Multimodal assessment improves neuroprognosis performance in clinically unresponsive critical-care patients with brain injury.

Accurately predicting functional outcomes for unresponsive patients with acute brain injury is a medical, scientific and ethical challenge. This prospective study assesses how a multimodal approach combining various numbers of behavioral, neuroimaging and electrophysiological markers affects the performance of outcome predictions. We analyzed data from 349 patients admitted to a tertiary neurointensive care unit between 2009 and 2021, categorizing prognoses as good, uncertain or poor, and compared these predictions with observed outcomes using the Glasgow Outcome Scale-Extended (GOS-E, levels ranging from 1 to 8, with higher levels indicating better outcomes). After excluding cases with life-sustaining therapy withdrawal to mitigate the self-fulfilling prophecy bias, our findings reveal that a good prognosis, compared with a poor or uncertain one, is associated with better one-year functional outcomes (common odds ratio (95% CI) for higher GOS-E: OR = 14.57 (5.70-40.32), P < 0.001; and 2.9 (1.56-5.45), P < 0.001, respectively). Moreover, increasing the number of assessment modalities decreased uncertainty (OR = 0.35 (0.21-0.59), P < 0.001) and improved prognostic accuracy (OR = 2.72 (1.18-6.47), P = 0.011). Our results underscore the value of multimodal assessment in refining neuroprognostic precision, thereby offering a robust foundation for clinical decision-making processes for acutely brain-injured patients. ClinicalTrials.gov registration: NCT04534777 .

What do windsurfers and kitesurfers in Germany know about surfer's ear and how is it influenced by protective measures?

OBJECTIVE: This study investigated the frequency of ear canal protection use and looked at its influence on external auditory exostosis severity and knowledge about external auditory exostosis among windsurfers and kitesurfers on the German coast. METHOD: This retrospective cross-sectional study interviewed 130 windsurfers and kitesurfers along the German coast on knowledge of external auditory exostosis, exposure time, use of neoprene hoods and earplugs, and otological complaints. Participants underwent bilateral video-otoscopic examination. RESULTS: Knowledge of external auditory exostosis was 'good' or 'excellent' in 78 of 130 (60 per cent) individuals and 'poor' or non-existent in 52 of 130 (40 per cent) individuals. Knowledge was positively correlated with hours of exposure, otological complaints and frequency of ear canal protection use. A significant negative influence of neoprene hood use on external auditory exostosis severity was shown. CONCLUSION: The positive effect of external auditory exostosis knowledge on the frequency of ear canal protection and the reduction of external auditory exostosis risk implies a need for health education on this topic.

Advances in treatments of patients with classical and emergent neurological toxicities of anticancer agents.

The neurotoxicity associated to the anticancer treatments has received a growing body of interest in the recent years. The development of innovating therapies over the last 20years has led to the emergence of new toxicities. Their diagnosis and management can be challenging in the clinical practice and further research is warranted to improve the understanding of their pathogenic mechanisms. Conventional treatments as radiation therapy and chemotherapy are associated to well-known and under exploration emerging central nervous system (CNS) and peripheral nervous system (PNS) toxicities. The identification of the risk factors and a better understanding of their pathogeny through a "bench to bedside and back again" approach, are the first steps towards the development of toxicity mitigation strategies. New imaging techniques and biological explorations are invaluable for their diagnosis. Immunotherapies have changed the cancer treatment paradigm from tumor cell centered to immune modulation towards an efficient anticancer immune response. The use of the immune checkpoints inhibitors (ICI) and CAR-T cells (chimeric antigen receptor) lead to an increase in the incidence of immune-mediated toxicities and new challenges in the neurological patient's management. The neurological ICI related adverse events (n-irAE) are rare but potentially severe and may present with both CNS and PNS involvement. The most frequent and well characterized, from a clinical and biological standpoint, are the PNS phenotypes: myositis and polyradiculoneuropathy, but the knowledge on CNS phenotypes and their treatments is expanding. The n-irAE management requires a good balance between dampening the autoimmune toxicity without impairing the anticancer immunity. The adoptive cell therapies as CAR-T cells, a promising anticancer strategy, trigger cellular activation and massive production of proinflammatory cytokines inducing frequent and sometime severe toxicity known as cytokine release syndrome and immune effector cell-associated neurologic syndrome. Their management requires a close partnership between oncologist-hematologists, neurologists, and intensivists. The oncological patient's management requires a multidisciplinary clinical team (oncologist, neurologist and paramedical) as well as a research team leading towards a better understanding and a better management of the neurological toxicities.

Long-term outcomes of switching to gonadotrophins versus continuing with clomiphene citrate, with or without intrauterine insemination, in women with normogonadotropic anovulation and clomiphene failure: follow-up study of a factorial randomized clinical trial.

STUDY QUESTION: What are the long-term outcomes after allocation to use of gonadotrophins versus clomiphene citrate (CC) with or without IUI in women with normogonadotropic anovulation and clomiphene failure? SUMMARY ANSWER: About four in five women with normogonadotropic anovulation and CC failure had a live birth, with no evidence of a difference in pregnancy outcomes between the allocated groups. WHAT IS KNOWN ALREADY: CC has long been used as first line treatment for ovulation induction in women with normogonadotropic anovulation. Between 2009 and 2015, a two-by-two factorial multicentre randomized clinical trial in 666 women with normogonadotropic anovulation and six cycles of CC failure was performed (M-ovin trial). This study compared a switch to gonadotrophins with continued treatment with CC for another six cycles, with or without IUI within 8 months. Switching to gonadotrophins increased the chance of conception leading to live birth by 11% over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. The addition of IUI did not significantly increase live birth rates. STUDY DESIGN, SIZE, DURATION: In order to investigate the long-term outcomes of switching to gonadotrophins versus continuing treatment with CC, and undergoing IUI versus continuing with intercourse, we conducted a follow-up study. The study population comprised all women who participated in the M-ovin trial. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participating women were asked to complete a web-based questionnaire. The primary outcome of this study was cumulative live birth. Secondary outcomes included clinical pregnancies, multiple pregnancies, miscarriage, stillbirth, ectopic pregnancy, fertility treatments, neonatal outcomes and pregnancy complications. MAIN RESULTS AND THE ROLE OF CHANCE: We approached 564 women (85%), of whom 374 (66%) responded (184 allocated to gonadotrophins; 190 to CC). After a median follow-up time of 8 years, 154 women in the gonadotrophin group had a live birth (83.7%) versus 150 women in the CC group (78.9%) (relative risk (RR) 1.06, 95% CI 0.96-1.17). A second live birth occurred in 85 of 184 women (49.0%) in the gonadotrophin group and in 85 of 190 women (44.7%) in the CC group (RR 1.03, 95% CI 0.83-1.29). Women allocated to gonadotrophins had a third live birth in 6 of 184 women (3.3%) and women allocated to CC had a third live birth in 14 of 190 women (7.4%). There were respectively 12 and 11 twins in the gonadotrophin and CC groups. The use of fertility treatments in the follow-up period was comparable between both groups. In the IUI group, a first live birth occurred in 158 of 192 women (82.3%) and while in the intercourse group, 146 of 182 women (80.2%) reached at least one live birth (RR: 1.03 95% CI 0.93-1.13; 2.13%, 95% CI -5.95, 10.21). LIMITATIONS, REASONS FOR CAUTION: We have complete follow-up results for 57% of the women.There were 185 women who did not respond to the questionnaire, while 102 women had not been approached due to missing contact details. Five women had not started the original trial. WIDER IMPLICATIONS OF THE FINDINGS: Women with normogonadotropic anovulation and CC failure have a high chance of reaching at least one live birth. In terms of pregnancy rates, the long-term differences between initially switching to gonadotrophins are small compared to continuing treatment with CC. STUDY FUNDING/COMPETING INTEREST(S): The original study received funding from the Dutch Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). A.H. reports consultancy for development and implementation of a lifestyle App, MyFertiCoach, developed by Ferring Pharmaceutical Company. M.G. receives unrestricted grants for scientific research and education from Ferring, Merck and Guerbet. B.W.M. is supported by an NHMRC Investigatorgrant (GNT1176437). B.W.M. reports consultancy for ObsEva and Merck and travel support from Merck. All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: This follow-up study was registered in the OSF Register, https://osf.io/pf24m. The original M-ovin trial was registered in the Netherlands Trial Register, number NTR1449.

[Pathophysiological and diagnostic aspects of Guillain-Barré syndrome]. / Syndrome de Guillain-Barré : physiopathologie et aspects diagnostiques.

Guillain-Barré syndrome (GBS) is the most common cause of acute neuropathy. It usually onset with a rapidly progressive ascending bilateral weakness with sensory disturbances, and patients may require intensive treatment and close monitoring as about 30% have a respiratory muscle weakness and about 10% have autonomic dysfunction. The diagnosis of GBS is based on clinical history and examination. Complementary examinations are performed to rule out a differential diagnosis and to secondarily confirm the diagnosis. GBS is usually preceded by an infectious event in ≈ 2/3 of cases. Infection leads to an immune response directed against carbohydrate antigens located on the infectious agent and the formation of anti-ganglioside antibodies. By molecular mimicry, these antibodies can target structurally similar carbohydrates found on host's nerves. Their binding results in nerve conduction failure or/and demyelination which can lead to axonal loss. Some anti-ganglioside antibodies are associated with particular variants of GBS: the Miller-Fisher syndrome, facial diplegia and paresthesias, the pharyngo-cervico-brachial variant, the paraparetic variant, and the Bickerstaff brainstem encephalitis. Their semiological differences might be explained by a distinct expression of gangliosides among nerves. The aim of this review is to present pathophysiological aspects and the diagnostic approach of GBS and its variants.

Toxic-metabolic encephalopathy in adults: Critical discussion and pragmatical diagnostic approach.

Toxic-metabolic encephalopathy (TME) results from an acute cerebral dysfunction due to different metabolic disturbances including medications or illicit-drugs. It can lead to altered consciousness, going from delirium to coma, which may require intensive care and invasive mechanical ventilation. Even if it is a life-threatening condition, TME might have an excellent prognosis if its etiology is rapidly identified and treated adequately. This review summarizes the main etiologies, their differential diagnosis, and diagnostic strategy and management of TME with a critical discussion on the definition of TME.

[Laser Doppler vibrometric measurements on human temporal bones]. / Laser-Doppler-vibrometrische Messungen an humanen Felsenbeinen.

Laser Doppler vibrometric (LDV) measurements on human temporal bones represent the standard method for predicting the performance of active middle ear implants (AMEI) and are used as preclinical tests in the development, approval process, and indication expansion of AMEI. The quality of the coupling of the floating mass transducer to the mobile structures of the middle ear is decisive for the performance of the implant and patients' hearing perception. The cochlea can be stimulated via the oval window (forward stimulation) or the round window (reverse stimulation). For forward stimulation, the ASTM standard F2504-05 defines a method to ensure physiologically normal properties of the temporal bones used in the experiments. For reverse stimulation, which depends even more critically on the quality of the temporal bone, a comparable standard method is lacking. Appropriate preparation and storage of the human petrous bone as well as suitable LDV test setups with respect to calibration and reproducibility of measuring positions and angles provide results that allow a comparison of different types of coupling and also correlate well with clinical data.

[Evaluation of standardized questionnaires for diagnosis and differentiation of obstructive and patulous Eustachian tube dysfunction]. / Untersuchung standardisierter Anamnesefragebögen zur Diagnostik und Differenzierung von obstruktiven und klaffenden Tubenfunktionsstörungen.

BACKGROUND: Patulous Eustachian tube (ET) dysfunction can impair quality of life (QOL) due to autophony, pressure sensation, and an altered impression of sound. In cases of nonspecific complaints the diagnosis of patulous ET can be difficult, and its distinction from chronic obstructive ET dysfunction is particularly challenging. Since there is currently a lack of standardized diagnostic and therapeutic options, a structured diagnostic workup is essential for accurate diagnosis of this condition. The Eustachian Tube Dysfunction Patient Questionnaire (ETDQ-7) was established by McCoul et al. in 2012 for investigating chronic obstructive ET dysfunction. The Patulous Eustachian Tube Handicap Inventory-10 (PHI-10) was published by Kobayashi et al. in 2017 as an instrument to evaluate patulous ET. PATIENTS AND METHODS: The PHI-10 questionnaire was translated into German and validated in a total of 83 patients (41 healthy subjects, 13 patients with tinnitus, 11 patients with patulous ET, and 18 patients with chronic obstructive ET dysfunction). In addition, the PHI-10 (German) was compared to ETDQ­7. RESULTS: The results of the English version of the PHI-10 questionnaire could be confirmed using the German version. The German version of the PHI-10 and the results of the PHI-10 and ETDQ­7 for each group of patients are presented. The ETDQ­7 leads to false-positive results in patients with patulous ET and the PHI-10 generates false-positive results in patients with chronic obstructive ET dysfunction. Both questionnaires result in false-positive results in patients with tinnitus. CONCLUSION: The PHI-10 and ETDQ­7 (German) can be recommended as an additional tool for preoperative assessment of ET dysfunction. However, they insufficiently discriminate between patulous and obstructive ET dysfunction and are not suitable for patients with tinnitus. The strength of the two questionnaires lies in their suitability for use in monitoring therapeutic success during follow-up.

Passage of uranium through human cerebral microvascular endothelial cells: influence of time exposure in mono- and co-culture in vitro models.

PURPOSE: Depleted uranium (DU) has several civilian and military applications. The effects of this emerging environmental pollutant on human health raise some concerns. Previous experimental studies have shown that uranium (U) exposure can disturb the central nervous system. A small quantity of U reaches the brain via the blood, but the effects on the blood-brain barrier (BBB) remain unclear. MATERIALS AND METHODS: In the present work, two cell culture models were exposed to DU for different times to study its cytotoxicity, paracellular permeability and extracellular concentration of U. The well-known immortalized human cerebral microvascular endothelial cells, hCMEC/D3, were cultured on the filter in the first model. In the second model, human primary cells of pericytes were cultured under the filter to understand the influence of cell environment after U exposure. RESULTS: The results show that U is not cytotoxic to hCMEC/D3 cells or pericytes until 500 µM (1.6 Bq.L-1). In addition, acute or chronic low-dose exposure of U did not disturb permeability and was conserved in both cell culture models. However, U is able to reach the brain compartment. During the first hours of exposure, the passage of U to the abluminal compartment was significantly reduced in the presence of pericytes. Electronic microscopy studies evidenced the formation of needlelike structures, like urchin-shaped precipitates, from 1 h of exposure. Analytical microscopy confirmed the U composition of these precipitates. Interestingly, precipitated U was detected only in endothelial cells and not in pericytes. U was localized in multilamellar or multivesicular bodies along the endo-lysosomal pathway, suggesting the involvement of these traffic vesicles in U sequestration and/or elimination. CONCLUSIONS: We show for the first time the in vitro passage of U across a human cerebral microvascular endothelial cells, and the intracellular localization of U precipitates without any cytotoxicity or modification of paracellular permeability. The difference between the results obtained with monolayers and co-culture models with pericytes illustrates the need to use complex in vitro models in order to mimic the neurovascular unit. Further in vivo studies should be performed to better understand the passage of U across the blood-brain barrier potentially involved in behavioral consequences.

Gonadotrophins or clomiphene citrate in women with normogonadotropic anovulation and CC failure: does the endometrium matter?

STUDY QUESTION: Is endometrial thickness (EMT) a biomarker to select between women who should switch to gonadotropins and those who could continue clomiphene citrate (CC) after six failed ovulatory cycles? SUMMARY ANSWER: Using a cut-off of 7 mm for EMT, we can distinguish between women who are better off switching to gonadotropins and those who could continue CC after six earlier failed ovulatory CC cycles. WHAT IS ALREADY KNOWN: For women with normogonadotropic anovulation, CC has been a long-standing first-line treatment in conjunction with intercourse or intrauterine insemination (IUI). We recently showed that a switch to gonadotropins increases the chance of live birth by 11% in these women over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. It is unclear whether EMT can be used to identify women who can continue on CC with similar live birth rates without the extra costs of gonadotropins. STUDY DESIGN, SIZE, DURATION: Between 8 December 2008 and 16 December 2015, 666 women with CC failure were randomly assigned to receive an additional six cycles with a change to gonadotropins (n = 331) or an additional six cycles continuing with CC (n = 335), both in conjunction with intercourse or IUI. The primary outcome was conception leading to live birth within 8 months after randomisation. EMT was measured mid-cycle before randomisation during their sixth ovulatory CC cycle. The EMT was available in 380 women, of whom 190 were allocated to gonadotropins and 190 were allocated to CC. PARTICIPANTS/MATERIALS, SETTING, METHODS: EMT was determined in the sixth CC cycle prior to randomisation. We tested for interaction of EMT with the treatment effect using logistic regression. We performed a spline analysis to evaluate the association of EMT with chance to pregnancy leading to a live birth in the next cycles and to determine the best cut-off point. On the basis of the resulting cut-off point, we calculated the relative risk and 95% CI of live birth for gonadotropins versus CC at EMT values below and above this cut-off point. Finally, we calculated incremental cost-effectiveness ratios (ICER). MAIN RESULTS AND THE ROLE OF CHANCE: Mid-cycle EMT in the sixth cycle interacted with treatment effect (P < 0.01). Spline analyses showed a cut-off point of 7 mm. There were 162 women (45%) who had an EMT ≤ 7 mm in the sixth ovulatory cycle and 218 women (55%) who had an EMT > 7 mm. Among the women with EMT ≤ 7 mm, gonadotropins resulted in a live birth in 44 of 79 women (56%), while CC resulted in a live birth in 28 of 83 women (34%) (RR 1.57, 95% CI 1.13-2.19). Per additional live birth with gonadotropins, the ICER was €9709 (95% CI: €5117 to €25 302). Among the women with EMT > 7 mm, gonadotropins resulted in a live birth in 53 of 111 women (48%) while CC resulted in a live birth in 52 of 107 women (49%) (RR 0.98, 95% CI 0.75-1.29). LIMITATIONS, REASONS FOR CAUTION: This was a post hoc analysis of a randomised controlled trial (RCT) and therefore mid-cycle EMT measurements before randomisation during their sixth ovulatory CC cycle were not available for all included women. WIDER IMPLICATIONS OF THE FINDINGS: In women with six failed ovulatory cycles on CC and an EMT ≤ 7 mm in the sixth cycle, we advise switching to gonadotropins, since it improves live birth rate over continuing treatment with CC at an extra cost of €9709 to achieve one additional live birth. If the EMT > 7 mm, we advise to continue treatment with CC, since live birth rates are similar to those with gonadotropins, without the extra costs. STUDY FUNDING/COMPETING INTEREST(S): The original MOVIN trial received funding from the Dutch Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). C.B.L.A. reports unrestricted grant support from Merck and Ferring. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva, IGENOMIX and Guerbet. All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Netherlands Trial Register, number NTR1449.

Atypical Deep Cerebral Vein Thrombosis with Hemorrhagic Venous Infarction in a Patient Positive for COVID-19.

There is growing evidence that Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has a neurotropic and neuroinvasive potential. In particular, neurologic complications associated with the infection by SARS-CoV-2 include strokes that may result from a dysregulated inflammatory response to the infection. We report an atypical deep cerebral vein thrombosis complicated with hemorrhagic venous infarction in a patient positive for SARS-CoV-2 with no risk factors for thrombosis.

Multifactorial effects of hyperglycaemia, hyperinsulinemia and inflammation on bone remodelling in type 2 diabetes mellitus.

Bones undergo continuous cycles of bone remodelling that rely on the balance between bone formation and resorption. This balance allows the bone to adapt to changes in mechanical loads and repair microdamages. However, this balance is susceptible to upset in various conditions, leading to impaired bone remodelling and abnormal bones. This is usually indicated by abnormal bone mineral density (BMD), an indicator of bone strength. Despite this, patients with type 2 diabetes mellitus (T2DM) exhibit normal to high BMD, yet still suffer from an increased risk of fractures. The activity of the bone cells is also altered as indicated by the reduced levels of bone turnover markers in T2DM observed in the circulation. The underlying mechanisms behind these skeletal outcomes in patients with T2DM remain unclear. This review summarises recent findings regarding inflammatory cytokine factors associated with T2DM to understand the mechanisms involved and considers potential therapeutic interventions.

[Metabolic encephalopathies]. / Encéphalopathies métaboliques.

Metabolic encephalopathies (ME) are a common cause of admission to emergency rooms, to hospitalization wards or to intensive care units. They could account for 10 to 20% of causes of comatose states in ICU and could be associated to a poor outcome especially in older patients. Nevertheless, they are often reversible and are associated with a favorable outcome when diagnosed and rapidly treated. They correspond to an altered brain functioning secondary to the deficiency of a substance that is mandatory for the normal brain functioning or to the accumulation of a substance that can be either endogenous or exogenous. It preferably occurs in co-morbid patients, complicating its diagnosis and its management. Altered brain functioning, going from mild neuropsychological impairment to coma, movement disorders especially myoclonus and the absence of any obvious differential diagnosis are highly suggestive of the diagnosis. Whereas some biological samplings and brain MRI are essential to rule out differential diagnosis, some others, such as electroencephalogram, may be able to propose important clues in favor of the diagnosis. Once simple symptomatic measures are introduced, the treatment consists mainly in the correction of the cause. Specific treatment options are only seldom available for ME; this is the case for hepatic encephalopathy and some drug-induced encephalopathies. We will successively describe in this review the main pathophysiological mechanisms, the main causes, favoring circumstances of ME, the differential diagnosis to rule out and the etiological work-up for the diagnosis. Finally, a diagnostic and therapeutic strategy for the care of patients with ME will be proposed.

Gonadotrophins versus clomiphene citrate with or without IUI in women with normogonadotropic anovulation and clomiphene failure: a cost-effectiveness analysis.

STUDY QUESTION: Are six cycles of ovulation induction with gonadotrophins more cost-effective than six cycles of ovulation induction with clomiphene citrate (CC) with or without IUI in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC? SUMMARY ANSWER: Both gonadotrophins and IUI are more expensive when compared with CC and intercourse, and gonadotrophins are more effective than CC. WHAT IS KNOWN ALREADY: In women with normogonadotropic anovulation who ovulate but do not conceive after six cycles with CC, medication is usually switched to gonadotrophins, with or without IUI. The cost-effectiveness of these changes in policy is unknown. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation of ovulation induction with gonadotrophins compared with CC with or without IUI in a two-by-two factorial multicentre randomized controlled trial in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC. Between December 2008 and December 2015 women were allocated to six cycles with gonadotrophins plus IUI, six cycles with gonadotrophins plus intercourse, six cycles with CC plus IUI or six cycles with CC plus intercourse. The primary outcome was conception leading to a live birth achieved within 8 months of randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a cost-effectiveness analysis on direct medical costs. We calculated the direct medical costs of ovulation induction with gonadotrophins versus CC and of IUI versus intercourse in six subsequent cycles. We included costs of medication, cycle monitoring, interventions, and pregnancy leading to live birth. Resource use was collected from the case report forms and unit costs were derived from various sources. We calculated incremental cost-effectiveness ratios (ICER) for gonadotrophins compared to CC and for IUI compared to intercourse. We used non-parametric bootstrap resampling to investigate the effect of uncertainty in our estimates. The analysis was performed according to the intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: We allocated 666 women in total to gonadotrophins and IUI (n = 166), gonadotrophins and intercourse (n = 165), CC and IUI (n = 163), or CC and intercourse (n = 172). Mean direct medical costs per woman receiving gonadotrophins or CC were €4495 versus €3006 (cost difference of €1475 (95% CI: €1457-€1493)). Live birth rates were 52% in women allocated to gonadotrophins and 41% in those allocated to CC (relative risk (RR) 1.24:95% CI: 1.05-1.46). The ICER was €15 258 (95% CI: €8721 to €63 654) per additional live birth with gonadotrophins. Mean direct medical costs per woman allocated to IUI or intercourse were €4497 versus €3005 (cost difference of €1510 (95% CI: €1492-€1529)). Live birth rates were 49% in women allocated to IUI and 43% in those allocated to intercourse (RR = 1.14:95% CI: 0.97-1.35). The ICER was €24 361 (95% CI: €-11 290 to €85 172) per additional live birth with IUI. LIMITATIONS, REASONS FOR CAUTION: We allowed participating hospitals to use their local protocols for ovulation induction and IUI, which may have led to variation in costs, but which increases generalizability. Indirect costs generated by transportation or productivity loss were not included. We did not evaluate letrozole, which is potentially more effective than CC. WIDER IMPLICATIONS OF THE FINDINGS: Gonadotrophins are more effective, but more expensive than CC, therefore, the use of gonadotrophins in women with normogonadotropic anovulation who have not conceived after six ovulatory CC cycles depends on society's willingness to pay for an additional child. In view of the uncertainty around the cost-effectiveness estimate of IUI, these data are not sufficient to make recommendations on the use of IUI in these women. In countries where ovulation induction regimens are reimbursed, policy makers and health care professionals may use our results in their guidelines. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by the Netherlands Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). The Eudract number for this trial is 2008-006171-73. The Sponsor's Protocol Code Number is P08-40. CBLA reports unrestricted grant support from Merck and Ferring. BWM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva and Guerbet. TRIAL REGISTRATION NUMBER: NTR1449.

Neonatal abstinence syndrome and early childhood morbidity and mortality in Washington state: a retrospective cohort study.

OBJECTIVE: The objective of the study was to evaluate the association between neonatal abstinence syndrome (NAS) and long-term childhood morbidity and infant mortality. STUDY DESIGN: We conducted a cohort study of infants born in Washington State during 1990 to 2008 who were diagnosed with NAS (n=1900) or were unexposed (n=12,283, frequency matched by birth year). 5-year hospital readmissions and infant mortality were ascertained. RESULTS: Children with history of NAS had increased risk of readmission during the first 5 years of life relative to unexposed children; this remained statistically significant after adjustment for maternal age, maternal education, gestational age and intrapartum smoking status (readmission rates: NAS=21.3%, unexposed=12.7%, adjusted relative risk (aRR) 1.54, 95% confidence interval (CI) 1.37 to 1.73). NAS was associated with increased unadjusted infant mortality risk, but this did not persist after adjustment (aRR 1.94, 95% CI 0.99 to 3.80). CONCLUSION: The observed increased risk for childhood hospital readmission following NAS diagnosis argues for development of early childhood interventions to prevent morbidity.Journal of Perinatology advance online publication,.