Clinical outcomes of uninterrupted embryo culture with or without time-lapse-based embryo selection versus interrupted standard culture (SelecTIMO): a three-armed, multicentre, double-blind, randomised controlled trial.

BACKGROUND: Time-lapse monitoring is increasingly used in fertility laboratories to culture and select embryos for transfer. This method is offered to couples with the promise of improving pregnancy chances, even though there is currently insufficient evidence for superior clinical results. We aimed to evaluate whether a potential improvement by time-lapse monitoring is caused by the time-lapse-based embryo selection method itself or the uninterrupted culture environment that is part of the system. METHODS: In this three-armed, multicentre, double-blind, randomised controlled trial, couples undergoing in-vitro fertilisation or intracytoplasmic sperm injection were recruited from 15 fertility clinics in the Netherlands and randomly assigned using a web-based, computerised randomisation service to one of three groups. Couples and physicians were masked to treatment group, but embryologists and laboratory technicians could not be. The time-lapse early embryo viability assessment (EEVA; TLE) group received embryo selection based on the EEVA time-lapse selection method and uninterrupted culture. The time-lapse routine (TLR) group received routine embryo selection and uninterrupted culture. The control group received routine embryo selection and interrupted culture. The co-primary endpoints were the cumulative ongoing pregnancy rate within 12 months in all women and the ongoing pregnancy rate after fresh single embryo transfer in a good prognosis population. Analysis was by intention to treat. This trial is registered on the ICTRP Search Portal, NTR5423, and is closed to new participants. FINDINGS: 1731 couples were randomly assigned between June 15, 2017, and March 31, 2020 (577 to the TLE group, 579 to the TLR group, and 575 to the control group). The 12-month cumulative ongoing pregnancy rate did not differ significantly between the three groups: 50·8% (293 of 577) in the TLE group, 50·9% (295 of 579) in the TLR group, and 49·4% (284 of 575) in the control group (p=0·85). The ongoing pregnancy rates after fresh single embryo transfer in a good prognosis population were 38·2% (125 of 327) in the TLE group, 36·8% (119 of 323) in the TLR group, and 37·8% (123 of 325) in the control group (p=0·90). Ten serious adverse events were reported (five TLE, four TLR, and one in the control group), which were not related to study procedures. INTERPRETATION: Neither time-lapse-based embryo selection using the EEVA test nor uninterrupted culture conditions in a time-lapse incubator improved clinical outcomes compared with routine methods. Widespread application of time-lapse monitoring for fertility treatments with the promise of improved results should be questioned. FUNDING: Health Care Efficiency Research programme from Netherlands Organisation for Health Research and Development and Merck.

Economic evaluation of endometrial scratching before the second IVF/ICSI treatment: a cost-effectiveness analysis of a randomized controlled trial (SCRaTCH trial).

STUDY QUESTION: Is a single endometrial scratch prior to the second fresh IVF/ICSI treatment cost-effective compared to no scratch, when evaluated over a 12-month follow-up period? SUMMARY ANSWER: The incremental cost-effectiveness ratio (ICER) for an endometrial scratch was €6524 per additional live birth, but due to uncertainty regarding the increase in live birth rate this has to be interpreted with caution. WHAT IS KNOWN ALREADY: Endometrial scratching is thought to improve the chances of success in couples with previously failed embryo implantation in IVF/ICSI treatment. It has been widely implemented in daily practice, despite the lack of conclusive evidence of its effectiveness and without investigating whether scratching allows for a cost-effective method to reduce the number of IVF/ICSI cycles needed to achieve a live birth. STUDY DESIGN, SIZE, DURATION: This economic evaluation is based on a multicentre randomized controlled trial carried out in the Netherlands (SCRaTCH trial) that compared a single scratch prior to the second IVF/ICSI treatment with no scratch in couples with a failed full first IVF/ICSI cycle. Follow-up was 12 months after randomization.Economic evaluation was performed from a healthcare and societal perspective by taking both direct medical costs and lost productivity costs into account. It was performed for the primary outcome of biochemical pregnancy leading to live birth after 12 months of follow-up as well as the secondary outcome of live birth after the second fresh IVF/ICSI treatment (i.e. the first after randomization). To allow for worldwide interpretation of the data, cost level scenario analysis and sensitivity analysis was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: From January 2016 until July 2018, 933 women with a failed first IVF/ICSI cycle were included in the trial. Data on treatment and pregnancy were recorded up until 12 months after randomization, and the resulting live birth outcomes (even if after 12 months) were also recorded.Total costs were calculated for the second fresh IVF/ICSI treatment and for the full 12 month period for each participant. We included costs of all treatments, medication, complications and lost productivity costs. Cost-effectiveness analysis was carried out by calculating ICERs for scratch compared to control. Bootstrap resampling was used to estimate the uncertainty around cost and effect differences and ICERs. In the sensitivity and scenario analyses, various unit costs for a single scratch were introduced, amongst them, unit costs as they apply for the United Kingdom (UK). MAIN RESULTS AND THE ROLE OF CHANCE: More live births occurred in the scratch group, but this also came with increased costs over a 12-month period. The estimated chance of a live birth after 12 months of follow-up was 44.1% in the scratch group compared to 39.3% in the control group (risk difference 4.8%, 95% CI -1.6% to +11.2%). The mean costs were on average €283 (95% CI: -€299 to €810) higher in the scratch group so that the point average ICER was €5846 per additional live birth. The ICER estimate was surrounded with a high level of uncertainty, as indicated by the fact that the cost-effectiveness acceptability curve (CEAC) showed that there is an 80% chance that endometrial scratching is cost-effective if society is willing to pay ∼€17 500 for each additional live birth. LIMITATIONS, REASONS FOR CAUTION: There was a high uncertainty surrounding the effects, mainly in the clinical effect, i.e. the difference in the chance of live birth, which meant that a single straightforward conclusion could not be ascertained as for now. WIDER IMPLICATIONS OF THE FINDINGS: This is the first formal cost-effectiveness analysis of endometrial scratching in women undergoing IVF/ICSI treatment. The results presented in this manuscript cannot provide a clear-cut expenditure for one additional birth, but they do allow for estimating costs per additional live birth in different scenarios once the clinical effectiveness of scratching is known. As the SCRaTCH trial was the only trial with a follow-up of 12 months, it allows for the most complete estimation of costs to date. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organization for funding healthcare research. A.E.P.C., F.J.M.B., E.R.G. and C.B. L. reported having received fees or grants during, but outside of, this trial. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL5193/NTR 5342).

Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH).

STUDY QUESTION: Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/111 for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI). LIMITATIONS, REASONS FOR CAUTION: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organisation for funding healthcare research. J.S.E. Laven reports grants and personal fees from AnshLabs (Webster, Tx, USA), Ferring (Hoofddorp, The Netherlands) and Ministry of Health (CIBG, The Hague, The Netherlands) outside the submitted work. A.E.P. Cantineau reports 'other' from Ferring BV, personal fees from Up to date Hyperthecosis, 'other' from Theramex BV, outside the submitted work. E.R. Groenewoud reports grants from Titus Health Care during the conduct of the study. A.M. van Heusden reports personal fees from Merck Serono, personal fees from Ferring, personal fees from Goodlife, outside the submitted work. F.J.M. Broekmans reports personal fees as Member of the external advisory board for Ferring BV, The Netherlands, personal fees as Member of the external advisory board for Merck Serono, The Netherlands, personal fees as Member of the external advisory for Gedeon Richter, Belgium, personal fees from Educational activities for Ferring BV, The Netherlands, grants from Research support grant Merck Serono, grants from Research support grant Ferring, personal fees from Advisory and consultancy work Roche, outside the submitted work. C.B. Lambalk reports grants from Ferring, grants from Merck, grants from Guerbet, outside the submitted work. TRIAL REGISTRATION NUMBER: Registered in the Netherlands Trial Register (NL5193/NTR 5342). TRIAL REGISTRATION DATE: 31 July 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2016.

Endometrial scratching in women with implantation failure after a first IVF/ICSI cycle; does it lead to a higher live birth rate? The SCRaTCH study: a randomized controlled trial (NTR 5342).

BACKGROUND: Success rates of assisted reproductive techniques (ART) are approximately 30%, with the most important limiting factor being embryo implantation. Mechanical endometrial injury, also called 'scratching', has been proposed to positively affect the chance of implantation after embryo transfer, but the currently available evidence is not yet conclusive. The primary aim of this study is to determine the effect of endometrial scratching prior to a second fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle on live birth rates in women with a failed first IVF/ICSI cycle. METHOD: Multicenter randomized controlled trial in Dutch academic and non-academic hospitals. A total of 900 women will be included of whom half will undergo an endometrial scratch in the luteal phase of the cycle prior to controlled ovarian hyperstimulation using an endometrial biopsy catheter. The primary endpoint is the live birth rate after the 2nd fresh IVF/ICSI cycle. Secondary endpoints are costs, cumulative live birth rate (after the full 2nd IVF/ICSI cycle and over 12 months of follow-up); clinical and ongoing pregnancy rate; multiple pregnancy rate; miscarriage rate and endometrial tissue parameters associated with implantation failure. DISCUSSION: Multiple studies have been performed to investigate the effect of endometrial scratching on live birth rates in women undergoing IVF/ICSI cycles. Due to heterogeneity in both the method and population being scratched, it remains unclear which group of women will benefit from the procedure. The SCRaTCH trial proposed here aims to investigate the effect of endometrial scratching prior to controlled ovarian hyperstimulation in a large group of women undergoing a second IVF/ICSI cycle. TRIAL REGISTRATION: NTR 5342 , registered July 31st, 2015. PROTOCOL VERSION: Version 4.10, January 4th, 2017.

Health-related quality of life in women with newly diagnosed polycystic ovary syndrome randomized between clomifene citrate plus metformin or clomifene citrate plus placebo.

STUDY QUESTION: What is the health-related quality of life (HRQoL) in women with polycystic ovary syndrome (PCOS) undergoing ovulation induction with clomifene citrate (CC) combined with metformin compared with those using CC combined with placebo? SUMMARY ANSWER: Overall quality of life in women with PCOS treated with CC plus metformin was significantly lower than in women treated with CC plus placebo. WHAT IS KNOWN ALREADY: There are no data on HRQoL in adult women who receive ovulation induction with the purpose of conceiving. Women with PCOS have higher scores on depression and anxiety scales and lower QoL scores than women without PCOS. STUDY DESIGN, SIZE AND DURATION: This study was a secondary analysis of a multi-centre RCT completed between June 2001 and May 2004. The randomization was stratified per centre, and the centres received blinded, numbered containers with medication. There were172 women available for the HRQoL assessment: 85 were allocated to metformin and 87 were allocated to placebo. PARTICIPANTS, SETTING AND METHODS: The Rotterdam Symptom Checklist (RSCL), a standard self-administered questionnaire, was used to assess physical symptoms, psychological distress, activity levels and overall HRQoL. MAIN RESULTS AND THE ROLE OF CHANCE: In the intention to treat analysis, we found differences between the treatment groups with respect to physical symptoms and overall HRQoL. Physical well-being was significantly impaired in women allocated to metformin but not in women allocated to placebo. The increase in physical symptoms in the metformin group was caused by side-effects typical of metformin, and was most pronounced at Week 1 (mean difference 12 [95% confidence interval (CI): 8-16] and still apparent at Week 16 [mean difference 7 (95% CI 2-12]. Overall well-being was significantly impaired in the metformin group compared with the placebo group [mean difference 13 (95% CI 6-20)]. LIMITATIONS AND REASONS FOR CAUTION: RSCL measurements were available only for three quarters of the participants. Although the number of missing questionnaires and the baseline measurements, were comparable between the treatment groups, some form of selection bias cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: Our finding that metformin was more burdensome than placebo, strengthens the recommendation that CC only and not CC plus metformin should be the drug of choice in this patient population. STUDY FUNDING/COMPETING INTEREST(S): None of the authors declared a conflict of interest. There was no study funding. TRIAL REGISTRATION NUMBER: ISRCTN55906981.

Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycystic ovary syndrome?

BACKGROUND: An RCT among newly diagnosed, therapy naive women with polycystic ovary syndrome (PCOS) showed no significant differences in ovulation rate, ongoing pregnancy rate or spontaneous abortion rate in favour of clomifene citrate plus metformin compared with clomifene citrate. We wanted to assess whether there are specific subgroups of women with PCOS in whom clomifene citrate plus metformin leads to higher pregnancy rates. METHODS: Subgroup analysis based on clinical and biochemical parameters of 111 women randomized to clomifene citrate plus metformin compared with 114 women randomized to clomifene citrate plus placebo. The data for age, BMI, waist-hip ratio (WHR) and plasma testosterone were available in all women, 2 h glucose in 80% of women and homeostatic model assessment for assessing insulin sensitivity (HOMA) in 50% of women. RESULTS: Of the women who were allocated to the metformin group, 44 women (40%) reached an ongoing pregnancy. In the placebo group, 52 women (46%) reached an ongoing pregnancy. There was a significantly different chance of an ongoing pregnancy for metformin versus placebo between subgroups based on age and WHR (P = 0.014). There was a positive effect of metformin versus placebo on pregnancy rate in older women (>or=28 years) with a high WHR, a negative effect of metformin versus placebo in young women (<28 years) regardless of their WHR and no effect in older, not viscerally obese women. No significant differences in effect of treatment were found for groups based on BMI, 2 h glucose, HOMA or plasma testosterone. CONCLUSIONS: Metformin may be an effective addition to clomifene citrate in infertile women with PCOS, especially in older and viscerally obese patients.

Apple proliferation resistance in apomictic rootstocks and its relationship to phytoplasma concentration and simple sequence repeat genotypes.

In an effort to select and characterize apple rootstock resistant to apple proliferation (AP), progenies from seven apomictic rootstock selections and their parental apomictic species, Malus sieboldii and M. sargentii, were compared to standard stocks M 9 and M 11. Seedlings derived from open pollinated mother plants were grafted with cv. Golden Delicious and grown under natural infection conditions. The progenies differed greatly in resistance to the AP agent 'Candidatus Phytoplasma mali'. Progenies of M. sieboldii and its descendent rootstock selections D2212, 4608, 4551, and D1131 showed a high level of resistance, whereas progenies of M. sargentii and its descendent selections D1111 and C1828 proved susceptible. M 9 and M 11 showed an intermediate level of resistance. Phytoplasma titer in roots of the M. sieboldii and M. sargentii progeny groups was similarly low, whereas the concentration in the standard stocks was 100 to 5,000 times higher. In trees on most of the resistant stocks, only a minority was colonized in the scion, while in trees on susceptible and standard stocks, infection rate was often higher. Also, the titer in the top of trees on resistant stocks was usually lower than in trees on susceptible and standard stocks. Four progenies derived from open pollinated M. sieboldii and M. sieboldii descendents were subjected to DNA typing using simple sequence repeat (SSR) markers. This study revealed that the selected groups consisted mainly of mother-like plants (apomicts) and type I hybrids (unreduced mother genotype plus one male allele at each locus). Type II hybrids (full recombinants) and autopollinated offspring were rare. In the 4608 progeny, trees grown on type I hybrid rootstocks were significantly less affected than trees on mother-like stocks. In other progenies with fewer or no type I hybrids, trees on type II hybrids and autopollinated offspring suffered considerably more from disease than trees on mother-like stocks.

Membranes of the mitotic apparatus of mammalian cells.

HeLa cells in mitosis are fixed by KMnO4 to obtain a good preservation of membranes. Inside and around the mitotic apparatus a vesicular, a tubular and a cisternal type of membranes are demonstrated. Small spherical or ellipsoidal vesicles are distributed at random in the spindle area. Zones around the poles and in the midbody of telophase cells are almost free from vesicles. Elements of the tubular ER are often aggregated in parallel arrays at the periphery of the spindle region, thus resembling dictyosomes. During telophase tubular ER is most prominent at the cleavage furrow. Layers of concentrically arranged flat cisternae surround the spindle region during the middle stages of mitosis. Radiating from the poles such membranes form large asters, thereby interrupting the concentric arrangement. This pattern might act as a barrier against larger cytoplasmic organelles or as a cisternal system to bring about an oriented transport of molecules from or to the poles. Fragments of the two large indentations of the nuclear envelops in prophase are aggregated in the spindle region and later on contribute to form new envelopes around the daughter nuclei.

Deacetylcolchicine conjugated to a heme-nonapeptide act with both soluble tubulin and microtubules polymerized in vitro.

A heme-nonapeptide with peroxidase-like activity was conjugated to pure deacetylcolchicine. This conjugated colchicine derivative competitively inhibits colchicine binding to soluble tubulin and is also able to depolymerize microtubules in vitro. Cytochemical studies show that at substoichiometric concentrations of the derivative, microtubules from the same sample are decorated to varying extents. These findings indicate that the binding of the colchicine-derivative to microtubules causes them to depolymerize.

Long-term treatment with moclobemide. An open-label, non-comparative, multiple-distributed study in patients with a major depressive episode as defined by DSM-III.

Evaluation of 247 patients receiving long-term moclobemide treatment showed that it was effective as an antidepressant, as measured both by decrease in HAMD mean total score and the doctor's evaluation of therapeutic effect. In patients who had been treated for 6 months or less, results were less favourable (ratings of 'very good' or 'good' in 31.5%, compared with 81.3% in patients treated for more than 6 months). This was due to a higher number of drop-outs, as a result of insufficient efficacy in the first 6 months. In those patients who responded favourably, 9.2% relapsed within 6 months of commencing treatment; of the remaining responders, 16% relapsed during months 7-12. In terms of the doctor's evaluation of side-effects, tolerability was 'very good' or 'good' in 88.2%.

Development and validation of the injury severity assessment survey/parent report: a new injury severity assessment survey.

OBJECTIVE: To develop and pilot test a telephone-based survey instrument that enables parents to identify and characterize the body region and severity of childhood injuries using the Abbreviated Injury Scale (AIS) scoring system. DESIGN: A prospective cross-sectional survey. SETTING: The emergency department of an urban, tertiary care, pediatric trauma center. PARTICIPANTS: One hundred forty-seven parents of children younger than 18 years and seen in the emergency department for acute treatment of an unintentional injury. INTERVENTIONS: None. MAIN OUTCOME MEASURE: The degree of agreement, measured as sensitivity, specificity, and kappa statistic, between medical record information and parents' responses to the telephone survey regarding the identification and characterization of clinically significant (AIS > or =2) injuries. RESULTS: The survey, known as the Injury Severity Assessment Survey/Parent Report, was developed via a systematic review of the AIS 1990 manual. Answers to questions were developed in a way that enabled automated coding of responses into AIS scores or ranges of scores. The sensitivity of the survey (its ability to detect injuries scoring 2 or more on the AIS that were documented in the medical record) varied somewhat by the body region of injury, ranging from 88% for head, face, neck, and spine injuries to 95% for extremity injuries. Intermediate sensitivity (92%) was noted for the detection of significant chest and abdomen injuries. The specificity of the survey (its ability to rule out the presence of a significant injury when one was not documented in the medical record) was more than 95% in each of the 3 body region groups. The kappa statistics for the 3 body region groups ranged from 0.89 to 0.92. CONCLUSIONS: A new telephone-based survey has been developed that enables parents to characterize their child's injuries by body region and to differentiate between minor injuries and more significant injuries using a well-established injury classification system. This survey has a significant advantage over previous telephone-based or written surveys of childhood injuries and may be particularly valuable in population-based (e.g., random-digit dial surveys) or multi-institutional studies of pediatric injuries.

Glutathione content but not gamma glutamyl cysteine synthetase mRNA expression predicts cisplatin resistance in head and neck cancer cell lines.

PURPOSE: To correlate cellular glutathione content and gamma-glutamyl cysteine synthetase (gamma GCS) mRNA expression with cisplatin sensitivity in a panel of seven head and neck squamous cancer cell lines. METHODS: Cisplatin IC50 was determined for each cell line using a sodium tetreazolium (XTT) assay. Cellular glutathione content was measured by using a previously reported enzymic method. gamma GCS mRNA expression was measured using an RNase protection assay. RESULTS: Total cellular glutathione was an excellent predictor of cisplatin sensitivity in this series of cell lines. The IC50 for cisplatin in the cell line with the highest glutathione concentration was approximately 90 times higher than in the cell line with the lowest glutathione concentration. Regression analysis showed a highly statistically significant positive correlation between cisplatin IC50 and cellular glutathione (coefficient of determination R2 = 0.81, P = 0.0012). Some-what surprisingly, in contrast to previous studies in ovarian cancer, gamma GCS mRNA expression in these cell lines was not significantly predictive of either total cellular glutathione or cisplatin sensitivity (R2 = 0.005, P = 0.84). As expected, treatment of resistant cell lines with buthionine sulfoximine resulted in decreased cellular glutathione and enhanced cisplatin sensitivity. CONCLUSIONS: Our results suggest that glutathione may be an important determinant of cisplatin sensitivity in clinical head and neck cancer. Since cisplatin is the most active chemotherapy drug for the treatment of this disease, this correlation may have important clinical relevance. The lack of correlation between glutathione level and gamma GCS expression suggests that salvage or alternate synthetic pathways may be critical in these cells.

Safety and efficacy during long-term treatment with moclobemide.

Safety aspects [adverse events, blood pressure and heart rate, weight, and laboratory tests (liver parameters, hemoglobin, leukocytes)] of long-term treatment in 1,120 patients are discussed. Adverse events during this long-term treatment were also compared with those of a subgroup of these patients who, before long-term treatment, were treated on a short-term basis (n = 706). Efficacy [Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression of Efficacy (CGI), and occurrence of relapses and recurrences] in a homogeneous sample of 485 patients is also discussed. The adverse events most frequently observed during long-term treatment were insomnia, headache, and dizziness. Insomnia and headache were also most often occurring in the compared sample of patients with short-term treatment, whereas dizziness during this treatment period ranked at the fifth position. Supine and standing mean blood pressure did not consistently change during long-term treatment, the most prominent increases in comparison with baseline were seen in the period > 1 year of treatment (6.3 mm Hg supine/7.2 mm Hg standing). Comparison of blood pressure values in the hypertensive range at baseline and during long-term treatment revealed no statistical difference (McNemar test p = 0.07829). Mean heart rate slightly decreased during long-term treatment (by a maximum of 6.3 beats/min supine, 8.2 beats/min standing). Mean weight did not change between baseline and treatment end point. There were 23 patients with a weight loss of 10 kg or more and 16 patients with a weight gain of 10 kg or more. For none of the laboratory parameters tested was there a statistical significance regarding shifts from normal to pathological values. HAM-D mean total scores in the above-mentioned subgroup of patients decreased from 25.05 points at baseline (n = 485) to 7.88 points after 1 year of treatment (n = 139). Seventy-five patients who had favorably responded to treatment (total responders n = 300) relapsed during the first 6 months of treatment. During the second half-year of treatment the recurrence rate was 14.8%, and during the third 6 months the recurrence rate was 12.2%. CGI in the same subsample of patients in whom HAMD was evaluated (n = 485) compared with those patients who did not drop out during the short-term period up to 44 days and entered long-term treatment (n = 401) showed that the percentage of the ratings "no change/worse" was higher in the sample that also included patients who withdrew from treatment during the short-term period.(ABSTRACT TRUNCATED AT 400 WORDS)

The use of absorbable sutures in laser-assisted microvascular anastomoses.

The efficacy of the laser in performing microvascular anastomoses has been well established in the laboratory using a number of wavelengths. These studies have concluded that laser-assisted microvascular anastomoses are at least comparable to, if not superior to, ordinary suture techniques. The advantages have been the diminished foreign body reaction that occurs as a consequence of using only a few stay sutures to hold the vessels in approximation while the laser bonding is performed, as well as the rapidity of the surgery. We have already shown that absorbable sutures (polyglactin 910) are as efficacious as standard nonabsorbable sutures (nylon) in both arterial and venous microanastomoses. The current study was undertaken to see if the foreign body reaction could be diminished even further by the use of absorbable 10.0 sutures and compare these findings to laser-assisted microvascular anastomoses performed with nonabsorbable sutures. The carbon dioxide milliwatt laser was used to perform laser-assisted microvascular anastomoses in rat femoral arteries and veins. Patency rates and histological response were compared at intervals of 3 days and 1, 2, 4, 8, and 12 weeks postoperatively. Both arterial and venous patency rates were comparable (overall absorbable, 91.2%-52/57; overall nonabsorbable, 87.7%-50/57), as was the degree of inflammation and fibrosis. We conclude that absorbable sutures can be used for laser-assisted microvascular anastomoses and have the potential of allowing healing to occur without any foreign material within the surgical site.

Microvascular anastomoses. An evaluation of laser-assisted technique.

The carbon dioxide milliwatt laser was used to perform microvascular anastomoses in 23 rat femoral arteries and 21 femoral veins. This technique was compared with conventionally sutured controls and then evaluated histologically at intervals of three to four days and 1, 2, 3, 4, 6, 8, and 12 weeks postoperatively. Patency rates in both methods, for arteries and veins, were comparable, confirming the feasibility of laser-assisted microvascular anastomoses. Moreover, the major benefit of the laser procedure was to allow for fewer sutures, thereby diminishing a foreign body reaction.

The efficacy of absorbable suture for microvascular anastomoses.

Although microvascular anastomoses are routinely performed with nonabsorbable sutures, a foreign body reaction can be stimulated that acts as a nidus for inflammation, infection, and possible thrombosis. Absorbable sutures should be able to diminish this reaction. There are sparse data describing the use of absorbable sutures for both arterial and venous anastomoses. This investigation compares standard microvascular anastomotic technique using nonabsorbable 10-0 sutures (nylon) with absorbable 10-0 sutures (polyglactin 910), using a previously reported tubed superficial epigastric flap model in rats. Patency rates and histologic responses are compared at intervals of 3 days and 1, 2, 8 and 12 weeks postoperatively. Arterial and venous patency rates were similar for both materials (overall nonabsorbable, 85.9%; overall absorbable, 84.4%). A somewhat increased inflammatory response was noted in the arterial absorbable group at 1 week and in both the venous and arterial nonabsorbable groups at 8 and 12 weeks postoperatively. The later finding most probably represents the continued presence of the nylon sutures. The incidence of intraluminal thrombosis was greater for nonabsorbable suture, occurring in two arterial and four venous anastomoses, compared with only one absorbable suture venous anastomosis. We conclude that nonabsorbable suture is as efficacious as standard absorbable material in both arterial and venous microanastomoses with the potential benefit of diminished foreign body reaction.

[Separate measurements of compact and spongy bone density using a transverse rotation scanner. Determination of mineral content of the radius using a least squares algorithm]. / Getrennte Messung von Kompakta- und Spongiosadichte mit einem Transversal-Rotations-Scanner. Bestimmung des Mineralgehalts am Radius mit einem Least-Square-Algorithmus.

The absorption profile of the distal forearm, which depends on bone mineralisation, was measured using a high resolution microcomputer-controlled transverse rotational scanner with a tightly collimated I-125 photon source and a scintillation counter. Reconstruction of the anatomical structures within the measured area occurred in two stages. Subsequently the linear attenuation coefficient for soft tissues, compacta and spongiosa was obtained by a "least-square" algorithm. The absorption coefficient of the compacta and spongiosa provided a measure of bone mineralisation. Correlation between the reconstructed images and the calculated results and measurements was tested by calculation. Ten measurements of a model and of in vivo bones resulted in a coefficient of variation of 1.8% and 3.3% for the compacta and 2.5% and 3.8% for the spongiosa. Relative deviation from the standard varied from +1.3% to -1.0%, depending on mineral content. This new, technically simple procedure for the separate determination of the compacta and spongiosa in the distal radius is useful for the early recognition of changes in bone mineralisation which are usually apparent first in the spongiosa.

[Direct and indirect parameters of free thyroxine. I. Method, quality control and in vitro experiments on storage of samples and effect of drugs]. / Direkte und indirekte Parameter für das freie Thyroxin. I. Methodik, Qualitätskontrolle sowie in-vitro Experimente zur Probenbehandlung und zu Medikamenteneinflüssen.

The clinical applicability of direct FT4 determinations by the radioimmunoassays ImmoPhase, GammaCoat, Liquisol, Amerlex and LisoPhase is tested in comparison to the FT4 index and the T4/TBG ratio. Part I of this study deals with technical aspects concerning quality control as well as with in-vitro experiments concerning storage of samples and interference of drugs. The precision of FT4-RIAs is satisfactory; inter-assay coefficients of variation are generally lower than 10% for medium hormone concentrations. Because of a change of the standard curve calibration by the manufacturer of the Liquisol kit, the inter-assay variability (17%) of this assay is unacceptably high. The comparison of working ranges shows that the sensitivity of all FT4 assays is sufficient. However, the upper limits of working ranges of the Liquisol and LisoPhase kits are too low. Storing the samples in form of serum yields lower values for any FT4 parameter than storing as whole blood. This unexpected observation is true for room temperature as well as for refrigeration at 4 degrees C. To be sure, the values of indirect FT4 parameters from serum and whole blood coincide somewhat better especially when the samples are stored in the refrigerator. Repeated thawing and refreezing does not influence the results of FT4-RIAs significantly. In vitro testing of drug interferences by addition of therapeutic doses of primidone, phenobarbital, phenytoin and acetylsalicylic acid yields significant effects only for the last quoted pharmaceutical. While the FT4 levels of the Liquisol and LisoPhase assays rise with the acetylsalicylic acid dose according to expectations, the values of the Amerlex and GammaCoat assays decrease. With regard to handling of the tests, there are no special technical problems for all FT4-RIAs tested.

[Evaluation of functional scintigraphy of gastric emptying by the principal component method (author's transl)]. / Zur Auswertung von funktionsszintigraphischen Magenentleerungsuntersuchungen mit der Hauptkomponent enmethode.

Gastric emptying of a standard semifluid test-meal, labeled with 99mTc-DTPA, was studied by functional scintigraphy in 88 subjects (normals, patients with duodenal and gastric ulcer before and after selective proximal vagotomy with and without pyloroplasty). Gastric emptying curves were analysed by the method of principal components. Patients after selective proximal vagotomy with pyloroplasty showed an rapid initial emptying, whereas this was a rare finding in patients after selective proximal vagotomy without pyloroplasty. The method of principal components is well suited for mathematical analysis of gastric emptying; nevertheless the results are difficult to interpret. The method has advantages when looking at larger collectives and allows a separation into groups with different gastric emptying.

[Direct and indirect parameters for free thyroxine. II. Diagnostic accuracy in disorders of thyroid function and binding protein anomalies]. / Direkte und indirekte Parameter für das freie Thyroxin. II. Diagnostische Treffsicherheit bei Schilddrüsenfunktions-störungen und Transportprotein-Anomalien.

Part II of the study concerning the clinical applicability of direct and indirect parameters for free thyroxine evaluates the diagnostic accuracy of the FT4-RIAs ImmoPhase, GammaCoat, Liquisol, Amerlex and LisoPhase in relation to FT4 index and T4/TBG ratio. This comparison of methods is done on a thoroughly classified collection (n = 640) of patients with normal and impaired thyroid function including patients with binding protein anomalies (pregnancy, estrogen-medication, phenytoin therapy, renal protein loss). FT4 normal ranges of a given kit harmonize well with data of the manufacturers and of the literature. On the other hand, the normal ranges of the various kits are not comparable. The differentiation of euthyroidism from hyper- or hypothyroidism can be made without problems using any of these methods, with the exception of the FT4-RIA GammaCoat. As expected, patients with euthyroid goiter show, on the average, slightly lower parameters for FT4. In pregnancy all direct and indirect parameters for FT4 have a tendency to lower values after the first trimester. This trend is most distinct for the T4/TBG ratio. A weak negative correlation of FT4 parameters with basal TSH, which does not exceed the upper normal range, however, can be interpreted in the sense of a relative hypothyroxinemia. Under contraceptive estrogen medication FT4 parameters do not fall outside the normal range, with the exception of the FT4-RIA ImmoPhase assay which yields a significantly increased frequency of high FT4 levels. On therapy with phenytoin FT4 values are generally lower than in controls. FT4 parameters in patients with renal protein loss of more than 2 g daily do not behave uniformly. While three of the FT4-RIAs tested (ImmoPhase, GammaCoat, Amerlex) show a tendency to lower values, the results of the remaining FT4 parameters do not differ significantly from the distribution of normals. The study leads to the conclusion that indirect FT4 parameters are still useful in the diagnosis of thyroid function; currently available FT4 radioimmunoassays may yield comparable results. With regard to the varying quality of the various commercial test kits, the choice between FT4-RIAs and indirect FT4 parameters does not depend primarily on clinical but on technical viewpoints.