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Background We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1–2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. Methods This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18–59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. Findings Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744–2746) for the low-dose group, 2269 (1792–2873) for the medium-dose group, and 2895 (2294–3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85–135) in the low-dose group, 110 (87–140) in the medium-dose group, and 141 (111–179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836–11 815) in the low-dose group, 2338 (593–9226) in the medium-dose group, and 7069 (1361–36 725) in the high-dose group. Interpretation Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination. Funding Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Invasive disease due to group B Streptococcus infection (Streptococcus agalactiae) results in a wide spectrum of clinical disease. In North America, serotypes Ia, Ib, II, III, and V are most frequently associated with invasive disease. Group B Streptococcus remains a continued source of morbidity and mortality in high-risk populations, including pregnant women, neonates, and the elderly; an increasing incidence of invasive disease has been observed in non-pregnant adults. Group B Streptococcus remains the most common culture-confirmed neonatal bacterial infection in the United States and is a significant source of neonatal morbidity globally. Intrapartum antibiotic prophylaxis has reduced the incidence of early onset neonatal disease without a notable impact on the incidence of late onset neonatal disease. Penicillin G remains the mainstay of therapy although reduced penicillin susceptibility has been observed in select isolates. Increased frequency of resistance to non-beta-lactam antibiotics, including clindamycin, erythromycin, and fluoroquinolones, has been observed with some isolates demonstrating resistance to vancomycin. The development and implementation of strategies to identify hosts, treat judiciously with antimicrobials with the narrowest spectra, and prevent invasive disease, with vaccines, are essential to reduce the burden of group B Streptococcus disease.

Einleitung: Durch Datenlinkage ist es moglich unterschiedliche Datenquellen, z. B. Befragungsdaten mit Routinedaten der gesetzlichen Krankenversicherung (GKV) zusammenzufuhren, um von den jeweiligen Vorteilen zu profitieren. Da es sich dabei um personenbezogene Daten handelt, ist es notwendig, hierfur das Einverstandnis der betroffenen Personen einzuholen. Bisherige Untersuchungen legen nah, dass die Bereitschaft, diese Daten zu Forschungszwecken freizugeben, nicht uneingeschrankt vorhanden ist, was die Anzahl der Studienteilnehmer einschrankt und zu einem Selektionsbias fuhren kann. Ziel dieser Studie ist es, die Bereitschaft zur Datenzusammenfuhrung von Befragungsdaten mit Daten der GKV am Beispiel von Patientinnen und Patienten mit primarem Mammakarzinom zu untersuchen und Zusammenhange mit soziodemografischen Merkmalen aufzuzeigen. Methode: Im Rahmen der jahrlich stattfindenden Befragung von Patientinnen und Patienten mit primarem Mammakarzinom in den nach den Anforderungen des Landes Nordrhein-Westfalen zertifizierten Brustzentren wurden alle eingeschlossenen Patientinnen und Patienten hinsichtlich ihrer Bereitschaft zur Datenzusammenfuhrung befragt. Dabei wurde zwischen den Versicherten der AOK Rheinland/Hamburg und allen anderen Versicherten unterschieden: Aufgrund einer Kooperation mit der AOK Rheinland/Hamburg wurde von ihren Versicherten das tatsachliche Einverstandnis zur Datenzusammenfuhrung eingeholt. Alle anderen Patienten wurden nach ihrer Krankenkassenzugehorigkeit und ihrer generellen Einstellung zur Verknupfung ihrer Daten befragt. Ergebnisse: Insgesamt sind 2 387 Fragebogen zum Datenlinkage eingegangen. Dies entspricht einem Rucklauf von 49,3%. Die Zustimmungsquote liegt bei den Versicherten der AOK Rheinland/Hamburg bei 89,6%. Etwas geringer (75,7%) fallt die positive Einstellung zum hypothetischen Datenlinkage bei den Versicherten aller anderen Kassen aus. Unter der Annahme, dass alle Non-Responder ein Datelinkage ablehnen, liegt der Anteil, der dem Datenlinkage positiv gegenuber eingestellten Patientinnen bei immer noch 38,1%. Einen signifikanten Einfluss auf den Rucklauf hatten im Gesamtmodell die Krankenkassenzugehorigkeit (gesetzlich vs. privat) und die Muttersprache. Fur die tatsachliche Zustimmung konnten wir im multiplen Modell keine signifikanten Einflussfaktoren identifizieren. Schlussfolgerung: Bisher liegen nur wenige Daten zur Akzeptanz der Datenverknupfung bei akut erkrankten Patienten vor. Auch wenn sich die hier vorgestellten Ergebnisse lediglich auf Brustkrebspatientinnen beziehen, konnen sie Probleme und Chancen beim Datenlinkage aufzeigen.

Accurate determination of tissue concentration of ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) using T2 * MR relaxometry is still challenging. We present a reliable quantification method for local USPIO amount with the estimation of the liver specific relaxivity r2 * using monodisperse (59) Fe-core-labeled USPIO ((59) FeUSPIO). Dynamic and relaxometric in vivo characteristics of unlabeled monodisperse USPIO were determined in MRI at 3 T. The in vivo MR studies were performed for liver tissue with (59) FeUSPIO using iron dosages of 9 (n = 3), 18 (n = 2) and 27 (n = 3) µmol Fe kg(-1) body weight. The R2 * of the liver before and after USPIO injection (∆R2 *) was measured and correlated with (59) Fe activity measurements of excised organs by a whole body radioactivity counter (HAMCO) to define the dependency of ∆R2 * and (59) FeUSPIO liver concentration and calculate the r2 * of (59) FeUSPIO for the liver. Ultrastructural analysis of liver uptake was performed by histology and transmission electron microscopy. ∆R2 * of the liver revealed a dosage-dependent accumulation of (59) FeUSPIO with a percentage uptake of 70-88% of the injection dose. Hepatic ∆R2 * showed a dose-dependent linear correlation to (59) FeUSPIO activity measurements (r = 0.92) and an r2 * in the liver of 481 ± 74.9 mm(-1) s(-1) in comparison to an in vitro r2 * of 60.5 ± 3.3 mm(-1) s(-1) . Our results indicate that core-labeled (59) FeUSPIO can be used to quantify the local amount of USPIO and to estimate the liver-specific relaxivity r2 *.

Purpose To assess the feasibility of a 7 Tesla (T) MR cholangiopancreatography (MRCP) protocol to image the morphology and detect and intraindividually monitor pathological changes of the biliopancreatic tract in a mouse model of primary sclerosing cholangitis (PSC). Materials and Methods Six female Mdr2(Abcb)−/− mice, a well-established model of PSC, were imaged five times during weeks 10–19. Three wild-type controls were imaged at age 15 weeks. MRCP acquisition with three-dimensional fast recovery fast spin echo sequences (3D-FRFSE) was performed using three sequences with different resolutions, repetition times (TR), and with/without respiration-gating in a 7T preclinical MRI system. Image quality and visualization of five biliopancreatic structures were evaluated by three independent readers. Results Image quality was rated diagnostically sufficient in 86% of the datasets acquired without gating and in 100% for the respiration-gated sequences. Intrahepatic ducts were well visualized (≥97%) in Mdr2−/− mice. Stenoses and dilatations of the biliary ducts were intraindividually monitored. Progression and regression of bile duct pathologies were sufficiently assessed during the observation time. Conclusion High-quality respiration-gated MRCP of the Mdr2−/− PSC model at 7T allows for in vivo imaging of murine biliopancreatic tract and monitoring of bile duct pathologies, permitting longitudinal intraindividual studies in murine models of inflammatory bile duct diseases. J. Magn. Reson. Imaging 2014;40:1355–1364. © 2013 Wiley Periodicals, Inc.

A simple, fast, efficient, and widely applicable method to radiolabel the cores of monodisperse superparamagnetic iron oxide nanoparticles (SPIOs) with (59)Fe was developed. These cores can be used as precursors for a variety of functionalized nanodevices. A quality control using filtration techniques, size-exclusion chromatography, chemical degradation methods, transmission electron microscopy, and magnetic resonance imaging showed that the nanoparticles were stably labeled with (59)Fe. Furthermore, the particle structure and the magnetic properties of the SPIOs were unchanged. In a second approach, monodisperse SPIOs stabilized with (14)C-oleic acid were synthesized, and the stability of this shell labeling was studied. In proof of principle experiments, the (59)Fe-SPIOs coated with different shells to make them water-soluble were used to evaluate and compare in vivo pharmacokinetic parameters such as blood half-life. It could also be shown that our radiolabeled SPIOs embedded in recombinant lipoproteins can be used to quantify physiological processes in closer detail than hitherto possible. In vitro and in vivo experiments showed that the (59)Fe label is stable enough to be applied in vivo, whereas the (14)C label is rapidly removed from the iron core and is not adequate for in vivo studies. To obtain meaningful results in in vivo experiments, only (59)Fe-labeled SPIOs should be used.

Purpose: Magnetic particle imaging (MPI) is a new radiologic imaging modality. For the first time, a commercial preclinical scanner is installed. The goal of this study was to establish a workflow between MPI and magnetic resonance imaging (MRI) scanners for a complete in vivo examination of a mouse and to generate the first co-registered in vivo MR-MP images. Materials and Methods: The in vivo examination of five mice were performed on a preclinical MPI scanner and a 7 Tesla preclinical MRI system. MRI measurements were used for anatomical referencing and validation of the injection of superparamagnetic iron oxide (SPIO) particles during a dynamic MPI scan. We extracted MPI data of the injection phase and co-registered it with MRI data. Results: A workflow process for a combined in vivo MRI and MPI examination was established. A successful injection of ferucarbotran was proven in MPI and MRI. MR-MPI co-registration allocated the SPIOs in the inferior vena cava and the heart during and shortly after the injection. Conclusion: The acquisition of preclinical MPI and MRI data is feasible and allows the combined analysis of MR-MPI information. Key Points: • The first commercial preclinical MPI system was installed and has been tested successfully in an in vivo experiment. • This MPI system can detect SPIO in vivo in a mouse model. • First time performance of a combined in vivo MPI-MRI examination. • Co-registered MR-MPI allows high temporal resolution imaging of the vascular SPIO distribution. Citation Format: • Kaul MG., Weber O, Heinen U et al. Combined Preclinical Magnetic Particle Imaging and Magnetic Resonance Imaging: Initial Results in a Mouse. Fortschr Rontgenstr 2015; 187: 347 – 352

For the first time a commercial preclinical magnetic particle imaging scanner is available. It was our goal to organize a workflow between MPI and magnetic resonance imaging (MRI) and to generate the first fused MR-MP images.

The purpose of this study was to evaluate tumour response and toxicity to ifosfamide and continuous infusion etoposide in metastatic or locally advanced soft tissue sarcoma, with dose escalations under G-CSF (granulocyte colony-stimulating factor) support. Of 92 eligible patients (median age 51 years), 85% had tumours of high-grade malignancy and 82% had metastatic disease. Chemotherapy, the baseline dose, consisted of etoposide 600 mg/m2 as a 72 h infusion and ifosfamide 1500 mg/ m2/day for 3 days, followed by G-CSF support (VIG regimen). Stepwise 10% dose escalations were performed depending on haematological toxicity. For patients considered operable after induction chemotherapy, surgical resection of all identifiable residual tumour was attempted. Complete and partial response rates were 11% and 31%, for an overall response rate of 42% (95% CI 31-52%). Forty-eight per cent of courses were dose escalated by a median of 20%. Complete responders had significantly higher, and patients with progressive disease had significantly lower, dose levels than other patients. None of 20 patients with liver metastases responded despite high dose levels. Compared to a preceding pilot study, the addition of G-CSF led to significantly higher dose levels, improved schedule adherence and less haematological toxicity, but no apparent increase in response rate. In view of the modest dose of ifosfamide applied in this study, it is possible that the prolonged infusion of etoposide made a significant contribution to the regimen's antitumour activity, although this can only be determined definitively in a randomised study.

Superparamagnetic iron oxide nanoparticles (SPIO) can be used to image physiological processes and anatomical, cellular and molecular changes in diseases. The clinical applications range from the imaging of tumors and metastases in the liver, spleen and bone marrow, the imaging of lymph nodes and the CNS, MRA and perfusion imaging to atherosclerotic plaque and thrombosis imaging. New experimental approaches in molecular imaging describe undirected SPIO trapping (passive targeting) in inflammation, tumors and associated macrophages as well as the directed accumulation of SPIO ligands (active targeting) in tumor endothelia and tumor cells, areas of apoptosis, infarction, inflammation and degeneration in cardiovascular and neurological diseases, in atherosclerotic plaques or thrombi. The labeling of stem or immune cells allows the visualization of cell therapies or transplant rejections. The coupling of SPIO to ligands, radio- and/or chemotherapeutics, embedding in carrier systems or activatable smart sensor probes and their externally controlled focusing (physical targeting) enable molecular tumor therapies or the imaging of metabolic and enzymatic processes. Monodisperse SPIO with defined physicochemical and pharmacodynamic properties may improve SPIO-based MRI in the future and as targeted probes in diagnostic magnetic resonance (DMR) using chip-based µNMR may significantly expand the spectrum of in vitro analysis methods for biomarker, pathogens and tumor cells. Magnetic particle imaging (MPI) as a new imaging modality offers new applications for SPIO in cardiovascular, oncological, cellular and molecular diagnostics and therapy. Key Points: Citation Format

Background In spite of multimodular treatment, the therapeutic options for esophageal carcinoma are limited, and metastases remain the leading cause of tumor-related mortality. Expression of the chemokine receptor CXCR4 significantly correlates with poor survival rates in patients with esophageal carcinoma and is associated with lymph node and bone marrow metastases. The aim of this study was to evaluate the effect of the CXCR4 antagonist CTCE-9908 on metastatic homing and primary tumor growth in vitro and in vivo in an orthotopic xenograft model of esophageal cancer. Materials and methods OE19 cells were examined for stromal cell–derived factor 1 alpha–mediated migration under CTCE-9908 treatment. The CTCE-9908 treatment was further evaluated in an in vitro proliferation assay and orthotopic esophageal model, accompanied by magnetic resonance imaging. Tumor and metastases were immunohistochemically examined for CXCR4 expression. Results CTCE-9908 has an inhibitory effect on stromal cell–derived factor 1 alpha–mediated migration and proliferation of OE19 cells. Treatment with CTCE-9908 in the orthotopic esophageal model leads to a reduction of metastatic spread and primary tumor growth. This was confirmed by magnetic resonsance imaging. Treatment with CTCE-9908 results in altered CXCR4 expression pattern exhibiting a high degree of variability. Conclusion CTCE-9908 effectively inhibits OE19 cell migration and proliferation in vitro, reduces metastases to lung, liver, and lymph nodes in vivo, and moreover leads to tumor growth reduction in an orthotopic model of esophageal carcinoma.

Plasma levels of oestradiol (Oe2), oestrone (Oe1), oestrone sulphate (Oe1S), androstenedione, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), sex hormone-binding globulin (SHBG) and the gonadotrophins (FSH and LH) were determined in 20 postmenopausal women with breast cancer treated with the anti-oestrogen droloxifene (3-hydroxytamoxifen). Plasma oestrogens were measured before and after 3, 6 and 12 months of therapy. The other hormones were measured before and after 6 months of therapy. Droloxifene treatment had no significant influence on plasma levels of Oe2. Plasma levels of Oe1 and Oe1S increased during treatment (mean increase of 11·9-15·9% and 24·5–69·4% respectively after different time-intervals on treatment). The Oe1S/Oe1 and Oe1S/Oe2 ratios increased by mean values of 13·8–45·2% and 25·9–52·4% respectively. Plasma SHBG increased significantly by a mean value of 73·9%, while FSH and LH fell non-significantly by 19·7% and 20·4% respectively. Plasma levels of testosterone, androstenedione, DHEA and DHEAS all increased during treatment, but none of these alterations were of statistical significance. While the influence of droloxifene on plasma SHBG resembled that which is seen during treatment with tamoxifen, its influence on plasma oestrogens and the gonadotrophins seems to be different. Possible explanations of such differences and the clinical implications of alterations in plasma hormones during treatment with droloxifene are discussed. Journal of Endocrinology (1995) 146, 359–363

The influence of epidural block with bupivacaine (Marcaine-adrenalin) on fetal heart rate, uterine activity, and the frequency and intensity of contractions was studied in twenty-five nulliparae at term. Uterine activity was found to decrease during the first 30 minutes following epidural block. In the time interval 30 to 40 minutes after epidural block uterine activity increased again and attained the same level as during the last 10 minutes before analgesia. The frequency of uterine contractions did not decrease after the block. The lower levels of uterine contractility were due only to a lower amplitude of the contractions. The regularizing effect of epidural analgesia on incoordinate uterine action was noted. The recording of fetal heart rate in the time interval studied revealed no pathological findings. Mode of delivery, mean labour duration and Apgar scores after epidural block were comparable with earlier studies of a larger patient population. This study suggest that epidural analgesia does not induce any important changes in fetal heart rate but temporarily decreases uterine activity.

Lumbar epidural analgesia with bupivacaine was administered to 33 women for relief of pain during labor. At delivery blood samples were drawn from the umbilical cord vessels and from a maternal peripheral vein. Blood samples were also collected from the neonate and its mother, 1, 4, and 20 hours after delivery. Analyses of bupivacaine concentrations were carried out in all samples with a gas-chromatographic technique. The drug concentration in the umbilical vein (UV) was usually higher than the corresponding umbilical artery value (UA), but with increasing time interval between the last bupivacaine injection and delivery the UAUV drug concentration ratio rose. After delivery the rate of drug decline in blood was similar in mother and newborn infant. The clinical condition of the infant was unrelated to the drug concentration in the umbilical cord vessels.

Blood coagulation and fibrinolysis were studied in 20 premenopausal women undergoing abdominal hysterectomy under general anaesthesia (GA) or high epidural analgesia (EDA). As expected, the adrenocortical stress response was suppressed in the EDA group. The Factor VIII complex (F VIII:C, F VIII R:Ag = von Willebrand factor), known to be related to adrenocortical activity and/or vessel wall reactivity, was found to increase less in the EDA group. With regard to all the other variables analysed there were no significant differences between the groups. With both anaesthetic procedures activation of coagulation could be demonstrated by a decrease in prekallikrein, F X and antithrombin as well as by an increase in fibrinopeptide A levels. A decrease in plasminogen and alpha 2-antiplasmin suggested activation of the fibrinolytic system and a decrease in prekallikrein and kallikrein inhibition activity (C-1-esterase inhibitor) an activation of the kallikrein system. In this study only the differences in F VIII complex could explain the previously reported higher thromboembolic frequency after GA as compared to EDA.

Pethidine (100 mg) was administered i.m. to women in labor at different times before delivery. The interval before respiration in the newborn became sustained was shorter if pethidine was given less than one hour before delivery. The respiratory rate of the newborn increased after naloxone injection in 40 per cent of the cases, mostly when intrauterine exposure to pethidine exceeded one hour. The plasma concentrations of pethidine and norpethidine were measured in mother and newborn. The concentrations in the umbilical vein and artery indicted a continuous net transfer of pethidine from mother to fetus for approximately two hours. This correlated with the clinical finding of maximal neonatal depression 2-3 hours after maternal injection. The concentrations of norpethidine increased with a longer time interval between injection and delivery, but were probably too low to have any effect on the newborn. Neonatal depression seems to be related to the amount of unmetabolized pethidine that has been transferred from mother to fetus but not to norpethidine as had been suspected earlier.

Summary— In a randomised phase II study, 5 of 24 patients with metastatic renal carcinoma responded to treatment with interferon (IFN) (Roferon A, Roche, Basle, Switzerland) (18 times 106 u i.m. 3 times/week). The combination of IFN with vinblastine (0.1 mg/kg every third week) yielded a response rate of 16% (4 of 25 patients). Three patients continue to show a response (2 complete, 1 partial) more than 20 months after cessation of treatment. Flu-like symptoms represented the major side effect and often led to modification or discontinuation of treatment. It was concluded that IFN is the treatment of choice in patients with metastatic renal carcinoma who are candidates for medical treatment. The significance of additional vinblastine is uncertain.

Caesarean section was performed in 10 patients under general anaesthesia and in 10 other patients under epidural block. The foetal heart rate was monitored continuously during anaesthesia and operation with a scalp electrode and a cardio-tocograph. There was no major difference between the two anaesthetic techniques in their effect on the foetal heart rate. The most common finding was a reduction of the beat-to-beat variation. The operative time was longer in the epidural group than in the general anaesthesia group, due to a higher frequency of Pfannenstiel incisions and repeat caesarean sections in the epidural group. Clinically, all newborns seemed to be unaffected, with normal Apgar scores. Epidural block seems to be a good alternative to general anaesthesia for caesarean section, particularly when a long operative time is expected.

A case of arterio-venous fistula of the uterus is presented. The literature is reviewed and the etiology is discussed. Special attention should be paid to the occurrence of a previous pregnancy.

Twenty-four full-term nulliparae and their babies were studied. Twelve received lumbar epidural analgesia with bupivacaine (Marcain-adrenalinr`) and twelve conventional obstetrical analgesia with meperidine (Petidinr`), chlorpromazine (Hibernalr`), nitrous oxide and a pudendal nerve block with prilocaine (Citanestr`). The acid-base balance was determined in fetal and maternal blood during labour and in neonatal blood after birth. The newborn infants were placed in incubators after birth and several clinical parameters were recorded during the first two hours. Epidural analgesia to the mothers resulted in a lower degree of metabolic acidosis than conventional obstetrical analgesia. The clinical and blood-chemical parameters recorded in this study indicated no harmful effects on the newborn infants after epidural analgesia to the mothers.

Twelve healthy women received a pudendal block with 0.25% bupivacaine-adrenaline for uncomplicated vaginal delivery. Bupivacaine concentration in the newborn was low and about 25% of maternal concentration. Analgesia lasted about 4½ hours and no maternal or foetal side effects were noted.

Seventy-four patients with carcinoma in situ (CIS) of the vulva were followed over a 10-year period. The mean age was 52.8 years (range 21 to 90 years). Pruritus was the most common symptom. Forty per cent of the women were asymptomatic. Twenty-three per cent had a history of carcinoma in situ of the uterine cervix. Single lesions of CIS were found in the perineal area in 22 per cent, in the labia major and minor in 23 per cent, and in the clitoris in 7 per cent. Forty-two per cent of the patients had CIS in two or more of those areas. Seven of 74 patients (10%) had previously been irradiated for pelvic malignant tumours. Three women developed invasive squamous cell carcinoma of the vulva, two of them were previously irradiated. All 74 patients were treated surgically in different ways. Out of 38 women with histologically free margins of surgery, 6 had recurrence of dysplasia or CIS.

C-film, a 5 X 5 cm piece of water-soluble polyvinyl alcohol film, containing the spermicide nonylphenoxypolyethoxyethanol, was used as the sole contraceptive method by 237 women for 1866 months. 14 pregnancies occurred for a pregnancy rate of 9/100 woman-years. However, 11 of the women failed to use the method as instructed for a theoretical method failure rate of about 2/100 woman years. 156 women observed for 12 months or longer were analyzed by the life-table method. They showed an overall pregnancy rate of 6.5% and a continuation rate of 68.6%. Among the reasons for stopping were difficulty in applying the film properly, complaints about the sharp edges (especially if a package had been opened for a few weeks and air had come in contact with individual films,) and problems with inserting the interleaved silver foil as well as the film. Male insertion was tried but discontinued after reports of higher failure rates. C-film should not be offered as an alternative to oral contraception or IUDs but will increase the reliability of an IUD or condom and may be used alone to postpone pregnancy, for women approaching menopause, and where absolute protection against pregnancy is not required.

There were 44 young men who participated in strenuous combat courses of 4 d (course I) or 5 d (course II), almost without sleep. They were tested and examined clinically each morning. Groups 1 and 2 had no organized sleep, whereas groups 3 and 4 got 3 and 6 h, respectively, in the middle of each course. Substantial impairment was observed in all tests, as well as clinical symptoms toward the end of the courses for groups 1 and 2. In the vigilance test, the reaction time task, the code test, and the profile of mood-state, significant impairment was observed even after 24 h. Complaints of symptoms came first. Disturbance of senses and behaviour appeared later. Group 4 had significantly better results than groups 1 and 2 in clinical symptoms and all tests, except the positive score in mood-state. Group 3 occupied an intermediate position. Corresponding results were obtained in the two separate courses. In the morning following the course, recovery after 4 h of sleep was less extensive for courses II than course I participants.

Lumbar epiduval analgesia with bupivacaine was given to 37 women for uncomplicated labor. After the blcokade serial determinations of pH and bupivacaine concentration were made in fetal scalp blood and maternal venous blood and there was continuous monitoring of the fetal heart rate. Fetal scalp blood pH was within normal limits and no pathologic FHR tracings were elicited by the blockade, although a temporary decrease of the baseline fetal heart rate irregularity was seen in about one-fifth of the cases. Fetal drug concentrations were low and about one-fourth of corresponding maternal values. After reinjection of bupivacaine the degree of drug accumulation was fairly similar in fetal and maternal blood.

A report on 2 types of inert IUDs is presented. The characteristics and method of implantation of the Dalkon Shield and the Dalkon Shield Small are described. The Dalkon Shield was implanted in 198 patients, with a 1.6% frequency of expulsion, 1.1 frequency of gravidity, and an 82.4% continuation rate. The Dalkon Shield Small was implanted in 97 patients with a 0% frequency of expulsion, a 3.7% frequency of gravidity, and a 65.8% continuation rate.

Lumbar epidural block was given for pain relief to 296 women in labour. Bupivacaine was used as the analgesic agent and the technique is described in detail. Satisfactory analgesia was obtained in 92% of the cases during the first stage of labour and in 84% during the second stage of labour. The frequency of instrumental deliveries and of occipitio-posterior position increased but the clinical condition of the newborn seemed to be unaffected.

Thirty-three full-term nulliparae and their babies were studied. Twenty-one received lumbar epidural analgesia with bupivacaine (Marcain-adrenalinr`) and twelve conventional obstetrical analgesia with meperidine (Petidinr`), chlorpromazine (Hibernalr`), nitrous oxide and a pudendal nerve block with prilocaine (Citanestr`). Glucose, lactate, potassium, sodium, chloride, total protein, haemoglobin and haematocrit were determined in fetal and maternal blood during labour and in neonatal blood after birth. This study revealed a high level of plasma sodium in scalp blood of both ‘epidural’ and ‘control’ series probably related to water loss during labour. Furthermore, administration of epidural analgesia to women in labour resulted in lower lactate concentrations in these women and their babies compared with those receiving conventional obstetric analgesia.