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.

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.

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.

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.

Risk of unplanned visits for colorectal cancer outpatients receiving chemotherapy: a case-crossover study.

AIM: This study was conducted to evaluate the impact of chemotherapy on the risk of unplanned visit in a cohort of colorectal cancer outpatients. Chief complaints for unplanned visits and risk factors for hospital admission were also analyzed. PATIENTS AND METHODS: Clinical data of 229 consecutive colorectal cancer patients who were unexpectedly presented to our acute oncology clinic between 2006 and 2009 were reviewed. A case-crossover statistical analysis was applied to study the association between exposure to chemotherapy (trigger event) and the occurrence of unplanned visit (acute outcome) in three time windows (7, 15, and 21 days from the closest previous chemotherapy treatment). Cox model was used to assess the risk factors for hospitalization. RESULTS: There were 469 unplanned visits registered. Most of the patients had Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 (80 %) and advanced cancer stage (78 %). The majority of unplanned visits (72 %) occurred within 30 days since last chemotherapy. The most frequent presenting complaints were pain, fatigue, and anorexia. The two time windows associated with higher risk of visit were 15 and 21 days from last treatment, both for early (odds ratio [OR] 3.8, CI 1.4-10.2 and OR 3.8, CI 1.4-10.2) and advanced disease stage (OR 1.71, CI 1-2.9 and OR 3, CI 1.5-5.9). Of the unplanned visits, 10 % resulted in hospital admission. Presenting with multiple symptoms and with deteriorated PS were both predictors for hospitalization. CONCLUSION: Chemotherapy exposition triggers the need for unplanned visits over the second and third week after treatment. The prompt and effective management of unexpected events may be cost- and time-saving and reduce pressure on oncology services.

The prevalence of vegetative and minimally conscious states: a systematic review and methodological appraisal.

OBJECTIVES: To systematically review prevalence studies of vegetative state (VS) and minimally conscious state (MCS) in geographically defined populations, to appraise study methods and assess sources of heterogeneity. METHODS: MEDLINE, EBM Reviews, and EMBASE databases were searched using key terms. Two reviewers independently identified pertinent articles and screened the references for additional studies. Studies measuring the prevalence of VS and/or MCS in a defined population were included, and information on characteristics, methods, and results was extracted. Heterogeneity was quantified through the statistic I. RESULTS: We identified 5 cross-sectional prevalence surveys of VS and 1 of MCS. Prevalence ranged from 0.2 cases per 100,000 inhabitants to 3.4 for VS and was 1.5 per 100,000 for MCS. Relevant heterogeneity (I = 99.0%) prevented us from calculating a summary estimate. The prevalence of trauma cases varied from 21.9% to 53.8%. Variability pertaining to diagnostic criteria, definition of case, and methods of ascertainment was found. CONCLUSION: In the few prevalence studies of VS and MCS that were identified, the estimates showed high variability and could not be pooled. Future studies should consider using comparable methods for the definition, ascertainment, and confirmation of cases.

Long-term observational, non-randomized study of enzyme replacement therapy in late-onset glycogenosis type II.

OBJECTIVES: Type II glycogenosis (GSDII) is a lysosomal storage disorder due to acid alpha-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase (rhGAA) has been demonstrated to be effective in the treatment of infantile forms of GSDII, but little information is available concerning late-onset phenotypes. Long-term follow-up studies are not available at present. The aim of this study was to evaluate the ERT long-term effects in late-onset GSDII. METHODS: Twenty-four patients, including 7 juveniles and 17 adults, received bi-weekly infusion of rhGAA (20 mg/kg) for at least 36 months. Clinical conditions, muscular function (6-min walking test, 6MWT; Walton scale, WS), respiratory function (vital capacity, VC; forced expiratory volume, FEV1; arterial pCO(2)), and muscle enzymes were assessed every 6 months. RESULTS: The 6MWT improved in both juvenile and adult patients (p = 0.01, p = 0.0002, respectively), as well as in patients with moderate to severe muscle function impairment (WS >3.5; p = 0.002). An overall improvement in WS was also observed (p = 0.0003). VC and FEV1 remained unchanged, while pCO(2) decreased (p = 0.017). Muscle enzymes decreased significantly (p < 0.0001). Two patients (8%) showed transient secondary events during ERT. CONCLUSIONS: Long-term ERT with rhGAA was shown to be safe, well tolerated, and effective in improving motor function and in stabilizing respiratory function in late-onset GSDII. The response pattern showed a progressive clinical improvement during the follow-up period in juvenile patients, while in adults it reached and maintained a plateau after the first year of treatment.

Validation of discharge diagnosis coding for amyotrophic lateral sclerosis in an Italian regional healthcare database.

Objectives: (a) to estimate the accuracy of International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code for amyotrophic lateral sclerosis (ALS) in the Hospital Discharge Database (HDD) of the Italian region Friuli-Venezia Giulia; (b) to identify the predictors of a true positive ALS code; (c) to compare incident and prevalent cases obtained from HDD with those identified in a retrospective population-based study. Methods: Records of all patients discharged 2010-2014 with an ICD-9-CM code for ALS and other motor neuron diseases were extracted from the HDD. For each record, all the available clinical documentation was evaluated to confirm or reject the diagnosis of ALS. ALS incident and prevalent cases were identified. Validity measures were calculated both overall and stratified by patient and hospitalization characteristics. Adjusted odds ratio (aOR), with 95% confidence interval (95%CI), of a true positive code was estimated using unconditional logistic regression. Results: ALS code had sensitivity 92.9%, specificity 75.3%, positive predictive value (PPV) 92.3%, and negative predictive value (NPV) 76.8%. A true positive ALS code was predicted by concurrent codes for respiratory interventions (aOR: 3.82; 95%CI: 2.09-6.99), primary position code (2.78; 1.68-4.62), non-programed hospitalization (2.06; 1.18-3.61), male patient (1.56; 1.06-2.29), and hospitalization length <14 days (1.42; 1.07-2.84). Two hundred and thirty-six prevalent and 187 incident cases were identified, 84% of those detected in the population-based study. Conclusion: ALS code shows very good accuracy and identifies a high percentage of true positive, incident and prevalent cases, but additional sources and an algorithm based on selected variables may further improve case identification.

Anticholinergic Burden and Fractures: A Systematic Review with Methodological Appraisal.

INTRODUCTION: Medications with anticholinergic activity (MACs) are used to treat diseases common in older adults. Evidence on the association between anticholinergic burden (AB) and increased risk of fractures and osteoporosis or reduced bone mineral density (BMD) is inconsistent. Our aim was to conduct a systematic review of observational studies on AB with fractures and osteoporosis or reduced BMD and provide methodological appraisal of included studies. METHODS: We searched MEDLINE, EMBASE, Science Citation Index and CENTRAL as well as grey literature from database inception up to August 2020. Eligibility criteria were: observational design, AB-exposure measured through a scale, fracture of any type or osteoporosis or reduced BMD as outcome, and reported measure of association between exposure and outcome. No restrictions related to time, language or type of data were applied. Eligibility and risk of bias assessment as well as data extraction were performed independently by two reviewers. Risk of bias of the included studies was assessed using the Newcastle-Ottawa Scale and the RTI Item Bank. RESULTS: The majority of the nine included studies had low risk of bias but heterogeneous methodology. No study used a new user design. Seven studies reported an increased risk of fractures associated with AB. In four studies using the Anticholinergic Risk Scale (ARS), adjusted risk of fractures was increased by 2-61% for ARS = 1, by 0-97% for ARS = 2, by 19-84% for ARS = 3, and by 56-96% for ARS ≥ 4; in three studies the ARS was aggregated, risk increased by 39% for ARS = 1-2 and 17% for ARS = 2-3. Two studies reported increased risk of fractures of 14 and 52% in the highest AB-category and one study reported that change in ARS of ≥ 3 during hospitalization was associated with a 321% increased risk in fractures. Two studies did not find an association between AB and fractures. The association between AB and osteoporosis or reduced BMD could only be assessed in two studies, one reporting increased risk of lower BMD at Ward's triangle, the other reporting no association between AB and BMD T-score change at the femoral neck. DISCUSSION: Our study suggests an association between AB and increased risk of fractures with possible dose-exposure gradient in studies using the ARS. The low number of studies and heterogeneity of methods calls for the conduct of more studies. We conducted a study investigating the risk of fractures associated with anticholinergic burden, which is the result of taking one or more medication with anticholinergic activity. The results of our study suggest that persons who experience anticholinergic burden might have a higher risk of fractures. However, since we were only able to include nine studies, more studies conducted in a similar way are needed.

Individual Antidepressants and the Risk of Fractures in Older Adults: A New User Active Comparator Study.

OBJECTIVE: To determine the risk of hip-pelvis and other non-vertebral fractures in older adults using antidepressants (ADs). METHODS: We conducted a case-control study nested in a cohort of new users of ADs aged ≥65 years without prior hip-pelvis or other non-vertebral fractures, identified in the German Pharmacoepidemiological Research Database (GePaRD) during 2005-2014. Cases were patients first hospitalized for hip-pelvis or other non-vertebral fractures. Up to 100 controls per case were selected using incidence density sampling. AD use was ascertained at index date (ID) based on the supply of last dispensing. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression with current users of mirtazapine as reference (active comparator). RESULTS: A total of 39,853 cases of hip-pelvis fracture (80% women, median age 81 years) and 31,577 cases of other fractures (84% women, median age 79 years) were matched to >3 million controls. For hip-pelvis fracture, aORs in current users were about 1.3 with little variation between individual ADs, ranging from 1.33 for citalopram (95% CI 1.27-1.39) to 1.28 for amitriptyline (1.21-1.35). For other fractures, the aORs were highest in current users of citalopram (1.50; 1.42-1.58) and duloxetine (1.54; 1.39-1.71) and lowest for amitriptyline (1.18; 1.11-1.26) and trimipramine (1.16; 1.03-1.29). For all examined ADs, the aORs were higher for other fractures than for hip-pelvis fracture. CONCLUSION: The risk of fractures varies between ADs, but for most agents is higher than the risk for mirtazapine. When treating older adults with ADs, prescribers should carefully consider the risk profile of individual ADs regarding fractures, which are a major health problem in this population.

The accuracy of discharge diagnosis coding for Amyotrophic Lateral Sclerosis in a large teaching hospital.

To evaluate the accuracy of hospital discharge data as a source of Amyotrophic Lateral Sclerosis (ALS) cases for epidemiological studies or disease registries, a validation study was performed. All records of patients discharged in 2005 and 2006 with principal or secondary International Classification of Diseases, 9th rev., Clinical Modification (ICD 9 CM) diagnosis code of ALS (335.20), other anterior horn cell disease (335), spinal cord disease (336), hereditary and idiopathic peripheral neuropathy (356), inflammatory and toxic neuropathy (357), myoneural disorders (358), muscular dystrophies and myopathies (359), were selected from the electronic archive of discharge data of the University Hospital of Udine, Friuli Venezia Giulia Region, North East Italy. Corresponding clinical documentation was reviewed to ascertain the presence of El Escorial criteria, the gold standard. Sensitivity of the ICD 9 CM discharge code 335.20 was 93% (95%CI: 82-99%) and decreased to 91% (95%CI: 77-98%) when suspect ALS was excluded. Specificity was 99% (95%CI: 97-99%). The ICD 9 CM discharge code 335.20 can identify a high percentage of hospitalizations of patients truly affected by ALS and of patients with no ALS, among selected neurological diagnostic codes. To ensure complete ALS case ascertainment, prospective population-based registries or epidemiologic studies require active prospective surveillance and use of multiple sources, among them hospital discharge archives can provide accurate information.

Predictors of diagnostic delay in amyotrophic lateral sclerosis: a cohort study based on administrative and electronic medical records data.

Objectives: To characterize the timing and pathway of amyotrophic lateral sclerosis (ALS) diagnosis and to identify predictors of delayed diagnosis in a retrospective cohort. Methods: The cohort included all patients with incident ALS between 2010 and 2014 in Friuli-Venezia Giulia (FVG) region, Italy, admitted to two University Hospitals. Information on demographics, clinical presentation, and healthcare use was obtained from health databases and electronic medical records (EMRs). Total diagnostic time (TDT), the interval between ALS symptoms onset and diagnosis, was compared between patient groups through Wilcoxon-Mann-Whitney test. The adjusted odds ratio (aOR), with 95% confidence interval (95% CI), of having a TDT ≥12 months was estimated using unconditional logistic regression. Results: Among 134 patients, median TDT (interquartile range [IQR]) was 11.5 months (7.1-18.3), shorter in those aged <60 years vs. ≥60 years (8.1; 5.1-11.1 vs. 12.4; 7.4-21.5; p = 0.0064), first referred to a neurologist vs. other specialist (10.2; 6.1-16.3 vs. 13.2; 8.1-24.5; p = 0.0386) and without neurologic comorbidities (11.1; 7.1-16.5 vs. 19.7; 8.8-33.7; p = 0.0243). TDT was ≥12 months in 64 (48.5%) patients and was predicted by male sex (aOR: 2.47; 95% CI: 1.06-5.75), age at onset ≥60 years (11.46; 3.13-41.9), spinal onset (2.04; 1.00-5.93), and prior therapies or first referral to a non-neurologist (3.15; 1.36-7.29). Conclusions: In this cohort, delayed diagnosis was common, particularly in older patients and in those with neurological comorbidities. Timely referral to a neurologist may improve diagnostic timing.

Antidepressants and the risk of traumatic brain injury in the elderly: differences between individual agents.

OBJECTIVE: To determine the association of individual antidepressants (ADs) with the risk of traumatic brain injury (TBI) in the elderly. PATIENTS AND METHODS: We conducted a case-control study nested in a cohort of new users of ADs aged ≥65 years, identified in the German Pharmacoepidemiological Research Database during 2005-2014. Cases were patients first hospitalized for TBI. Up to 100 controls per case were selected using incidence density sampling. AD use was ascertained at the index date based on the supply of last dispensing (adding 150% of the defined daily doses [DDDs]; in sensitivity analysis, no additional DDDs were considered). We estimated adjusted ORs (aORs) and 95% CIs using conditional logistic regression. RESULTS: Among 701,309 cohort members, 16,750 cases were identified and matched to 1,673,320 controls (in both groups: 70.4% women; median age 80 years). Compared with remote users of the same AD, current users had an aOR (95% CI) of 1.87 (1.56-2.24) for duloxetine, 1.74 (1.41-2.15) for escitalopram, 1.70 (1.58-1.83) for citalopram, 1.66 (1.40-1.97) for sertraline, 1.64 (1.24-2.15) for fluoxetine and 1.57 (1.20-2.06) for paroxetine. The aOR was lower for amitriptyline (1.45; 1.32-1.58), trimipramine (1.17; 0.99-1.38) and opipramol (1.11; 0.99-1.25). Mirtazapine had an aOR of 1.03 (0.94-1.12). Sensitivity analysis confirmed the findings. CONCLUSION: The large variability between individual ADs shows the importance of considering the safety of individual agents rather than focusing on class alone.