Long-Term Safety of In Utero Exposure to Anti-TNFα Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study.

OBJECTIVES: The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs in utero with that of children who were not exposed to the drugs. METHODS: Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared using the log-rank test. Cox-regression analysis was performed to identify potential predictive factors for severe infections in the offspring. RESULTS: The study population comprised 841 children, of whom 388 (46%) had been exposed to anti-TNFα agents. Median follow-up after delivery was 47 months in the exposed group and 68 months in the non-exposed group. Both univariate and multivariate analysis showed the incidence rate of severe infections to be similar in non-exposed and exposed children (1.6% vs. 2.8% per person-year, hazard ratio 1.2 (95% confidence interval 0.8-1.8)). In the multivariate analysis, preterm delivery was the only variable associated with a higher risk of severe infection (2.5% (1.5-4.3)). CONCLUSIONS: In utero exposure to anti-TNFα drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children.

A 1-year follow-up study on checkpoint inhibitor-induced colitis: results from a European consortium.

BACKGROUND: Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis. MATERIALS AND METHODS: This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed. RESULTS: Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis. CONCLUSIONS: Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.

Histopathological features of tissue alterations induced by low frequency ultrasound with cavitational effects on human adipose tissue.

Low frequency, high energy level ultrasound (US) induces physical effects on tissues called ultrasonic cavitation (UC). Endermic US therapy has recently been proposed as a method to reduce non-invasively the amount of adipose tissue. Very few published studies have dealt with the biological effects of such therapies on human adipose tissue. The aim of this study is to evaluate, through histopathological examination, the effects of various levels of ultrasonic radiation on supravital human adipose tissue. Four ex vivo human tissue samples were treated as follows: sample 1: no US radiation; sample 2: US radiation 2,5 W/cm2 for 15 minutes; sample 3: US radiation 5 W/cm2 for 15 minutes; sample 4: infiltration of 30 ml physiological saline and US radiation, 5 W/cm2 for 15 minutes. For lower levels of ultrasonic energy, interruption of the adipocytic membranes was evident both in the surface and in the deeper cutaneous and subcutaneous layers, with focal dissolution and homogenization of the surface dermal fascia. For higher levels of ultrasonic energy, alterations of the adipocytes and of the collagen fibers were greater, resulting in the dissolution of the cells and of the interlobular fibrous septa. Both effects were amplified by tumescent saline infiltration. The histological lesions demonstrated in adipocytes confirm the theoretical premises of a possible usefulness in the treatment of localized adiposis. The alterations observed in the connective stroma could have positive effects on the structural re-organization and consequently on the in vivo external appearance of the treated areas.

Size of bladder cancers: correlation among different types of measurement.

OBJECTIVE: It was the aim of this study to evaluate the accuracy of the measurement of tumor size comparing the objective size with that measured by preoperative cystoscopy, by preoperative ultrasound (US) and with the diameter described by the operator before the transurethral resection. PATIENTS AND METHODS: This study included 100 patients with bladder papillary endoscopic features of single or multiple neoplasms who were candidates for transurethral resection. The sizes of the same neoplasms measured during preoperative cystoscopy, preoperative US and described by the operator before the transurethral resection were evaluated. A statistical analysis of the errors of measurement was performed if compared with an objective measurement done with an ureteral catheter. RESULTS: The statistical analysis of the data shows that there are no substantial differences between the objective and subjective measurement, and therefore, the measurements reported by individual operators are reliable. On the contrary, the diameters given by preoperative cystoscopy and US differ significantly from the objective measurement. CONCLUSIONS: This study shows that the most reliable measurement is the subjective measurement made directly by the urologist in the operating room.

Achievement of sustained deep remission with adalimumab in a patient with both refractory ulcerative colitis and seronegative erosive rheumatoid arthritis.

Inflammatory bowel disease (IBD) is commonly associated with peripheral inflammatory arthritis, and it has been estimated that as many as 12% of IBD patients report these manifestations. However, rheumatoid arthritis (RA) is rarely associated with ulcerative colitis (UC). Among all the biological agents available, nine have been currently approved for the treatment of RA. Conversely, only Infliximab and recently Adalimumab have been approved for UC. In particular, the efficacy of Adalimumab in UC has been demonstrated by both recent randomized controlled trials and real-life studies. Moreover, Adalimumab is a well-established treatment for RA. Herein, we describe a patient with RA and UC treated successfully with ADA.

The 'ability' paradigm in vocational rehabilitation: challenges in an Ontario injured worker retraining program.

INTRODUCTION: In recent years, a focus on workers' ability, rather than impairment, has guided disability management services. However, a challenge with the notion of 'ability' is identification of the border between ability and inability. This article considers this gray zone of disability management in the case of a workers' compensation vocational retraining program for injured workers in Ontario. METHODS: In-depth interviews and focus groups were conducted with a purposive sample of 71 participants who were directly involved with the vocational retraining process. Workers in the program had on average incurred injury 3 years earlier. Procedural and legal documents were also analyzed. Principles of grounded theory and discourse analysis guided the data gathering and analysis. RESULTS: A program focus on worker abilities did not allow for consideration of unresolved medical problems. Concepts such as maximum medical rehabilitation distracted attention from workers' ongoing chronic and unstable health situations, and incentive levers to employers directed some of the least capable workers into the program. As well, communication pathways for discussing health problems were limited by rules and provider reluctance to reveal problems. Therefore, workers completing the program were deemed 'employable', while ongoing and problematic health conditions preventing employment remained relatively uncharted and invisible. CONCLUSIONS: This study reinforces how the shift in disability management paradigm to a focus on ability and return to work requires consideration of environmental conditions, including policies and programs and implementation. A focus on the environment in which worker ability can be enacted might be as important as a focus on improving individual worker characteristics.

Effect of Argon on the Properties of Copper Nitride Fabricated by Magnetron Sputtering for the Next Generation of Solar Absorbers.

Copper nitride, a metastable semiconductor material with high stability at room temperature, is attracting considerable attention as a potential next-generation earth-abundant thin-film solar absorber. Moreover, its non-toxicity makes it an interesting eco-friendly material. In this work, copper nitride films were fabricated using reactive radio frequency (RF) magnetron sputtering at room temperature, 50 W of RF power, and partial nitrogen pressures of 0.8 and 1.0 on glass and silicon substrates. The role of argon in both the microstructure and the optoelectronic properties of the films was investigated with the aim of achieving a low-cost absorber material with suitable properties to replace the conventional silicon in solar cells. The results showed a change in the preferential orientation from (100) to (111) planes when argon was introduced in the sputtering process. Additionally, no structural changes were observed in the films deposited in a pure nitrogen environment. Fourier transform infrared (FTIR) spectroscopy measurements confirmed the presence of Cu-N bonds, regardless of the gas environment used, and XPS indicated that the material was mainly N-rich. Finally, optical properties such as band gap energy and refractive index were assessed to establish the capability of this material as a solar absorber. The direct and indirect band gap energies were evaluated and found to be in the range of 1.70-1.90 eV and 1.05-1.65 eV, respectively, highlighting a slight blue shift when the films were deposited in the mixed gaseous environment as the total pressure increased.

The educational role of IBD nurses in Italy in vaccinations: do not miss the moment for COVID-19.

OBJECTIVE: The role of nurses has great educational-scientific potential in COVID-19 vaccination. The aim of this work is to clarify whether the educational role of IBD nurses in vaccination is perceived by IBD patients. MATERIALS AND METHODS: A cross-sectional study was carried out, through a questionnaire, to evaluate how many IBD patients received health education about vaccinations from the dedicated nurses (IBD nurses). RESULTS: There were four hundred questionnaires, 310 patients (77.5%) answered all questions. The nurse does not appear to help educate patients on influenza vaccination (66.1%) or pneumococcal vaccination (81.6%). Disclosed patients have many doubts about the new COVID-19 vaccination (74.4%) and many seek information (74.8%) and think that the nurse can provide the necessary information (70%). CONCLUSIONS: IBD nurses do not seem very active in the vaccination education role, and they do not meet patients' expectations, which are conversely very high.

Changes in admissions, and hospitalization outcomes of IBD patients in an Italian tertiary referral center over a 13-year period.

OBJECTIVE: The management of Inflammatory Bowel Disease (IBD) has changed significantly in recent years, mainly due to the introduction of biologic medications, however, other factors may also have a role. The aim of this study was to evaluate the evolution of IBD admissions, including trends, modality of admission and rates of surgical intervention, in a tertiary care center. PATIENTS AND METHODS: Hospitalization of patients with a diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) were identified between 2000 and 2013, using ICD-9-CM codes for IBD, from our hospital database. The following parameters were evaluated for each admission: type of admission (ordinary vs. day care service), mode of admission (elective vs. emergency care, for ordinary admissions only), admission code, surgical procedures and complication rates. Comparison between pre- and post-biologic therapy introduction years was also performed. RESULTS: Between 2000 and 2013 a total of 8834 IBD-related admissions were recorded. Hospitalizations increased linearly reaching a peak in 2006, with a downward trend in the following years. The downward trend was especially marked for patients younger than 40 years. No significant differences in hospitalization trends between CD and UC were recorded. Disease flare represented the cause of hospitalization in approximately 50% of cases. Overall, 10.8% of patients underwent surgery with no difference between the two conditions. Complications occurred in 28.7% of admissions. CONCLUSIONS: Hospitalizations for IBD patients have decreased in recent years, especially in younger patients. However, a significant proportion of patients are still admitted to complete diagnostic workup, indicating the need to better implement outpatient services. A clear reduction in surgery occurrence over time could not be observed in our study.

New biological agents for the treatment of the "high risk" IBD patients.

BACKGROUND: Several new biological drugs have been introduced in the last decade or are under investigation for the treatment of IBD. They include anti TNFalpha agents, anti adhesion molecules, anti IL-12/23, anti IL-6R and others. Their role in IBD therapy will be discussed in regard of the association of chronic inflammation and cancer in the gut. The risk of colorectal cancer is increased in ulcerative colitis (UC) and, to some extent, in Crohn's disease (CD). This association is well known from many years. However, the mechanisms linking chronic inflammation and carcinogenesis are beginning to be elucidated only recently. RESULTS AND CONCLUSIONS: Experimental data indicate that several cytokines could play a role in promoting tumour development. In this perspective, the anti cytokine agents could be not only powerful tools in treating inflammation but also efficacious in preventing the onset of inflammation associated colorectal cancer.

Severe eosinophilic asthma and aspirin-exacerbated respiratory disease associated to eosinophilic gastroenteritis treated with mepolizumab: a case report.

BACKGROUND: Mepolizumab (MEP) is the first anti Interleukin (IL)-5 add-on therapy approved for the treatment of severe refractory eosinophilic asthma. CASE PRESENTATION: We describe here the case of a 49 years-old woman with Aspirin-exacerbated respiratory disease (AERD), chronic rhinosinusitis, nasal polyposis and eosinophilic gastroenteritis successfully treated with MEP. Several laboratory and clinical items improved during therapy; moreover MEP showed to be useful as steroid sparing agent. CONCLUSIONS: This case supports that the use of mepolizumab can be effective also in other eosinophilic conditions different from asthma and this opens to new therapeutic perspectives.

Structural and spectral characterisation of Er3+ and Nd3+ doped Ga-La-S-Se glasses.

In this work, the spectroscopy of Er3+ and Nd3+ doped Se-GLS glasses was studied. A structural comparison between doped and non-doped samples was done to assess the differences between the glasses. For this comparison, Raman spectroscopy and thermal analysis were employed. The spectral properties of the samples were studied in order to identify the mechanisms responsible for quenching the fluorescence lifetime of the dopants. In particular, cross-relaxation and concentration quenching were observed in Nd3+ doped samples, whilst co-operative upconversion, radiation trapping and concentration quenching were observed in Er3+ doped samples. The results obtained demonstrated the fundamental role of the phonon energy in the mechanism of fluorescence. The low phonon energy of chalcogenides decreased the rate of non-radiative processes promoting co-operative upconversion. This effect could be exploited to design new lasers and sensitizers for solar energy harvesters.

Optimal number of multiple rapid swallows needed during high-resolution esophageal manometry for accurate prediction of contraction reserve.

BACKGROUND: Multiple rapid swallows (MRS) is a provocative test for assessment of contraction reserve, however reproducibility on repetitive MRS is incompletely understood. Our aim was to determine the optimal number of MRS sequences for consistent assessment of contraction reserve. METHODS: One hundred and fifty-nine consecutive patients (79 IEM and 80 normal motility) who underwent high-resolution manometers were enrolled. Ten single swallows (SS) and 10 MRS were performed. Gold standard for evaluation of the contraction reserve was the ratio between the mean DCI of 10 MRS and the mean DCI of 10 SS (MRS/SS DCI ratio). Rates of false negatives and false positives were calculated for increasing numbers of MRS sequences, using either mean DCI or the MRS with the highest DCI. KEY RESULTS: According to the gold standard, 50 IEM and 50 normal motility patients had contraction reserve. With progressively increasing numbers of MRS sequences, contraction reserve was detected using mean MRS DCI within three and four MRS sequences in IEM and normal motility respectively, whereas two and three MRS sequences were needed using the MRS sequence with the highest DCI. False positives were much higher with highest DCI method compared with mean DCI, (22% vs 9% respectively in IEM; 24% vs 9% in normal motility) when three MRS sequences were considered. CONCLUSIONS & INFERENCES: At least three MRS are needed to reliably assess contraction reserve. The mean DCI of the three MRS sequences is the best variable to utilize as evidence of contraction reserve.

Gastro-esophageal reflux and antisecretory drugs use among patients with chronic autoimmune atrophic gastritis: a study with pH-impedance monitoring.

BACKGROUND: Patients with chronic autoimmune atrophic gastritis (CAAG) often refer digestive symptoms and are prescribed antisecretory medications. Aims were to investigate: (i) gastro-esophageal reflux (GER), (ii) psychopathological profile, (iii) frequency of use and clinical benefit of antisecretory drugs. METHODS: Prospective observational study on 41 CAAG patients who underwent: 24 h multichannel intra-luminal impedance-pH (MII-pH) monitoring off-therapy, standardized medical interview and psychological questionnaire (i.e., SCL-90R). The medical interview was repeated at least 1 month after MII-pH in patients who were using antisecretory drugs. Statistical analysis was performed calculating median (10th-90th percentiles) and risk ratios (RR) with 95% confidence interval. KEY RESULTS: Median intra-gastric pH was 6.2 (4.6-7.0). One patient had acid reflux (AC) associated with symptoms, five had increased total reflux number and four had symptoms associated to non-acid reflux (NA) (patients referred as 'GER positive'). Using patients 'GER negative' with normal SCL-90R as reference, the RR of being symptomatic in patients GER positive was 2.1 (1.1-4.1) if SCL-90R was normal and 0.9 (0.5-1.7) if it was altered (difference in RR significant being p = 0.04). Seventeen/28 (61%) symptomatic patients were on antisecretory drugs, which were stopped in 16 of them according to results of MII-pH and clinical evaluation after 574 days (48-796) showed that symptoms were unchanged. CONCLUSIONS & INFERENCES: In patients with CAAG (i) AC reflux rarely occurred whereas increased NA reflux was not infrequent both being related to symptoms in some patients, (ii) psychopathological profile has a role in symptoms' occurrence, (iii) antisecretory drugs were generally inappropriately used and clinically ineffective.

Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study.

BACKGROUND: Psoriasis is an emerging paradoxical side effect in patients with inflammatory bowel disease (IBD) when treated with anti-TNF alpha. Patients with severe skin lesions unresponsive to topical therapy need to withdraw from treatment. AIM: To estimate the incidence of paradoxical psoriasis in a large cohort of IBD patients treated with anti-TNF alpha and to analyse its clinical correlates. METHODS: A retrospective cohort study on all IBD patients who started anti-TNF alpha at our IBD Centre from January 2008 to December 2013 was performed. Proportional hazards regression models were used to estimate the association between each predictor and time to the development of psoriasis. Time-dependent predictors were updated at each available time point. RESULTS: Four hundred and two patients were included. Participants contributed a total of 839 person-years of follow-up, during which 42 incident cases of psoriasis were recorded, with an incidence rate of five per 100 person-years. Cox-regression survival analysis revealed smoking as independent predictor of psoriasis (HR: 2.37, 95% CI: 1.36-4.48; P = 0.008). Conversely, concomitant immunosuppressive therapy was inversely related to psoriasis (HR: 0.33, 95% CI: 0.12-0.92; P = 0.03). CONCLUSIONS: Paradoxical psoriasis is a relevant side effect of anti-TNF alpha therapy, with an incidence rate of five per 100 person-years. Smoking is confirmed as the main risk factor for developing lesions. The combination therapy with anti-TNF alpha plus immunosuppressants is associated with a reduced risk of paradoxical psoriasis.

Acute systemic and splanchnic haemodynamic effects of L-carnitine in patients with cirrhosis.

L-carnitine (L-C) is a naturally occurring substance in mammalian tissues that has recently been proposed as a therapeutic agent in hepatic encephalopathy and liver steatosis. L-C also produces some acute, non-metabolic, haemodynamic effects that have not previously been studied in patients with cirrhosis. Therefore, the authors evaluated the acute effect of i.v. administration of L-C (30 mg/kg) on systemic and splanchnic haemodynamics in ten patients (L-C group) with chronic liver disease (Child-Pugh's class A: 4, B: 3, C: 3 patients) and a control group composed of ten patients with similar clinical characteristics (Child-Pugh's class A: 5, B: 2, C: 3 patients) who received placebo. Heart rate, cardiac index and pulmonary arterial pressure (measured by right heart catheterization) decreased slightly but significantly in the L-C group and the changes observed in stroke volume were highly correlated to the Pugh's score. Moreover, the hepatic venous pressure gradient (measured by hepatic vein catheterization) decreased significantly in the L-C group, whereas no changes occurred in the placebo group. The overall response to L-C was contradictory to that previously observed in animals and humans with normal liver function, and the extent seemed to depend on the severity of liver disease. The effect of the drug on cardiac index, heart rate and hepatic venous gradient could possibly be beneficial for patients with hyperdynamic circulatory condition and portal hypertension.

Combined protein C deficiency and protein C activated resistance as a cause of caval, peripheral, and cerebral venous thrombosis--a case report.

A 26-year-old woman suffered concomitant inferior vena cava, iliac, and femoral vein thrombosis and cerebral venous thrombosis. Ten days before symptom onset she had started using an oral contraceptive that contained low-dose ethynilestradiol and gestodene. Both protein C deficiency and protein C activated resistance were detected. To our knowledge, the association of cerebral, caval, and ilio-femoral-popliteal venous thrombosis has not been described previously. The severity of the clinical features could be a consequence of the two combined thrombophilic mechanisms and of the continuation of the oral contraceptive. A thrombophilic disorder should be considered in young patients with thromboembolic disease. Because of the high prevalence of the genetic deficiency causing protein C activated resistance, it is probably worthwhile to perform general screening before prescription of oral contraceptives.

[In vitro effect of asbestos fibers on short-term cultures of human lymphocytes]. / Studio dell'effetto in vitro di fibre di asbesto su colture a breve termine di linfociti umani.

The endocellular incorporation of asbestos fibres seems to be capable to induce on Chinese hamster cell cultures numerical and structural chromosome aberrations. In the present study asbestos fibres have been added at different concentrations to human cultured lymphocytes which have been harvested at 48 and 72 h, respectively. The results do not show significant difference in the distribution of chromatid and chromosome-type aberrations between the control cultures and the cultures treated with asbestos.