Intradermal vaccination of HPV-16 E6 synthetic peptides conjugated to an optimized Toll-like receptor 2 ligand shows safety and potent T cell immunogenicity in patients with HPV-16 positive (pre-)malignant lesions.

BACKGROUND: Amplivant is a molecularly optimized Toll-like receptor 2 ligand that can be covalently conjugated to tumor peptide antigens. In preclinical models, amplivant-adjuvanted synthetic long peptides (SLPs) strongly enhanced antigen presentation by dendritic cells, T cell priming and induction of effective antitumor responses. The current study is a first-in-human trial to investigate safety and immunogenicity of amplivant conjugated to human papillomavirus (HPV) 16-SLP. METHODS: A dose escalation phase I vaccination trial was performed in 25 patients treated for HPV16 positive (pre-)malignant lesions. Amplivant was conjugated to two SLPs derived from the two most immunodominant regions of the HPV16 E6 oncoprotein. The vaccine, containing a mix of these two conjugates in watery solution without any other formulation, was injected intradermally three times with a 3-week interval in four dose groups (1, 5, 20 or 50 µg per conjugated peptide). Safety data were collected during the study. Peptide-specific T cell immune responses were determined in blood samples taken before, during and after vaccination using complementary immunological assays. RESULTS: Toxicity after three amplivant-conjugated HPV16-SLP vaccinations was limited to grade 1 or 2, observed as predominantly mild skin inflammation at the vaccination site and sometimes mild flu-like symptoms. Adverse events varied from none in the lowest dose group to mild/moderate vaccine-related inflammation in all patients and flu-like symptoms in three out of seven patients in the highest dose group, after at least one injection. In the lowest dose group, vaccine-induced T cell responses were observed in the blood of three out of six vaccinated persons. In the highest dose group, all patients displayed a strong HPV16-specific T cell response after vaccination. These HPV16-specific T cell responses lasted until the end of the trial. CONCLUSIONS: Amplivant-conjugated SLPs can safely be used as an intradermal therapeutic vaccine to induce robust HPV16-specific T cell immunity in patients previously treated for HPV16 positive (pre-) malignancies. Increased vaccine dose was associated with a higher number of mild adverse events and with stronger systemic T cell immunity. TRIAL REGISTRATION NUMBERS: NCT02821494 and 2014-000658-12.

Efficacy of combined oral contraceptives for depressive symptoms and overall symptomatology in premenstrual syndrome: pairwise and network meta-analysis of randomized trials.

OBJECTIVE: Combined oral contraceptives are often considered a treatment option for women with premenstrual syndrome or premenstrual dysphoric disorder also seeking contraception, but evidence for this treatment is scarce. We aimed to determine (1) the level of evidence for the efficacy of combined oral contraceptives in managing premenstrual depressive symptoms and overall premenstrual symptomatology and (2) the comparative efficacy of combined oral contraceptives (the International Prospective Register of Systematic Reviews registration number CRD42020205510). DATA SOURCES: We searched Cochrane Central Register of Controlled Trials, PubMed, Web of Science, PsycINFO, EMCare, and Embase from inception to June 3, 2021. STUDY ELIGIBILITY CRITERIA: All randomized clinical trials that evaluated the efficacy of combined oral contraceptives in women with premenstrual syndrome or premenstrual dysphoric disorder were considered eligible for inclusion in this meta-analysis. STUDY APPRAISAL AND SYNTHESIS METHODS: A random effect Bayesian pairwise and network meta-analysis was conducted with change in premenstrual depressive symptoms and overall premenstrual symptomatology between baseline and 3 cycles as outcome. Certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: Of 3664 records, 9 eligible trials were included that studied 1205 women with premenstrual syndrome or premenstrual dysphoric disorder (mean age per study range, 24.6-36.5 years). The pairwise meta-analysis revealed that combined oral contraceptives were more efficacious than placebo in treating overall premenstrual symptomatology (standardized mean difference, 0.41; 95% credible interval, 0.17-0.67), but not premenstrual depressive symptoms specifically (standardized mean difference, 0.22; 95% credible interval, -0.06 to 0.47). However, none of the combined oral contraceptives were more effective than each other in reducing premenstrual depressive symptoms and overall premenstrual symptomatology. CONCLUSION: Combined oral contraceptives may improve overall premenstrual symptomatology in women with premenstrual syndrome or premenstrual dysphoric disorder, but not premenstrual depressive symptoms. There is no evidence for one combined oral contraceptive being more efficacious than any other.

Uterine rupture in pregnancy after an intervention complicated by uterine perforation: Case report and systematic review of literature.

OBJECTIVES: The present study is a descriptive study of characteristics of women who had a uterine rupture during pregnancy with a history of uterine perforation and no previous caesarean section. STUDY DESIGN: We present a case report of a woman with a uterine rupture in pregnancy subsequent to a perforation made by uterine sounding and we performed a systematic review including all case-reports of uterine ruptures after perforation during dilatation and curettage or due to uterine sounding. RESULTS: 14 case-reports were included in this review. 12 out of 14 women presented with abdominal pain prior to the uterine rupture. In eight out of 14 cases an abdominal ultrasound was performed and in five ultrasounds a uterine wall defect was detected, in two other cases free fluid was visible and in one case fetal bradycardia was seen. Neonatal outcome was uneventful in six cases, there where two immature fetuses born and in two cases there was fetal demise. CONCLUSION: Uterine rupture in a (supposed) unscarred uterus is a relatively unknown complication. We recommend clinicians to be aware of uterine rupture in pregnant women with abdominal pain and a history of uterine manipulation. When a uterine rupture is suspected and mother and fetus are in suspected good condition, an ultrasound examination could be an easy and fast next step.

Vaginal misoprostol prior to insertion of an intrauterine device: an RCT.

BACKGROUND: Misoprostol is an agent that may ripen the cervix in nonpregnant women. Here, we investigate whether vaginal misoprostol administered prior to intrauterine device (IUD) insertion reduces the number of failed insertions, insertion-related complications and pain during insertion. METHODS: We conducted a double-blinded, multicenter randomized controlled trial among patients requesting an IUD. Nulli- and multi-parous women were included, and both copper-containing and levonorgestrel-releasing IUDs were used. Participants were allocated to either 400 µg misoprostol or placebo (administered 3h prior to IUD insertion). The primary outcome measure was failed insertion. Secondary outcome measures were insertion-related complications, pain, difficulty of insertion and side-effects. RESULTS: Two hundred and seventy participants were randomized. After drop out for various reasons (mainly no show), 199 participants had an IUD inserted; 102 received misoprostol and 97 received placebo. Only three insertions failed; two in the misoprostol group and one in the placebo group [P = 0.59, relative risk (RR) 1.9, 95% confidence interval (CI) 0.2-20.6]. The overall incidence of insertion-related complications was 21.8% in the misoprostol versus 19.1% in the placebo group (mainly vasovagal-like reactions) and did not differ between groups (P = 0.65, RR 1.1, 95% CI 0.7-2.0). No difference in pain scores between groups was found. Side-effects were more common in the misoprostol group (P = 0.05, RR 1.3, 95% CI 1.0-1.7). CONCLUSION: The study showed no benefit for use of misoprostol prior to IUD insertion. However, there is a tendency of possible harm regarding side-effects. Therefore, we would not recommend standard pretreatment with misoprostol. The trial was registered in the European Clinical Trials Database EudraCT 2006-006897-60.

Unintended pregnancies after Essure sterilization in the Netherlands.

OBJECTIVE: To analyze the data of cases of unintended pregnancies after Essure sterilization. DESIGN: Retrospective case series analysis. SETTING: National multicenter. PATIENT(S): Ten cases of unintended pregnancies after Essure sterilization in the Netherlands were reported from August 2002 through May 2008. INTERVENTION(S): Data on the hysteroscopic Essure sterilization procedures and postprocedure confirmation tests of the reported cases were reviewed and analyzed by two authors. The causes of the unintended pregnancies were determined in agreement with the physicians who performed the sterilizations. MAIN OUTCOME MEASURE(S): Most pregnancies occurred in patients with only one device placement and bilateral occlusion on hysterosalpingography (HSG). Other cases included misinterpretation of HSG, undetected abnormal device position by ultrasound, one undetected preprocedure pregnancy, and two patient failures to follow up with the physician advice. CONCLUSION(S): The risk of pregnancy after hysteroscopic sterilization may be reduced by strictly following the follow-up protocol, performing a urinary pregnancy test on the day of the procedure, and instructing the patient to return for the follow-up visit. A procedure with only a single device placement in a patient without a history of tubectomy of the heterolateral tube should be considered unsuccessful.

Immobilisation versus immediate mobilisation after intrauterine insemination: randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of 15 minutes of immobilisation versus immediate mobilisation after intrauterine insemination. DESIGN: Randomised controlled trial. Setting One academic teaching hospital and six non-academic teaching hospitals. PARTICIPANTS: Women having intrauterine insemination for unexplained, cervical factor, or male subfertility. INTERVENTIONS: 15 minutes of immobilisation or immediate mobilisation after insemination. MAIN OUTCOME MEASURE: Ongoing pregnancy per couple. RESULTS: 391 couples were randomised; 199 couples were allocated to 15 minutes of immobilisation after intrauterine insemination, and 192 couples were allocated to immediate mobilisation (control). The ongoing pregnancy rate per couple was significantly higher in the immobilisation group than in the control group: 27% (n=54) versus 18% (34); relative risk 1.5, 95% confidence interval 1.1 to 2.2 (crude difference in ongoing pregnancy rates: 9.4%, 1.2% to 17%). Live birth rates were 27% (53) in the immobilisation group and 17% (32) in the control group: relative risk 1.6, 1.1 to 2.4 (crude difference for live birth rates: 10%, 1.8% to 18%). In the immobilisation group, the ongoing pregnancy rates in the first, second, and third treatment cycles were 10%, 10%, and 7%. The corresponding rates in the mobilisation group were 7%, 5%, and 5%. CONCLUSION: In treatment with intrauterine insemination, 15 minutes' immobilisation after insemination is an effective modification. Immobilisation for 15 minutes should be offered to all women treated with intrauterine insemination. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53294431.