Real-world experience with the IUB Ballerine MIDI copper IUD: an observational study in the French-speaking region of Switzerland.

Objective: The aim of the study was to assess the acceptability of the intrauterine ball IUB Ballerine MIDI copper intrauterine device (IUD), using real-world data collected from users and physicians. Methods: In this retrospective, observational study, conducted in the French-speaking region of Switzerland, healthy women (n= 207) who had had an IUB Ballerine MIDI inserted ≥12 months before enrolment, and their physicians completed questionnaires relating to device insertion, user experience and outcome. Questions relating to current menstrual patterns, physical comfort and product satisfaction were only posed to women still using the device. Results: The mean age at insertion was 30.8 ± 7.2 years, with an average 14.2 ± 2.9 month lapse from time of insertion until study commencement. At the time of the study, 140 (67.6%) women were still using the device. The expulsion rate was 5.3% (n= 11) and the pregnancy rate was 1.4% (n= 3). Most of the women still using the device reported no to moderate pain or cramps (80.7%). The majority of women reported moderate to high (65.7%) satisfaction with the device, with 81.4% claiming they would recommend it to friends and relatives. Over 84.8% of physicians reported that the device was easy to insert, with no difficulties encountered during the procedure. Conclusions: The IUB Ballerine MIDI was demonstrated to be safe and acceptable in different clinical settings and risk groups among a socioeconomically and demographically diverse study population.

Barriers to Cervical Cancer Screening in Geneva (DEPIST Study).

OBJECTIVES: Cervical screening is only efficient if a large part of eligible women participate. Our aim was to identify sociodemographic barriers to cervical screening and consider self-reported reasons to postpone screening. METHODS: Between September 2011 and June 2015, a questionnaire addressing reasons for nonparticipation in cervical screening was completed by 556 women who had not undergone a Pap test in the preceding 3 years. Pearson χ test was used to analyze differences between subgroups. Logistic regression was used to explore the association between sociodemographic characteristics and reasons for nonparticipation. RESULTS: The main reasons for nonparticipation in cervical cancer screening were practical barriers, such as lack of time and the cost of screening. These barriers were more likely to be reported by working women, women who were not sexually active, and those without health insurance. Younger women, non-European women living in Switzerland, and childless women were more likely to have never participated in a screening program before (adjusted odds ratio [aOR], 3.15; 95% CI, 1.41-6.98; aOR, 2.76; 95% CI, 1.48-5.16; aOR, 1.74; 95% CI, 1.03-2.99, respectively). CONCLUSIONS: Practical considerations seem to play a more important role in screening participation than emotional reasons and other beliefs. Particular attention should be paid to immigrant communities, where women seem more likely to skip cervical screening.

Feasibility of at-home self-sampling for HPV testing as an appropriate screening strategy for nonparticipants in Switzerland: preliminary results of the DEPIST study.

OBJECTIVE: Nonattendees to cervical cancer screening are at a higher risk of developing cervical cancer. This study assessed women's willingness to perform a home-based self-sampling for human papillomavirus testing (Self-HPV) and explored the feasibility of establishing a home-based Self-HPV screening strategy in Switzerland. MATERIALS AND METHODS: Underscreened women (n = 158) who had not underwent a Pap test in the preceding 3 years were recruited between September 2011 and September 2013. Participants completed 2 questionnaires evaluating reasons for non-attendance at a screening program, sociodemographic issues, and satisfaction with and acceptability of the Self-HPV. Descriptive data and multivariate logistic regression were used to identify variables associated with women's willingness to perform at-home self-sampling for HPV testing. RESULTS: Lack of time because of work or childcare was the most common reason for nonattendance at a screening program. One hundred six women (82%) preferred the Self-HPV because it is easy to perform, convenient, comfortable, and private. Women were more likely to accept the Self-HPV as a future screening strategy if they had missed cervical cancer screening in the past because of lack of time (odds ratio [OR] = 6.2, 95% confidence interval [CI] = 1.6-23.6; p < .01). Twenty-six women felt pain during self-sampling. Previous negative experiences with screening and stress during sampling were associated with higher risk for pain (OR = 7.14, 95% CI = 2.0-25.3, p < .01 and OR = 4.73, 95% CI = 1.5-14.5, p < .01, respectively). CONCLUSIONS: The Self-HPV was accepted by nonattendees of cervical cancer screening programs. Self-sampling may promote screening among the unscreened and underscreened population of women in Switzerland while overcoming some practical barriers.

Radiosurgery with the world's first fully robotized Leksell Gamma Knife PerfeXion in clinical use: a 200-patient prospective, randomized, controlled comparison with the Gamma Knife 4C.

OBJECTIVE: The world's first Leksell Gamma Knife PerfeXion (Elekta Instrument AB, Stockholm, Sweden) for radiosurgery of the head and neck became operational at Timone University Hospital in Marseille on July 10, 2006. To allow strict evaluation of the capabilities, advantages, disadvantages, and limitations of this new technology, patients were enrolled in a prospective, randomized trial. METHODS: In 66 working days, between July 10 and December 20, 2006, 363 patients were treated by gamma knife surgery at Timone University Hospital, Marseille. Of these patients, 200 were eligible for the comparative prospective study (inclusion criteria were informed consent obtained, tumor or vascular indication, and no previous radiosurgery or radiotherapy). In accordance with the blinded randomization process, 100 patients were treated with the Leksell Gamma Knife 4C (Elekta Instrument AB) and Gamma Knife 100 (Elekta Instrument AB) with the Leksell Gamma Knife PerfeXion. Dose planning parameters, dosimetry measurements on the patient's body, workflow, patient comfort, quality assurance procedure, and a series of other treatment-related parameters were systematically and prospectively evaluated in both arms of the trial. RESULTS: No technical failure of the treatment procedure was encountered. The new dose-planning system led to the use of composite shots in 39.4% of the patients. The median number of different collimator sizes used was larger with the PerfeXion than with the 4C (2 and 1, respectively). The mean number of isocenters used was lower (10.67 and 13.08, respectively). The median total treatment time was significantly shorter with the PerfeXion (40 and 60 minutes, respectively), but there was no significant difference in the median radiation time (34.02 and 33.40 minutes, respectively). The procedure was performed using only a single run in 98.99% of the PerfeXion cases and in 42% of the 4C cases. Collision risk on the 4C forced us to change the frame gamma angle for at least 1 shot in 24% of the patients and led to treatment in manual mode for at least 1 shot in 21% of the patients. Collision risk requiring technical adaptation did not occur with the PerfeXion. In 1 patient treated with the PerfeXion, the system required a direct collision check. In terms of dose to structures outside the target area, the PerfeXion delivers 8.2 times less to the vertex, 10 times less to the thyroid, 12.9 times less to the sternum, and 15 times less to the gonads. CONCLUSION: Our prospective study indicates that procedures with the PerfeXion were collision-free, even with very eccentric lesions (e.g., multiple metastases). The duration of the surgical procedure, the amount of time required for nurse, physicist, and physician intervention on the machine, and the duration of the quality assurance procedure were all shown to be dramatically reduced with the PerfeXion gamma knife. Patient protection is greatly improved with the PerfeXion. In our experience, the technological advances of the Leksell Gamma Knife PerfeXion will make a very significant contribution to future progress in head and neck radiosurgery.

The role of TNF-related activation-induced cytokine-receptor activating NF-kappa B interaction in acute allograft rejection and CD40L-independent chronic allograft rejection.

We analyzed the role of TNF-related activation-induced cytokine (TRANCE), a member of the TNF family expressed on activated T cells that shares functional properties with CD40L, and its receptor-activating NF-kappaB (RANK) which is mostly expressed on mature dendritic cells, during allogenic responses in vivo using a rodent heart allograft model. TRANCE mRNA was strongly up-regulated in acutely rejected allografts on days 4 and 5 posttransplantation whereas RANK was detected as early as day 1 but did not show further up-regulation during the first week. Immunofluoresence analyses of heart allografts showed that 80 and 100% of TRANCE and RANK-expressing cells were T cells and APCs, respectively. We show for the first time that short-term TRANCE blockade using a mouse RANKIg fusion molecule can significantly prolong heart allograft survival in both rat and mouse models. Similarly, rat heart allografts transduced with a RANKIg encoding recombinant adenovirus exhibited a significant prolongation of survival (14.3 vs 7.6 days, p < 0.0001). However, TRANCE blockade using RANKIg did not appear to inhibit allogeneic T and B cell priming humoral responses against RANKIg. Interestingly, TRANCE blockade induced strong up-regulation of CD40 ligand (CD40L) mRNA in allografts. Combined CD40L and TRANCE blockade resulted in significantly decreased chronic allograft rejection lesions as well as allogeneic humoral responses compared with CD40L blockade alone. We conclude that TRANCE-RANK interactions play an important role during acute allograft rejection and that CD40L-independent allogeneic immune responses can be, at least in part, dependent on the TRANCE pathway of costimulation.

CTLA4Ig adenoviral gene transfer induces long-term islet rat allograft survival, without tolerance, after systemic but not local intragraft expression.

Genetic engineering using recombinant adenoviruses offers an opportunity to modify islet grafts in order to prevent allograft rejection. We have used an adenovirus coding for CTLA4Ig to compare its efficacy in preventing islet rejection depending on local or systemic production after gene transfer either into the islets or intramuscularly, respectively. Islet allograft survival was also evaluated using recombinant CTLA4Ig administered intraperitoneally or incubated ex vivo with islets prior to transplantation. Transduction of islets with 10(3) or 10(4) plaque-forming units (pfu) per islets of AdCTLA4Ig prolonged islet survival (mean +/- standard deviation [SD] days = 19.5 +/- 5.8 and 19.5 +/- 5.6, respectively, vs. 10.6 +/- 2.4 in control islets, p < 0.001), with low levels of circulating CTLA4Ig. In contrast, long-term survival (>60 days) was obtained after intramuscular injection of AdCTLA4Ig that resulted in sustained high levels of circulating CTLA4Ig. Islets incubated in vitro with CTLA4Ig did not show prolonged survival (10.3 +/- 2.5 days). Graft rejection was delayed after one injection of CTLA4Ig (23 +/- 7.6 days, p < 0.003 vs. control). Recipients of long-term surviving grafts after intramuscular AdCTLA4Ig gene transfer were not tolerant because second islet grafts of donor origin were rejected. These recipients also had a strong inhibition of humoral responses against nominal antigens, whereas animals receiving transduced islets showed normal responses. These data demonstrate that local production of CTLA4Ig after gene transfer was as efficient as a single injection of CTLA4Ig in preventing graft rejection. Furthermore, intramuscular gene transfer of CTLA4Ig was the most efficient way to induce long-term islet graft survival but no donor-specific tolerance was induced.

Active suppression of allogeneic proliferative responses by dendritic cells after induction of long-term allograft survival by CTLA4Ig.

Costimulatory blockade using cytotoxic T lymphocyte-associated antigen 4 immunoglobulin (CTLA4Ig) efficiently down-regulates immune responses in animal models and is currently used in autoimmune and transplantation clinical trials, but the precise cellular and molecular mechanisms involved remain unclear. Rats that received allogeneic heart transplants and were treated with adenoviruses coding for CTLA4Ig show long-term allograft survival. The immune mechanisms regulating induction of long-term allograft acceptance were analyzed in splenocytes using mixed leukocyte reactions (MLRs). MLRs of splenocytes but not purified T cells from CTLA4Ig-treated rats showed higher than 75% inhibition compared with controls. Splenocytes from CTLA4Ig-treated rats inhibited proliferation of naive and allogeneically primed splenocytes or T cells. MLR suppression was dependent on soluble secreted product(s). Production of soluble inhibitory product(s) was triggered by a donor antigen-specific stimulation and inhibited proliferation in an antigen-nonspecific manner. CTLA4Ig levels in the culture supernatant were undetectable and neither interleukin-10 (IL-10), transforming growth factor beta 1 (TGF beta 1), IL-4, nor IL-13 were responsible for suppression of MLRs. Inhibition of nitric oxide (NO) production or addition of IL-2 could not restore proliferation independently, but the combined treatment synergistically induced proliferation comparable with controls. Stimulation of APCs using tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) or CD40L and addition of IL-2 normalized MLRs of CTLA4Ig-treated splenocytes. Finally, dendritic cells (DCs), but not T cells, from CTLA4Ig-treated rats inhibited naive MLRs. Altogether, these results provide evidence that after in vivo CTLA4Ig treatment, splenocytes, and in particular DCs, can inhibit alloantigen-induced proliferative responses through secretion of inhibitory products, thus promoting alloantigen-specific tolerance in vivo.

Heteroplasmy analysis in the Polish patients with 11778A mutation responsible for Leber hereditary optic neuropathy.

We have analysed the heteroplasmy level in 11 individuals from 3 families harbouring the mitochondrial 11778A mutation responsible for Leber hereditary optic neuropathy using last cycle hot PCR. The mutation level exceeded 90% both in affected and in unaffected individuals. We also checked whether any of the families belonged to the J haplogroup of mitochondrial DNA and obtained a negative result.

Prolonged blockade of CD40-CD40 ligand interactions by gene transfer of CD40Ig results in long-term heart allograft survival and donor-specific hyporesponsiveness, but does not prevent chronic rejection.

Previous work on blockade of CD40-CD40 ligand interaction in mice and primates with anti-CD40 ligand mAbs has resulted in a moderate prolongation of allograft survival without the development of true allograft tolerance. In this study, we show in rats that adenovirus-mediated gene transfer of CD40Ig sequences into the graft resulted in prolonged (>200 days) expression of CD40Ig and in long-term (>300 days) survival. Recipients expressing CD40Ig displayed strongly (>90%) inhibited mixed leukocyte reactions and alloantibody production at early (days 5 and 17) and late time points (>100 day) after transplantation, but showed limited inhibition of leukocyte infiltration and cytokine production as evaluated by immunohistology at early time points (day 5). Recipients of long-surviving hearts showed donor-specific hyporesponsiveness since acceptance of second cardiac allografts was donor specific. Nevertheless, long-term allografts (>100 days) displayed signs of chronic rejection vasculopathy. Occluded vessels showed leukocyte infiltration, mainly composed of CD4(+) and CD8(+) cells, macrophages, and mast cells. These recipients also showed antidonor CTL activity. Recipients expressing CD40Ig did not show nonspecific immunosuppression, as they were able to mount anticognate immune responses that were partially inhibited at early time points and were normal thereafter. We conclude that gene transfer-mediated expression of CD40Ig resulted in a highly efficient inhibition of acute heart allograft rejection in rats. This treatment induced donor-specific inhibition of certain alloreactive mechanisms in the short-, but not the long-term, which resulted in long-term survival of allografts concomitant with the development of chronic rejection.