Real-World Outcomes of Dual Advanced Therapy in Children and Young Adults with Inflammatory Bowel Disease.

BACKGROUND: Data are limited on the safety and efficacy of combining advanced therapies for refractory patients with IBD. AIM: To evaluate the real-world efficacy and safety of dual advanced therapy (DAT), combining 2 biologics or a biologic with a small molecule, in children and young adults with refractory IBD. METHODS: Primary outcome of this single IBD center cohort was DAT remission (clinical and biomarker remission) at first assessment (T1). Secondary outcomes included remission at T2, if DAT de-intensification (De-I) occurred and T3, if T2 DAT re-intensification (Re-I) occurred. Efficacy and safety outcomes were described. RESULTS: Of the 30 patients [43% female, 30% CD, median age of 18.3 [15.1-19.8] years], all 11 UST + TOFA achieved T1 remission; 6/10 De-I failed at T2; and 4/4 Re-I achieved T3 remission. Of 9 VDZ + TOFA, 6 achieved T1 remission; 5/6 De-I failed at T2; and 1/1 failed T3 Re-I. Of 4 UST + VDZ, 3 achieved T1 remission; 2/3 De-I failed at T2; and 0 had Re-I. Of 5 UST + UPA, 4 achieved T1 remission; 1/5 De-I failed at T2 but recaptured T3 remission post-Re-I. One VDZ + OZA achieved T1 remission and maintained T2 remission post-De-I to OZA monotherapy. At last follow-up, 43% were on original DAT, 17% on one of original DAT, and 40% neither. One UST + TOFA patient developed mild leukopenia and another developed septic arthritis and venous thromboembolism on VDZ + TOFA and prednisone. CONCLUSION: Most children and young adults treated with DAT achieved remission with minimal safety events; however, de-intensification had limited success.

Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab. Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models. Results and discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p<0.11) [corrected] higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD.

Corrigendum: Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.

[This corrects the article DOI: 10.3389/fimmu.2024.1342477.].

Determining the Accuracy of Intestinal Ultrasound Scores as a Prescreening Tool in Crohn's Disease Clinical Trials.

INTRODUCTION: High rates of screen failure for the minimum Simple Endoscopic Score for Crohn's Disease (SES-CD) plague Crohn's disease (CD) clinical trials. We aimed to determine the accuracy of segmental intestinal ultrasound (IUS) parameters and scores to detect segmental SES-CD activity. METHODS: A single-center, blinded, cross-sectional cohort study of children and young adult patients with CD undergoing IUS and ileocolonoscopy, comparing segmental IUS bowel wall thickness (BWT), hyperemia (modified Limberg score [MLS]), and scores to detect segmental SES-CD activity: (i) SES-CD ≤2, (ii) SES-CD ≥6, and (iii) SES-CD ≥4 in the terminal ileum (TI) only. Primary outcome was accuracy of BWT, MLS, and IUS scores to detect SES-CD ≤2 and SES-CD ≥6. Secondary outcomes were accuracy of TI BWT, MLS, and IUS scores to detect SES-CD ≥4 and correlation with the SES-CD. RESULTS: Eighty-two patients (median [interquartile range] age 16.5 [12.9-20.0] years) underwent IUS and ileocolonoscopy of 323 bowel segments. Segmental BWT ≤3.1 mm had a similar high accuracy to detect SES-CD ≤2 as IUS scores (area under the receiver operating curve [AUROC] 0.833 [95% confidence interval 0.76-0.91], 94% sensitivity, and 73% specificity). Segmental BWT ≥3.6 mm and ≥4.3 mm had similar high accuracy to detect SES-CD ≥6 (AUROC 0.950 [95% confidence interval 0.92-0.98], 89% sensitivity, 93% specificity) in the colon and an SES-CD ≥4 in the TI (AUROC 0.874 [0.79-0.96], 80% sensitivity, and 91% specificity) as IUS scores. Segmental IUS scores strongly correlated with the SES-CD. DISCUSSION: Segmental IUS BWT is highly accurate to detect moderate-to-severe endoscopic inflammation. IUS may be the ideal prescreening tool to reduce unnecessary trial screen failures.

Choosing the Right Therapy at the Right Time for Pediatric Inflammatory Bowel Disease: Does Sequence Matter.

Despite the enlarging therapeutic armamentarium, IBD is still plagued by a therapeutic ceiling. Precision medicine, with the selection of the "rights," may present a solution, and this review will discuss the critical process of pairing the right patient with right therapy at the right time. Firstly, the review will discuss the shift to and evidence behind early effective therapy. Then, it delves into promising future strategies of patient profiling to identify a patients' biological pathway(s) and prognosis. Finally, the review lays out practical considerations that drive treatment selection, particularly the impact of the therapeutic sequence.

A Single-Center Experience with Dupilumab for Atopic or Psoriasiform Dermatitis in Patients with Inflammatory Bowel Disease.

INTRODUCTION: Dupilumab blocks IL4/IL13 and is used in atopic disease. There are concerns that blockade may lead to inflammatory bowel disease (IBD) inception or activity. Limited data exist on the use of this therapy in patients with IBD; we aimed to describe our experience using dupilumab in IBD to treat concomitant atopic dermatitis (AD) or anti-TNF-induced dermatitis. METHODS: We analyzed the electronic medical records (2018-2022) in a single, tertiary care center to identify patients with IBD on dupilumab. Clinical and demographic data were gathered, including disease location/behavior, personal/family history of atopy, indication for and response to dupilumab, IBD medication history, and adverse events. RESULTS: Seventeen patients (65% Crohn's) were identified with IBD on dupilumab for dermatitis; 9 for severe AD and 8 for a worsened dermatitis, either AD or psoriasiform dermatitis (PD), induced by anti-TNF. They were treated for a median 1.2 [IQR 0.6-2.3] years. All patients had a dermatologic response to dupilumab and remained on dupilumab at last follow-up. No adverse events were identified, including no increase in IBD activity. In those with dermatitis worsened or induced by anti-TNF, all started dupilumab in combination with another biologic: 3 with anti-TNF, 4 with ustekinumab, and 1 with vedolizumab. Seven of the eight had a response to the initial combination of biologics; however, one patient using dupilumab-anti-TNF ultimately changed to combination dupilumab-ustekinumab to achieve resolution of the dermatitis. CONCLUSION: Dupilumab is safe and effective for dermatitis in patients with IBD, both primary atopic dermatitis and dermatitis induced or worsened by anti-TNF.

Outcomes of Children with Inflammatory Bowel Disease who Develop Anti-tumour Necrosis Factor-induced Skin Reactions.

BACKGROUND AND AIMS: Anti-tumour necrosis factor [anti-TNF] induced skin reactions are common adverse events in paediatric inflammatory bowel disease [IBD]. We aimed to report on outcomes of children with anti-TNF induced skin reactions who switched to ustekinumab [UST] vs. continued anti-TNF therapy. METHODS: Charts were reviewed for paediatric IBD patients with anti-TNF induced skin reactions. Skin reactions, including psoriasiform dermatitis [PD], were classified as mild or severe based on a severity score. Primary outcome was frequency of skin resolution at 6 months. Secondary outcomes were combined clinical remission and skin resolution at 6 months and skin resolution at latest follow-up. RESULTS: A total of 111/638 [17%] children ([85, 21%] infliximab [IFX]; [26, 11%] adalimumab [ADA]) developed skin reactions. Eighty [72%] had PD, 25 [23%] infections, and four [4%] alopecia areata; 71 [64%] continued anti-TNF; and 40 [36%] switched to UST. In all, 73 [66%] had severe reactions and were more likely to switch to UST than if mild (37 [51%] vs. 3 [8%]; p <0.0001). Switching to UST had a higher rate and odds of resolution (29 [73%] vs. 24 [34%]; p <0.0001; odds ratio [OR] = 19.7, 95% confidence interval [CI]: 5.6, 69.5; p <0.0001) and combined remission (21 [52%] vs. 22 [31%]; p = 0.03; OR = 8.5, 95% CI: 2.5, 28.4; p = 0.0005] vs. continuing anti-TNF at 6 months. CONCLUSIONS: Children who switched to UST after anti-TNF induced skin reactions were more likely to have improved outcomes than those who continued anti-TNF therapy. Future studies are needed to determine immune mechanisms of anti-TNF induced skin reactions and treatment response.

Precision Medicine in Pediatric Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) describes a heterogenous group of diseases characterized by chronic inflammation of the intestinal tract. The IBD subtypes, Crohn's disease, ulcerative colitis, and IBD-Unspecified, each have characteristic features, but heterogeneity remains even among the subtypes. There has been an explosion of new knowledge on the possible pathogenesis of IBD over the last 2 decades mirroring innovation and refinement in technology, particularly the generation of large scale - "-omic" data. This knowledge has fostered a veritable renaissance of novel diagnostics, prognostics, and therapeutics, with patients with IBD seeing hope bloom in the increasingly large armamentarium of IBD therapies. However, while there are increased numbers of therapies and more pathways being targeted, the number of medications for IBD is still finite and the efficacy has reached a plateau. Precision medicine (PM) is much needed to rationally select and optimize IBD therapies in the new reality of wider but still limited choice with a concurrent, increasingly fine resolution on the significance and utility of clinical, genetic, microbial, and proteomic characteristics that define individual patients. PM is a rapidly changing art, but this review will strive to detail the current state and future directions of PM in pediatric IBD.

Outcomes of Primary Ileocolic Resection for Pediatric Crohn Disease in the Biologic Era.

OBJECTIVES: Current clinical algorithms position surgery as the last option in pediatric Crohn disease (CD). Studies suggest improved outcomes with earlier surgery, but pediatric postoperative outcomes data in the biologic era are limited. We aimed to describe the preoperative management and postoperative outcomes in a pediatric CD cohort who underwent ileocolic resection (ICR) at a tertiary care inflammatory bowel disease center over the last decade. METHODS: Single-center, retrospective study of pediatric (<18 years) CD patients who underwent ICR between 2008 and 2019 with primary outcome of rate of endoscopic recurrence (Rutgeerts' >i2) at 2 years post-ICR. Key secondary outcomes included endoscopic remission (Rutgeerts' i0), frequency of 30-day postoperative complications, anthropometric changes, and histologic recurrence. Uni- and multivariable analyses examined associations of clinical/laboratory characteristics with endoscopic recurrence. Factors predictive of 30-day complications were also analyzed. RESULTS: Seventy-eight children underwent ICR a median of 17.8 months (interquartile range [IQR] 2.6-53.9) from diagnosis. Median age at diagnosis and surgery was 13.8 (11.1-16.7) and 16.8 years (15.1-17.8), respectively. In the 41 patients with >1 post-operative endoscopy, the rate of endoscopic recurrence was 46% at 2 years (median time to recurrence: 10 [7-20] months). Histologic recurrence was present in 44% in endoscopic remission (κ = 0.11, P = 0.53). Endoscopic recurrence was associated with younger age at diagnosis and longer disease duration. 30-day complications occurred at a rate of 18%; only 1% experienced severe complications. All anthropometric measures significantly improved after surgery. CONCLUSIONS: Given the inherent risk of postoperative recurrence associated with age and disease duration, children would benefit from postoperative surveillance and effective prophylaxis.

Approach to the Management of Recently Diagnosed Inflammatory Bowel Disease Patients: A User's Guide for Adult and Pediatric Gastroenterologists.

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are chronic, progressive, immune-mediated diseases of adults and children that have no cure. IBD can cause significant morbidity and lead to complications such as strictures, fistulas, infections, and cancer. In children, IBD can also result in growth impairment and pubertal delays. IBD is highly heterogenous, with severity ranging from mild to severe and symptoms ranging from mild to debilitating. Delay in IBD diagnosis, especially in Crohn's disease, is common and associated with adverse outcomes. Early diagnosis and prompt institution of treatment are the cornerstones for improving outcomes and maximizing health. Early diagnosis requires a low threshold of suspicion and red flags to guide early specialist referral at the primary provider level. Although the armamentarium of IBD medications is growing, many patients will not respond to treatment, and the selection of first-line therapy is critical. Risk stratification of disease severity, based on clinical, demographic, and serologic markers, can help guide selection of first-line therapy. Clinical decision support tools, genomics, and other biomarkers of response to therapy and risk of adverse events are the future of personalized medicine. After starting appropriate therapy, it is important to confirm remission using objective end points (treat to target) with continued control of inflammation with adjustment of therapy using surrogate biomarkers (tight control). Lastly, IBD therapy extends far beyond medications, and other aspects of the overall health and wellbeing of the patient are critical. These include preventive health, nutrition, and psychobehavioral support addressing patients' concerns around complementary therapy and medication adherence, prevention of disability, and ensuring open communication.

Dual Biologic and Small Molecule Therapy for the Treatment of Refractory Pediatric Inflammatory Bowel Disease.

BACKGROUND: Nontraditional combination of existing therapies is often the only option to avoid surgery in refractory inflammatory bowel disease (IBD) patients. We aim to assess the efficacy and safety of concomitant use of 2 biologic therapies or combination of biologic and tofacitinib in a refractory pediatric IBD cohort. METHODS: As part of an ongoing single-center observational cohort study of therapeutic outcomes in pediatric IBD patients (younger than 18 years), data were collected for patients receiving dual therapy. Primary outcome was 6 months of steroid-free remission. Secondary outcomes included time to steroid-free remission, change in serum biomarkers (C-reactive protein and erythrocyte sedimentation rate) and albumin between baseline and 6 months, and adverse events. RESULTS: Sixteen children (9 ulcerative colitis/IBD-unspecified, 7 Crohn's disease), with a disease duration of 3 (2.1-5.0) years, initiated dual therapy at an age of 15.9 (13.5-16.8) years after failing ≥2 biologic therapies. Nine (56%) were treated with vedolizumab/tofacitinib, 4 (25%) with ustekinumab/vedolizumab, and 3 (19%) with ustekinumab/tofacitinib. Twelve (75%; 7 ulcerative colitis/IBD-unspecified, 5 Crohn's disease ) achieved steroid-free remission at 6 months. Erythrocyte sedimentation rate and C-reactive protein decreased (P = 0.021 and P = 0.015, respectively) and albumin increased (P = 0.003) between baseline and 6 months. One patient on 30 mg of vedolizumab/tofacitinib and prednisone daily developed septic arthritis and a deep vein thrombosis. CONCLUSIONS: Our data suggest that dual therapy may be an option for patients with limited therapeutic options remaining. Safety concerns should always be at the forefront of decision-making, and larger studies are needed to help confirm the preliminary safety data observed.

Working toward evidence-based guidelines for cost-of-care conversations between patients and physicians: A systematic review of the literature.

RATIONALE: As healthcare costs continue to rise, so does the importance of having cost-of-care conversations during medical office visits, especially for patients from vulnerable populations and patients with high-cost illnesses such as cancer. Such conversations remain relatively rare, however, even though physicians and patients say they want to have them. Furthermore, there is a lack of evidence-based guidelines for encouraging cost conversations and improving their quality. OBJECTIVE: The purpose of this project was to conduct a systematic review of the cost-of-care conversations literature, focusing on empirical studies to characterize the state of the literature and provide a foundation for developing evidence-based guidelines for these important conversations. METHOD: We searched seven electronic databases and identified an initial list of 1,986 records, 54 of which met inclusion criteria. We reviewed those articles to identify study purpose, use of theory, conceptual and operational definitions of cost conversations, sample characteristics, research methods, variables relevant to cost conversations, and relevant study findings. RESULTS: Results revealed that this literature (a) consists overwhelmingly of cross-sectional survey research set in the United States, (b) defines cost conversations chiefly as those focused on healthcare or medication costs (either in general or out-of-pocket), (c) is focused primarily on establishing incidence/frequency of cost conversations but also considers patient/provider desire for, attitudes/beliefs toward, and perceived barriers to cost conversations, and (d) lacks theoretical guidance. There were very few findings that could provide actionable evidence to guide quality conversations about reducing cost of care. We offer observations and recommendations for the next steps in cost conversations research so that patients and physicians can work together to promote quality care at affordable costs.

De Novo Crohn's Disease of the Pouch in Children Undergoing Ileal Pouch-Anal Anastomosis for Ulcerative Colitis.

BACKGROUND: Approximately 10% of children with ulcerative colitis (UC) undergo colectomy with ileal pouch-anal anastomosis (IPAA). We aimed to describe the postoperative outcomes, with an emphasis on chronic pouch inflammation including de novo Crohn disease (CD) at a tertiary care inflammatory bowel disease center. METHODS: Electronic medical records of all children who underwent colectomy ≤18 years between 2008 and 2017 were reviewed. Clinical and laboratory data were recorded. Primary outcome was frequency of chronic pouch inflammation including de novo CD. Secondary outcomes included early (≤30 days from index surgery) and late postoperative complications. Descriptive statistics (median and interquartile range) summarized the data and univariate analysis tested associations with outcomes. RESULTS: Fifty-eight children underwent colectomy and 56 completed IPAA. Median age at diagnosis was 14 years (12-16.2) and at colectomy 16.2 years (14.2-17.7) with median follow-up of 13 months (5-43). Sixty-six percent underwent 3-stage IPAA and 78% were biologic exposed. Eleven had chronic pouchitis, 73% antibiotic refractory and 25% met criteria for de novo CD by median of 19 months (9-41). A total of 21% and 50% experienced early and late surgical complications, most commonly ileus and recurrent IPAA stricture. The pouch failure rate was 3.6%. Chronic pouch inflammation was associated with a later diagnosis of de novo CD (P = 0.0025). CONCLUSIONS: In pediatric UC, CD is not uncommon after IPAA. Chronic pouch inflammation often precedes a diagnosis of de novo CD. Families should be informed of the short- and long-term outcomes in children before UC surgery.

Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Recurrent Clostridium difficile infection (RCDI) increases morbidity and mortality in patients with inflammatory bowel disease (IBD). Fecal microbiota transplant (FMT) is known to be very effective for RCDI in non-IBD patients with cure rates up to 91%. The same success rates of FMT have not been reported in patients with IBD with RCDI, and the data in pediatrics are limited. We aimed to determine the effectiveness of FMT for RCDI in established pediatric patients with IBD. METHODS: We performed a retrospective chart review of pediatric patients with IBD and RCDI (≥3 episodes) who underwent FMT via colonoscopy at a tertiary care IBD center. The primary outcome was the rate of RCDI within 60 days post-FMT. The secondary outcomes were recurrence rate by 6 months, rate of colectomy, and time to recurrence. RESULTS: Of the 8 eligible patients, 6 had ulcerative colitis, 1 had IBD-unspecified, and 1 had Crohn disease. Median (interquartile range) age was 13 (11-14) years. All patients were on vancomycin at FMT. Two patients (25%) had RCDI by 60 days post-FMT and another 3 patients had RCDI between 60 days and 6 months. The median time to recurrence was 101 (40-139) days. Two patients (25%) who developed recurrence went to colectomy after FMT. CONCLUSIONS: With a cure rate of 75% at 60 days, FMT administered for the treatment of RCDI may be an effective treatment option in pediatric IBD. However, there appears to be a significant rate of late recurrence of C difficile infection after 60 days in these patients.

Direct access cancer testing in primary care: a systematic review of use and clinical outcomes.

BACKGROUND: Direct access (DA) testing allows GPs to refer patients for investigation without consulting a specialist. The aim is to reduce waiting time for investigations and unnecessary appointments, enabling treatment to begin without delay. AIM: To establish the proportion of patients diagnosed with cancer and other diseases through DA testing, time to diagnosis, and suitability of DA investigations. DESIGN AND SETTING: Systematic review assessing the effectiveness of GP DA testing in adults. METHOD: MEDLINE, Embase, and the Cochrane Library were searched. Where possible, study data were pooled and analysed quantitatively. Where this was not possible, the data are presented narratively. RESULTS: The authors identified 60 papers that met pre-specified inclusion criteria. Most studies were carried out in the UK and were judged to be of poor quality. The authors found no significant difference in the pooled cancer conversion rate between GP DA referrals and patients who first consulted a specialist for any test, except gastroscopy. There were also no significant differences in the proportions of patients receiving any non-cancer diagnosis. Referrals for testing were deemed appropriate in 66.4% of those coming from GPs, and in 80.9% of those from consultants; this difference was not significant. The time from referral to testing was significantly shorter for patients referred for DA tests. Patient and GP satisfaction with DA testing was consistently high. CONCLUSION: GP DA testing performs as well as, and on some measures better than, consultant triaged testing on measures of disease detection, appropriateness of referrals, interval from referral to testing, and patient and GP satisfaction.

Effect of oil pulling in promoting oro dental hygiene: A systematic review of randomized clinical trials.

AIM: To critically appraise and evaluate the evidence from randomized clinical trials (RCTs) examining the effectiveness of oil pulling on oro dental hygiene. METHODS: We conducted electronic searches in Medline, Embase, Amed, The Cochrane Library and Cinahl databases from inception to February 2015, and assessed reporting quality using the Cochrane risk of bias criteria. We included RCTs that compared oil pulling using conventional cooking oils with a control intervention. Our primary outcomes were measures of oro dental hygiene using validated scales. RESULTS: Electronic searches yielded 26 eligible studies, of which five RCTs comprising a total of 160 participants were included. The studies varied in reporting quality, lasted between 10 and 45 days, and compared oil pulling with chlorhexidine, placebo or routine dental hygiene practice. Three studies reported no significant differences in post intervention plaque index scores between oil pulling and control groups (Chlorhexidine mouthwash +/- Placebo): p=0.28, 0.94, and 0.38, respectively. Two studies reported no significant difference in post-intervention modified gingival index score between oil pulling and Chlorhexidine mouthwash groups (p=0.32 and 0.64). CONCLUSION: The limited evidence to date from clinical trials suggests that oil pulling may have beneficial effects on oro dental hygiene as seen for the short period of time investigated. Given that this is a potentially cost-effective intervention, this practice might be of particular benefit. Future clinical trials should be more rigorous and better reported.

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

BACKGROUND: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. OBJECTIVE: To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. METHODS Search methods: We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. Selection criteria: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. Data collection and analysis: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. MAIN RESULTS: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage ...

Clinical and periprocedural pain management for uterine artery embolization.

Uterine artery embolization has Level A data supporting excellent safety and efficacy in treating symptomatic uterine leiomyomata. However, there is a perception that either postprocedural pain is severe or poorly managed by the physician performing these procedures. This has led some primary care physicians to omit this procedure from the patients' options or to steer patients away from this procedure. A few simple techniques (pruning of the vascular tree and embolizing to 5-10 beat stasis) and fastidious pre-, intra-, and post-procedural management can nearly eliminate significant pain associated with embolization. Specifically, early implementation of long-acting low-dose narcotics, antiemetics and anti-inflammatory medications is critical. Finally, the use of a superior hypogastric nerve block, which takes minutes to perform and carries a very low risk, significantly reduces pain and diminishes the need for narcotics; when this technique was used in a prospective study, all patients were able to be discharged the day of the procedure. In the authors' experience, patients treated in this manner largely recover completely within 5 days and have a far less traumatic experience than patients traditionally treated with only midazolam (Versed) and fentanyl citrate (fentanyl) intraprocedurally, and narcotics and nonsteroidal antiinflammatory drugs postprocedurally.

No association between educational level and pancreatic cancer incidence in the European Prospective Investigation into Cancer and Nutrition.

INTRODUCTION: Until now, studies examining the relationship between socioeconomic status and pancreatic cancer incidence have been inconclusive. AIM: To prospectively investigate to what extent pancreatic cancer incidence varies according to educational level within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: In the EPIC study, socioeconomic status at baseline was measured using the highest level of education attained. Hazard ratios by educational level and a summary index, the relative indices of inequality (RII), were estimated using Cox regression models stratified by age, gender, and center and adjusted for known risk factors. In addition, we conducted separate analyses by age, gender and geographical region. RESULTS: Within the source population of 407, 944 individuals at baseline, 490 first incident primary pancreatic adenocarcinoma cases were identified in 9 European countries. The crude difference in risk of pancreatic cancer according to level of education was small and not statistically significant (RII=1.14, 95% CI 0.80-1.62). Adjustment for known risk factors reduced the inequality estimates to only a small extent. In addition, no statistically significant associations were observed for age groups (adjusted RII(≤ 60 years)=0.85, 95% CI 0.44-1.64, adjusted RII(>60 years)=1.18, 95% CI 0.73-1.90), gender (adjusted RII(male)=1.20, 95% CI 0.68-2.10, adjusted RII(female)=0.96, 95% CI 0.56-1.62) or geographical region (adjusted RII(Northern Europe)=1.14, 95% CI 0.81-1.61, adjusted RII(Middle Europe)=1.72, 95% CI 0.93-3.19, adjusted RII(Southern Europe)=0.75, 95% CI 0.32-1.80). CONCLUSION: Despite large educational inequalities in many risk factors within the EPIC study, we found no evidence for an association between educational level and the risk of developing pancreatic cancer in this European cohort.