Temporal and regional differences in the incidence of hospital-diagnosed endometriosis: a Danish population-based study.

INTRODUCTION: Due to diagnostic challenges, normalization of symptoms and an overall lack of awareness among both patients and physicians, endometriosis is an underdiagnosed disease. This can result in delayed treatment and potentially worsening of the disease. Despite initiatives, such as patients' support organizations and specialized endometriosis referral centers, differences in awareness, socioeconomic factors and lifestyle, combined with varying distances to specialized referral centers, could result in regional differences in the degree of underdiagnosing. This study aims to explore temporal and regional variations in the incidence of endometriosis based on the Danish hospital discharge register, and shed light on the degree of underdiagnosing of endometriosis in Denmark. MATERIAL AND METHODS: This registry-based cohort study included all women aged 15-55 living in Denmark from 1990-2017. Participants were identified through the Danish Civil Registration system and endometriosis diagnoses received at a hospital were obtained from the Danish National Patient Registry. Incidence rates of diagnosed endometriosis were calculated for each year of the study period and for each municipality in Denmark. A Cox regression analysis, stratified by calendar time and adjusted for ethnic origin, household composition, highest educational level and family socioeconomic status, was performed to estimate the association between residence and likelihood of receiving a hospital-based diagnosis of endometriosis. RESULTS: The nationwide incidence rate of hospital-diagnosed endometriosis was 7.89 (95% confidence interval [CI] 7.80-7.99) per 10 000 person-years and the prevalence in 2017 was 1.63%. The results showed an overall increase in the incidence of diagnosed endometriosis of 46.8% (95% CI 32.9-62.2) during the study period and also displayed significant regional differences. After adjustments, women living in northern Jutland had the highest probability of receiving a hospital-based diagnosis of endometriosis (hazard ratio 1.13, 95% CI 1.09-1.18), whereas women living in northern Zealand had the lowest probability (hazard ratio 0.63, 95% CI 0.60-0.67) compared with eastern Jutland. These regional differences have become more evident over time. CONCLUSIONS: Our results reveal significant regional differences in the incidence of hospital-diagnosed endometriosis, suggesting that a significant number of women may be left behind without a diagnosis. Further studies are needed to assess the underlying reasons for the significant regional differences.

Multidimensional Assessment of Functional Outcomes in Schizophrenia: Results From QUALIFY, a Head-to-Head Trial of Aripiprazole Once-Monthly and Paliperidone Palmitate.

Background: QUALIFY was a 28-week, randomized, open-label, head-to-head trial that assessed improvements across multiple measures in stable patients with schizophrenia with aripiprazole once-monthly 400 mg vs paliperidone palmitate. Methods: Secondary effectiveness assessments included physician-rated readiness for work using the Work Readiness Questionnaire, the Clinical Global Impression-Severity and Clinical Global Impression-Improvement scales, and quality of life with the rater-blinded Heinrichs-Carpenter Quality of Life Scale. Patients assessed their treatment satisfaction and quality of life with Subjective Well-Being under Neuroleptic Treatment-short version and Tolerability and Quality of Life questionnaires. Results: Odds of being ready for work at week 28 were significantly higher with aripiprazole once-monthly 400 mg vs paliperidone palmitate (adjusted odds ratio, 2.67; 95% CI, 1.39-5.14; P=.003). Aripiprazole once-monthly 400 mg produced numerically or significantly greater improvements from baseline vs paliperidone palmitate in all Quality of Life Scale items. With aripiprazole once-monthly 400 mg vs paliperidone palmitate at week 28, there were significantly more Clinical Global Impression-Severity and Clinical Global Impression-Improvement responders (adjusted odds ratio, 2.26; P=.010, and 2.51; P=.0032) and significantly better Clinical Global Impression-Improvement scores (least squares mean treatment difference, -0.326; 95% CI, -0.60 to -0.05; P=.020). Numerically larger improvements with aripiprazole once-monthly 400 mg vs paliperidone palmitate were observed for patient-rated scales Subjective Well-Being under Neuroleptic Treatment-short version and Tolerability and Quality of Life. Partial correlations were strongest among clinician-rated and among patient-rated scales but poorest between clinician and patient-rated scales. Conclusions: Consistently greater improvements were observed with aripiprazole once-monthly 400 mg vs paliperidone palmitate across all measures. Partial correlations between scales demonstrate the multidimensionality of various measures of improvement. More patients on aripiprazole once-monthly 400 mg were deemed ready to work by the study end. Trial registry: National Institutes of Health registry, NCT01795547, https://clinicaltrials.gov/ct2/results?id=NCT01795547).

Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation.

Loss of either hepatocyte growth factor activator inhibitor (HAI)-1 or -2 is associated with embryonic lethality in mice, which can be rescued by the simultaneous inactivation of the membrane-anchored serine protease, matriptase, thereby demonstrating that a matriptase-dependent proteolytic pathway is a critical developmental target for both protease inhibitors. Here, we performed a genetic epistasis analysis to identify additional components of this pathway by generating mice with combined deficiency in either HAI-1 or HAI-2, along with genes encoding developmentally co-expressed candidate matriptase targets, and screening for the rescue of embryonic development. Hypomorphic mutations in Prss8, encoding the GPI-anchored serine protease, prostasin (CAP1, PRSS8), restored placentation and normal development of HAI-1-deficient embryos and prevented early embryonic lethality, mid-gestation lethality due to placental labyrinth failure, and neural tube defects in HAI-2-deficient embryos. Inactivation of genes encoding c-Met, protease-activated receptor-2 (PAR-2), or the epithelial sodium channel (ENaC) alpha subunit all failed to rescue embryonic lethality, suggesting that deregulated matriptase-prostasin activity causes developmental failure independent of aberrant c-Met and PAR-2 signaling or impaired epithelial sodium transport. Furthermore, phenotypic analysis of PAR-1 and matriptase double-deficient embryos suggests that the protease may not be critical for focal proteolytic activation of PAR-2 during neural tube closure. Paradoxically, although matriptase auto-activates and is a well-established upstream epidermal activator of prostasin, biochemical analysis of matriptase- and prostasin-deficient placental tissues revealed a requirement of prostasin for conversion of the matriptase zymogen to active matriptase, whereas prostasin zymogen activation was matriptase-independent.

Uncrewed aerial vehicle with onboard winch system for rapid, cost-effective, and safe oceanographic profiling in hazardous and inaccessible areas.

Interactions between coastal waters and marine-terminating glaciers in the Polar Regions play a significant role in global sea level rise fueled by a rapidly warming Arctic. The risk of glacier calving, and the abundance of ice, can make it impossible for surface vessels to access the waters near glacier termini. Alternative methods using manned aircraft are expensive. As a result, oceanographic measurements are limited near glacier termini. We present an uncrewed aerial vehicle (UAV) with an on-board winch system that allows oceanographic profiling in remote, hazardous areas using a commercial conductivity, temperature, and depth (CTD) sensor payload. The UAV is optimized for easy handling and deployment and is capable of high-speed and efficient cruise flight. An autopilot system provides pilot assistance and autonomous flight capabilities. The total weight of the UAV including payload is 6.5 kg with an endurance of 24 min. Testing of the system was conducted in South Greenland during winter conditions in March 2023 with successful profiles collected near a glacier terminus (<5 m) and in small openings in ice mélange (2.2 m). The system proved capable, reliable, and efficient. Further development of the system will allow other sensors for an even more flexible measurement suite.

Indications, anaesthesia and postoperative protocol for replantation and revascularization in the hand in Nordic countries.

In this survey, we compared the current postoperative practices in the largest replantation units of four Nordic countries. The topics included were indication for surgery, anaesthesia, postoperative monitoring, use of antibiotics, anticoagulation and postoperative intravenous fluids, change of dressings, duration of bed rest and hospital stay, hand therapy and follow-up after discharge. Although there were many similarities between the units in the postoperative protocols, we found a large variety of practices. There is no robust evidence to assess or support or reject most of the strategies in postoperative care. The differences in practice warrant prospective studies in order to establish an evidence-based postoperative protocol for replantation surgery.

Danish translation, cross-cultural adaptation, and electronic migration of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project Endometriosis Patient Questionnaire.

Objectives: This study aims to translate and cross-culturally adapt the standard version of the World Endometriosis Research Foundation (WERF) EPHect Endometriosis Patient Questionnaire (EPQ) into Danish and to ensure equivalence of a Danish electronic version. Methods: The translation, cultural adaption, and electronic migration followed recommendations from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the Critical Path Institute. Ten women with endometriosis were enrolled for cognitive debriefing of the paper version (pEPQ) after translation and back translation. The questionnaire was then migrated into an electronic version (eEPQ) and subsequently tested for usability and measurement equivalence by five women with endometriosis. Results: Cross-cultural alterations were needed for medical terms, response options for ethnicity, the educational system, and measurement units. Thirteen questions were altered after back translation, while 21 underwent minor changes after cognitive debriefing. After testing the eEPQ, 13 questions were altered. Questions tested for measurement equivalence across the two modes of administration were found comparable. The median time-to-complete the pEPQ and eEPQ was 62 min (range: 29-110) and 63 min (range: 31-88), respectively. General comments included the questionnaire being relevant but long and repetitive. Conclusions: We find the the Danish pEPQ and eEPQ similar and comparable to the original English instrument. However, attention must be drawn to questions regarding measurement units, ethnicity, and educational systems before cross-country comparison. The Danish pEPQ and eEPQ are suitable for obtaining subjective data on women with endometriosis.

A prospective study of health care resource utilisation and selected costs of schizophrenia in France.

BACKGROUND: Schizophrenia is among the most burdensome and costly illnesses worldwide. To estimate the cost of schizophrenia in France, a longitudinal study was carried out between 1998 and 2002. The main objective of this study was to describe and update the cost of schizophrenia in a longitudinal, representative sample of French patients. The second objective was to identify cost drivers in the treatment of schizophrenia. METHODS: Based on a cohort of 288 French schizophrenic patients during 2 years of prospective follow-up, this study collected clinical, patient reported outcomes, quality of life, functioning, patient management, care giver involvement and resource utilisation data every 6 months. For each service, information was collected on the type of service, the frequency of attendance and type of intervention provided to the patient. Unit costs were based on available French databases. Mean service use and costs over the five time points were estimated using between-effects regression models. RESULTS: In the total sample of 288 patients aged 18-64 years, the mean total cost (€ 3 534) was mainly accounted for by the cost of inpatient treatment (€ 1 390) and day care (€ 1 331). The estimate of the annual cost for direct medical health care for all French schizophrenic patients was € 1 581 million, including € 621 million for inpatient treatment and € 595 million for day care (77%). The costs for medication accounted for 16.1% of total annual costs. The remaining costs (6.9%) included visits to psychiatrists, general practitioners, other physicians and psychologists. The direct resource allocation showed inpatient treatment as the main direct cost. Unemployment was identified as a major indirect cost of schizophrenia treatment. Positive and depressive schizophrenia symptoms at baseline and relapse occurrence during the follow-up period were associated with a higher cost of treatment. Health satisfaction or negative symptoms of schizophrenia at baseline were associated with lower costs. CONCLUSION: Several cost drivers were identified. Based on the results obtained in France, we suggest further analysis of mechanisms that influence the service-specific costs for schizophrenia in other areas of the world.

Inter- and intra-rater reliability of the Oberg-Manske-Tonkin classification of congenital upper limb anomalies.

On two occasions, five surgeons classified a cohort of 150 consecutive patients with congenital upper limb anomalies according to the Oberg-Manske-Tonkin classification (2020 update). We estimated reliability for the main anomaly code by means of Cohen's kappa (Κ) for ten rater pairs for five common and easily distinguishable anomalies (Group 1), and for all the other anomalies (Group 2). Inter-rater reliability for all patients (n = 150) was substantial, almost perfect for Group 1 (n = 64), but only moderate for Group 2 (n = 86). Intra-rater reliability was higher for all groups. We suggest simplifications to the Oberg-Manske-Tonkin classification and highlight specific requirements for instructions to increase its reliability.Level of evidence: I.

Is laparoscopic excision for superficial peritoneal endometriosis helpful or harmful? Protocol for a double-blinded, randomised, placebo-controlled, three-armed surgical trial.

INTRODUCTION: Placebo-controlled surgical designs are recommended to ascertain treatment effects for elective surgeries when there is genuine doubt about the effectiveness of the surgery. Some elective surgeries for pain have been unable to show an effect beyond sham surgery, suggesting contributions from contextual factors. However, the nature of contextual factors in elective surgery is largely unexplored. Further, methodological difficulties in placebo-controlled surgical trials impact the ability to estimate the effectiveness of a surgical procedure. These include an overall lack of testing the success of blinding, absence of comparison to a no-surgery control group and dearth of test for neuropathic pain.For women with peritoneal endometriosis, there is uncertainty regarding the pain-relieving effect of surgery. Surgery may put patients at risk of complications such as postsurgical neuropathic pain, without guarantees of sufficient pelvic pain relief. The planned placebo-controlled trial aims to examine the effect of surgery on pelvic pain, widespread pain and neuropathic pain symptoms in women with peritoneal endometriosis, and to test the contribution of contextual factors to pain relief. METHODS AND ANALYSIS: One hundred women with peritoneal endometriosis will be randomised to either diagnostic laparoscopy with excision of endometrial tissue (active surgery), purely diagnostic laparoscopy (sham surgery) or delayed surgery (no-surgery control group). Outcomes include pelvic pain relief, widespread pain, neuropathic pain symptoms and quality of life. Contextual factors are also assessed. Assessments will be obtained at baseline and 1, 3 and 6 months postrandomisation. Mixed linear models will be used to compare groups over time on all outcome variables. ETHICS AND DISSEMINATION: The trial is approved by the Regional Ethics Committee in the Central Denmark Region (1-10-72-152-20). The trial is funded by a PhD scholarship from Aarhus University, and supported by a grant from 'Helsefonden' (20-B-0448). Findings will be published in international peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT05162794.

Discovery of a novel insect neuropeptide signaling system closely related to the insect adipokinetic hormone and corazonin hormonal systems.

Neuropeptides and their G protein-coupled receptors (GPCRs) play a central role in the physiology of insects. One large family of insect neuropeptides are the adipokinetic hormones (AKHs), which mobilize lipids and carbohydrates from the insect fat body. Other peptides are the corazonins that are structurally related to the AKHs but represent a different neuropeptide signaling system. We have previously cloned an orphan GPCR from the malaria mosquito Anopheles gambiae that was structurally intermediate between the A. gambiae AKH and corazonin GPCRs. Using functional expression of the receptor in cells in cell culture, we have now identified the ligand for this orphan receptor as being pQVTFSRDWNAamide, a neuropeptide that is structurally intermediate between AKH and corazonin and that we therefore named ACP (AKH/corazonin-related peptide). ACP does not activate the A. gambiae AKH and corazonin receptors and, vice versa, AKH and corazonin do not activate the ACP receptor, showing that the ACP/receptor couple is an independent and so far unknown peptidergic signaling system. Because ACP is structurally intermediate between AKH and corazonin and the ACP receptor between the AKH and corazonin receptors, this is a prominent example of receptor/ligand co-evolution, probably originating from receptor and ligand gene duplications followed by mutations and evolutionary selection, thereby yielding three independent hormonal systems. The ACP signaling system occurs in the mosquitoes A. gambiae, Aedes aegypti, and Culex pipiens (Diptera), the silkworm Bombyx mori (Lepidoptera), the red flour beetle Tribolium castaneum (Coleoptera), the parasitic wasp Nasonia vitripennis (Hymenoptera), and the bug Rhodnius prolixus (Hemiptera). However, the ACP system is not present in 12 Drosophila species (Diptera), the honeybee Apis mellifera (Hymenoptera), the pea aphid Acyrthosiphon pisum (Hemiptera), the body louse Pediculus humanus (Phthiraptera), and the crustacean Daphnia pulex, indicating that it has been lost several times during arthropod evolution. In particular, this frequent loss of hormonal systems is unique for arthropods compared with vertebrates.

The Drosophila genes CG14593 and CG30106 code for G-protein-coupled receptors specifically activated by the neuropeptides CCHamide-1 and CCHamide-2.

Recently, a novel neuropeptide, CCHamide, was discovered in the silkworm Bombyx mori (L. Roller et al., Insect Biochem. Mol. Biol. 38 (2008) 1147-1157). We have now found that all insects with a sequenced genome have two genes, each coding for a different CCHamide, CCHamide-1 and -2. We have also cloned and deorphanized two Drosophila G-protein-coupled receptors (GPCRs) coded for by genes CG14593 and CG30106 that are selectively activated by Drosophila CCH-amide-1 (EC(50), 2×10(-9) M) and CCH-amide-2 (EC(50), 5×10(-9) M), respectively. Gene CG30106 (symbol synonym CG14484) has in a previous publication (E.C. Johnson et al., J. Biol. Chem. 278 (2003) 52172-52178) been wrongly assigned to code for an allatostatin-B receptor. This conclusion is based on our findings that the allatostatins-B do not activate the CG30106 receptor and on the recent findings from other research groups that the allatostatins-B activate an unrelated GPCR coded for by gene CG16752. Comparative genomics suggests that a duplication of the CCHamide neuropeptide signalling system occurred after the split of crustaceans and insects, about 410 million years ago, because only one CCHamide neuropeptide gene is found in the water flea Daphnia pulex (Crustacea) and the tick Ixodes scapularis (Chelicerata).

Identification of the Drosophila and Tribolium receptors for the recently discovered insect RYamide neuropeptides.

One year ago, we discovered a new family of insect RYamide neuropeptides, which has the C-terminal consensus sequence FFXXXRYamide, and which is widely occurring in most insects, including the fruitfly Drosophila melanogaster and the red flour beetle Tribolium castaneum (F. Hauser et al., J. Proteome Res. 9 (2010) 5296-5310). Here, we identify a Drosophila G-protein-coupled receptor (GPCR) coded for by gene CG5811 and its Tribolium GPCR ortholog as insect RYamide receptors. The Drosophila RYamide receptor is equally well activated (EC(50), 1×10(-9)M) by the two Drosophila RYamide neuropeptides: RYamide-1 (PVFFVASRYamide) and RYamide-2 (NEHFFLGSRYamide), both contained in a preprohormone coded for by gene CG40733. The Tribolium receptor shows a somewhat higher affinity to Tribolium RYamide-2 (ADAFFLGPRYamide; EC(50), 5×10(-9)M) than to Tribolium RYamide-1 (VQNLATFKTMMRYamide; EC(50), 7×10(-8)M), which might be due to the fact that the last peptide does not completely follow the RYamide consensus sequence rule. There are other neuropeptides in insects that have similar C-terminal sequences (RWamide or RFamide), such as the FMRFamides, sulfakinins, myosuppressins, neuropeptides F, and the various short neuropeptides F. Amazingly, these neuropeptides show no cross-reactivity to the Tribolium RYamide receptor, while the Drosophila RYamide receptor is only very slightly activated by high concentrations (>10(-6)M) of neuropeptide F and short neuropeptide F-1, showing that the two RYamide receptors are quite specific for activation by insect RYamides, and that the sequence FFXXXRYamide is needed for effective insect RYamide receptor activation. Phylogenetic tree analyses and other amino acid sequence comparisons show that the insect RYamide receptors are not closely related to any other known insect or invertebrate/vertebrate receptors, including mammalian neuropeptide Y and insect neuropeptide F and short neuropeptide F receptors. Gene expression data published in Flybase (www.flybase.org) show that the Drosophila CG5811 gene is significantly expressed in the hindgut of adult flies, suggesting a role of insect RYamides in digestion or water reabsorption.

Cloning and identification of an oxytocin/vasopressin-like receptor and its ligand from insects.

More than 20 years ago, an oxytocin/vasopressin-like peptide, CLITNCPRGamide, was isolated from the locust, Locusta migratoria [Proux JP, et al. (1987) Identification of an arginine vasopressin-like diuretic hormone from Locusta migratoria. Biochem Biophys Res Commun 149:180-186]. However, no similar peptide could be identified in other insects, nor could its prohormone be cloned, or its physiological actions be established. Here, we report that the recently sequenced genome from the red flour beetle Tribolium castaneum contains a gene coding for an oxytocin/vasopressin-like peptide, identical to the locust peptide, which we named inotocin (for insect oxytocin/vasopressin-like peptide) and a gene coding for an inotocin G protein-coupled receptor (GPCR). We cloned the Tribolium inotocin preprohormone and the inotocin GPCR and expressed the GPCR in CHO cells. This GPCR is strongly activated by low concentrations of inotocin (EC(50), 5 x 10(-9) M), demonstrating that it is the inotocin receptor. Quantitative RT-PCR (qPCR) showed that in adult Tribolium, the receptor is mainly expressed in the head and much less in the hindgut and Malpighian tubules, suggesting that the inotocin/receptor couple does not play a role in water homeostasis. Surprisingly, qPCR also showed that the receptor is 30x more expressed in the first larval stages than in adult animals. The inotocin/receptor couple can also be found in the recently sequenced genome from the parasitic wasp Nasonia vitripennis but not in any other holometabolous insect with a completely sequenced genome (12 Drosophila species, the malaria mosquito Anopheles gambiae, the yellow fever mosquito Aedes aegypti, the silk worm Bombyx mori, and the honey bee Apis mellifera), suggesting that this neuropeptide system is confined to basal holometabolous insects. Furthermore, we identified an oxytocin/vasopressin-like peptide and receptor in the recently sequenced genome from the water flea Daphnia pulex (Crustacea). To our knowledge, this is the first report on the molecular cloning of an oxytocin/vasopressin-like receptor and its ligand from arthropods.

A pharmacoeconomic analysis of sertindole in the treatment of schizophrenia in Sweden.

BACKGROUND: Atypical antipsychotics have similar clinical efficacy in the treatment of schizophrenia; variability in their tolerability represents the discerning factor in treatment choices. Sertindole has a relatively good tolerability profile that favours long-term patient adherence and, therefore, is associated with lower rates of relapse and rehospitalization. AIM: A model was developed to compare the cost-effectiveness of a 5-year treatment strategy starting with sertindole versus olanzapine, risperidone, aripiprazole or the typical antipsychotic agent, haloperidol. METHODS: The model was based on published trials and local clinical practice, and considered costs from the perspective of the Swedish National Health Insurance Board. RESULTS: All atypical agents were clinically superior and more cost-effective than haloperidol with a cost per quality-adjusted life year gained of approximately 490,000 Swedish kroner. Sertindole was associated with the lowest direct and indirect medical costs, driven by its tolerability profile. CONCLUSIONS: Sertindole represents a useful alternative to the current treatment options available in Sweden. CLINICAL IMPLICATIONS: The relatively good tolerability profile of sertindole translates into lower costs of schizophrenia management, primarily driven by substantially lower direct and indirect costs. Sertindole appears to be a clinically and cost-effective alternative in the management of patients with schizophrenia in Sweden.

Centennial response of Greenland's three largest outlet glaciers.

The Greenland Ice Sheet is the largest land ice contributor to sea level rise. This will continue in the future but at an uncertain rate and observational estimates are limited to the last few decades. Understanding the long-term glacier response to external forcing is key to improving projections. Here we use historical photographs to calculate ice loss from 1880-2012 for Jakobshavn, Helheim, and Kangerlussuaq glacier. We estimate ice loss corresponding to a sea level rise of 8.1 ± 1.1 millimetres from these three glaciers. Projections of mass loss for these glaciers, using the worst-case scenario, Representative Concentration Pathways 8.5, suggest a sea level contribution of 9.1-14.9 mm by 2100. RCP8.5 implies an additional global temperature increase of 3.7 °C by 2100, approximately four times larger than that which has taken place since 1880. We infer that projections forced by RCP8.5 underestimate glacier mass loss which could exceed this worst-case scenario.

Escitalopram and duloxetine in major depressive disorder: a pharmacoeconomic comparison using UK cost data.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) are approved for the treatment of major depressive disorder (MDD). The allosteric SSRI escitalopram has been shown to be at least as clinically effective as the SNRIs venlafaxine and duloxetine in MDD, with a better tolerability profile. In addition, escitalopram has been shown to be cost saving compared with venlafaxine. OBJECTIVE: To evaluate the cost effectiveness of escitalopram versus duloxetine in the treatment of MDD, and to identify key cost drivers. METHODS: The pharmacoeconomic evaluation was conducted alongside a 24-week, double-blind, multinational randomized study (escitalopram 20 mg/day and duloxetine 60 mg/day) in outpatients with MDD, aged 18-65 years, with Montgomery-Asberg Depression Rating Scale (MADRS) score >or=26 and Clinical Global Impression Severity (CGI-S) score >or=4, and baseline duration of the current depressive episode of 12 weeks to 1 year.The analysis was conducted on the full analysis set (FAS), which included all patients with >or=1 valid post-baseline health economic assessment. Effectiveness outcomes of the cost-effectiveness analyses (CEA) included the change in Sheehan Disability Scale (SDS) score (primary CEA), treatment response (MADRS score decrease >or=50%) and remission (MADRS score

Evaluation of patients on sertindole treatment after failure of other antipsychotics: a retrospective analysis.

BACKGROUND: Use of the atypical antipsychotic sertindole was suspended for four years due to safety concerns. During the suspension, the regulatory authorities required further studies, including this one, to be conducted. The purpose of this study was to determine if a subset of patients with psychotic illness exists which particularly benefits from sertindole treatment after failure of other antipsychotic drugs, including atypical antipsychotics. METHODS: This was a retrospective single-arm observational crossover study of 344 patients, who served as their own controls. Patients mainly from the Sertindole Safety Study who had shown good response to sertindole, and who had followed up to four alternating six month periods of treatment with sertindole and other antipsychotics, were included. (In Period 1 patients took non-sertindole treatment, in Period 2, sertindole was taken, in Period 3, patients reverted to non-sertindole treatment, and in Period 4, sertindole was taken again.) Patient records for each period of treatment were assessed for objective data: number and duration of hospitalizations due to worsening of psychotic symptoms; the amount of self-harming behaviour; indicators of social status. Retrospective evaluation of changes in clinical symptoms from the patients' records was also conducted. Dates and reasons for stopping and/or switching medication were also recorded. RESULTS: There was improvement in all objective measured parameters during the periods of sertindole treatment. In particular, the average number of hospitalizations per year due to worsening of psychotic symptoms was reduced in the following way in the group studied over four treatment periods: Period 1 (non-sertindole treatment) 3.4; Period 2 (sertindole treatment) 1.0; Period 3 (non-sertindole treatment) 2.0; Period 4 (sertindole treatment) 1.8. The duration of hospitalizations also decreased significantly during the periods of sertindole treatment. Results showed that patients improved in objective social parameters when switched to sertindole treatment; assessment of the patients' affective lives showed a significant increase in the number of patients having a stable relationship during sertindole treatment; and assessment of the number of patients employed showed an increase after the first and second switch to sertindole treatment (from Period 1 to Period 2 and from Period 3 to Period 4, respectively). Adverse events and lack of efficacy were the main reasons for switching to sertindole. CONCLUSION: A group of patients benefited from sertindole after other antipsychotic treatments, including that with atypical antipsychotics, had failed. Further studies are needed to investigate if there is a specific patient profile that corresponds to these responders.

The Sertindole Safety Survey: a retrospective analysis under a named patient use programme in Europe.

BACKGROUND: After sertindole's suspension, health authorities established a specific named-patient use (NPU) programme in order to supply sertindole to patients who did not respond to or did not tolerate alternative treatments. This programme provided the possibility of prospectively following an exhaustive cohort of patients treated with sertindole after its suspension. A survey was performed to assess sertindole's modalities of prescription, assess and document any serious adverse events (SAEs), and assess the mortality rate within the NPU cohort. METHODS: The study comprised a survey of sertindole-treated patients in eleven European countries. All patients treated with sertindole within the NPU programme were eligible for the study. RESULTS: 1,432 patients were included in the study. The reason for sertindole prescription was lack of efficacy (approximately 50%) or adverse events (approximately 20%) of other antipsychotic treatments. The mean sertindole dose was 13.4 mg daily. Lack of efficacy and adverse events were reported as reasons for sertindole discontinuation.A total of 97 SAEs were recorded, including ten fatal outcomes, which occurred during the study period or within thirty days after sertindole discontinuation. The all-cause mortality rate was 0.51 per 100 Person-Years of Exposure (95% Poisson confidence interval: 0.23-0.97). QTc prolongation was reported in 15 patients (1.05% of total patients), being a rate of 0.85 per 100 Person-Years of Exposure [95% CI: 0.48-1.41]. CONCLUSION: Although prescribing and supplying sertindole were subject to administrative constraints, a significant number of patients were treated with sertindole, thus supporting the need for sertindole in specific cases. TRIAL REGISTRATION NUMBER: Not applicable.

Is endometriosis associated with irritable bowel syndrome? A cross-sectional study.

OBJECTIVES: Previous studies have found a high prevalence of irritable bowel syndrome (IBS). However, data on this relation in women without bowel endometriosis is limited. The aim of this study was to compare the prevalence of IBS in women with endometriosis to the prevalence in women without endometriosis and to investigate if the prevalence of IBS was associated with bowel involved endometriosis. STUDY DESIGN: Information for this cross-sectional study was collected through an online questionnaire. A total of 373 women completed the questionnaire. After exclusions, 254 with endometriosis and 102 without endometriosis were included (N = 356). Endometriosis was identified by self-reported diagnosis. IBS was identified by; 1. self-reported diagnosis prior to the study and 2. fulfillment of ROME III diagnostic criteria in this study. Odds ratios were calculated to estimate the strength of the association between IBS and endometriosis. A separate analysis, restricted to women without bowel involved endometrioses, was conducted. Adjustment for potential confounders (age, gastroenterological comorbidities and length of education) was performed. RESULTS AND CONCLUSIONS: The prevalence of IBS was higher in women with endometriosis compared to the women without endometriosis (OR = 5.32 (CI: 2.88; 9.81)). In the analysis restricted to women without bowel involved endometriosis, the prevalence was also higher in women with endometriosis compared to women without endometriosis (OR = 6.54 (CI95% 3.22; 13.29)). Thus, this study found a higher prevalence of IBS in women with endometriosis compared to women without endometriosis. This finding seems to be unrelated to bowel involvement. This opens new perspectives in relation to treatment of endometriosis.

Five-year results after collagenase treatment of Dupuytren disease.

This study assesses the joint-specific sustained effect of collagenase clostridium histolyticum treatment of Dupuytren disease over a 5-year follow-up period. The study includes 107 consecutive treatments in patients with extension deficits greater than 20° affecting the metacarpophalangeal or proximal interphalangeal joints. Success was defined as no follow-up treatment due to relapse or maintained extension deficit less than 20°. The 5-year estimate of no follow-up treatment was 79% (95% CI: 64-88) for metacarpophalangeal and 49% (95% CI: 26-69) for proximal interphalangeal joints, which was a significant difference (log-rank test, p = 0.0044). For those who did not undergo re-treatment, a non-significant relapse was found for metacarpophalangeal joints and a 65% (34°, 95% CI: 24-46) relapse for proximal interphalangeal joints. We conclude that treating metacarpophalangeal joints with collagenase clostridium histolyticum is effective with acceptable recurrence rates. However, when treating proximal interphalangeal joints with collagenase clostridium histolyticum, patients should be informed of the high risk of recurrence and the greater chance of need for further treatment. LEVEL OF EVIDENCE: II.