cross-sectional survey that investigated the prevalence of QTc lengthening among people with psychiatric illnesses in Italy. AP polypharmacy was tested for evidence of association with AP dose and QTc interval using the Baron and Kenny mediational model. A total of 725 patients were included in this analysis. Of these, 186 (26%) were treated with two or more AP drugs (AP polypharmacy). The mean cumulative AP dose was significantly higher in those receiving AP polypharmacy (prescribed daily dose/defined daily dose = 2.93, standard deviation 1.31) than monotherapy (prescribed daily dose/defined daily dose = 0.82, standard deviation 0.77) (z = -12.62, p < 0.001). Similarly, the mean QTc interval was significantly longer in those receiving AP polypharmacy (mean = 420.86 milliseconds, standard deviation 27.16) than monotherapy (mean = 413.42 milliseconds, standard deviation 31.54) (z = -2.70, p = 0.006). The Baron and Kenny mediational analysis showed that, after adjustment for confounding variables, AP dose mediates the association between polypharmacy and QTc interval. The present study found that AP polypharmacy is associated with QTc interval, and this effect is mediated by AP dose. Given the high prevalence of AP polypharmacy in real-world clinical practice, clinicians should consider not only the myriad risk factors for QTc prolongation in their patients, but also that adding a second AP drug may further increase risk as compared with monotherapy.

The long-term maintenance of a stable condition is an important aim of schizophrenia therapy, which frequently requires the switch between 2 antipsychotic agents. This 8-week multicenter study, conducted in Italy, evaluates the switch from a previous antipsychotic to ziprasidone. Adult acute schizophrenic patients requiring a change in antipsychotic for lack of efficacy or tolerability issues took ziprasidone 20 − 80 mg/bid. Dosages could be adjusted during the study. The primary efficacy outcomes were the differences in positive and negative syndrome scale (PANSS) and clinical global impression severity (CGI-S) scores from baseline to study end. Other efficacy variables were clinical global impression improvement, global assessment of functioning, patient preference scale and drug attitude inventory. 189 patients were evaluated; the mean (±SD) ziprasidone dose was 95.9±34.5 mg/day. PANSS and CGI-S scores significantly decreased throughout the study. All secondary outcomes significantly improved at the end of the study vs. baseline values. Ziprasidone was well tolerated; 13 patients reported a QTc prolongation (mild in 12 patients). Notwithstanding the limitations of any non-comparative study, these results suggest that ziprasidone may be an effective and well-tolerated option in acute schizophrenia patients who discontinued a previous antipsychotic agent.

BACKGROUND AND STUDY AIM: The aim of this study was to assess the prevalence of nonpolypoid lesions (NPLs) in Italy and their risk of containing neoplasia or advanced histology. PATIENTS AND METHODS: This was a multicenter cross-sectional observational study on consecutive patients undergoing total colonoscopy over a 3-month period in 80 Italian centers. RESULTS: In all, 27,400 total colonoscopies were analyzed. Cancer was diagnosed in 801 patients (2.9 %). A total of 6553 precancerous lesions were detected in 5609 patients. Of these, 4154 patients (74.1 %) had polypoid lesions and 1455 patients (25.9 %) had NPLs. Therefore, the prevalence of NPLs was 5.3 % (95 %CI 5.0 - 5.6). NPLs larger than 10 mm were detected in 254 patients (17.5 %). NPLs were more predominant in the proximal colon (OR 2.92, 95 %CI 2.56 - 3.43; P < 0.0001 vs. polypoid lesions). Neoplastic tissue was diagnosed in 79.0 % and advanced histology (high-grade intraepithelial neoplasia or more) in 20.9 % of resected lesions. The risk of advanced histology was similar for polypoid and nonpolypoid lesions when adjusted for size. Depressed lesions had the highest risk of advanced histology (OR 10.56, 95 %CI 6.02 - 18.55; P < 0.0000 vs. flat-elevated). Age was an independent predictor of both neoplasia and advanced histology ( P = 0.0001). CONCLUSIONS: NPLs are relatively common in the Italian population, with a prevalence similar to that in other Western series. NPLs are not more aggressive than polypoid lesions, except for those with depressed morphology. Georg Thieme Verlag KG Stuttgart. New York.

Anorectal manometry provides an objective assessment of anal sphincter pressure and rectal sensitivity and anorectal reflexes in response to distension. However, its clinical utility is hampered by a lack of standardized protocols and normative data from healthy subjects. Previous studies have used water-perfused systems in normal subjects, but some adopted a rapid pull-through technique; others did not evaluate rectal sensations and others did not carefully exclude patients with functional bowel disorders. Objective To evaluate anorectal function in healthy adults without functional bowel disorders, using a water-perfused system with the stationary technique in order to obtain normative values for anorectal manometry. Method Fifty-two healthy volunteers with no Rome II diagnostic criteria for functional bowel disorders, including only nulliparous women, underwent anorectal manometry with a water-perfused system, according to a standardized protocol. Results Maximum squeeze pressure of the anal sphincter as well as the area under the pressure-time curve during squeeze was significantly lower in women than men (P < 0.01), while sphincter length, resting pressure, volume thresholds for reflex inhibitory recto-anal and rectal sensations were similar. Conclusions This study describes a protocol for stationary anorectal manometry using a water-perfused system, and a method for analysing the various parameters obtained during the procedure, as recently suggested in the international literature. It supplies normative data obtained in a population of healthy subjects including nulliparous women, with no functional bowel disorders.

The reproducibility of electrocardiographic (ECG) recordings in syncopal recurrences and the diagnostic role of nonsyncopal arrhythmias are not well known. The objective of this study was to analyse the reproducibility of the ECG findings recorded with implantable loop recorders in 41 patients with suspected neurally-mediated syncope who were included in the International Study on Syncope of Uncertain Origin-2 study and that had > or =2 events recorded by implantable loop recorders. In these patients, the electrocardiogram obtained with the first documented syncope (index syncope) was compared with other recorded events. Twenty-two patients had > or =2 syncopes, and their electrocardiograms were reproducible in 21 (95%): 15 with sinus rhythm, 5 with asystole, and 1 with ventricular tachycardia; 1 had asystole at first syncope and sinus rhythm at recurrent syncope. In 32 patients with nonsyncopal episodes, an arrhythmia was documented in 9, and all of them had the same arrhythmia during the index syncope (100% reproducibility); conversely, when sinus rhythm was documented (23 patients) during nonsyncopal episodes, an arrhythmia was still documented in 6 during the index syncope (70% reproducibility; p = 0.0004). In conclusion, the ECG findings during the first syncope are highly reproducible in subsequent syncopes. The presence of an arrhythmia during nonsyncopal episodes is also highly predictive of the mechanism of syncope, but the presence of sinus rhythm does not rule out the possibility of arrhythmia during syncope. Therefore the finding of an arrhythmia during a nonsyncopal episode allows the etiologic diagnosis of syncope, and eventually to anticipate treatment, without waiting for syncope

Clinically relevant animal models of mammary carcinogenesis are crucial for the development and evaluation of new breast cancer chemopreventive agents. The neu-induced retroviral rat mammary carcinogenesis model is based on the direct in situ transfer of the activated neu oncogene into the mammary epithelium using a replication-defective retroviral vector. The resulting mammary carcinomas in intact Wistar-Furth rats exhibit a mixed hormonal response in the same proportion as has been observed in women. In intact rats, ∼50% of mammary carcinomas can be prevented by tamoxifen treatment. In ovariectomized animals, the mammary carcinomas are hormonally nonresponsive and cannot be prevented by tamoxifen. We evaluated the efficacy of retinoic X receptor–selective retinoids (rexinoids) in this novel model of mammary carcinogenesis. The rexinoids LG100268 and bexarotene (LG1069, Targretin) were highly efficacious in the prevention of neu-induced mammary carcinomas. Dietary LG100268 at 100 mg/kg diet decreased tumor multiplicity by 32% (P = 0.0114) in intact rats and 50% (P < 0.0001) in ovariectomized rats. Bexarotene treatment at a dose of 250 mg/kg diet was associated with reductions in tumor multiplicity of 84% (P < 0.0001) and 86% (P < 0.0001) in intact and ovariectomized animals, respectively. In addition to tumor multiplicity, proliferation and apoptosis were modulated by bexarotene treatment independently of estrogen signaling. The neu-induced retroviral rat mammary carcinogenesis model represents a valuable addition to existing rodent chemoprevention models. The model is useful for assessing the efficacy of chemopreventive agents, specifically those compounds that target hormonally nonresponsive tumors. (Cancer Res 2006; 66(13): 6884-91)

Genetic susceptibility to breast cancer is influenced by high- and low-penetrance genes. The low-penetrance genes contributing to increased and decreased risk likely exist at appreciable frequencies in the human population. To identify high-frequency, low-penetrance modifier genes, we are using a rat genetic model. Eight quantitative trait loci, named mammary carcinoma susceptibility (Mcs) loci, have been genetically identified in two rat strains, Wistar-Kyoto (WKy) and Copenhagen. These strains are resistant to developing mammary cancer compared with susceptible Wistar-Furth (WF) female rats. Here we provide physical evidence of the existence of Mcs5 in the resistant WKy rat and further narrow the candidate region defining the QTL. Two congenic rat lines (C and D) containing large segments of the WKy Mcs5 QTL on chromosome 5 were generated on a WF background. The minimal WKy interval from markers D5Wox7 and D5Uwm37 (line C) conferred resistance to developing 7,12-dimethylbenz- [a]anthracene (DMBA)-induced mammary carcinomas. Line C females that were homozygous for the WKy allele at this interval averaged 1.1+/-0.3 carcinomas/rat compared with 6.9+/-0.4 average carcinomas/rat for WF control females (P

Coronavirus disease 2019 (COVID-19) is a major worldwide threat caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly spreading to a global pandemic. As of May 11, 2020, 4,176,346 cases have been reported worldwide, 219,814 in Italy, and of them, 81,871 occurred in the Lombardy region.1 Although the respiratory manifestations of COVID-19 have been widely described, the impact on the gastrointestinal (GI) system remains less clear. The reported prevalence of digestive symptoms ranges from 3% to 79%, depending on the setting,2–5 but data on GI endoscopic and histologic findings in COVID-19 patients are lacking. Therefore, the aim of this study is to describe the GI endoscopic and histologic findings in COVID-19 patients.

Purpose: Whether deferring surgery after endoscopic self-expandable metal stent (SEMS) placement for neoplastic stricture, and operating patients in a quasi-elective situation, may result in similar oncologic outcomes to elective operations is unclear. This study aimed to evaluate the disease-free survival (DFS) rates of patients who underwent an interval colon resection after SEMS placement or an elective operation with comparable cancer stages. Methods: From a prospective dataset, we retrospectively selected patients with the following characteristics: (1) left-sided colon cancer and (2) cancer stage I to III. Exclusion criteria were as follows: (1) palliative surgery and (2) emergency operation. Then we stratified patients into two groups: (A) full-elective left colon resection and (B) quasi-elective left colon resection, defined as surgery performed after SEMS placement for obstructive colon cancer. DFS function was studied by the Kaplan-Meier method. Results: After 1:2 matching based on cancer stage, 106 patients of the group A were compared with 53 patients of group B. In each group, there were 9.4% of stage I, 39.4% of stage II, and 50.9% of stage III patients. The rate of technical failure in SEMS placement was 3.8%. After a mean follow-up of 54months, 16 (15.1%) patients in the full-elective groups and 10 (18.9%) in the quasi-elective group experience cancer recurrence (log rank = 0.588). DFS curve did not reach the median value. Conclusions: SEMS placement with interval colon resection for obstructive neoplastic strictures seems to provide similar long-term oncologic outcomes to operations performed in an elective setting when a low rate of technical failure is achieved.

Background The incidence of biliary tract pathology is growing with an age-related trend, and progresses as the population ages. Endoscopic Retrograde Cholangiopancreatography (ERCP) represents the gold standard for treatment in these cases, but evidence about its safety in the elderly is still debated. Methods We retrospectively analyzed the clinical records of all patients aged ≥65 undergoing ERCP between July 2013 and July 2015. Of 387 ERCP cases, 363 (~ 94%) were completed entirely. The mean age of the study population (n = 363) was 79.9 years old (range 70–95), with 190 subjects aged 70–79 and 173 older than 80. We recorded demographics, Charlson Comorbidity index (CCI), American Society of Anesthesiologists (ASA) physical status classification score, indication for the use of the ERCP procedure, and clinical outcomes. Then, we tested all variables to identify the potential risk factors for complications associated with the procedure. Results The older group (those ≥80 years old) showed significantly more patients with ASA Classes III-IV than the younger one (those ≤79 years old). Interestingly, the CCI was higher in the younger group (p = 0.009). The overall complication rate was 17.3% without inter-group differences. Older age, sex, CCI and intra-ERCP procedures were not related to a higher risk of complications, and the multivariate regression did not identify any of the considered variables to be an independent risk factor for complications. Conclusion ERCP appears as safe in the patients aged 80 years and older, as it is in those aged 70–79 years old in our study, however, a selection bias may affect these findings. A study including a comprehensive geriatric assessment will contribute to shedding light on this issue.

Background:Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions.Methods:In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses.Results:Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and co-administration of a ‘known’ risk drug as a further risk factor.Conclusions:These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs.

Background According to Rome criteria, chronic constipation (CC) includes functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C). Some patients do not meet these criteria (No Rome Constipation, NRC). The aim of the study was is to evaluate the various clinical presentation and management of FC, IBS-C and NRC in Italy. Methods During a 2-month period, 52 Italian gastroenterologists recorded clinical data of FC, IBS-C and NRC patients, using Bristol scale, PAC-SYM and PAC-QoL questionnaires. In addition, gastroenterologists were also asked to record whether the patients were clinically assessed for CC for the first time or were in follow up. Diagnostic tests and prescribed therapies were also recorded. Results Eight hundred seventy-eight consecutive CC patients (706 F) were enrolled (FC 62.5%, IBS-C 31.3%, NRC 6.2%). PAC-SYM and PAC-QoL scores were higher in IBS-C than in FC and NRC. 49.5% were at their first gastroenterological evaluation for CC. In 48.5% CC duration was longer than 10 years. A specialist consultation was requested in 31.6%, more frequently in IBS-C than in NRC. Digital rectal examination was performed in only 56.4%. Diagnostic tests were prescribed to 80.0%. Faecal calprotectin, thyroid tests, celiac serology, breath tests were more frequently suggested in IBS-C and anorectal manometry in FC. More than 90% had at least one treatment suggested on chronic constipation, most frequently dietary changes, macrogol and fibers. Antispasmodics and psychotherapy were more frequently prescribed in IBS-C, prucalopride and pelvic floor rehabilitation in FC. Conclusions Patients with IBS-C reported more severe symptoms and worse quality of life than FC and NRC. Digital rectal examination was often not performed but at least one diagnostic test was prescribed to most patients. Colonoscopy and blood tests were the “first line” diagnostic tools. Macrogol was the most prescribed laxative, and prucalopride and pelvic floor rehabilitation represented a “second line” approach. Diagnostic tests and prescribed therapies increased by increasing CC severity. Electronic supplementary material The online version of this article (doi:10.1186/s12876-016-0556-7) contains supplementary material, which is available to authorized users.

BACKGROUND: The efficacy and safety of self-expandable metallic stent (SEMS) placement as a bridge to elective surgery or definitive palliation versus emergency operation to treat colorectal obstruction is debated. This study aimed to evaluate the outcomes of patients with colorectal obstruction treated using different strategies. METHODS: Subjects admitted to the authors' department with colorectal obstruction (n = 134) were studied prospectively. They underwent endoscopic stenting as a bridge to elective surgery (SEMS group: n = 49) or for definitive palliation (n = 34). A total of 51 patients underwent immediate surgery without stenting (NO-SEMS). Treatment was decided by the senior on-call surgeon. RESULTS: Placement of SEMS was technically successful in 95.3 % and clinically successful in 98.7 % of cases. The short-term complications in the SEMS group were perforation (n = 1, 1.2 %), migration (n = 4, 4.9 %), occlusion (n = 4, 4.9 %), colon bleeding (n = 3, 3.7 %), and abdominal pain (n = 6, 7.4 %). The postoperative complication rate was 32.7 % in the SEMS group versus 60.8 % in the NO-SEMS group (P = 0.005), with a significant reduction in wound infections (26.5 vs 54.9 %; P = 0.004), abdominal abscess (14.3 vs 39.2 %; P = 0.006), respiratory morbidity (10.2 vs 37.3 %; P = 0.002), and intensive care treatment (10.2 vs 33.3 %; P = 0.007). The median postoperative hospital stay was 10 versus 15 days (P = 0.001). The in-hospital mortality rate in both groups was 2 %. Long-term follow-up evaluation showed less incisional hernia (6.3 vs 22.0 %; P = 0.04) and definitive stoma formation (6.3 vs 26.0 %; P = 0.01) in the SEMS group than in the NO-SEMS group, respectively. Kaplan-Meier survival curves showed a benefit for the SEMS group (log-rank test, 0.004). The long-term SEMS-related complication rate for the palliative patients was 43.8 %. The hospital readmission rate for SEMS complications was 34.4 %. Overall clinical success was 81.2 %. CONCLUSIONS: In case of colorectal obstruction, endoscopic colon stenting as a bridge to elective operation should be considered as the treatment of choice for resectable patients given the significant advantages for short- and long-term outcomes. Palliative stenting is effective but associated with a high rate of long-term complications.

Background Endoscopic mucosal resection (EMR) is an effective therapeutic technique well-standardized worldwide for the treatment of gastrointestinal neoplasm limited to the mucosal layer. To date, no study has compared technical and clinical differences based on the number of EMRs performed per year. This study aimed to compare EMR technical success, complications, and clinical outcome between low-volume centers (LVCs) and high-volume centers (HVCs). A total of nine endoscopic centers were included in the study. Methods This prospective study investigated consecutive patients with sessile polyps or flat colorectal lesions 1 cm or larger referred for EMR. Results A total of 427 lesions were resected in 384 patients at nine endoscopic centers. Males accounted for 60.4 % and females for 39.6 % of the patients. Most of the EMRs (84.8 %) were performed in HVCs and only 15.2 % in LVCs. All the lesions were resected in only one session. Argon plasma coagulation was performed on the margins of piecemeal resection in 15.7 % of the patients in HVCs only. Complete excision was achieved for 98.6 % of the lesions in HVCs and 98.8 % of the lesions in LVCs. The complication rate was 4.4 % in HVCs and 4.6 % in LVCs (p = 0.94). Delayed bleeding occurred in 2.5 % of the HVC cases and 3.1 % of the LVC cases. Perforation occurred in 1.9 % of the HVC cases and 1.5 % of the LVC cases (p = 1.00). Recurrences were experienced with 15 % of the lesions: 15.5 % in HVCs and 14 % in LVCs (p = 0.79). Conclusions The study showed that EMR can be performed also in LVC.

Sclerosing mesenteritis is a rare, idiopatic, usually benign, inflammatory process of the mesenteric adipose tissue. The most common site of involvement is the small bowel mesentery. We present a case of sclerosing mesenteritis of the rectosigmoid colon as a cause of severe abdominal pain, abdominal obstruction, and ischemic colic mucosal lesions. Contrast enema, colonoscopy, angiography, and CT were the imaging modalities used. A 20 cm diameter, fibrotic mass causing extensive compression of rectosigmoid colon was found at laparotomy. Histological examination showed extended fibrosis, inflammatory cells infiltration, lipophages, and granulomas within the mesenteric adipose tissue associated with erosive colitis. Clinical presentation and treatment are discussed.