Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1+/- and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1+/- mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission.

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BackgroundA short acting spinal anesthetic facilitates smooth flow since quick recovery of motor function will facilitate unassisted ambulation. The aim of this study was to estimate the effective dose (ED90) of intrathecal 2-chloroprocaine 1% in outpatient knee arthroscopy.MethodsTwo cohorts were included in two different hospitals. In cohort I, a randomized biased-coin up-and-down design with 40 patients was used to find the ED90. Four dose-levels of plain 2-chloroprocaine 1% were used: 25, 30, 35 and 40 mg. The identified primary outcome, the ED90, was validated in 50 patients in cohort II with an open label design. Secondary outcomes included time to complete recovery from motor and sensory block with spinal injection as time zero, peak sensory block level, urine retention and time until hospital discharge.ResultsForty patients were included in the final analysis in cohort I. The ED90 was estimated at 27.8 mg, successful spinal anesthesia was obtained in 38 patients (95%). Fifty patients were included in the final analysis in cohort II, 49 patients had successful anesthesia with a fixed round dose of 28 mg. In this Cohort, peak sensory block was T10/T11 (range: (L4–T4)). The median time to full recovery of the motor block was 60 min (45–60) and 90 min (75–105) for the sensory block. The mean time to hospital discharge was 2.9 hours (0.7).ConclusionThe ED90 of 2-chloroprocaine 1% in knee arthroscopy was estimated to be 27.8 mg. In an external population, the ED90 resulted in successful anesthesia in 98% of the patients (95% CI 89% to 100%).Trial registration numberNetherlands Trial Registry (NL6769).

Objectives Endometriosis is characterized by a long interval between onset of symptoms and diagnosis. Detailed information about the patients’ perspective on the diagnostic delay of endometriosis is scarce. The aim of this study was to identify strengths and weaknesses in the diagnostic process of endometriosis from the patients’ perspective. Methods Qualitative study with semi-structured focus groups. Participants were women between 18 and 45 years old with a recently confirmed diagnosis. The focus groups were audio recorded and fully transcribed. Grounded theory methodology was applied for data analysis. Results Six focus groups were organized, in which 23 women participated. Mean time from start of symptoms to diagnosis was 8.5 years. Dominant themes were knowledge about normal menstruation and endometriosis, being believed and acknowledged by medical staff, and collaboration between health care providers including fast referral to a gynaecologist. Barriers to a timely referral and diagnosis were young age, normalization of symptoms and a lack of awareness in general practitioners. Facilitating factors included adequate knowledge and skills of the general practitioner, a desire for pregnancy and persisting in a request for specialist consultation by the patient. Conclusions The diagnostic process of endometriosis is hampered by delayed consultation, inadequate appraisal of symptoms by general practitioners and the interaction between patients and medical professionals. Efforts should be made to increase public awareness and to provide medical staff with sufficient knowledge and skills to adequately acknowledge presented symptoms.

Endometriosis is a common and complex disease that is difficult to diagnose and treat. 1,2 Centralization of care in expertise centers can contribute to a multidisciplinary approach to both diagnosing and treating endometriosis. However, until June 2020, no criteria for endometriosis expertise centers in the Netherlands were established. The aim of centralization of endometriosis care is to improve treatment for women with endometriosis by shortening the delay in diagnosis and reducing morbidity, leading to an improvement of their quality of life. This aim is in accordance with the advices of the European Society of Human Reproduction and Embryology (ESHRE), the World Endometriosis Society (WES), and the National Institute for Health and Care Excellence (NICE). Centralization of surgery has already proved to be successful in other disciplines in terms of improving clinical outcome. 3,4 A retrospective multicenter study in France shows a correlation between surgical experience and postoperative complications in the treatment of deep infiltrating endometriosis. 5 Already in 2006, D'Hooghe and Hummelshoj discussed in their opinion paper how the treatment of and research into endometriosis could be improved by the implementation of multidisciplinary centers and networks of excellence. 6 In 2011, the WES formulated two consensus statements clarifying the importance of endometriosis expertise centers. 7 WES initiated a consensus workshop regarding centralization of care in 2017, where the following advices were formulated: the centralization of endometriosis care is necessary, with a specific focus on surgery, fertility, pain, and psychosocial guidance, seeking adequate support and the proper mode in each local context (WES, personal communication).In a number of European countries such as Denmark (2001), Germany (2005, and France (2017), expertise centers to centralize endometriosis care have been implemented (Table 1). [8][9][10]