Cervical cancer incidence in Denmark: Disentangling determinants of time trend.

Cervical cancer is a preventable disease. Nevertheless, stagnation has been seen in incidence rates also in countries with well-functioning healthcare. On this basis, we investigated associations between control interventions and changes in cervical cancer incidence in Denmark from 2009 to 2022. Data on human papillomavirus (HPV)-vaccination were retrieved from Staten's Serum Institute; on screening recommendations from Danish Health Authority, on screening performance from Danish Quality Database for Cervical Screening; and on cervical cancer incidence from Nordcan and Danish Cancer Register. We reported coverage with HPV vaccination (1+ dose); coverage with cervical cell samples; number of women with primary HPV tests; proportion of non-normal cell samples without timely follow-up; number of conizations; and cervical cancer incidence rates. In 2022, all women aged ≤29 had been offered childhood HPV vaccination with coverage of 80%-90%. By 2020-2022, the cervical cancer incidence rate in women aged 20-29 was 3 per 100,000; at level of disease elimination. In 2017, women aged 70+ were offered a one-time HPV screening, and by 2020-2022, the old-age peak in cervical cancer incidence had largely disappeared. From 2009 to 2022, proportion of non-normal cell samples without timely follow-up decreased from 20% to 10%, and conventional cytology was largely replaced by SurePath liquid-based cytology; these factors could explain the steady decrease in cervical cancer incidence rate. Implementation of primary HPV screening in women aged 30-59 in 2021 was reflected in a, probably temporary, increase in the 2022 cervical cancer incidence rate. In conclusion, combined interventions with childhood HPV vaccination; one-time HPV screening of elderly women; and better management of screening broke previous stagnation in cervical cancer incidence rate.

Combined oral contraceptive pill for primary dysmenorrhoea.

BACKGROUND: Dysmenorrhoea (painful menstrual cramps) is common and a major cause of pain in women. Combined oral contraceptives (OCPs) are often used in the management of primary dysmenorrhoea, but there is a need for reporting the benefits and harms. Primary dysmenorrhoea is defined as painful menstrual cramps without pelvic pathology. OBJECTIVES: To evaluate the benefits and harms of combined oral contraceptive pills for the management of primary dysmenorrhoea. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date 28 March 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing all combined OCPs with other combined OCPs, placebo, or management with non-steroidal anti-inflammatory drugs (NSAIDs). Participants had to have primary dysmenorrhoea, diagnosed by ruling out pelvic pathology through pelvic examination or ultrasound. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary outcomes were pain score after treatment, improvement in pain, and adverse events. MAIN RESULTS: We included 21 RCTs (3723 women). Eleven RCTs compared combined OCP with placebo, eight compared different dosages of combined OCP, one compared two OCP regimens with placebo, and one compared OCP with NSAIDs. OCP versus placebo or no treatment OCPs reduce pain in women with dysmenorrhoea more effectively than placebo. Six studies reported treatment effects on different scales; the result can be interpreted as a moderate reduction in pain (standardised mean difference (SMD) -0.58, 95% confidence interval (CI) -0.74 to -0.41; I² = 28%; 6 RCTs, 588 women; high-quality evidence). Six studies also reported pain improvement as a dichotomous outcome (risk ratio (RR) 1.65, 95% CI 1.29 to 2.10; I² = 69%; 6 RCTs, 717 women; low-quality evidence). The data suggest that in women with a 28% chance of improvement in pain with placebo or no treatment, the improvement in women using combined OCP will be between 37% and 60%. Compared to placebo or no treatment, OCPs probably increase the risk of any adverse events (RR 1.31, 95% CI 1.20 to 1.43; I² = 79%; 7 RCTs, 1025 women; moderate-quality evidence), and may also increase the risk of serious adverse events (RR 1.77, 95% CI 0.49 to 6.43; I² = 22%; 4 RCTs, 512 women; low-quality evidence). Women who received OCPs had an increased risk of irregular bleeding compared to women who received placebo or no treatment (RR 2.63, 95% CI 2.11 to 3.28; I² = 29%; 7 RCTs, 1025 women; high-quality evidence). In women with a risk of irregular bleeding of 18% if using placebo or no treatment, the risk would be between 39% and 60% if using combined OCP. OCPs probably increase the risk of headaches (RR 1.51, 95% CI 1.11 to 2.04; I² = 44%; 5 RCTs, 656 women; moderate-quality evidence), and nausea (RR 1.64, 95% CI 1.17 to 2.30; I² = 39%; 8 RCTs, 948 women; moderate-quality evidence). We are uncertain of the effect of OCP on weight gain (RR 1.83, 95% CI 0.75 to 4.45; 1 RCT, 76 women; low-quality evidence). OCPs may slightly reduce requirements for additional medication (RR 0.63, 95% CI 0.40 to 0.98; I² = 0%; 2 RCTs, 163 women; low-quality evidence), and absence from work (RR 0.63, 95% CI 0.41 to 0.97; I² = 0%; 2 RCTs, 148 women; low-quality evidence). One OCP versus another OCP Continuous use of OCPs (no pause or inactive tablets after the usual 21 days of hormone pills) may reduce pain in women with dysmenorrhoea more effectively than the standard regimen (SMD -0.73, 95% CI -1.13 to 0.34; 2 RCTs, 106 women; low-quality evidence). There was insufficient evidence to determine if there was a difference in pain improvement between ethinylestradiol 20 µg and ethinylestradiol 30 µg OCPs (RR 1.06, 95% CI 0.65 to 1.74; 1 RCT, 326 women; moderate-quality evidence). There is probably little or no difference between third- and fourth-generation and first- and second-generation OCPs (RR 0.99, 95% CI 0.93 to 1.05; 1 RCT, 178 women; moderate-quality evidence). The standard regimen of OCPs may slightly increase the risk of any adverse events over the continuous regimen (RR 1.11, 95% CI 1.01 to 1.22; I² = 76%; 3 RCTs, 602 women; low-quality evidence), and probably increases the risk of irregular bleeding (RR 1.38, 95% CI 1.14 to 1.69; 2 RCTs, 379 women; moderate-quality evidence). Due to lack of studies, it is uncertain if there is a difference between continuous and standard regimen OCPs in serious adverse events (RR 0.34, 95% CI 0.01 to 8.24; 1 RCT, 212 women), headaches (RR 0.94, 95% CI 0.50 to 1.76; I² = 0%; 2 RCTs, 435 women), or nausea (RR 1.08, 95% CI 0.51 to 2.30; I² = 23%; 2 RCTs, 435 women) (all very low-quality evidence). We are uncertain if one type of OCP reduces absence from work more than the other (RR 1.12, 95% CI 0.64 to 1.99; 1 RCT, 445 women; very low-quality evidence). OCPs versus NSAIDs There were insufficient data to determine whether OCPs were more effective than NSAIDs for pain (mean difference -0.30, 95% CI -5.43 to 4.83; 1 RCT, 91 women; low-quality evidence). The study did not report on adverse events. AUTHORS' CONCLUSIONS: OCPs are effective for treating dysmenorrhoea, but they cause irregular bleeding, and probably headache and nausea. Long-term effects were not covered in this review. Continuous use of OCPs was probably more effective than the standard regimen but safety should be ensured with long-term data. Due to lack of data, we are uncertain whether NSAIDs are better than OCPs for treating dysmenorrhoea.

Iron supplements in pregnant women with normal iron status: A systematic review and meta-analysis.

INTRODUCTION: Effects of daily iron supplementation in iron replete pregnancy are unclear. This systematic review aimed to assess benefits and harms of oral iron supplements in pregnant women without anemia and iron deficiency. MATERIAL AND METHODS: We predefined and registered a protocol in PROSPERO (CRD42020186210) and performed the review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. We searched for randomized clinical trials (RCTs) and observational studies comparing daily oral iron supplementation with no iron supplements in non-anemic iron replete pregnant women. Searches were conducted in MEDLINE (by PubMed), EMBASE (by OVID), Cochrane Library, and ClinicalTrials.gov from inception to September 2022 without language restrictions. Two authors independently screened records, extracted data, and assessed risk of bias using the revised Cochrane risk of bias tool (RoB2). One author read full-texts, assessed certainty of evidence by GRADE and conducted meta-analyses using a random-effects model. Primary outcomes included iron deficiency anemia, iron deficiency, hemoglobin >130 g/L, elevated iron status, small for gestational age newborns, low birthweight newborns, preterm birth, and congenital anomalies. RESULTS: Eight RCTs (2822 women) but no observational studies were eligible for inclusion. Daily oral iron supplementation in pregnancy probably reduces iron deficiency anemia at term (risk ratio [RR]: 0.51, 95% confidence interval [CI]: 0.38-0.70; 4 RCTs, 1670 women; I2 = 13%; moderate-certainty evidence) and the incidence of low birthweight babies (RR: 0.30, 95% CI: 0.13-0.68; 2 RCTs, 361 infants; I2 = 0%; moderate-certainty evidence). In addition, it may reduce iron deficiency at term (RR: 0.74, 95% CI: 0.60-0.92; 4 RCTs, 1663 women; I2 = 58%; low-certainty evidence) and the incidence of small for gestational age babies (RR: 0.39, 95% CI: 0.17-0.86; 1 RCT, 213 infants; I2 not estimable; low-certainty evidence). CONCLUSIONS: Daily iron supplementation in iron replete non-anemic pregnant women probably reduces the risk of maternal iron deficiency anemia at term and low birthweight.

Iatrogenic bladder injury following gynecologic and obstetric surgery: A systematic review and meta-analysis.

INTRODUCTION: Iatrogenic bladder injury is a rare complication following obstetric and gynecologic surgery and only sparse information is available regarding length of transurethral catheterization following injuries, suturing techniques including choice of suture, and complications. The primary aim of this systematic review was to evaluate length of transurethral catheterization in relation to complications following iatrogenic bladder injury. Second, we aimed to evaluate the number of complications following repair of iatrogenic bladder injuries and to describe suture technique and best choice of suture. MATERIAL AND METHODS: A systematic review and meta-analysis was conducted, and the results were presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, and Medline electronic databases were searched, and followed by screening from two independent reviewers. Studies published between January 2000 and March 2023 describing methods of bladder injury repair following obstetric or gynecologic benign surgery were included. Data extraction was done using Covidence. We performed a meta-analysis on complications after repair and explored this with a meta-regression analysis (Metafor package R) on length of catheterization to determine if length of catheterization influenced the risk of complication. A risk of bias tool from Cochrane was used to assess risk of bias and the study was registered in PROSPERO (CRD42021290586). RESULTS: Out of 2175 articles, we included 21 retrospective studies, four prospective studies, and one case-control study. In total, 595 bladder injuries were included. Cesarean section was the most prominent surgery type, followed by laparoscopically assisted vaginal hysterectomy. We found no statistically significant association between length of transurethral catheterization and numbers of complications following repair of iatrogenic bladder injuries. More than 90% of injuries were recognized intraoperatively. Approximately 1% had complications following iatrogenic bladder injury repair (0.010, 95% confidence interval 0.0015-0.0189, 26 studies, 595 participants, I2 = 4%). CONCLUSIONS: Our review did not identify conclusive evidence on the length of postoperative catheterization following bladder injury warranting further research. However, the rate of complications was low following iatrogenic bladder injury with a wide range of repair approaches.

Endocervical sampling in women with suspected cervical neoplasia: a systematic review and meta-analysis of diagnostic test accuracy studies.

OBJECTIVE: Endocervical sampling in women with suspected cervical neoplasia can be performed by either endocervical brush or endocervical curettage. This study aimed to estimate the diagnostic accuracy, discomfort, and number of inadequate samples with either test. DATA SOURCES: Four bibliographic databases were searched on June 9, 2022, with no date or language restrictions. STUDY ELIGIBILITY CRITERIA: We included all diagnostic studies and randomized clinical trials that compared the endocervical brush with endocervical curettage in women with an indication for colposcopy. METHODS: The review protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021222406). Two authors independently screened studies, extracted data, performed the risk-of-bias assessment (Quality Assessment of Diagnostic Accuracy Studies-2), and rated the certainty of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. A meta-analysis of diagnostic test accuracy was performed using a bivariate random-effects model. RESULTS: We included 7 studies: 4 diagnostic cohort studies and 3 randomized clinical trials. The reference standard was conization or hysterectomy. Risk of bias and concern about applicability were high for some of the studies in patient selection and flow and timing. Overall pooled sensitivity was 81% (95% confidence interval, 48-95; 799 women; 7 studies; low quality of evidence) for endocervical brush and 70% (95% confidence interval, 42-89; 761 women; 7 studies; low quality of evidence) for endocervical curettage. Overall pooled specificity was 73% (95% confidence interval, 36-93; 799 women; 7 studies; low quality of evidence) for endocervical brush and 81% (95% confidence interval, 56-94; 761 women; 7 studies; low quality of evidence) for endocervical curettage. The risk ratio for inadequate samples with endocervical curettage compared with endocervical brush was 2.53 (95% confidence interval, 0.58-11.0; P=.215; low-certainty evidence). Two studies reported on patient discomfort; one found less discomfort in the endocervical brush group, and the other found no difference. CONCLUSION: No difference was found between endocervical brush and endocervical curettage in diagnostic accuracy, inadequate sampling rate, and adverse effects based on low-quality of evidence. Variation in the characteristics of women and the resulting diagnostic pathways make the external validity limited.

Human papillomavirus vaccination in women undergoing excisional treatment for cervical intraepithelial neoplasia and subsequent risk of recurrence: A systematic review and meta-analysis.

INTRODUCTION: In this review and meta-analysis we aimed to investigate whether human papilloma virus (HPV) vaccination administered after excisional treatment of cervical intraepithelial neoplasia (CIN) is associated with a reduced risk of recurrence of CIN grade 2 or worse (CIN2+). MATERIAL AND METHODS: We performed a systematic literature search in three online databases through June 2021. Observational studies and randomized controlled trials (RCTs) were eligible for inclusion if the prophylactic HPV vaccine was administered after excisional treatment for histologically verified CIN. Only English language literature was included. The primary outcome measure was recurrence of CIN2+ after treatment. A meta-analysis was performed using fixed and random-effects models, and results were reported as pooled odds ratios (OR) with 95% confidence intervals (95% CI). Quality assessment was performed using ROB2-tool for RCTs and ROBINS-I for observational studies. The protocol was registered in PROSPERO (CRD42021238257). RESULTS: A total of 1561 studies were identified, of which nine, including 19 971 women, were included. Two studies were RCTs and seven were observational studies. Using the fixed-effect model on the two RCTs, the OR for recurrence of CIN2+ was 0.29 (95% CI 0.16-0.53). Due to considerable heterogeneity in observational studies, the random-effects model was used to estimate pooled OR for CIN2+ recurrence in these studies. Thus, using unadjusted data from observational studies, the OR for CIN2+ recurrence was 0.35 (95% CI 0.18-0.67), whereas when using adjusted data, the OR for CIN2+ recurrence was 0.54 (95% CI 0.21-1.35). However, quality assessment revealed a serious risk of bias for the majority of the studies included. CONCLUSIONS: HPV vaccination post-treatment was associated with a significantly reduced risk of CIN2+ recurrence when using unadjusted estimates from observational studies and RCTs. We found no significant effect of HPV vaccination on risk of CIN2+ recurrence when using the outcome measure from observational studies with the least risk of bias. Large, well-designed randomized placebo-controlled trials are needed to determine whether post-treatment HPV vaccination should be recommended to all women undergoing excisional treatment for CIN.

Multivitamin use and risk of preeclampsia: A systematic review and meta-analysis.

INTRODUCTION: Preeclampsia is associated with adverse maternal and neonatal outcomes. It is unclear whether multivitamin use reduces the risk of preeclampsia. This systematic review and meta-analysis aimed to evaluate the association between multivitamin use and the risk of preeclampsia. MATERIAL AND METHODS: We searched PubMed, Embase and the Cochrane Library from database inception to July 2021. Randomized controlled trials (RCTs), case-control and cohort studies assessing the association between multivitamin use and risk of preeclampsia were eligible. Studies of treatment with a single micronutrient were excluded. Relative risks and 95% confidence intervals (95% CI) were calculated using random-effects models. RoB2, the Newcastle Ottawa Scale and GRADE were used to assess risk of bias and quality of evidence. The protocol was registered in PROSPERO (no. CRD42021214153). RESULTS: Six studies were included (33 356 women). Only two RCTs were found, both showing a significantly decreased risk of preeclampsia in multivitamin users. These studies were not compatible for meta-analysis due to clinical heterogeneity. A meta-analysis of observational studies using a random-effects model showed an unchanged risk of preeclampsia following multivitamin use (relative risk 0.85, 95% CI 0.69-1.03). The quality of evidence according to GRADE was very low. CONCLUSIONS: Very weak evidence suggests that multivitamin use might reduce the risk of preeclampsia; however, more research is needed. Large RCTs should be prioritized. The results of this review do not allow any final conclusions to be drawn regarding a preventive effect of multivitamin use in relation to preeclampsia.

Simulation-Based Ultrasound Training in Obstetrics and Gynecology: A Systematic Review and Meta-Analysis.

OBJECTIVE: The purpose of this systematic review and meta-analysis was to examine the effects of simulation-based ultrasound training (SIM-UT) in obstetrics and gynecology compared to non-SIM-UT on trainee learning, clinical performance, patient-relevant outcomes, and cost of training. METHODS: A systematic search was performed in June 2019 in PubMed, Embase, and Scopus using search terms for the topic and the intervention as well as certain MESH terms. Inclusion criteria were defined in accordance with the PICO question. Studies published in any language involving SIM-UT in obstetrics and gynecology compared to non-SIM-UT or no training were included. The outcomes included effects on health care provider learning and clinical performance, patient-relevant outcomes, and cost of training. Two authors evaluated the study quality with the MERSQI instrument and the Oxford Quality Scoring System. A meta-analysis was planned for the included randomized controlled trials. RESULTS: 15 studies were included, and 11 studies were eligible for meta-analysis. SIM-UT was significantly superior to clinical training only and theoretical teaching with standard mean differences (SMD) of 0.84 (0.08-1.61) and 1.20 (0.37-2.04), respectively. However, SIM-UT was not superior to live model training; SMD of 0.65 (-3.25-4.55). Of all studies included in the meta-analysis, 91 % favored SIM-UT over clinical training alone, theoretical teaching, or in some cases live model training. CONCLUSION: In the field of obstetrics and gynecology, SIM-UT in addition to clinical training markedly improves trainee learning, clinical performance, as well as patient-perceived quality of care.

Industry sponsorship and research outcome.

BACKGROUND: Clinical research affecting how doctors practice medicine is increasingly sponsored by companies that make drugs and medical devices. Previous systematic reviews have found that pharmaceutical-industry sponsored studies are more often favorable to the sponsor's product compared with studies with other sources of sponsorship. A similar association between sponsorship and outcomes have been found for device studies, but the body of evidence is not as strong as for sponsorship of drug studies. This review is an update of a previous Cochrane review and includes empirical studies on the association between sponsorship and research outcome. OBJECTIVES: To investigate whether industry sponsored drug and device studies have more favorable outcomes and differ in risk of bias, compared with studies having other sources of sponsorship. SEARCH METHODS: In this update we searched MEDLINE (2010 to February 2015), Embase (2010 to February 2015), the Cochrane Methodology Register (2015, Issue 2) and Web of Science (June 2015). In addition, we searched reference lists of included papers, previous systematic reviews and author files. SELECTION CRITERIA: Cross-sectional studies, cohort studies, systematic reviews and meta-analyses that quantitatively compared primary research studies of drugs or medical devices sponsored by industry with studies with other sources of sponsorship. We had no language restrictions. DATA COLLECTION AND ANALYSIS: Two assessors screened abstracts and identified and included relevant papers. Two assessors extracted data, and we contacted authors of included papers for additional unpublished data. Outcomes included favorable results, favorable conclusions, effect size, risk of bias and whether the conclusions agreed with the study results. Two assessors assessed risk of bias of included papers. We calculated pooled risk ratios (RR) for dichotomous data (with 95% confidence intervals (CIs)). MAIN RESULTS: Twenty-seven new papers were included in this update and in total the review contains 75 included papers. Industry sponsored studies more often had favorable efficacy results, RR: 1.27 (95% CI: 1.17 to 1.37) (25 papers) (moderate quality evidence), similar harms results RR: 1.37 (95% CI: 0.64 to 2.93) (four papers) (very low quality evidence) and more often favorable conclusions RR: 1.34 (95% CI: 1.19 to 1.51) (29 papers) (low quality evidence) compared with non-industry sponsored studies. Nineteen papers reported on sponsorship and efficacy effect size, but could not be pooled due to differences in their reporting of data and the results were heterogeneous. We did not find a difference between drug and device studies in the association between sponsorship and conclusions (test for interaction, P = 0.98) (four papers). Comparing industry and non-industry sponsored studies, we did not find a difference in risk of bias from sequence generation, allocation concealment, follow-up and selective outcome reporting. However, industry sponsored studies more often had low risk of bias from blinding, RR: 1.25 (95% CI: 1.05 to 1.50) (13 papers), compared with non-industry sponsored studies. In industry sponsored studies, there was less agreement between the results and the conclusions than in non-industry sponsored studies, RR: 0.83 (95% CI: 0.70 to 0.98) (six papers). AUTHORS' CONCLUSIONS: Sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard 'Risk of bias' assessments.

Surgery versus conservative management of endometriomas in subfertile women. A systematic review.

INTRODUCTION: Endometriomas are present in up to 44% of all women with endometriosis and have a detrimental effect on fertility. However, it is controversial whether endometriomas should be surgically removed before assisted reproduction technology. Our purpose was to evaluate whether surgical stripping of endometriomas in subfertile women improves the chance of a live birth. Secondary outcomes were impact on ovarian reserve and pain. MATERIAL AND METHODS: We conducted a systematic review and meta-analysis with results reported in accordance to the PRISMA guidelines. A summary of findings table was developed using GRADE. We searched Medline and Embase. Two reviewers performed the screening. RESULTS: Of 686 manuscripts, we included one randomized controlled trial and nine retrospective cohort studies, mostly of low quality. The odds ratio for live birth after surgery [compared with conservative management before in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)] was 0.87 (95% CI 0.64-1.18, six studies, I2  = 3%; ⨁◯◯◯, VERY LOW quality). The mean difference of antral follicle count was -2.09 (95% CI -4.84 to 0.67, four studies). No difference was observed regarding antral follicle count between the two groups (MD -2.09, 95% CI -4.84 to 0.67, four studies, ⨁◯◯◯, VERY LOW quality). Pain outcome was not reported in the included studies. CONCLUSION: The very low quality evidence suggests no difference in odds ratio of live birth between women who underwent surgery for endometriomas before IVF/ICSI compared with conservative management. Further high quality studies are needed, but due to a lack of convincing evidence favoring surgery, we recommend considering conservative treatment if the only indication is subfertility.

Assessment of Adverse Events in Protocols, Clinical Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis.

BACKGROUND: Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials. METHODS AND FINDINGS: We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were "bothersome," a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that "all adverse events were recorded." For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student's t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs. CONCLUSIONS: In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.

Critical appraisal of clinical practice guidelines.

Ten questions to assess to what degree a clinical practice guideline is likely to be trustworthy: 1) Do the authors have conflicts of interests? 2) Is the clinical question relevant? 3) Have relevant stakeholders been involved? 4) Have methods for study selection been described? 5) Is there a link between evidence and recommendations (transparent methods)? 6) Has the certainty of evidence been assessed? 7) Have the methods for reaching recommendations been described? 8) Are the recommendations unambiguous? 9) Are the recommendations relevant in your situation? 10) Is there an implementation strategy?

Screening outcome of HPV-vaccinated women: Data from the Danish Trial23 cohort study.

BACKGROUND: Danish women-who were HPV-vaccinated as girls-are now reaching an age where they are invited to cervical cancer screening. Because of their expected lower cervical cancer risk, we must reassess our screening strategies. We analyzed Danish HPV-vaccinated women's outcomes after the first screening test at age 23. METHODS AND FINDINGS: Our study was embedded in Danish routine cytology-based screening. We conducted an observational study and included women born in 1994, offered the 4-valent HPV vaccine at age 14, and subsequently invited to screening at age 23. Cervical cytology was used for diagnostics and clinical management. Residual material was HPV tested with Cobas® 4800/6800. The most severe histology diagnosis within 795 days of screening was found through linkage with the Danish National Pathology Register. We calculated the number of women undergoing follow-up (repeated testing and/or colposcopy) per detected cervical intraepithelial neoplasia (CIN2+). A total of 6021 women were screened; 92% were HPV-vaccinated; 12% had abnormal cytology; 35% were high-risk HPV-positive, including 0.9% HPV16/18 positive, and 20% had follow-up. In women that were cytology-abnormal and HPV-positive (Cyt+/HPV+), 610 (98.5%) had been followed up, and 138 CIN2+ cases were diagnosed, resulting in 4.4 (95% CI 3.9-5.2) women undergoing follow-up per detected CIN2+. In contrast to recommendations, 182 (12.2%) cytology-normal and HPV-positive (Cyt-/HPV+) women were followed up within 795 days, and 8 CIN2+ cases were found, resulting in 22.8 (95% CI 13.3-59.3) women undergoing follow-up per detected CIN2+. CONCLUSION: Overall, HPV prevalence was high in HPV-vaccinated women, but HPV16/18 had largely disappeared. In the large group of cytology-normal and HPV-positive women, 23 had been followed up per detected CIN2+ case. Our data indicated that primary HPV screening of young HPV-vaccinated women would require very effective triage methods to avoid an excessive follow-up burden. TRIAL REGISTRATION: Trial registration number: NCT0304955.

Sulphonylurea monotherapy for patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a growing health problem worldwide. Whether sulphonylureas show better, equal or worse therapeutic effects in comparison with other antidiabetic interventions for patients with T2DM remains controversial. OBJECTIVES: To assess the effects of sulphonylurea monotherapy versus placebo, no intervention or other antidiabetic interventions for patients with T2DM. SEARCH METHODS: We searched publications in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS and CINAHL (all until August 2011) to obtain trials fulfilling the inclusion criteria for our review. SELECTION CRITERIA: We included clinical trials that randomised patients 18 years old or more with T2DM to sulphonylurea monotherapy with a duration of 24 weeks or more. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias. The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes were other patient-important outcomes and metabolic variables. Where possible, we used risk ratios (RR) with 95% confidence intervals (95% CI) to analyse the treatment effect of dichotomous outcomes. We used mean differences with 95% CI to analyse the treatment effect of continuous outcomes. We evaluated the risk of bias. We conducted trial sequential analyses to assess whether firm evidence could be established for a 10% relative risk reduction (RRR) between intervention groups. MAIN RESULTS: We included 72 randomised controlled trials (RCTs) with 22,589 participants; 9707 participants randomised to sulphonylureas versus 12,805 participants randomised to control interventions. The duration of the interventions varied from 24 weeks to 10.7 years. We judged none of the included trials as low risk of bias for all bias domains. Patient-important outcomes were seldom reported.First-generation sulphonylureas (FGS) versus placebo or insulin did not show statistical significance for all-cause mortality (versus placebo: RR 1.46, 95% CI 0.87 to 2.45; P = 0.15; 2 trials; 553 participants; high risk of bias (HRB); versus insulin: RR 1.18, 95% CI 0.88 to 1.59; P = 0.26; 2 trials; 1944 participants; HRB). FGS versus placebo showed statistical significance for cardiovascular mortality in favour of placebo (RR 2.63, 95% CI 1.32 to 5.22; P = 0.006; 2 trials; 553 participants; HRB). FGS versus insulin did not show statistical significance for cardiovascular mortality (RR 1.36, 95% CI 0.68 to 2.71; P = 0.39; 2 trials; 1944 participants; HRB). FGS versus alpha-glucosidase inhibitors showed statistical significance in favour of FGS for adverse events (RR 0.63, 95% CI 0.52 to 0.76; P = 0.01; 2 trials; 246 participants; HRB) and for drop-outs due to adverse events (RR 0.28, 95% CI 0.12 to 0.67; P = 0.004; 2 trials; 246 participants; HRB).Second-generation sulphonylureas (SGS) versus metformin (RR 0.98, 95% CI 0.61 to 1.58; P = 0.68; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 0.92, 95% CI 0.60 to 1.41; P = 0.70; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.79 to 1.18; P = 0.72; 4 trials; 1642 participants; HRB), meglitinides (RR 1.44, 95% CI 0.47 to 4.42; P = 0.52; 7 trials; 2038 participants; HRB), or incretin-based interventions (RR 1.39, 95% CI 0.52 to 3.68; P = 0.51; 2 trials; 1503 participants; HRB) showed no statistically significant effects regarding all-cause mortality in a random-effects model. SGS versus metformin (RR 1.47; 95% CI 0.54 to 4.01; P = 0.45; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 1.30, 95% CI 0.55 to 3.07; P = 0.55; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.73 to 1.28; P = 0.80; 4 trials; 1642 participants; HRB) or meglitinide (RR 0.97, 95% CI 0.27 to 3.53; P = 0.97; 7 trials, 2038 participants, HRB) showed no statistically significant effects regarding cardiovascular mortality. Mortality data for the SGS versus placebo were sparse. SGS versus thiazolidinediones and meglitinides did not show statistically significant differences for a composite of non-fatal macrovascular outcomes. SGS versus metformin showed statistical significance in favour of SGS for a composite of non-fatal macrovascular outcomes (RR 0.67, 95% CI 0.48 to 0.93; P = 0.02; 3018 participants; 3 trials; HRB). The definition of non-fatal macrovascular outcomes varied among the trials. SGS versus metformin, thiazolidinediones and meglitinides showed no statistical significance for non-fatal myocardial infarction. No meta-analyses could be performed for microvascular outcomes. SGS versus placebo, metformin, thiazolidinediones, alpha-glucosidase inhibitors or meglitinides showed no statistical significance for adverse events. SGS versus alpha-glucosidase inhibitors showed statistical significance in favour of SGS for drop-outs due to adverse events (RR 0.48, 95% CI 0.24 to 0.96; P = 0.04; 9 trials; 870 participants; HRB). SGS versus meglitinides showed no statistical significance for the risk of severe hypoglycaemia. SGS versus metformin and thiazolidinediones showed statistical significance in favour of metformin (RR 5.64, 95% CI 1.22 to 26.00; P = 0.03; 4 trials; 3637 participants; HRB) and thiazolidinediones (RR 6.11, 95% CI 1.57 to 23.79; P = 0.009; 6 trials; 5660 participants; HRB) for severe hypoglycaemia.Third-generation sulphonylureas (TGS) could not be included in any meta-analysis of all-cause mortality, cardiovascular mortality or non-fatal macro- or microvascular outcomes. TGS versus thiazolidinediones showed statistical significance regarding adverse events in favour of TGS (RR 0.88, 95% CI 0.78 to 0.99; P = 0.03; 3 trials; 510 participants; HRB). TGS versus thiazolidinediones did not show any statistical significance for drop-outs due to adverse events. TGS versus other comparators could not be performed due to lack of data.For the comparison of SGS versus FGS no meta-analyses of all-cause mortality, cardiovascular mortality, non-fatal macro- or microvascular outcomes, or adverse events could be performed.Health-related quality of life and costs of intervention could not be meta-analysed due to lack of data.In trial sequential analysis, none of the analyses of mortality outcomes, vascular outcomes or severe hypoglycaemia met the criteria for firm evidence of a RRR of 10% between interventions. AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs to support the decision as to whether to initiate sulphonylurea monotherapy. Data on patient-important outcomes are lacking. Therefore, large-scale and long-term randomised clinical trials with low risk of bias, focusing on patient-important outcomes are required.

Underreporting of conflicts of interest in clinical practice guidelines: cross sectional study.

BACKGROUND: Conflicts of interest affect recommendations in clinical guidelines and disclosure of such conflicts is important. However, not all conflicts of interest are disclosed. Using a public available disclosure list we determined the prevalence and underreporting of conflicts of interest among authors of clinical guidelines on drug treatments. METHODS: We included up to five guidelines published from July 2010 to March 2012 from each Danish clinical specialty society. Using the disclosure list of the Danish Health and Medicines Authority, we identified author conflicts of interest and compared them with the disclosures in the guidelines. For each guideline we extracted methodological characteristics of guideline development. RESULTS: Forty-five guidelines from 14 specialty societies were included. Of 254 authors, 135 (53%) had conflicts of interest, corresponding to 43 of the 45 guidelines (96%) having one or more authors with a conflict of interest. Only one of the 45 guidelines (2%) disclosed author conflicts of interest. The most common type of conflict of interest (83 of the 135) was being a consultant, an advisory board member or a company employee. Only 10 guidelines (22%) described the methods used for guideline development, 27 (60%) used references in the text and 11 (24%) graded the types of evidence. CONCLUSIONS: Conflicts of interest were common, but disclosures were very rare. Most guidelines did not describe how they were developed and many did not describe the evidence behind specific recommendations. Publicly available disclosure lists may assist guideline issuing bodies in ensuring that all conflicts are disclosed.