Harnessing regulatory T cells to establish immune tolerance.

Engineered regulatory T (Treg) cells have emerged as precision therapeutics aimed at inducing immune tolerance while reducing the risks associated with generalized immunosuppression. This Viewpoint highlights the opportunities and challenges for engineered Treg cell therapies in treating autoimmune and other inflammatory diseases.

The value of ultrasound guidance during IUD insertion in women with RVF uterus: A randomized controlled trial.

OBJECTIVE: The study objective is to evaluate the benefits of using ultrasound guidance during insertion of Intrauterine device IUD in women with retroverted flexed RVF uteri. STUDY DESIGN: A randomized controlled trial conducted on 400 women with RVF uteri eligible for IUD insertion. They were randomly divided into 2 groups. Group 1 underwent IUD insertion under ultrasound guidance while in group 2 no ultrasound guidance was used. The primary outcome measure was the(Visual Analogue Scale) VAS pain score reported by the women during insertion. Other outcome included easiness of insertion, the procedure time and occurrence of complications as nausea, vomiting, abdominal cramps, failure of insertion, uterine perforation and bleeding. RESULTS: The VAS pain score was significantly lower (2.36 ± 1.77 vs. 4.74 ± 2.35, p < 0.001), the insertion was much easier (score 4.0 ± 0.9 vs. 2.5 ± 1.27, p < 0.001) and the time needed for the procedure was significantly shorter (5.82 ± 2.56 vs. 9.4 ± 4.99 min, p < 0.001) in women within the ultrasound guided group when compared to control group. The total rate of complications was significantly lower (6 vs. 16 %, p 0.001) especially bleeding (2 vs. 9%, p = 0.002), abdominal cramps (10.5 vs. 28 %, p 0.012) and failure of the procedure (0 vs. 3%, p = 005) in ultrasound guided group women when compared to control. CONCLUSION: Insertion of Intrauterine device IUD under ultrasound guidance in women with Retroverted flexed RVF uterus easier and less painful than the blind standard technique.

Improvements to the live-attenuated Newcastle disease virus vaccine using Carbopol® 940 as a stabilizer.

BACKGROUND AND AIM: One strategy that can be used to stabilize vaccines is to convert them into a dry powder. This can protect the integrity of the active ingredients as well as vaccine antigenicity during manufacture, storage, and transport. This study highlights the potent adjuvant activity of Carbopol® when used alone to stabilize live-attenuated Newcastle disease virus (NDV) vaccines or when used in a formulation together with skimmed milk. Tolerability and potency of these formulations were compared with those obtained from other local live NDV vaccines produced locally by the Veterinary Serum and Vaccine Research Institute. MATERIALS AND METHODS: We evaluated the cellular and humoral immune responses to a locally prepared, live-attenuated LaSota virus vaccine. Vaccine formulations were stabilized with Carbopol® 940 alone or in combination with skimmed milk. RESULTS: Our results indicate that the use of Carbopol® 940 alone to stabilize a live-attenuated LaSota vaccine resulted in enhanced cellular and humoral immunity. The antibody titer was prolonged through the 6th week post-vaccination (5.0 log2). Full (100%) protection was observed in response to challenge with very virulent NDV at day 21 after vaccination; there were no clinical signs or lesions on examination. Addition of Carbopol® 940 to the live-attenuated vaccine formulation resulted in a more compact, stable, and high-quality lyophilized cake after freeze-dried lyophilization compared with that produced by stabilization with skimmed milk alone. CONCLUSION: Our data suggest that Carbopol® 940 may improve clinical responses to live-attenuated vaccines.

Dermoscopy as a useful tool for evaluating melasma and assessing the response to 1064-nm Q-switched Nd:YAG laser.

Melasma is a hard-to-manage disorder with considerable relapsing behavior. Dermoscopy emerged to help in comprehensive evaluation of pigmentary disorders and melasma. The aim of the study was to evaluate the potential role of dermoscopy in assessing melasma and monitoring the efficacy of 1064-nm low-fluence Q-switched neodymium:yttrium-aluminum-garnet (QS Nd:YAG) laser. A total of 31 patients with facial melasma were included. A total of five laser sessions were performed with 2-week intervals. Patients were evaluated at baseline and 2 weeks after the last session (at the 10th week) by using digital photography, modified melasma area and severity index (mMASI), and colorimetry, as well as dermoscopic score for pigment and vascular elements. Adverse effects were reported. Postlaser sessions, mMASI scores as well as the colorimetric melanin and erythema indices had showed significant improvement. The "dermoscopic score of pigmentary and vascular elements" displayed significant change and confirmed the improvement. Side effects were tolerable. mMASI, colorimetry, and dermoscopy had ascertained the efficacy of low-fluence 1064-nm QS Nd:YAG laser in melasma; however, dermoscopy is superior to other assessments as it can help in the diagnosis of melasma besides the follow-up assessment and can precisely detect the detailed changes in response to treatment.

"Comparative study between the efficacy of fractional CO2 laser, Q-switched Nd:YAG laser (1064 nm), and both types in treatment of keratosis pilaris".

The aim of this study was to assess and compare the efficacy of fractional CO2 laser, Q-switched Nd:YAG laser (1064 nm), and their combined use in treatment of keratosis pilaris. The study included twenty female patients. For each patient, three areas were randomly assigned to treatment by either fractional CO2 laser (area A) or Q-switched laser (1064 nm) (area C), or both types of laser (area B). All patients were assessed by digital photography at baseline and 1 month after the last session. Assessment was done by two non-blinded and two blinded investigators (blinded investigators do not know which area is treated with which machine and non-blinded knows). Patients reported the degree of satisfaction or any adverse effects also after 1 month from the last session. The three treatment modalities led to overall improvement in the KP lesions. According to patients' score and investigator two, area B showed statistically significant improvement compared to areas A and C (p=0.001 and p=0.039, respectively). The first blinded investigators' assessment revealed that there was statistically significant improvement in area C compared to A and B (p = 0.023). The assessment of both investigator one and the second blinded investigator revealed that there was improvement in the three areas with no statistically significant difference between them. Both fractional CO2 and Q-switched Nd:YAG laser (1064 nm) proved to be safe and effective in the treatment of keratosis pilaris regarding not only pigmentation but also follicular prominence; their combination may have an additive effect.

Effect of laser-assisted zona thinning, during assisted reproduction, on pregnancy outcome in women with endometriosis: randomized controlled trial.

OBJECTIVE: To compare the ICSI-ET outcomes in patients with endometriosis with or without laser-assisted zona pellucida thinning. DESIGN: Randomized controlled trial. SETTING: The study was conducted in the Obstetrics & Gynecology Department, Cairo University hospital, and two private IVF centers in Cairo & Beni-Suif from July 2015 to January 2017 upon infertile and known endometriosis patients who planned to do ICSI-ET. INTERVENTIONS: Before randomization, all patients received the same ovarian stimulation preparation, oocyte retrieval procedures, and the same intracytoplasmic sperm injection procedures. After randomization, laser-assisted hatching was performed only for embryos of 158 patients, while the other group (n = 150) no laser-assisted hatching was made. The verification of pregnancy was achieved by the serum hCG concentration 14 days after the embryo transfer, and the clinical pregnancy was confirmed 2 weeks later by the presence of gestational sac with pulsating fetal pole on vaginal ultrasonography. MEASUREMENTS: The main outcome measures were the clinical pregnancy rate and the clinical implantation rate. MAIN RESULTS: Both groups were comparable with regard their baseline characteristics, baseline hormonal profile, the ovarian stimulation characteristics, and the ovulation characteristics. The mean number of embryos developed per patient and the mean transferred number of embryos per patient were comparable between groups (p value > 0.05). The implantation rate was significantly higher (p value 0.002) in the study group than the control group with an odds ratio of 1.86 (CI 95% 1.24-2.80) and NNT 13.81 (CI 95% 8.35-39.94). The clinical pregnancy rate, was significantly (p value 0.022) higher in the study group than in the control group with an odds ratio of 1.79 (CI 95% 1.05-3.06) and NNT 9.57 (CI 95% 5.03-98.99). CONCLUSION: That laser-assisted hatching by thinning of the zona pellucida may be a suitable method to improve the ICSI-ET outcomes, in term of the implantation and the pregnancy rates, in cases of endometriosis. CLINICAL TRIAL REGISTRATION: Pan African Clinical Trials Registry (PACTR), http://www.pactr.org/ATMWeb/appmanager/atm/atmregistry?dar=true&tNo=PACTR201502001022393 , PACTR201602001467322.

Diagnostic accuracy of posterior cervical angle and cervical length in the prediction of successful induction of labor.

OBJECTIVE: To determine the accuracy of the posterior cervical angle (PCA) compared with the cervical length and the Bishop score in predicting the outcome of induction of labor (IOL). METHODS: The present prospective observational study included IOL candidates who had their PCA and cervical length assessed by transvaginal ultrasonography and the Bishop score at the Obstetrics and Gynecology Department, Kasr El-Aini Hospital, Cairo University, Cairo, Egypt, between April 1 and July 31, 2017. The accuracy of these tests in predicting successful IOL (defined as vaginal delivery) was compared. RESULTS: The analysis included 49 women with successful IOL and 21 women with unsuccessful IOL. The suggested cutoffs for the prediction of successful IOL were a PCA of more than 99.5°, a cervical length of less than 34 mm, and a Bishop score of more than five. The areas under the receiver operating characteristics curves for these three measures were not significantly different. However, a PCA of more than 99.5° had the best sensitivity (91.84%), specificity (90.48), positive predictive value (95.7%), negative predictive value (82.6%), positive likelihood ratio (9.64), and negative likelihood ratio (0.09) compared with the other two predictors. CONCLUSION: A PCA of more than 99.5° yielded the best accuracy in predicting successful IOL compared with the cervical length and the Bishop score. CLINICALTRIALS.GOV: NCT03113227.

Cervical Priming by Vaginal or Oral Misoprostol Before Operative Hysteroscopy: A Double-Blind, Randomized Controlled Trial.

STUDY OBJECTIVE: To evaluate whether misoprostol oral is as effective as vaginal tablets for cervical ripening. DESIGN: Randomized controlled trial involving a parallel, double-blinded study (Canadian Task Force Classification IB). SETTING: Department of Obstetrics and Gynecology, Cairo University Hospital, between January 2014 and January 2016. PATIENTS: Patients undergoing operative hysteroscopy for various indications. INTERVENTIONS: At 12 hours before hysteroscopy, the oral group received a 400-µg misoprostol tablet and 2 vaginal starch tablets. The vaginal group received 400 µg of misoprostol and 2 oral starch tablets. The control group received 2 oral starch and 2 vaginal starch tablets as placebo. Preoperative preparation was the same in all patients. MEASUREMENTS AND MAIN RESULTS: The main outcome measures were width of the endocervical canal, ease of dilatation, time to dilatation, and adverse effects. All subjects eligible for operative hysteroscopy (n = 430) were invited to participate. Twenty subjects refused, and 20 subjects were excluded. The enrolled subjects (n = 390) were randomized to oral misoprostol, vaginal misoprostol, or placebo. The differences in mean width of the endocervical canal between the oral and the control groups (4.79 ± 1.07 mm vs 3.92 ± 0.92 mm), and also between the vaginal and the control groups (4.25 ± 0.71 mm vs 3.92 ± 0.92 mm) were significant (p < .001 for both). Moreover, the difference in mean width of the endocervical canal between the oral and the vaginal groups was significant (4.79 ± 1.07 mm vs 4.25 ± 0.71 mm; p = .009). Cervical entry was easier in the oral and vaginal groups compared with the control group (mean Likert score, 4.25 ± 0.64 vs 4.22 ± 0.74 vs 2.55 ± 0.87; p < .001). In addition, the ease of cervical entry did not differ significantly between the oral and vaginal groups (p = .998). The mean time to dilatation was shorter in the oral group and the vaginal group (compared with the control group (48.98 ± 12.6 seconds vs 46.55 ± 15.32 seconds vs 178.05 ± 74.18 seconds; p < .001), but the difference between the oral and vaginal groups was not significant (p = .987). Adverse effects were comparable between groups (p > .05). CONCLUSION: We found no statistically significant difference in the efficacy of cervical priming between oral misoprostol and vaginal misoprostol.

The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34(+) Cell Administration in Patients With Refractory Angina.

OBJECTIVES: This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34(+) cells would improve total exercise time (TET) and angina frequency in patients with refractory angina. BACKGROUND: IM administration of autologous CD34(+) cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials. METHODS: RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34(+) administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months. RESULTS: The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34(+) cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34(+)]). CONCLUSIONS: Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34(+) Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910).

Antagonist protocol versus clomiphene in unexplained infertility: A randomized controlled study.

OBJECTIVE: The primary purpose of this randomized controlled trial study was to compare clinical pregnancy rates and ovulation parameters in female patients of unexplained infertility undergoing intrauterine insemination (IUI) using an antagonist protocol versus a conventional clomiphene citrate protocol. MATERIALS AND METHODS: This was a multicenter parallel randomized controlled, open-label trial. A central randomization center used computer generated tables to allocate treatments. We conducted the study in two centers: Saudi Center and Samir Abbas and Assisted Reproductive Techniques Center of Cairo University, Cairo, Egypt between January 2011 and January 2014. Six hundred and twenty-two couples with unexplained infertility were randomized into two equal groups with 27 excluded after randomization: the antagonist protocol group and the clomiphene group. Antagonist protocol: human menopausal gonadotropins were given to 298 patients from Day 2 to reach a dominant follicle of 18-22 mm, intramuscularly. Then, orgalutrone (0.25 mg) was subcutaneously started from Day 6 or Day 7 until the day of human chorionic gonadotropins (hCG; that was given in the dose of 10,000 IU, intramuscularly) when follicles reached 18-22 mm. Afterward, the IUI of 0.5 mL was done from 34 hours to 36 hours using IUI catheter without guidance of ultrasonography and with an empty urinary bladder. The clomiphene citrate protocol was clomiphene citrate given 100 mg/d to 297 patients from Day 2 to Day 6 and follow up until day of hCG. The clinical pregnancy rate detected with ultrasound confirmed fetal heart pulsations at 6-weeks' gestation (4 weeks after IUI). The number of dominant follicles, level of serum estradiol, and luteinizing hormone at the day of hCG injection and the incidence of twin or triplet pregnancies in both groups were secondary outcome measures. RESULTS: The clinical pregnancy rate in the antagonist protocol group was significantly (p < 0.001) higher than in the clomiphene group. It was 80 patients (27%) in the antagonist protocol group versus 41 patients (14%) in the clomiphene group. The mean number of dominant follicles was significantly (p < 0.001) greater in the antagonist protocol group (4.36 ± 1.36 dominant follicles) compared with the clomiphene group (2.71 ± 0.96 dominant follicles). In addition, the rate of twin pregnancies was 15 cases in the antagonist protocol group versus six cases only in the clomiphene group (p = 0.047). The luteinizing hormone also was significantly lower in the antagonist group (2.1 ± 1.3) compared with that in the clomiphene group (9.5 ± 3.6). CONCLUSION: IUI clinical pregnancy rates were significantly higher by antagonist protocol.

Three-dimensional ultrasonography and power Doppler for discrimination between benign and malignant endometrium in premenopausal women with abnormal uterine bleeding.

BACKGROUND: Ultrasonography has been extensively used in women suspected of having a gynecological malignancy. The aim of this study is to evaluate the efficacy of 3D ultrasonography and power Doppler for discrimination between benign and malignant endometrium in premenopausal women with abnormal uterine bleeding. METHODS: This cross-sectional study included 78 premenopausal women with abnormal uterine bleeding scheduled for hysteroscopy and endometrial curettage. The endometrial thickness (ET), uterine artery pulsatility index (PI) and resistance index (RI), and endometrial volume (EV) and 3D power Doppler vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were measured and compared with hysteroscopic and histopathologic findings. RESULTS: The ET (P <0.001), EV (P <0.001), and endometrial VI (P <0.001) and VFI (P = 0.043) were significantly increased in patients with atypical endometrial hyperplasia and endometrial carcinoma (n = 10) than those with benign endometrium (n = 68); whereas, the uterine artery PI and RI and endometrial FI were not significantly different between the two groups. The best marker for discrimination between benign and malignant endometrium was the VI with an area under the ROC curve of 0.88 at a cutoff value of 0.81%. CONCLUSION: 3D ultrasonography and power Doppler, especially endometrial VI, may be useful for discrimination between benign and malignant endometrium in premenopausal women with abnormal uterine bleeding.

Delayed Start Versus Conventional GnRH Antagonist Protocol in Poor Responders Pretreated With Estradiol in Luteal Phase: A Randomized Controlled Trial.

OBJECTIVE: To compare the new delayed start protocol against the conventional gonadotropin (Gn)-releasing hormone antagonist protocol in poor responders (PORs). STUDY DESIGN: A total of 160 women with poor response to previous in vitro fertilization (IVF) cycle were randomized either to start Gn then Cetrotide 0.25 subcutaneously (sc) added when leading follicle (DF) reach >12 mm or Cetrotide 0.25 mg sc started first from day 2 to day 8 then Gn therapy was added and Cetrotide restarted when DF reach >12 mm. RESULTS: There was a statistically significant difference between conventional and delayed start protocols regarding the needed dose of Gn for stimulation (4368 ± 643 and 3798 ± 515), level of estradiol (E2; 778 ± 371 and 1076 ± 453), and endometrial thickness at human chorionic gonadotropin triggering (8.6 ± 1.8 and 9.8 ± 1.9), the number of DF (3.4 ± 1.5 and 4.9 ± 2.1), the number of retrieved follicles (2.4 ± 2.1 and 4.3 ± 2.5), and successful embryo transfer (13 vs 16), respectively (P < .05). There was a highly statistically significant difference between the 2 study groups regarding the number of oocytes fertilized (1.2 ± 2.0 vs 3.3 ± 1.4), metaphase II oocytes (0.9 ± 1.0 vs 2.7 + 1.6), and grade I embryos (0.7 ± 0.9 vs 2.1 + 1.1; P < .001). The chemical pregnancy, clinical pregnancy, and abortion rate showed a statistically significant difference between the 2 study groups (P value .003 and .006, respectively). CONCLUSION: Delayed start protocol significantly improved clinical pregnancy rate and IVF cycle parameters in PORs.

Studying navitoclax, a targeted anticancer drug, in healthy volunteers--ethical considerations and risk/benefit assessments and management.

BACKGROUND: Biopharmaceutical studies for anti-cancer drugs are typically conducted in cancer patients due to unacceptable toxicities to healthy volunteers. Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor that has been studied in cancer patients. METHODS: A strategy that integrated the evaluation of non-clinical toxicology data and clinical data in cancer patients was employed to assess the feasibility, determine doses and establish risk management plans for studying navitoclax in healthy volunteers. Two relative bioavailability/food effect studies with either a 25 mg dose or 50 and 100 mg doses of navitoclax were conducted sequentially in healthy female volunteers of non-childbearing potential. RESULTS/CONCLUSION: Navitoclax was well-tolerated in both studies in healthy volunteers, and did not impose risks beyond the minimal levels expected in healthy volunteer studies. Compared to a similar study in cancer patients, the studies in healthy volunteers generated higher quality data in a short period of time to support formulation selection.

Phase II clinical trial of CD34+ cell therapy to explore endpoint selection and timing in patients with critical limb ischemia.

BACKGROUND: A prior phase I/IIa clinical trial provided evidence for safety, feasibility and potential efficacy of i.m. injection of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ cells in patients with critical limb ischemia (CLI). METHODS AND RESULTS: A phase II trial of CD34+ cell therapy was conducted in patients with CLI to explore endpoint selection and timing. No-option CLI patients (n=11) underwent i.m. transplantation of G-CSF-mobilized CD34+ cells isolated by magnetic sorting. Ischemic rest pain scales improved from week 2 vs. baseline (P<0.05). Skin perfusion pressure (P=0.0175), transcutaneous partial oxygen pressure (P=0.0446) and pain-free walking distance (P=0.0056) improved from week 2, total walking distance from week 8 (P=0.0182) and toe brachial pressure index from week 12 (P=0.0174) vs. baseline. These parameters peaked at week 36 or 52. Rutherford's category improved from week 24 vs. baseline (P=0.0065). CLI-free ratio serially increased and peaked (85.7%) at week 36. Serial change in Rutherford's category correlated with that in Rest Pain Scale (P=0.0374), but not with that in any physiological parameters. CONCLUSIONS: Ischemic rest pain scales and physiological parameters improved relatively early after cell therapy, then plateaued later accompanied by recovery from the CLI state. Rutherford's category and CLI-free ratio at week 36 or later may be suitable endpoints in cell therapy clinical trials for CLI. Functional parameters should be evaluated independently of such clinical endpoints for ischemia severity. ( CLINICAL TRIAL REGISTRATION: URL: https://dbcentre3.jmacct.med.or.jp/jmactr/Default.aspx. Unique identifier: JMA-IIA00022)

A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study.

Preclinical trials indicate that CD34+ cells represent an effective angiogenic stem cell component. Early-phase clinical trials suggest that intramyocardial administration of autologous CD34+ cells may improve functional capacity and symptoms of angina. RENEW is a pivotal phase 3 trial designed to determine the efficacy of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ stem cells for the treatment for patients with refractory angina and chronic myocardial ischemia. Patients (n = 444) receiving maximally tolerated antianginal therapies and lacking conventional revascularization options with Canadian Cardiovascular Society class III or IV angina and ischemia on stress testing will be randomized 2:1:1 to cell therapy (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5) autologous CD34(+) cells/kg), active control (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial placebo injection), or open-label standard of care. The primary efficacy end point is change in exercise treadmill time in the treated vs active control patients, with 90% power to detect a 60-second difference in exercise time between cell-treated (n = 200) and active control (n = 100) patients. Key secondary end points include total number of anginal episodes per week and the incidence of independently adjudicated major adverse cardiac events and serious adverse events. RENEW will be the first adequately powered study aimed at definitively determining the efficacy of a cell therapy (intramyocardially delivered autologous CD34+ cells) for improvement of functional capacity in patients with refractory angina.

The evaluation and management of drug effects on cardiac conduction (PR and QRS intervals) in clinical development.

Recent advances in electrocardiographic monitoring and waveform analysis have significantly improved the ability to detect drug-induced changes in cardiac repolarization manifested as changes in the QT/corrected QT interval. These advances have also improved the ability to detect drug-induced changes in cardiac conduction. This White Paper summarizes current opinion, reached by consensus among experts at the Cardiac Safety Research Consortium, on the assessment of electrocardiogram-based safety measurements of the PR and QRS intervals, representing atrioventricular and ventricular conduction, respectively, during drug development.

A simple and relatively painless technique for hysterosalpingography, using a thin catheter and closing the cervix with the vaginal speculum: a pilot study.

OBJECTIVE: To evaluate the use of a thin catheter for hysterosalpingography (HSG) for reducing the pain experienced during the procedure. METHODS: Infertile women undergoing tubal patency tests were randomised into two groups. In the study group (n=66) a thin catheter originally designed for intrauterine insemination was used to inject the dye. Leakage of the dye was prevented using a vaginal speculum to press on the portiovaginalis of the cervix. The control group (n=23) underwent HSG using the standard metal cannula. Visual analogue scale (VAS) was used to evaluate the level of pain immediately after the procedure. The main outcome measures were the level of pain experienced by the patient during the procedure and the efficacy of the new technique. RESULTS: The mean (±SD) VAS was 11.2±3.1 in the study group and 54.7±10.1 in the metal cannula group (p<0.0001). During the dye injection, the VAS was 10.3±5.2 in the study group compared to 64.1±17.3 in the metal cannula group (p<0.0001). The new technique was successful in filling the uterine cavity with the dye and studying the fallopian tubes. CONCLUSIONS: Using a thin catheter for HSG and pressing on the cervix with the vaginal speculum to prevent leakage of the dye is a successful method to study the uterine cavity and fallopian tubes, and it significantly reduces the pain as compared to a metal cannula.

Evaluation of ventricular arrhythmias in early clinical pharmacology trials and potential consequences for later development.

This white paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of ventricular arrhythmias in early clinical pharmacology trials and their potential consequences for later clinical drug development. Ventricular arrhythmias are infrequent but potentially important medical events whose occurrence in early clinical pharmacology trials can dramatically increase safety concerns. Given the increasing concern with all potential safety signals and the resultant more extensive electrocardiographic monitoring of subjects participating in early phase trials, an important question must be addressed: Are relatively more frequent observations of ventricular arrhythmias related simply to more extensive monitoring, or are they genuinely related to the drug under development? The discussions in this paper provide current thinking and suggestions for addressing this question.