Enhancement of microbicidal efficacy of chemical disinfectants when combined with ultrasound technology.

AIMS: This study investigated the antimicrobial efficacy of ultrasound technology (US) in combination with two different disinfectants (Disinfectant A and Disinfectant B), containing peracetic acid (PAA) and quaternary ammonium compounds (QACs), respectively, against two sporigenic pathogens, Aspergillus brasiliensis and Bacillus subtilis. METHODS AND RESULTS: The microbicidal activity of the coupled treatment was compared with the use of the disinfectants alone, and the efficacy of the disinfection strategies was evaluated by the log reduction of the population of the microorganism inoculated onto stainless-steel surface. The combination treatment resulted in a log reduction of 5.40 and 3.88 (Disinfectant A + US) against A. brasiliensis and B. subtilis, at 850 and 500 ppm PAA, compared to 265 and 122 (Disinfectant A only). For Disinfectant B, in combination with US, showed a logarithmic reduction of 5.04 and 4.79 against A. brasiliensis and B. subtilis at 078% v v-1 and 392% v v-1 QACs, respectively, vs. 1.58 and 1.64 (Disinfectant B only). Moreover, no colonies or not statistically significant growth was observed within the US bath containing the disinfectant. CONCLUSIONS: The antimicrobial efficacy of the two disinfectants was greatly enhanced when used in combination with US, and this also makes it possible to avoid the overuse of chemicals for disinfection.

Intrauterine device-related uterine perforation incidence and risk (APEX-IUD): a large multisite cohort study.

BACKGROUND: Reports of perforation risk related to intrauterine devices (IUDs) inserted immediately post partum and among non-post-partum individuals are scarce, and previous studies with only 12-month follow-ups underestimate the risk. Breastfeeding at IUD insertion and insertion within 36 weeks post partum have been associated with increased risk of uterine perforation. The aim of these analyses was to compare the incidence and risks of IUD-related uterine perforations by non-post-partum and post-partum intervals at IUD insertion, and among post-partum individuals, to assess the impact of breastfeeding on these outcomes. METHODS: We did a multisite cohort study in the USA, using electronic health records (EHR). Study sites were three health-care systems and a site that used data from a health-care information exchange. The study population included individuals who were aged 50 years or younger and had an IUD insertion between Jan 1, 2001, and April 30, 2018. Individuals were excluded if they had not been in the health-care system for at least 12 months before IUD insertion. The primary outcome for this analysis was any IUD-related uterine perforation diagnosis for the first IUD insertion in this time period. Both complete and partial IUD-related perforations were identified. Chart abstraction was done to validate EHR-based algorithms or confirm perforations. The crude rate and cumulative incidence of uterine perforation were evaluated by non-post-partum and post-partum intervals at IUD insertion in the full cohort, and by breastfeeding status in a subcohort of post-partum individuals. Cox models estimated crude and adjusted hazard ratios (aHRs). FINDINGS: Data from 326 658 individuals in the full cohort and 94 817 individuals in the post-partum subcohort were analysed. In the full cohort, we identified 1008 uterine perforations (51·2% complete), with the 5-year cumulative incidence being the lowest in the non-post-partum group (0·29%, 95% CI 0·26-0·34). The aHR for the post-partum interval relative to non-post partum ranged from 2·73 (95% CI 1·33-5·63; 0 to 3 days post partum) to 6·71 (4·80-9·38; 4 days to ≤6 weeks post partum). The post-partum subcohort of individuals with breastfeeding information had 673 uterine perforations (62% complete), with a 5-year cumulative incidence of 1·37% (95% CI 1·24-1·52) and an increased risk with breastfeeding (aHR 1·37, 95% CI 1·12-1·66). INTERPRETATION: Although the risk for uterine perforation with IUD insertion 4 days to 6 weeks or less post partum is nearly seven times that of insertion non-post partum, perforation remains an incredibly rare event for all clinical time points. Despite a slight increased risk of perforation with breastfeeding at IUD insertion, the benefits of breastfeeding and effective contraception generally outweigh risks and should have little clinical impact. Therefore, IUD insertion timing should be based on individual desire for IUD contraception and patient convenience to assure an IUD insertion can occur. Careful follow-up of individuals at higher risk of uterine perforation is warranted. FUNDING: Bayer AG.

Association between menorrhagia and risk of intrauterine device-related uterine perforation and device expulsion: results from the Association of Uterine Perforation and Expulsion of Intrauterine Device study.

BACKGROUND: Intrauterine devices are effective instruments for contraception, and 1 levonorgestrel-releasing device is also indicated for the treatment of heavy menstrual bleeding (menorrhagia). OBJECTIVE: To compare the incidence of intrauterine device expulsion and uterine perforation in women with and without a diagnosis of menorrhagia within the first 12 months before device insertion STUDY DESIGN: This was a retrospective cohort study conducted in 3 integrated healthcare systems (Kaiser Permanente Northern California, Southern California, and Washington) and a healthcare information exchange (Regenstrief Institute) in the United States using electronic health records. Nonpostpartum women aged ≤50 years with intrauterine device (eg, levonorgestrel or copper) insertions from 2001 to 2018 and without a delivery in the previous 12 months were studied in this analysis. Recent menorrhagia diagnosis (ie, recorded ≤12 months before insertion) was ascertained from the International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes. The study outcomes, viz, device expulsion and device-related uterine perforation (complete or partial), were ascertained from electronic medical records and validated in the data sources. The cumulative incidence and crude incidence rates with 95% confidence intervals were estimated. Cox proportional hazards models estimated the crude and adjusted hazard ratios using propensity score overlap weighting (13-16 variables) and 95% confidence intervals. RESULTS: Among 228,834 nonpostpartum women, the mean age was 33.1 years, 44.4% of them were White, and 31,600 (13.8%) had a recent menorrhagia diagnosis. Most women had a levonorgestrel-releasing device (96.4% of those with and 78.2% of those without a menorrhagia diagnosis). Women with a menorrhagia diagnosis were likely to be older, obese, and have dysmenorrhea or fibroids. Women with a menorrhagia diagnosis had a higher intrauterine device-expulsion rate (40.01 vs 10.92 per 1000 person-years) than those without, especially evident in the first few months after insertion. Women with a menorrhagia diagnosis had a higher cumulative incidence (95% confidence interval) of expulsion (7.00% [6.70-7.32] at 1 year and 12.03% [11.52-12.55] at 5 years) vs those without (1.77% [1.70-1.84] at 1 year and 3.69% [3.56-3.83] at 5 years). The risk of expulsion was increased for women with a menorrhagia diagnosis vs for those without (adjusted hazard ratio, 2.84 [95% confidence interval, 2.66-3.03]). The perforation rate was low overall (<1/1000 person-years) but higher in women with a diagnosis of menorrhagia vs in those without (0.98 vs 0.63 per 1000 person-years). The cumulative incidence (95% confidence interval) of uterine perforation was slightly higher for women with a menorrhagia diagnosis (0.09% [0.06-0.14] at 1 year and 0.39% [0.29-0.53] at 5 years) than those without it (0.07% [0.06-0.08] at 1 year and 0.28% [0.24-0.33] at 5 years). The risk of perforation was slightly increased in women with a menorrhagia diagnosis vs in those without (adjusted hazard ratio, 1.53; 95% confidence interval, 1.10-2.13). CONCLUSION: The risk of expulsion is significantly higher in women with a recent diagnosis of menorrhagia. Patient education and counseling regarding the potential expulsion risk is recommended at insertion. The absolute risk of perforation for women with a recent diagnosis of menorrhagia is very low. The increased expulsion and perforation rates observed are likely because of causal factors of menorrhagia.

Association between intrauterine device type and risk of perforation and device expulsion: results from the Association of Perforation and Expulsion of Intrauterine Device study.

BACKGROUND: Intrauterine devices, including levonorgestrel-releasing and copper devices, are highly effective long-acting reversible contraceptives. The potential risks associated with intrauterine devices are low and include uterine perforation and device expulsion. OBJECTIVE: This study aimed to evaluate the risk of perforation and expulsion associated with levonorgestrel-releasing devices vs copper devices in clinical practice in the United States. STUDY DESIGN: The Association of Perforation and Expulsion of Intrauterine Device study was a retrospective cohort study of women aged ≤50 years with an intrauterine device insertion during 2001 to 2018 and information on intrauterine device type and patient and medical characteristics. Of note, 4 research sites with access to electronic health records contributed data for the study: 3 Kaiser Permanente-integrated healthcare systems (Northern California, Southern California, and Washington) and 1 healthcare system using data from a healthcare information exchange in Indiana (Regenstrief Institute). Perforation was classified as any extension of the device into or through the myometrium. Expulsion was classified as complete (not visible in the uterus or abdomen or patient reported) or partial (any portion in the cervix or malpositioned). We estimated the crude incidence rates and crude cumulative incidence by intrauterine device type. The risks of perforation and expulsion associated with levonorgestrel-releasing intrauterine devices vs copper intrauterine devices were estimated using Cox proportional-hazards regression with propensity score overlap weighting to adjust for confounders. RESULTS: Among 322,898 women included in this analysis, the incidence rates of perforation per 1000 person-years were 1.64 (95% confidence interval, 1.53-1.76) for levonorgestrel-releasing intrauterine devices and 1.27 (95% confidence interval, 1.08-1.48) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 0.22% (95% confidence interval, 0.20-0.24) and 0.63% (95% confidence interval, 0.57-0.68) for levonorgestrel-releasing intrauterine devices and 0.16% (95% confidence interval, 0.13-0.20) and 0.55% (95% confidence interval, 0.44-0.68) for copper intrauterine devices, respectively. The incidence rates of expulsion per 1000 person-years were 13.95 (95% confidence interval, 13.63-14.28) for levonorgestrel-releasing intrauterine devices and 14.08 (95% confidence interval, 13.44-14.75) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 2.30% (95% confidence interval, 2.24-2.36) and 4.52% (95% confidence interval, 4.40-4.65) for levonorgestrel-releasing intrauterine devices and 2.30% (95% confidence interval, 2.18-2.44) and 4.82 (95% confidence interval, 4.56-5.10) for copper intrauterine devices, respectively. Comparing levonorgestrel-releasing intrauterine devices with copper intrauterine devices, the adjusted hazard ratios were 1.49 (95% confidence intervals, 1.25-1.78) for perforation and 0.69 (95% confidence intervals, 0.65-0.73) for expulsion. CONCLUSION: After adjusting for potential confounders, levonorgestrel-releasing intrauterine devices were associated with an increased risk of uterine perforation and a decreased risk of expulsion relative to copper intrauterine devices. Given that the absolute numbers of these events are low in both groups, these differences may not be clinically meaningful.

Use of real-world evidence in regulatory decisions for rare diseases in the United States-Current status and future directions.

Following the release of the framework for the Real-World Evidence (RWE) Program, the US Food and Drug Administration (FDA) is actively evaluating and exploring ways to optimize the utility of real-world data (RWD) and RWE to support regulatory decision making. For rare conditions, conducting traditional randomized clinical trials may not always be feasible, and RWD and RWE have played and will continue to play an important role. We use three case examples-cerliponase alfa, asfotase alfa, and uridine triacetate-to illustrate how RWD from disease registries, medical records with chart review, and literature, respectively, have been used to generate RWE to support regulatory decisions for selected rare diseases. These examples highlight the need for improving data reliability and quality in existing data to expand use of RWD and RWE beyond "hard endpoints" and standardizing data collection for outcome measures in patient registries to expand its utility. We also discuss a recent FDA guidance for using RWE in supporting rare disease drug development, including its recommendations about using natural history studies as external control groups for single-arm interventional trials. The external control group needs to be comparable with the treated group. Selection bias and confounding are major concerns because of lack of randomization and unrecognized baseline differences. Use of valid epidemiological approaches can reduce these biases. Lastly, we discuss future directions to expand the use of RWD and RWE to support orphan drug approvals, including the need for including patient experience data as an important source of RWD.

Psychiatric Symptoms in Patients With Dementia: Do Caregivers and Doctors See the Same Thing?

PURPOSE: Neuropsychiatric symptoms (NPS) are common in Alzheimer Disease (AD). Treatment could be optimized by supplementing the clinician's impression of a patient with information from the caregiver. Yet the agreement between caregivers and physicians on the presence of NPS in patients with AD is understudied. METHODS: Data were obtained from a 2-staged survey in neurology outpatient offices. At stage 1, patients (n=403) were documented by their physicians, including an assessment on the presence of NPS. At stage 2, patients' CGs (n=171) were asked about the presence of NPS in the patients, based on questions from the Neuropsychiatric Inventory. Caregivers were screened for depression with the Depression Screening Questionnaire. PATIENTS: The study sample comprised patients with mild or moderate AD. RESULTS: NPS frequency varied between 52.6% [95% confidence interval (CI), 44.9%-60.3%] and 67.2% (95% CI, 59.7%-74.2%, reported by CGs) and 34.2% (95% CI, 26.8%-42.1%) and 50.9% (95% CI, 42.9%-58.9%, reported by physicians). Apathy, depression, aggression, and irritability occurred most frequently according to both sources. κ values were lowest for euphoria (κ=0.03; 95% CI, -0.08 to 0.25), and highest for depression (κ=0.26; 95% CI, 0.11-0.43). CG depression was associated with an increased probability (odds ratio=2.9; 95% CI, 1.2-6.7) of disagreement between caregivers and physicians on the patient's mental status. CONCLUSION: NPS, though very prevalent in dementia patients, are perceived differently by caregivers and physicians. This divergence increases depending on the psychological health of caregivers.

Anticholinergic burden before and after hospitalization in older adults with dementia: Increase due to antipsychotic medications.

OBJECTIVES: To evaluate changes in the use of antipsychotics and medications with anticholinergic activity (MACs) during hospitalization in older adults with dementia and factors associated with antipsychotic prescriptions and increased anticholinergic burden (ACB). METHODS AND DESIGN: This retrospective cohort study included all patients aged 65 years or older with a discharge diagnosis of dementia hospitalized at the university hospital of Udine, Italy, from 2012 to 2014. Medications dispensed within 3 months before and after hospitalization were identified in community-pharmacy dispensations while those prescribed at discharge were collected from Hospital Electronic Medical Records (EMR). ACB was assessed using the Anticholinergic Cognitive Burden score. RESULTS: Among 1908 patients included, at discharge, 37.0% used one or more antipsychotic (9.4% before and 12.6% after hospitalization), 68.6% used one or more MAC (49.1% and 45.7%, respectively), and ACB of 38.4% of patients increased at discharge mainly because of a higher use of antipsychotics with anticholinergic activity (33% at discharge vs 12% before hospitalization). Prescription of antipsychotics at discharge was associated with prior treatment with antipsychotics (adjusted odds ratio [aOR] 4.85; 95%CI, 3.37-6.97), psychiatric conditions, (4.39; 3.47-5.54) and discharge from surgical department (2.17; 1.32-3.55). An increased ACB was associated with psychiatric conditions (1.91; 1.52-2.39), discharge from surgical (1.75; 1.09-2.80) or medical department (1.50; 1.04-2.17), and with cardiac insufficiency (1.41; 1.00-1.99). CONCLUSIONS: ACB was higher at discharge, and antipsychotics were the main drivers of this increase. Clinicians treating older adults with dementia should be aware of the risks associated with antipsychotics and that some of these medications may increase the risk of anticholinergic effects.

MGMT pyrosequencing-based cut-off methylation level and clinical outcome in patients with glioblastoma multiforme.

AIM: MGMT promoter methylation has been associated with improved survival in glioblastoma multiforme treated with temozolomide. However, there is no consensus on specific cut-off levels of methylation. The aims of the study were to explore the prognostic impact of MGMT methylation status and to analyze the role of specific cut-off values. MATERIALS & METHODS: We analyzed 108 glioblastoma multiforme patients treated between 2008 and 2013 stratified according to three pyrosequencing-based quantitative methylation in: unmethylated (methylation <9%), intermediate (9-29%) and highly methylated (>29%). RESULTS: The three-class stratification has a prognostic impact (median progression-free survival: 7.97, 11.6 and 15 months respectively; p = 0.004; median OS: 13.2, 15.8 and 19.5 months, respectively; p = 0.0002), especially in patients exposed to temozolomide. CONCLUSION: Our study confirmed that the independent prognostic role of MGMT methylation status. An average level of methylation between all investigated CpGs of 9% may help discriminating between methylated and unmethylated tumors.

Cancer incidence in a cohort of asbestos-exposed workers undergoing health surveillance.

OBJECTIVES: To compare a local cohort of 2488 men occupationally exposed to asbestos and enrolled in a public health surveillance program with the 1995-2009 cancer incidence of the general population of Friuli Venezia Giulia (FVG) region, Northeast Italy, we conducted a historical cohort study. METHODS: Standardized incidence ratios (SIRs), with 95% confidence interval (95% CI), for specific cancer sites were estimated in the cohort and in subgroups of workers employed in shipbuilding between 1974 and 1994. For internal comparisons, we calculated incidence rate ratios (IRRs) for all cancers, lung cancer and mesothelioma, by level of exposure to asbestos and sector of employment adjusted for smoking habits and age at start of follow-up. RESULTS: Among cohort members the SIR was 8.82 (95% CI 5.95-12.61) for mesothelioma and 1.61 (95% CI 1.26-2.04) for lung cancer. In subgroup analyses, the SIR for lung cancer in subjects hired in shipbuilding between 1974 and 1984 was 2.09 (95% CI 1.32-3.13). In the overall cohort, a borderline increased incidence was also found for stomach cancer (SIR = 1.53 95% CI 0.96-2.31). Internal comparisons within the cohort show that among men with high asbestos exposure level the relative risk was almost threefold for lung cancer (IRR = 2.94 95% CI 1.01-8.57). CONCLUSIONS: This cohort experienced an excess in the incidence of both mesothelioma and lung cancer, showing increasing incidence rates at higher level of asbestos exposure. For lung cancer, the relative incidence was highest among workers hired in shipbuilding between 1974 and 1984.

Mortality in a cohort of asbestos-exposed workers undergoing health surveillance.

BACKGROUND: The coastal area of Friuli Venezia Giulia (FVG) region, north-eastern Italy, was characterized by work activities in which asbestos was used until the early 1990s, particularly in shipbuilding. A public health surveillance program (PHSP) for asbestos-exposed workers was established, although limited evidence exists about the efficacy of such programs in reducing disease occurrence and mortality. OBJECTIVES: To compare mortality in a cohort of 2,488 men occupationally exposed to asbestos, enrolled in a PHSP in FVG between the early 1990s and 2008, with that of the general population of FVG and Italy. METHODS: Standardized Mortality Ratios (SMR), with 95% Confidence Interval (95% CI), for all causes, all cancers, lung (LC) and pleural cancer (PC) were estimated in the cohort and in subgroups of workers with the first hire in shipbuilding that caused asbestos exposure (<1974, 1974-1984, 1985-1994). RESULTS: A strong excess in mortality for PC with reference to FVG (SMR=6.87, 95% CI 4.45-10.17) and Italian population (SMR=13.95, 95% CI 9.02-20.64) was observed. For LC, the FVG-based SMR was 1.49 (95% CI 1.17-1.89) and the Italy-based 1.43 (95% CI 1.12-1.81). Mortality among workers with the first hire in shipbuilding before 1974 was high for PC (FVG-based SMR=8.98, 95% CI 5.56-13.75; Italy-based SMR=18.41, 95% CI 11.40-28.17) and for LC (FVG-based SMR =1.60, 95% CI 1.18-2.11; Italy-based SMR=1.54, 95% CI 1.14-2.03). Further, for LC between 1974 and 1984, the FVG-based SMR was 2.45 (95% CI 1.06-4.82), and the Italy-based SMR was 2.33 (95% CI 1.01-4.60). CONCLUSIONS: This cohort experienced an excess mortality for pleural and lung cancer, compared with regional and national populations. For lung cancer, the excess was stronger in workers with the first hire in shipbuilding before 1985, suggesting a key role of asbestos exposure.

Comparison of the molecular profile of brain metastases from colorectal cancer and corresponding primary tumors.

AIM: Little is known about molecular biology of brain metastasis (BM) from colorectal cancer and its concordance with matched primary tumors. MATERIALS & METHODS: We identified 56 consecutive colorectal cancer patients who underwent neurosurgical resection of BM. Tumor samples were tested for KRAS, NRAS, BRAF and PIK3CA. The molecular profile of the brain lesion was compared with the corresponding primary tumor. RESULTS: The molecular profile concordance rate was 95.1%. Median survival after neurosurgery was 5.5 months (95% CI: 4.7-6.3); median overall survival was 24.0 months (95% CI: 15.6-32.4). CONCLUSION: In this cohort, we report a high frequency of KRAS mutations and a very high concordance rate between the molecular status of BM and that of matched primary tumors.

Colorectal cancer risk and nitrate exposure through drinking water and diet.

Ingested nitrate leads to the endogenous synthesis of N-nitroso compounds (NOCs), animal carcinogens with limited human evidence. We aimed to evaluate the risk of colorectal cancer (CRC) associated with nitrate exposure in drinking water and diet. A case-control study in Spain and Italy during 2008-2013 was conducted. Hospital-based incident cases and population-based (Spain) or hospital-based (Italy) controls were interviewed on residential history, water consumption since age 18, and dietary information. Long-term waterborne ingested nitrate was derived from routine monitoring records, linked to subjects' residential histories and water consumption habits. Dietary nitrate intake was estimated from food frequency questionnaires and published food composition databases. Odd ratios (OR) were calculated using mixed models with area as random effect, adjusted for CRC risk factors and other covariables. Generalized additive models (GAMs) were used to analyze exposure-response relationships. Interaction with endogenous nitrosation factors and other covariables was also evaluated. In total 1,869 cases and 3,530 controls were analyzed. Average waterborne ingested nitrate ranged from 3.4 to 19.7 mg/day, among areas. OR (95% CIs) of CRC was 1.49 (1.24, 1.78) for >10 versus ≤5 mg/day, overall. Associations were larger among men versus women, and among subjects with high red meat intake. GAMs showed increasing exposure-response relationship among men. Animal-derived dietary nitrate was associated with rectal, but not with colon cancer risk. In conclusion, a positive association between CRC risk and waterborne ingested nitrate is suggested, mainly among subgroups with other risk factors. Heterogeneous effects of nitrate from different sources (water, animal and vegetables) warrant further research.

Hospitalizations due to respiratory failure in patients with Amyotrophic Lateral Sclerosis and their impact on survival: a population-based cohort study.

BACKGROUND: Respiratory failure, infections and aspiration pneumonia, are the main causes of morbidity and mortality in Amyotrophic Lateral Sclerosis (ALS). In a population-based cohort, we assessed (a) hospital utilization and (b) impact of hospitalization for respiratory failure on survival. METHODS: All patients with incident ALS in Friuli Venezia Giulia region, Italy, from 2002 to 2009, were identified through multiple sources. Diagnosis was validated through clinical documentation review. For each patient, we extracted the records of all hospitalizations after ALS diagnosis from the regional hospitalization database. Cox proportional hazards model survival Hazard Ratio (HR), with 95 % Confidence Interval (95 % CI), was calculated. RESULTS: Out of 262 patients, 98.1 % had at least 1 and 58.0 % ≥3 hospitalizations. Emergency admissions occurred in 77.5 % of patients and a diagnosis of respiratory failure in 55.0 %. Patients underwent a total of 885 hospitalizations. The leading diagnosis was respiratory failure (31.6 % of hospitalizations). This diagnosis occurred most frequently in emergency (45.6 %) than in elective admissions (26.4 %). The second leading diagnosis was pneumonia (14.2 %), 24.9 and 6.3 % respectively. The leading procedure was mechanical ventilation (18.4 %), performed in 29.9 % of emergency and in 12.4 % of elective admissions. After adjustment for site of onset, age and diagnostic delay, a first hospitalization for respiratory failure had a strong adverse effect on survival (HR 4.00; 95 % CI 3.00; 5.34). CONCLUSIONS: Respiratory failure, pneumonia and aspiration pneumonia were major determinants of hospitalizations and emergency admissions and often dealt with in emergency admissions. A first hospitalization for respiratory failure had a strong adverse effect on survival. Strategies to improve home management of respiratory conditions in patients with ALS and to optimize hospital care utilization are needed.

Polypharmacy and the use of medications in inpatients with acquired brain injury during post-acute rehabilitation: A cross-sectional study.

BACKGROUND: This study assessed the use of medications during inpatient post-acute rehabilitation for acquired brain injury (ABI). MATERIALS AND METHODS: All inpatients with ABI undergoing post-acute rehabilitation in centres identified through the roster of the Italian Society for Rehabilitation Medicine were included. A designated physician in each centre collected information through a structured questionnaire. This study calculated (a) prevalence of medication use, (b) logistic regression Odds Ratio (OR), with 95% confidence interval (95% CI), of polypharmacy (≥ 6 medications). RESULTS: A total of 484 patients (median age = 52 years, 63.4% men, median time from acute event = 18.5 weeks) were included; 33.8% had Rancho Los Amigos Levels of Cognitive Functioning Scale (RLAS) score 1-2, 8.1% had a score of 7-8, of whom 92.0% received medications, 51.8% had a score of 6-10, of whom 83.9% had at least one psychotropic medication and 66.9% had two or more; 51.8% received anti-epileptics, 32.1% anti-depressants, 14.5% anti-psychotics, peaking in RLAS 4 (37.3%) and decreasing in RLAS 7-8. Polypharmacy was directly associated with age (55-64 years, OR = 2.1; 95% CI = 1.1-4.1; ≥ 65 years, OR = 1.7; 95% CI = 0.9-3.3), inversely with RLAS score (1-2 vs 7-8, OR = 4.3; 95% CI = 1.9-9.8). CONCLUSION: Polypharmacy and concurrent use of psychotropic medications was common, raising concern about drug-drug interactions. Safety and effectiveness of medications should be monitored, particularly when used concurrently.

[Not Available]. / Standardization of incidence rates of mesothelioma in the absence of national standards: sensitivity analysis in a cohort formerly exposed to asbestos.

INTRODUCTION: The incidence of mesothelioma in Italy shows wide geographical variation, with the highest incidence rates in Genoa and Friuli Venezia Giulia (FVG). For mesothelioma, national standard incidence rates are not available prior to the calendar year 2006. OBJECTIVES: To estimate the Standardized Incidence rate Ratio (SIR) of mesothelioma in a cohort of former workers undergoing health surveillance because of previous asbestos exposure, when sex-, age-, and calendar year-specific rates of the national standard are not available and the number of expected cases calculated from the regional rates is biased by the size of the study cohort. METHODS: We conducted a sensitivity analysis in a cohort of 2,488 men. We considered every Italian cancer registry available with complete data in the period 1995-2007 (N=14). We calculated, for each year and age group, the corresponding weighted mean rate of 10 registries of North-Italy (Mean W10), the weighted mean rate of all 14 registries available (Mean W14) and considered FVG standard rate. RESULTS: During the period 1995-2007, we observed 25 incident cases of mesothelioma with expected cases that varied between 2.00 (Mean W14) and 2.56 (FVG standard rate), with a SIR of 12.49 (CI95% 8.08-18.48) and 9.76 (CI95% 6.32-14.45) respectively. CONCLUSIONS: Our results show that the use of FVG rates as standard does not lead to significant distortions in the calculation of the expected cases. However, distortion is remarkable in the SIRs estimation. Using a weighted mean standard incidence rate may be a valid alternative for SIR estimate when national standard rates are not available.

The Use of Antidepressant Medication before and after the Diagnosis of Amyotrophic Lateral Sclerosis: A Population-Based Cohort Study.

BACKGROUND: The prevalent use of antidepressants (ATDs) in patients with Amyotrophic Lateral Sclerosis (ALS) varies across cross-sectional and clinic-based published studies. This population-based cohort study assesses the real-world prevalence of the use of ATDs, its trajectory and the association of incident use with clinical characteristics. METHODS: All patients with incident ALS in the Friuli Venezia Giulia region, Italy, from 2002 to 2009, were identified through multiple sources including health databases. Diagnosis was validated through clinical documentation review. ATDs prescriptions from 2000 to 2011 were obtained from regional database. The trajectory was estimated through generalized estimating equations for repeated measures logistic regression and the Hazard ratio (HR) of initiating ATDs through multivariate proportional hazard Cox regression. RESULTS: In this cohort of 261 ALS cases, age-, sex-adjusted prevalence of the use of ATDs was 37.3%, higher than in general population. The trajectory increased by 16% in 1-year period across diagnosis. Age ≤67 years at diagnosis (HR 1.28, 95% CI 0.84-1.95) and bulbar onset (1.43, 95% CI 0.90-2.26) were positively associated with initiating ATDs after diagnosis. CONCLUSIONS: More than one-third of patients used ATDs. Depression may occur more frequently than previously reported. Depression may precede motor alterations and be related to both ALS diagnosis and progression.

MGMT promoter methylation status in brain metastases from colorectal cancer and corresponding primary tumors.

BACKGROUND: Brain metastases (BM) from colorectal cancer are usually associated with poor prognosis. The aim of this retrospective study is to evaluate MGMT promoter methylation in BM and their corresponding primary colorectal cancer tumors. MATERIALS & METHODS: MGMT promoter methylation status was assessed by pyrosequencing in 53 consecutive patients resected for BM. A concordance analysis between BM and matched primary tumor was performed in 39 cases. RESULTS: MGMT methylation was found in 34 (64.2%) BM and in 25 corresponding primary tumors (64.1%). Median survival after neurosurgery was independent from MGMT promoter methylation (163 days for those with methylated MGMT versus 193 days for the unmethylated). CONCLUSION: Epigenetic MGMT promoter methylation was common and the concordance between primary and secondary lesions was high.

Prognostic role of KRAS, NRAS, BRAF and PIK3CA mutations in advanced colorectal cancer.

AIM: To explore the prognostic value of extended mutational profiling for metastatic colorectal cancer (mCRC). MATERIALS & METHODS: We retrospectively reviewed survival results of 194 mCRC patients that were assigned to four molecular subgroups: BRAF mutated; KRAS mutated codons 12-13 only; any of KRAS codons 61-146, PIK3CA or NRAS mutations and all wild-type. Point mutations were investigated by pyrosequencing. RESULTS: BRAF (5.2%) and KRAS 12-13 (31.9%) mutations were associated with poorer survival (HR 2.8 and 1.76, respectively). Presenting with right-sided colon cancer, not resected primary tumor, WBC >10 × 10(9)/l, receiving less chemotherapy or no bevacizumab were all associated with inferior outcome. The all-wild-type subgroup (39.2%) reported the longest survival. CONCLUSION: Extended mutational profile combined with clinical factors may impact on survival in mCRC.

Medication use during pregnancy, gestational age and date of delivery: agreement between maternal self-reports and health database information in a cohort.

BACKGROUND: Health databases are a promising resource for epidemiological studies on medications safety during pregnancy. The reliability of information on medications exposure and pregnancy timing is a key methodological issue. This study (a) compared maternal self-reports and database information on medication use, gestational age, date of delivery; (b) quantified the degree of agreement between sources; (c) assessed predictors of agreement. METHODS: Pregnant women recruited in a prenatal clinic in Friuli Venezia Giulia (FVG) region, Italy, from 2007 to 2009, completed a questionnaire inquiring on medication use during pregnancy, gestational age and date of delivery. Redeemed prescriptions and birth certificate records were extracted from regional databases through record linkage. Percent agreement, Kappa coefficient, prevalence and bias-adjusted Kappa (PABAK) were calculated. Odds Ratio (OR), with 95% confidence interval (95% CI), of ≥ 1 agreement was calculated through unconditional logistic regression. RESULTS: The cohort included 767 women, 39.8% reported medication use, and 70.5% were dispensed at least one medication. Kappa and PABAK indicated almost perfect to substantial agreement for antihypertensive medications (Kappa 0.86, PABAK 0.99), thyroid hormones (0.88, 0.98), antiepileptic medications (1.00, 1.00), antithrombotic agents (0.70, 0.96). PABAK value was greater than Kappa for medications such as insulin (Kappa 0.50, PABAK 0.99), antihistamines for systemic use (0.50, 0.99), progestogens (0.28, 0.79), and antibiotics (0.12, 0.63). Adjusted OR was 0.48 (95% CI 0.26; 0.90) in ex- vs. never smokers, 0.64 (0.38; 1.08) in < high school vs. university, 1.55 (1.01; 2.37) in women with comorbidities, 2.25 (1.19; 4.26) in those aged 40+ vs. 30-34 years. Gestational age matched exactly in 85.2% and date of delivery in 99.5%. CONCLUSIONS: For selected medications used for chronic conditions, the agreement between self-reports and dispensing data was high. For medications with low to very low prevalence of use, PABAK provides a more reliable measure of agreement. Maternal reports and dispensing data are complementary to each other to increase the reliability of information on the use of medications during pregnancy. Birth certificates provide reliable data on the timing of pregnancy. FVG health databases are a valuable source of data for pregnancy research.

Prescribing practice and off-label use of psychotropic medications in post-acute brain injury rehabilitation centres: a cross-sectional survey.

OBJECTIVE: Guidance on pharmacotherapy of neurobehavioural sequelae post-acquired brain injury (ABI) is limited. Clinicians face the choice of prescribing off-label. This survey assesses prescribing practice and off-label use of psychotropic medications in Italian brain injury rehabilitation centres and factors associated with atypical antipsychotics use. MATERIALS AND METHODS: Centres were identified through the roster of the Italian Society for Rehabilitation Medicine. Information was collected through a structured questionnaire. This study calculated the prevalence of centres reporting to use off-label individual medications and unconditional logistic regression Odds Ratio (OR), with 95% confidence interval (95% CI) of atypical antipsychotics use. RESULTS: Psychotropic medications were commonly used. More than 50% of the 35 centres (participation ratio 87.5%) reported to use off-label selected antipsychotics, mostly for agitation (90.5%) and behavioural disturbances (19.0%), and antidepressants, mostly for insomnia (37.5%) and pain (25.0%). Atypical antipsychotic use was directly associated with age <40 years (OR = 2.68; 95% CI = 1.25-5.76), recent ABI (1.74; 0.74-4.09), not with reported off-label use (0.98; 0.44-2.18). CONCLUSION: In clinical practice, the effectiveness and safety of medications, in particular off-label, should be systematically monitored. Studies are needed to improve the quality of evidence guiding pharmacotherapy and to evaluate effectiveness and safety of off-label prescribing.