Epidemiology, treatment patterns, and disease burden of cytomegalovirus in hematopoietic cell transplant recipients in selected countries outside of Europe and North America: A systematic review.

BACKGROUND: Cytomegalovirus (CMV) disease impacts morbidity and mortality in hematopoietic cell transplant (HCT) recipients. This systematic review summarized data on the epidemiology, management, and burden of CMV post-HCT outside of Europe and North America. METHODS: The MEDLINE, Embase, and Cochrane databases were searched for observational studies and treatment guidelines in HCT recipients across 15 selected countries from Asia-Pacific, Latin America, and Middle East (search period: 1 January 2011-17 September 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatments, refractory, resistant CMV, and burden. RESULTS: Of 2708 references identified, 68 were eligible (67 studies and one guideline; 45/67 studies specific to adult allogeneic HCT recipients). The rates of CMV infection and disease within 1 year of allogeneic HCT were 24.9%-61.2% (23 studies) and 2.9%-15.7% (10 studies), respectively. Recurrence occurred in 19.8%-37.9% of cases (11 studies). Up to 10% of HCT recipients died of CMV-related causes. In all countries, first-line treatment for CMV infection/disease involved intravenous ganciclovir or valganciclovir. Conventional treatments were associated with serious adverse events such as myelosuppression (10.0%) or neutropenia only (30.0%, 39.8%) and nephrotoxicity (11.0%) (three studies), frequently leading to treatment discontinuation (up to 13.6%). Refractory CMV was reported in 2.9%, 13.0%, and 28.9% of treated patients (three studies) with resistant CMV diagnosed in 0%-10% of recipients (five studies). Patient-reported outcomes and economic data were scarce. CONCLUSION: The incidence of CMV infection and disease post-HCT is high outside of North America and Europe. CMV resistance and toxicity highlight a major unmet need with current conventional treatments.

Epidemiology, management, and burden of cytomegalovirus in solid organ transplant recipients in selected countries outside of Europe and North America: A systematic review.

BACKGROUND: Cytomegalovirus (CMV) is a frequent infectious complication following solid organ transplantation (SOT). Considering significant differences in healthcare systems, a systematic review was conducted to describe the epidemiology, management, and burden of CMV post-SOT in selected countries outside of Europe and North America. METHODS: MEDLINE, Embase, and Cochrane databases were searched for observational studies in SOT recipients across 15 countries in the regions of Asia, Pacific, and Latin America (search period: January 1, 2011 to September 17, 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatment patterns and guidelines, refractory and/or resistant CMV, patient-reported outcomes, and economic burden. RESULTS: Of 2708 studies identified, 49 were eligible (n = 43/49; 87.8% in adults; n = 34/49, 69.4% in kidney recipients). Across studies, selection of CMV preventive strategy was based on CMV serostatus. Overall, rates of CMV infection (within 1 year) and CMV disease post-SOT were respectively, 10.3%-63.2% (9 studies) and 0%-19.0% (17 studies). Recurrence occurred in 35.4%-41.0% cases (3 studies) and up to 5.3% recipients died of CMV-associated causes (11 studies). Conventional treatments for CMV infection/disease included ganciclovir (GCV) or valganciclovir. Up to 4.4% patients were resistant to treatment (3 studies); no studies reported on refractory CMV. Treatment-related adverse events with GCV included neutropenia (2%-29%), anemia (13%-48%), leukopenia (11%-37%), and thrombocytopenia (13%-24%). Data on economic burden were scarce. CONCLUSION: Outside of North America and Europe, rates of CMV infection/disease post-SOT are highly variable and CMV recurrence is frequent. CMV resistance and treatment-associated adverse events, including myelosuppression, highlight unmet needs with conventional therapy.

Knowledge, Attitudes and Practices toward Dengue Fever, Vector Control, and Vaccine Acceptance Among the General Population in Countries from Latin America and Asia Pacific: A Cross-Sectional Study (GEMKAP).

Dengue represents a major public health concern. With effective vaccines in development, it is important to identify motivational factors to maximize dengue vaccine uptake. A cross-sectional, quantitative, electronic survey was administered to a nationally representative adult population (n = 3800) in Argentina, Brazil, Colombia, Mexico, Indonesia, Malaysia, and Singapore. Willingness to vaccinate against dengue, and Knowledge, Attitudes, and Practices (KAP) toward dengue, vector control, prevention, and vaccination were determined. The Capability, Opportunity, Motivation for Behavior change (COM-B) framework was used to identify factors correlated with dengue vaccine(s) uptake. KAP scores (standardized, 0-100% scale) resulted in a low global score for Knowledge (48%) and Practice (44%), and a moderate score for Attitude (66%); scores were comparable across countries. Of all respondents, 53% had a high willingness (Score: 8-10/10) to vaccinate against dengue, which was higher (59%) in Latin America (Argentina, Brazil, Colombia, Mexico) than in Asia Pacific (40%) (Indonesia, Malaysia, Singapore). Key factors significantly (p < 0.05) associated with increased willingness to vaccinate included accessibility to the public (subsidies and incentives) and trust in the healthcare system and government. A common approach to dengue prevention across endemic countries--with some country-specific customization, including education, vaccination, and vector control (multi-pronged)--may reduce dengue burden and improve outcomes.

Indicators of suboptimal response to anti-tumor necrosis factor therapy in patients from China with inflammatory bowel disease: results from the EXPLORE study.

BACKGROUND: Prevalence of inflammatory bowel disease (IBD) is increasing in China. The EXPLORE study evaluated the incidence and indicators of suboptimal responses to first-line anti-tumor necrosis factor (TNF) in patients with ulcerative colitis (UC) or Crohn's disease (CD). We present results for the mainland China subgroup. METHODS: A retrospective chart review was performed in adults with IBD at 10 centers in mainland China who initiated anti-TNF therapy between 01 March 2010 and 01 March 2015. The cumulative incidence of suboptimal response to first-line anti-TNF therapy was assessed over 24 months using the Kaplan-Meier method. Indicators of suboptimal response were: dose escalation, discontinuation, augmentation with non-biologic therapy, or IBD-related surgery/hospitalization. At site initiation, a survey was conducted with participating physicians to identify barriers to anti-TNF use. RESULTS: Of 287 patients (72% male) examined, 16/35 (45.7%) with UC and 123/252 (48.8%) with CD experienced a suboptimal response to first-line anti-TNF therapy at any point during the observation period (median 27.6 and 40.0 months, respectively). At 1 and 2 years post anti-TNF initiation, the cumulative incidence of suboptimal response was 51.4% and 75.7% for UC and 45.4% and 57.0% for CD, respectively. Median time to first suboptimal response was 7.2 months for UC and 14.3 months for CD. The most frequent indicator of suboptimal response was discontinuation of anti-TNF therapy (9/16, 56.3%) for UC and IBD-related hospitalization for CD (69/123, 56.1%) followed by augmentation with non-biologic therapy for both cohorts (5/16, 31.3% for UC and 28/123, 22.8% for CD). Dose escalation was the least frequent indicator of suboptimal response to anti-TNF therapy (CD: 4/123, 3.3%; UC: not cited as an indicator). The cumulative incidence of suboptimal response within 4 months of first-line anti-TNF therapy (primary non-response) was over 30% in both cohorts. Financial reasons and reimbursement were identified by surveyed physicians as the most common barriers to prescribing an anti-TNF therapy. CONCLUSIONS: Over one-half of patients with IBD are at risk of experiencing a suboptimal response to first-line anti-TNF therapy at 2 years post-initiation in China. This study highlights a substantial unmet need associated with anti-TNF therapies in China. (Clinicaltrials.gov identifier: NCT03090139).

Vedolizumab and Anti-Tumour Necrosis Factor α Real-World Outcomes in Biologic-Naïve Inflammatory Bowel Disease Patients: Results from the EVOLVE Study.

BACKGROUND AND AIMS: This study aimed to compare real-world clinical effectiveness and safety of vedolizumab, an α4ß7-integrin inhibitor, and anti-tumour necrosis factor-α [anti-TNFα] agents in biologic-naïve ulcerative colitis [UC] and Crohn's disease [CD] patients. METHODS: This was a 24-month retrospective medical chart study in adult UC and CD patients treated with vedolizumab or anti-TNFα in Canada, Greece and the USA. Inverse probability weighting was used to account for differences between groups. Primary outcomes were cumulative rates of clinical effectiveness [clinical response, clinical remission, mucosal healing] and incidence rates of serious adverse events [SAEs] and serious infections [SIs]. Secondary outcomes included cumulative rates of treatment persistence [patients who did not discontinue index treatment during follow-up] and dose escalation and incidence rates of disease exacerbations and disease-related surgeries. Adjusted analyses were performed using inverse probability weighting. RESULTS: A total of 1095 patients [604 UC, 491 CD] were included. By 24 months, rates of clinical effectiveness were similar between groups, but incidence rates of SAEs (hazard ratio [HR] = 0.42 [0.28-0.62]) and SIs (HR = 0.40 [0.19-0.85]) were significantly lower in vedolizumab vs anti-TNFα patients. Rates of treatment persistence [p < 0.01] by 24 months were higher in vedolizumab patients with UC. Incidence rates of disease exacerbations were lower in vedolizumab patients with UC (HR = 0.58 [0.45-0.76]). Other outcomes did not significantly differ between groups. CONCLUSION: In this real-world setting, first-line biologic therapy in biologic-naïve patients with UC and CD demonstrated that vedolizumab and anti-TNFα treatments were equally effective at controlling disease symptoms, but vedolizumab has a more favourable safety profile.

Efficacy and safety of vedolizumab in ulcerative colitis in patients from Asian countries in the GEMINI 1 study.

BACKGROUND/AIMS: The efficacy and safety of vedolizumab in moderate to severely active ulcerative colitis (UC) have been demonstrated in the GEMINI 1 study (NCT00783718). This post-hoc exploratory analysis sought to establish the efficacy and safety of vedolizumab in a subgroup of patients from Asian countries with UC from GEMINI 1. METHODS: Efficacy outcomes of interest were clinical response, clinical remission and mucosal healing at week 6 (induction phase); and clinical remission, durable clinical response, durable clinical remission, mucosal healing and glucocorticoid-free remission at week 52 (maintenance phase). Differences in outcome rates between vedolizumab and placebo in Asian countries (Hong Kong, India, Malaysia, Singapore, South Korea, and Taiwan) were assessed using descriptive analyses, and efficacy and safety compared between Asian and non-Asian countries. RESULTS: During induction, in Asian countries (n = 58), clinical response rates at week 6 with vedolizumab and placebo were 55.2% and 24.1%, respectively (difference 31.0%; 95% confidence interval: 7.2%-54.9%). In non-Asian countries (n = 316), response rates at week 6 with vedolizumab and placebo were 45.9% and 25.8%, respectively. During maintenance, in Asian countries, clinical remission rates at 52 weeks with vedolizumab administered every 8 weeks, vedolizumab administered every 4 weeks and placebo were 9.1%, 36.8%, and 31.6%, respectively; corresponding rates for mucosal healing were 45.5%, 47.4%, and 47.4%, respectively. Vedolizumab was well-tolerated; adverse event frequency was comparable in Asian and non-Asian countries. CONCLUSIONS: In patients from Asian countries, the efficacy and safety of vedolizumab in treatment of UC were broadly consistent with that in the overall study population.

Efficacy and safety of vedolizumab in Crohn's disease in patients from Asian countries in the GEMINI 2 study.

BACKGROUND/AIMS: The efficacy and safety of vedolizumab in moderate-to-severely active Crohn's disease (CD) were demonstrated in the GEMINI 2 study (NCT00783692). This post-hoc exploratory analysis aimed to assess the efficacy and safety of vedolizumab in the subgroup of patients from Asian countries. METHODS: During the induction phase (doses at day 1, 15), clinical remission, enhanced clinical response, and change in C-reactive protein at 6 weeks; during the maintenance phase, clinical remission, enhanced clinical response, glucocorticoid-free remission and durable clinical remission at 52 weeks, were the efficacy outcomes of interest. Efficacy and safety of vedolizumab compared to placebo were assessed in Asian countries (Hong Kong, India, Malaysia, Singapore, South Korea, and Taiwan) using descriptive analyses. RESULTS: During the induction phase, in Asian countries (n = 51), 14.7% of the vedolizumab-treated patients achieved clinical remission at week 6 compared to none with placebo (difference, 14.7%; 95% confidence interval, 15.8%-43.5%). In non-Asian countries (n = 317), the remission rate at week 6 with vedolizumab was 14.5%. During maintenance, in Asian countries, clinical remission rates at 52 weeks with vedolizumab administered every 4 weeks, vedolizumab administered every 8 weeks and placebo were 41.7%, 36.4%, and 0%, respectively; while enhanced clinical response rates were 41.7%, 63.6%, and 42.9%, respectively. During induction, 39.7% of patients with vedolizumab experienced an adverse event compared to 58.8% of patients with placebo, and vedolizumab was generally well-tolerated. CONCLUSIONS: This post-hoc analysis demonstrates the treatment effect and safety of vedolizumab in moderateto-severely active CD in patients from Asian countries.

Early Intervention With Vedolizumab on Longer Term Surgery Rates in Crohn's Disease: Post Hoc Analysis of the GEMINI Phase 3 and Long-term Safety Programs.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory bowel disease that, with progression, may require surgical intervention. AIM: To determine whether vedolizumab treatment of CD earlier in the disease course (≤2 or ≤5 years disease duration) influences risk of CD-related surgery after accounting for probability of response. METHODS: Post hoc analyses of data from CD patients treated with vedolizumab in the GEMINI 2, GEMINI 3, and GEMINI LTS trials (N=1253) evaluated CD-related surgery (bowel resection or colectomy) with stratification by probability of response to vedolizumab (low/intermediate or high). Analyses used a previously validated clinical decision support tool and both logistic regression and Cox proportional hazard analyses. RESULTS: In total, 113 (9.0%) vedolizumab-treated patients required CD-related surgery. Surgical rates were 6.1% and 9.8% for the high and low/intermediate probability of response groups, respectively. Risk of surgery was lower for patients with a high probability of response versus those with a low/intermediate probability of response (HR 0.50; 95%CI 0.29 to 0.85). For patients with a low/intermediate probability of vedolizumab response, there was a consistent trend for association between earlier treatment (≤2 or ≤5 years since diagnosis) and a lower risk of surgery relative to later treatment (≤2 years versus >2 years: OR 0.77, 95%CI 0.38 to 1.58; ≤5 years versus >5 years: OR 0.61, 95%CI 0.37 to 1.00). CONCLUSIONS: Earlier intervention with vedolizumab may be associated with lower rates of surgery. Use of the clinical decision support tool may help identify patients most likely to benefit from earlier intervention with vedolizumab.

Incidence of suboptimal response to tumor necrosis factor antagonist therapy in inflammatory bowel disease in newly industrialised countries: The EXPLORE study.

BACKGROUND: Incidence of inflammatory bowel disease (IBD) is increasing in newly industrialised countries (NICs); however, data on suboptimal response to anti-tumor necrosis factor (anti-TNF) agents are limited. OBJECTIVES: To assess incidence and indicators of suboptimal response to first anti-TNF therapy in IBD patients in NICs. METHODS: A chart review was conducted in ten countries from Asia-Pacific (APAC), Latin America (LatAm), and Russia and the Middle East (RME) regions among patients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD), initiating anti-TNF therapy in 2010-2015. The cumulative incidence of suboptimal response to anti-TNF therapy was assessed using the following indicators: dose escalation or discontinuation, augmentation with non-biologic therapy, IBD-related hospitalization, or surgery. RESULTS: The study included 1,674 patients (570 UC; 1,104 CD). At 24 months, 32.9% of UC (APAC: 45.1%; LatAm: 38.2%; RME: 23.8%) and 41.2% of CD patients (APAC: 54.1%; LatAm: 42.5%; RME: 29.5%) had experienced suboptimal response. The most frequent first indicator was non-biologic therapy augmentation in LatAm (41.7%), IBD-related hospitalization in RME (UC: 50.7%; CD:37.3%) and in APAC for CD (39.1%), and anti-TNF discontinuation in APAC for UC (38.3%). CONCLUSION: Suboptimal response to anti-TNF agents is common in IBD patients in NICs. Observed regional differences in the incidence and indicators may reflect local practice and anti-TNF restrictions in IBD management. NCT REGISTRATION NUMBER: NCT03090139.

A retrospective observational study of early experiences of vedolizumab treatment for inflammatory bowel disease in the UK: The REVIVE study.

Results from clinical trials show that vedolizumab is an efficacious treatment for inflammatory bowel disease, namely Crohn's disease (CD) and ulcerative colitis (UC). However, there is limited evidence from real-world clinical practice, especially on early clinical experiences in the UK.To describe real-world early experiences of vedolizumab to treat CD and UC in the UK.A retrospective, chart review study of patients with CD or UC treated with vedolizumab across 5 UK hospitals. All eligible adults (≥18 years at initiation) with a diagnosis of CD and ≥14 weeks of data or UC and ≥10 weeks of data available following vedolizumab initiation were included.Data were analyzed for 112 patients (CD: 66; UC: 46). Patients with CD had a median of 7.4 (interquartile range 5.7-9.4) months follow-up and patients with UC had a median of 7.4 (5.6-10.2) months follow-up post-vedolizumab initiation. Most patients, 80% (53/66) with CD and 89% (41/46) with UC, remained on vedolizumab treatment at the time of data collection. No new safety signals were identified during the study.These results add to the body of evidence supporting vedolizumab as an effective and well-tolerated treatment for CD and UC in real-world clinical practice.

Systematic review with meta-analysis: real-world effectiveness and safety of vedolizumab in patients with inflammatory bowel disease.

BACKGROUND: Selective patient recruitment can produce discrepancies between clinical trial results and real-world effectiveness. METHODS: A systematic literature review and meta-analysis were conducted to assess vedolizumab real-world effectiveness and safety in patients with ulcerative colitis (UC) or Crohn's disease (CD). MEDLINE, MEDLINE In-Process, EMBASE, and Cochrane databases were searched for real-world studies of vedolizumab in adult patients with UC/CD reporting clinical response, remission, corticosteroid-free remission, UC/CD-related surgery or hospitalization, mucosal healing, or safety published from May 1, 2014-June 22, 2017. Response and remission rates were combined in random-effects meta-analyses. RESULTS: At treatment week 14, 32% of UC patients [95% confidence interval (CI) 27-39%] and 30% of CD patients (95% CI 25-34%) were in remission; and at month 12, 46% for UC (95% CI 37-56%) and 30% for CD (95% CI 20-42%). For UC, the rates of corticosteroid-free remission were 26% at week 14 (95% CI 20-34%) and 42% at month 12 (95% CI 31-53%); for CD they were 25% at week 14 (95%, CI 20-31%) and 31% at month 12 (95%, CI 20-45%). At month 12, 33-77% of UC and 6-63% of CD patients had mucosal healing. Nine percent of patients reported serious adverse events. CONCLUSIONS: Vedolizumab demonstrated real-world effectiveness in patients with moderate-to-severely active UC or CD, with approximately one-half and one-third of patients, respectively, in remission at treatment month 12. These findings are consistent with clinical trial data and support the long-term benefit-risk profile of vedolizumab.

The economic burden of tuberous sclerosis complex in the UK: A retrospective cohort study in the Clinical Practice Research Datalink.

BACKGROUND: Tuberous sclerosis complex (TSC) is a multi-system genetic disorder characterized by the development of diverse clinical manifestations. The complexity of this disease is likely to result in substantial challenges and costs in disease management throughout the patient's lifetime. This retrospective database study aims to quantify healthcare resources utilized by TSC patients. METHODS: TSC patients in the Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database were identified between January 1987 and June 2013. Analyses were conducted over the most recent 3-year period of data and stratified by pediatric (< 18) and adult patients. Prescriptions, procedures, diagnostic tests, and healthcare encounters were reported in comparison with a matched comparator cohort. Costs and key economic drivers by primary organ system manifestations were also examined. RESULTS: A total of 286 patients with TSC were identified and consistently reported 2-fold greater resource use than the matched presumably healthy controls. Despite this comparatively greater resource use, half of TSC patients did not record any procedures, and 20% of patients did not record any diagnostic tests; however, inpatient hospitalizations were greater for the TSC cohort (3.1 vs 1.3), but length of stay was comparable. TSC patients had costs totaling £12,681 per patient over the 3-year period, a figure 2.7-fold greater than the total costs in the comparator cohort (£4,777). Costs for patients with specific primary manifestations were even greater, with brain manifestations incurring £22,139 per affected patient. Kidney and nervous system manifestations were the main cost drivers. CONCLUSIONS: The economic burden of TSC and its impact on NHS healthcare resources is mostly attributable to the broad spectrum of manifestations that develop within multiple organ systems. TSC patients may benefit from co-ordinated care based on their requirement for high numbers of healthcare visits across specialties.

The clinical profile of tuberous sclerosis complex (TSC) in the United Kingdom: A retrospective cohort study in the Clinical Practice Research Datalink (CPRD).

BACKGROUND: Tuberous Sclerosis Complex (TSC) is a multi-system genetic disorder characterised by the development of benign growths and diverse clinical manifestations, varying in severity, age at onset and with high clinical burden. AIMS: This longitudinal study aims to describe the broad spectrum of clinical manifestation profiles in a large, representative cohort of TSC patients in the UK in order to better understand disease complexity. METHODS: TSC patients in the Clinical Practice Research Datalink (CPRD) and linked Hospital Episodes Statistics (CPRD-HES) were retrospectively identified between 1987 and 2013. Available history was extracted for each patient and clinical diagnosis, procedure and medication records reviewed. A random selection of patients from the CPRD-HES was used as a Comparator cohort. RESULTS: Three hundred and thirty-four TSC patients with a mean (SD) age of 30.3 (18.6) years were identified (53% female). TSC was diagnosed at mean age 3.2 (4.2) years. Epilepsy and psychiatric manifestations were reported frequently in paediatric (77% and 55%, respectively) and adult patients (66% and 68%, respectively). The prevalence of manifestations in the TSC cohort was markedly higher versus the Comparator cohort. The majority of paediatric (46%) and adult TSC patients (62%) developed clinical manifestations affecting at least three organ systems and forty-nine distinctive organ system manifestation profiles were identified. CONCLUSIONS: TSC patients present with multiple and complex clinical manifestations and profiles that necessitate the co-ordinated action of a multidisciplinary team in order to improve the quality and efficiency of care.

Allergy immunotherapy prescribing trends for grass pollen-induced allergic rhinitis in Germany: a retrospective cohort analysis.

BACKGROUND: Allergy immunotherapy is an effective treatment for patients with allergic rhinitis whose symptoms are unresolved with pharmacotherapy. Allergy immunotherapy for grass pollen-induced allergic rhinitis is available in three modalities: subcutaneous immunotherapy and sublingual immunotherapy as a tablet or drop. This study aimed to understand trends in allergy immunotherapy prescribing and practice patterns for grass allergies in adult and paediatric patients in Germany. METHODS: A retrospective cohort study was conducted using IMS Disease Analyzer in Germany. Patients with an allergy immunotherapy prescription for grass pollen (Anatomical Therapeutic Chemical [ATC] classification code V01AA02) from September 2005 to December 2012 were included in the study. General Practitioners (GPs), dermatologists, Ear, Nose and Throat (ENT)-specialists, paediatricians and pneumologists were included as the allergy immunotherapy prescribing physicians in the study. Descriptive analyses were conducted on patient characteristics at index and prescribing physician specialty; a test for trend was conducted for timing of initiation of first allergy immunotherapy prescription in each annual prescribing season. RESULTS: Eighteen thousand eight hundred fifty eligible patients were identified during the study period. The majority of patients received subcutaneous immunotherapy; however, the proportion of patients receiving sublingual immunotherapy tablets increased from 8 % in 2006/2007 to 29 % in 2011/2012 (p < 0.001). Initiation of subcutaneous immunotherapy and Oralair® generally peaked during each prescribing year in two seasons (September-October and January) while GRAZAX® prescriptions peaked in autumn (September-October). ENT-specialists and dermatologists were the largest allergy immunotherapy prescribers in adults, while paediatricians and ENT-specialists were the largest prescribers of allergy immunotherapy in paediatric patients. CONCLUSIONS: Subcutaneous immunotherapy remained the dominant allergy immunotherapy modality for grass pollen-induced allergic rhinitis in Germany for adult and paediatric patients; however, there was a marked increase in proportion of patients receiving sublingual immunotherapy tablets from 2006/2007 to 2011/2012, after their introduction to the market in 2006. ENT-specialists, dermatologists and paediatricians were responsible for the majority of prescribing. The predominance of particular modalities within certain physician specialties likely reflects different treatment goals or needs.

Severity of liver disease among chronic hepatitis C patients: an observational study of 4594 patients in five European countries.

BACKGROUND AND AIM: Assessment of the severity of liver disease following infection with hepatitis C virus (HCV) is important in treatment selection and prognosis. As invasive liver biopsy procedures are regarded as the reference method to assess the stage of fibrosis, it is important to identify patient characteristics that are predictive of liver fibrosis severity. The aim of the study was to describe the distribution of liver severity scores, clinical characteristics, and physicians' assessment of fibrosis among HCV patients in five European countries. METHODS: This cross-sectional study retrospectively reviewed the medical records of patients who were chronically infected with HCV in 2006. Patients managed for HCV at any of 60 sites in France, Germany, Italy, Spain, and the UK were included. Data collected included patient demographics and clinical characteristics. A combination of univariate and multivariate regression analyses were used to identify predictors of fibrosis severity and factors associated with undergoing biopsy. RESULTS: Four thousand five hundred and ninety-four chronically infected HCV patients were included in this analysis. Management approaches differed between countries, with variations in biopsy use (59.3-18.4%) and preferred fibrosis scoring systems. Where histology results were available, 43.4%, 23.8%, and 32.9% had mild, moderate, and severe fibrosis, respectively. Factors associated with undergoing a biopsy included male gender and co-infection with hepatitis B virus. Chronic alcoholism, a lower first platelet count, and older age were predictors of increased liver fibrosis severity. CONCLUSIONS: These data suggest that there are major differences in how specialists manage their HCV patients across five major European countries.

Challenges in quantifying the patient-reported burden of herpes zoster and post-herpetic neuralgia in the UK: learnings from the Zoster Quality of Life (ZQOL) study.

BACKGROUND: Acute presentation of herpes zoster (HZ) and the subsequent development of post-herpetic neuralgia (PHN) can have a significant impact on patients' lives. To date, evidence regarding the human and economic burden of HZ and PHN in the UK is limited. To address this knowledge gap a national, multicentre, large-scale real-world study was conducted to inform the scientific community and healthcare decision-makers. This paper outlines difficulties encountered and challenges to conducting real-world studies in the UK, methods used to overcome these hurdles and strategies that can be employed to promote and facilitate the conduct of future studies. FINDINGS: The Zoster Quality of Life (ZQOL) study is the first UK-wide and largest observational study investigating patient burden associated with HZ and PHN. A total of 383 patients (229 HZ; 154 PHN) over the age of 50 years were recruited from 42 primary and secondary/tertiary care centres. Patient-reported outcome (PRO) assessments of pain, quality of life and treatment satisfaction were completed by all participants and supplemented by clinical information from participating physicians.Key challenges encountered during the conduct of this study can be broadly categorised as follows: 1) identification of centres willing/able to participate in the study: lack of resources and limited research experience were major barriers to recruitment of centres for participation in the study; 2) obtaining local research & development (R&D) approval: lack of clearly defined processes and requirements specific to real-world studies and limited degree of standardisation between R&D departments in approval procedures led to significant variability in submission requirements and lead times for obtaining approval; 3) recruitment of study participants: rates of recruitment were slower than anticipated, meaning it was necessary to extend the study recruitment period and increase the number of participating centres. DISCUSSION: Initiatives designed to promote and facilitate the conduct of research in the UK are important for real-world studies. The ZQOL study shows that opportunities exist for real-word research. However, streamlining the R&D approval process where possible and further incentivising the participation of primary care centres in such studies would help to further facilitate the generation of real-world evidence to inform healthcare decisions.

Pulmonary function testing in the emergency department and medications prescribed at discharge: results of the Multinational Acute asthma Management, Burden, and Outcomes (MAMBO) study.

AIMS: To evaluate asthma care in the emergency department (ED), including use of pulmonary function testing (PFT) and how patients are treated when discharged. METHODS: Internet-based surveys were completed by 298 healthcare practitioners in seven countries on 1078 patients 15-70 years old with an acute asthma exacerbation. RESULTS: Less than 60% of patients received guideline-recommended therapy with a bronchodilator, corticosteroid, and supplemental oxygen. Patients undergoing PFT had significantly more courses of asthma therapy (2.3 vs 1.7; p < 0.001), and received more medications (5.7 vs 3.9; p < 0.001). At discharge, 17.9% of patients did not receive a prescription asthma medication and 12.8% did not receive a physician referral. Men (p<0.022), patients with more severe disease (p<0.0001), and those seen by a pulmonologist (p<0.0001), were more likely to be treated. CONCLUSIONS: Management of patients with acute asthma exacerbations diverged from guideline recommendations. Enhanced adherence to guidelines could lead to improved outcomes.

Cannabinoid signalling.

After their discovery, the two known cannabinoid receptors, CB(1) and CB(2), have been the focus of research into the cellular signalling mechanisms of cannabinoids. The initial assessment, mainly derived from expression studies, was that cannabinoids, via G(i/o) proteins, negatively modulate cyclic AMP levels, and activate inward rectifying K(+) channels. Recent findings have complicated this assessment on different levels: (1) cannabinoids include a wide range of compounds with varying profiles of affinity and efficacy at the known CB receptors, and these profiles do not necessarily match their biological activity; (2) CB receptors appear to be intrinsically active and possibly coupled to more than one type of G protein; (3) CB receptor signalling mechanisms are diverse and dependent on the system studied; (4) cannabinoids have other targets than CB receptors. The aim of this mini review is to discuss the current literature regarding CB receptor signalling pathways. These include regulation of adenylyl cyclase, MAP kinase, intracellular Ca(2+), and ion channels. In addition, actions of cannabinoids that are not mediated by CB(1) or CB(2) receptors are discussed.

Arachidonic acid mediates non-capacitative calcium entry evoked by CB1-cannabinoid receptor activation in DDT1 MF-2 smooth muscle cells.

Cannabinoid CB1-receptor stimulation in DDT1 MF-2 smooth muscle cells induces a rise in [Ca2+]i, which is dependent on extracellular Ca2+ and modulated by thapsigargin-sensitive stores, suggesting capacitative Ca2+ entry (CCE), and by MAP kinase. Non-capacitative Ca2+ entry (NCCE) stimulated by arachidonic acid (AA) partly mediates histamine H1-receptor-evoked increases in [Ca2+]i in DDT1 MF-2 cells. In the current study, both Ca2+ entry mechanisms and a possible link between MAP kinase activation and increasing [Ca2+]i were investigated. In the whole-cell patch clamp configuration, the CB-receptor agonist CP 55, 940 evoked a transient, Ca2+-dependent K+ current, which was not blocked by the inhibitors of CCE, 2-APB, and SKF 96365. AA, but not its metabolites, evoked a transient outward current and inhibited the response to CP 55,940 in a concentration-dependent manner. CP 55,940 induced a concentration-dependent release of AA, which was inhibited by the CB1 antagonist SR 141716. The non-selective Ca2+ channel blockers La3+ and Gd3+ inhibited the CP 55,940-induced current at concentrations that had no effect on thapsigargin-evoked CCE. La3+ also inhibited the AA-induced current. CP 55,940-induced AA release was abolished by Gd3+ and by phospholipase A2 inhibition using quinacrine; this compound also inhibited the outward current. The CP 55,940-induced AA release was strongly reduced by the MAP kinase inhibitor PD 98059. The data suggest that in DDT1 MF-2 cells, AA is an integral component of the CB1 receptor signaling pathway, upstream of NCCE and, via PLA2, downstream of MAP kinase.

Zinc Silicates: Very Efficient Heterogeneous Catalysts for the Addition of Primary Alcohols to Alkynes and Allenes.

There is an astonishing parallel between the mechanism generally accepted for the addition of water to CO2 catalyzed by the enzyme carbonic anhydrase and the mechanism calculated for the addition of methanol to allene catalyzed by the naturally occurring zinc silicate hemimorphite. The latter reaction was investigated in detail following the observation that hemimorphite as well as an amorphous zinc silicate prepared in situ are excellent heterogeneous catalysts for the addition of primary alcohols to alkynes and allenes [Eq. (1)].