Electron transport measurements in liquid xenon with Xenoscope, a large-scale DARWIN demonstrator.

The DARWIN observatory is a proposed next-generation experiment with 40 tonnes of liquid xenon as an active target in a time projection chamber. To study challenges related to the construction and operation of a multi-tonne scale detector, we have designed and constructed a vertical, full-scale demonstrator for the DARWIN experiment at the University of Zurich. Here, we present the first results from a several-months run with 343kg of xenon and electron drift lifetime and transport measurements with a 53cm tall purity monitor immersed in the cryogenic liquid. After 88days of continuous purification, the electron lifetime reached a value of (664±23)µs. We measured the drift velocity of electrons for electric fields in the range (25-75) V/cm, and found values consistent with previous measurements. We also calculated the longitudinal diffusion constant of the electron cloud in the same field range, and compared with previous data, as well as with predictions from an empirical model.

[Intravesical instillations for inflammatory and sensory chronic bladder diseases: Literature review and guide to clinical practice]. / Instillations endovésicales pour les cystopathies chroniques inflammatoires et douloureuses : revue de la littérature et guide de la pratique clinique.

INTRODUCTION: Inflammatory and sensory chronic bladder diseases have a significant impact on quality of life. These pathologies share alteration of the layer between urine and urothelium, making the use of topical agents appropriate. OBJECTIVES: Review the efficacy and tolerance of intravesical treatments for these pathologies. Give practical guidelines for the use of agents currently available in France. METHOD: A narrative review was performed in March 2021 using PubMed/MEDLINE, Google Scholar and the international guidelines. Pharmaceutical companies and pharmacies were interviewed. RESULTS: Although numerous molecules were tested over the last 5 decades, only dimethylsulfoxyde and glycosaminoglycans are available in France today. Results are promising: response rates are up to 95% and 84% respectively in bladder pain syndrome. In urinary tract infections, glycosaminoglycans could decrease annual number of cystitis by 2.56 (95% confidence interval (CI) -3.86, -1.26; P<0.001) and increase the time to first cystitis recurrence by 130 days (95% CI: 5.84 - 254.26; P=0.04). In radiation cystitis, results could be comparable to hyperbaric oxygen regarding pain and frequency of voiding (-1.31±1.3 visual analogic scale et -1.5±1.4 voiding per day, respectively, at 12 months, P<0.01). However, literature has a low level of evidence. CONCLUSION: Chronic bladder diseases have limited treatment options. Intravesical agents are a good alternative, although their cost is significant and their outcome uncertain.

Physical Constraint in Pediatric Dentistry: The Lived Experience of Parents.

BACKGROUND: The use of physical constraint in pediatric dentistry is highly controversial. Papoose boards in particular, which envelop and immobilize children during treatment procedures, have been described as barbaric devices even though their goal is to protect the patient. In this debate, the voice of parents is important but still missing in the scientific literature. AIM: To understand how parents or caregivers experienced physical constraint and the use of the papoose board on their children during regular dental treatment. DESIGN: We conducted qualitative research rooted in interpretive phenomenology. Accordingly, we performed in-depth individual interviews with a purposive sample of 7 parents or caregivers. The interviews took place in Montréal, Canada, after the children had been treated with a papoose board for nonemergency dental treatments. The discussions were audio recorded, transcribed, and thematically analyzed. RESULTS: Two perspectives emerged among participants. Some explained that the papoose board calmed their children, helped the dentist to complete the procedures, and made their experience less stressful. For others, the papoose board was a horrible and traumatizing experience, leading to feelings of guilt toward their children. They expressed anger toward the dentists for not allowing them enough time to decide and for imposing use of the device. CONCLUSION: Our study raises serious ethical concerns about this practice. We believe that using a papoose board should remain an extraordinary measure and, more generally, that dental professionals should reflect on the place of children and their families in clinical encounters. KNOWLEDGE TRANSFER STATEMENT: The findings of this study should encourage policy makers, dental professionals and ethicists to consider the following points: 1) the traumatizing experiences described by parents raise serious ethical concerns about the use of papoose boards; 2) the dental profession should reflect on the place of children and their families in the clinical encounter and grapple with the importance of consent and how to ensure consent in encounters involving children and their parents.

2021 opinion from the CUROPF on THE efficacy and safety of mid-urethral slings used in women WITH urinary stress incontinence.

OBJECTIVE: To determine the usefulness of mid-urethral slings (MUS) in the surgical management of women presenting with urinary stress incontinence (USI) METHOD: A consensus committee of multidisciplinary experts (CUROPF) was convened and focused on PICO questions concerning the efficacy and safety of MUS surgery compared to other procedures and concerning which approach (retropubic (RP) vs transobturator (TO)) should be proposed as a first-line MUS surgery for specific subpopulations (obese; intrinsic sphincteric deficiency (ISD); elderly) RESULTS: As compared to other procedures (urethral bulking agents, traditional slings and open colposuspension), the MUS procedure should be proposed as the first-line surgical therapy (strong agreement). MUS surgery can be associated with complications and proper pre-operative informed consent is mandatory (strong agreement). Mini-slings (SIS/SIMS) should only be proposed in clinical trials (strong agreement). Both RP and TO approaches may be proposed for the insertion of MUS (strong agreement). However, if the woman is willing to accept a moderate increase in per-operative risk, the RP approach should be preferred (strong agreement) since it is associated with higher very long-term cure rates and as it is possible to completely remove the sling surgically if a severe complication occurs. The RP approach should be used for the insertion of MUS in a woman presenting with ISD (strong agreement). Either the RP or TO approach should be used for the insertion of MUS in an obese woman presenting with USI (strong agreement). In very obese women (BMI ≥35-40kg/m2), weight loss should be preferred prior to MUS surgery and bariatric surgery should be discussed (strong agreement) CONCLUSION: The current Opinion provides an appropriate strategy for both the selection of patients and the best therapeutic approach in women presenting with USI.

[Complications of mid-urethral sling - A review from the Committee for Female Urology and Pelviperineology for the French Association of Urology]. / Complications des bandelettes sous urétrales : une revue de la littérature par le Comité d'urologie et pelvipérinéologie de la femme de l'Association française d'urologie.

INTRODUCTION: Placement of a mid-urethral sling is the gold standard in the surgical management of stress urinary incontinence in women in France. The cure rate of this material is no longer to be demonstrated, but the per- and post-operative complications are currently the subject of a growing controversy not only in Europe but also across the Channel and across the Atlantic, having led to the modification of operative indications. In France, recommendations are also evolving with a stricter framework for indications for surgery by multidisciplinary consultation meeting and an obligation for postoperative follow-up in the short and long term. OBJECTIVES: In this context, CUROPF realized a review of the literature bringing together the available scientific evidence concerning the occurrence of per- and post-operative complications relating to the installation of mid urethral sling. The bibliographic search was carried out using the Medline database and 123 articles were selected. RESULTS: Analysis of the data highlights various complications, depending on the implanted material, the patient and the indication for surgery. The retro-pubic mid urethral sling provides more bladder erosion during surgery (up to 14%), more suprapubic pain (up to 4%) and more acute urinary retention (up to 19,7%) and postoperative dysuria (up to 26%). The trans obturator mid-urethral sling is responsible for more vaginal erosion during the operation (up to 10,9%), more lower limb pain of neurological origin (up to 26,7%). The risk of developing over active bladder is similar in both procedures (up to 33%). But these risks of complications must be balanced by the strong impact of urinary incontinence surgery on the overall quality of life of these women. CONCLUSION: Thus, surgical failure and long term complications exist but should not limit the surgical management of stress urinary incontinence with mid urethral tape. Women should be treated with individualized decision-making process and long-term follow -up is necessary.

[Vaginal LASER therapy for genito-urinary disorders: A systematic review and statement from the Committee for Female Urology and Pelviperineology of the French Association of Urology]. / Utilisation du LASER vaginal pour le traitement des pathologies génito-urinaires : revue systématique de la littérature et position du CUROPF.

INTRODUCTION: Vaginal LASER therapy is increasingly used in the field of urogynecology, but several points remain unclear. Our goal was to produce a systematic review of available evidence and provide a critical appraisal of available data. METHODS: A systematic review until march 2020 was conducted using PubMed/MEDLINE, Cochrane and Embase databases. All studies about vaginal LASER use in the field of urogynecology were included. RESULTS: Forty studies have been included (8 for genitourinary syndrome of menopause, 19 for stress urinary incontinence, 3 for overactive bladder, 7 for urogenital prolapse, 3 for other indications). Data were heterogeneous, and level of evidence was weak or very weak. Few studies were comparative, and only 3 were randomized). Mild improvement of symptoms and quality of life and limited satisfaction were seen for genitourinary syndrome, stress urinary incontinence, overactive bladder and prolapse. Few adverse events were reported. However, major methodological biases were noted regarding efficacy and safety evaluation. No long-term results were available. CONCLUSIONS: While Vaginal LASER therapy seem to provide encouraging results, the level of evidence supporting its use was weak, especially regarding long-term outcomes. Studies of better quality are warranted before any recommendation can be made. Current use should be limited to clinical research.

The first dual-phase xenon TPC equipped with silicon photomultipliers and characterisation with 37 Ar.

For the first time, a small dual-phase (liquid/gas) xenon time projection chamber was equipped with a top array of silicon photomultipliers for light and charge readout. Here we describe the instrument in detail, as well as the data processing and the event position reconstruction algorithms. We obtain a spatial resolution of ∼ 1.5 mm in the horizontal plane. To characterise the detector performance, we show calibration data with internal 83 m Kr and 37 Ar sources, and we detail the production of the latter as well as its introduction into the system. We finally compare the observed light and charge yields down to electronic recoil energies of 2.82 keV to predictions based on NEST v2.0.

Neurons in the Nucleus papilio contribute to the control of eye movements during REM sleep.

Rapid eye movements (REM) are characteristic of the eponymous phase of sleep, yet the underlying motor commands remain an enigma. Here, we identified a cluster of Calbindin-D28K-expressing neurons in the Nucleus papilio (NPCalb), located in the dorsal paragigantocellular nucleus, which are active during REM sleep and project to the three contralateral eye-muscle nuclei. The firing of opto-tagged NPCalb neurons is augmented prior to the onset of eye movements during REM sleep. Optogenetic activation of NPCalb neurons triggers eye movements selectively during REM sleep, while their genetic ablation or optogenetic silencing suppresses them. None of these perturbations led to a change in the duration of REM sleep episodes. Our study provides the first evidence for a brainstem premotor command contributing to the control of eye movements selectively during REM sleep in the mammalian brain.

Comparison of screening CEDM and MRI for women at increased risk for breast cancer: A pilot study.

OBJECTIVES: Contrast enhanced digital mammography (CEDM) is a new breast imaging technology increasingly used in the diagnostic setting but its utility in the pure screening setting has not been reported. The goal of this pilot study is to prospectively compare screening CEDM to breast MRI in women with an increased risk for breast cancer. METHODS: In this IRB-approved HIPAA-compliant study, 318 women at increased breast cancer risk were consented (December 2012-May 2015) to undergo CEDM in addition to their scheduled MRI. CEDM was performed within 30days of screening MRI. CEDM was interpreted blinded to MRI. The reference standard was defined as a combination of pathology and 2-year imaging follow-up. RESULTS: Data from 307/318 patients were evaluable. Three cancers (two invasive cancers, one ductal carcinoma in situ) were detected at first round screening: MRI detected all three and CEDM detected the two invasive cancers. None of the three cancers was seen on the low energy mammograms which are comparable to conventional mammography. At 2year imaging follow up, there were 5 additional screen detected cancers and no palpable cancers. The positive predictive value 3 (PPV3) for CEDM was 15% (2/13, 95% CI: 2-45%) and 14% for MRI (3/21, 95% CI: 3-36%). The specificity of CEDM and MRI were 94.7% and 94.1% respectively. CONCLUSIONS: Both CEDM and MRI detected additional cancers not seen on conventional mammography, primarily invasive cancers. Our pilot data suggest that CEDM could be valuable as a supplemental imaging exam for women at increased risk for breast cancer who do not meet the criteria for MRI or for whom access to MRI is limited. Validation in larger multi institutional trials is warranted.

Dark Matter Search Results from the PICO-60 C_{3}F_{8} Bubble Chamber.

New results are reported from the operation of the PICO-60 dark matter detector, a bubble chamber filled with 52 kg of C_{3}F_{8} located in the SNOLAB underground laboratory. As in previous PICO bubble chambers, PICO-60 C_{3}F_{8} exhibits excellent electron recoil and alpha decay rejection, and the observed multiple-scattering neutron rate indicates a single-scatter neutron background of less than one event per month. A blind analysis of an efficiency-corrected 1167-kg day exposure at a 3.3-keV thermodynamic threshold reveals no single-scattering nuclear recoil candidates, consistent with the predicted background. These results set the most stringent direct-detection constraint to date on the weakly interacting massive particle (WIMP)-proton spin-dependent cross section at 3.4×10^{-41} cm^{2} for a 30-GeV c^{-2} WIMP, more than 1 order of magnitude improvement from previous PICO results.

Two crystal x-ray spectrometers for OMEGA experiments.

Two x-ray spectrometers have been built for x-ray spectroscopy of laser-produced plasmas on OMEGA at the Laboratory for Laser Energetics (LLE) by Commissariat à l'Energie Atomique et aux énergies alternatives (CEA). The accessible photon energy range is from 1.5 to 20 keV. The first spectrometer, called X-ray CEA Crystal Spectrometer with a Charge-Injection Device (XCCS-CID), records three spectra with three crystals coupled to a time integrated CID camera. The second one, called X-ray CEA Crystal Spectrometer (XCCS) with a framing camera, is time resolved and records four spectra with two crystals on the four frames of a framing camera. Cylindrical crystals are used in Johan geometry. Each spectrometer is positioned with a ten-inch manipulator inside the OMEGA target chamber. In each experiment, after choosing a spectral window, a specific configuration is designed and concave crystals are precisely positioned on a board with angled wedges and spacers. Slits on snouts enable 1D spatial resolution to distinguish spectra emitted from different parts of the target.

Dark Matter Search Results from the PICO-2L C3F8 Bubble Chamber.

New data are reported from the operation of a 2 liter C3F8 bubble chamber in the SNOLAB underground laboratory, with a total exposure of 211.5 kg days at four different energy thresholds below 10 keV. These data show that C3F8 provides excellent electron-recoil and alpha rejection capabilities at very low thresholds. The chamber exhibits an electron-recoil sensitivity of <3.5×10(-10) and an alpha rejection factor of >98.2%. These data also include the first observation of a dependence of acoustic signal on alpha energy. Twelve single nuclear recoil event candidates were observed during the run. The candidate events exhibit timing characteristics that are not consistent with the hypothesis of a uniform time distribution, and no evidence for a dark matter signal is claimed. These data provide the most sensitive direct detection constraints on WIMP-proton spin-dependent scattering to date, with significant sensitivity at low WIMP masses for spin-independent WIMP-nucleon scattering.

The EF-hand Ca(2+)-binding protein super-family: a genome-wide analysis of gene expression patterns in the adult mouse brain.

In mice, 249 putative members of the superfamily of EF-hand domain Ca(2+)-binding proteins, manifesting great diversity in structure, cellular localization and functions have been identified. Three members in particular, namely, calbindin-D28K, calretinin and parvalbumin, are widely used as markers for specific neuronal subpopulations in different regions of the brain. The aim of the present study was to compile a comprehensive atlas of the gene-expression profiles of the entire EF-hand gene superfamily in the murine brain. This was achieved by a meticulous examination of the in-situ hybridization images in the Allen Brain Atlas database. Topographically, our analysis focused on the olfactory bulb, cerebral cortex (barrel cortex in the primary somatosensory area), basal ganglia, hippocampus, amygdala, thalamus, hypothalamus, cerebellum, midbrain, pons and medulla, and on clearly identifiable sub-structures within each of these areas. The expression profiles of four family-members, namely hippocalcin-like 4, neurocalcin-δ, plastin 3 and tescalcin, that have not been hitherto reported, at either the mRNA (in-situ-hybridization) or the protein (immunohistochemical) levels, are now presented for the first time. The fruit of our analysis is a document in which the gene-expression profiles of all members of the EF-hand family genes are compared, and in which future possible neuronal markers for specific cells/brain areas are identified. The assembled information could afford functional clues to investigators, conducive to further experimental pursuit.

Thrombospondin 4 deficiency in mouse impairs neuronal migration in the early postnatal and adult brain.

In the post-natal rodent brain, neuronal precursors originating from the sub-ventricular zone (SVZ) migrate over a long distance along the rostral migratory stream (RMS) to eventually integrate the olfactory bulb neuronal circuitry. In order to identify new genes specifically expressed in the RMS, we have screened the Allen Brain Atlas Database. We focused our attention on Thrombospondin 4 (Thbs4), one of the 5 members of the Thrombospondin family of large, multidomain, extracellular matrix proteins. In post-natal and adult brain Thbs4 mRNA and protein are specifically expressed in the neurogenic regions, including the SVZ and along the entire RMS. RMS cells expressing Thbs4 are GFAP (Glial Fibrillary Acidic Protein) positive astrocytes. Histological analysis in both wild-type and Thbs4 knock-out mice revealed no major abnormality in the general morphology of these neurogenic regions. Nevertheless, immunostaining for doublecortin demonstrates that in Thbs4-KO, migration of newly formed neurons along the RMS is somehow impaired, with several neurons migrating out of the RMS. This is further supported by a Bromodeoxyuridine-based in vivo approach showing a decrease in the number of newly born neuronal precursors reaching the olfactory bulb, while proliferation in the SVZ is not affected compared to wild-type, both in young animals (P15) and in adults (8 to 12 weeks of age). Corroborating this observation, the number of Parvalbumin- and Calbindin-immunoreactive interneurons in the olfactory bulb is also reduced in Thbs4-KO. Together, these observations support a role for the astrocyte-secreted protein Thbs4 in the migration of newly form neurons within the RMS to the olfactory bulb.

Evaluation of peripheral versus central effects of GABA(B) receptor activation using a novel, positive allosteric modulator of the GABA(B) receptor ADX71943, a pharmacological tool compound with a fully peripheral activity profile.

BACKGROUND AND PURPOSE: The GABA(B) receptor agonist, baclofen, has shown promising effects in patients suffering from pain, post-traumatic stress disorder, alcoholism, overactive bladder and gastroesophageal reflux disease. However, baclofen's short duration of action and side effects limit its wider use. Here we characterized a novel, GABA(B) receptor positive allosteric modulator (PAM) ADX71943. EXPERIMENTAL APPROACH: In vitro, ADX71943 was assessed for pharmacological activity and selectivity using recombinant and native GABA(B) receptors. In vivo ADX71943 was assessed in the acetic acid-induced writhing (AAW) test in mice and formalin tests (FTs) in mice and rats. Marble burying (MB) and elevated plus maze (EPM) tests, rotarod, spontaneous locomotor activity (sLMA) and body temperature (BT) tests in mice and rats were used to investigate centrally-mediated effects. KEY RESULTS: In vitro, in the presence of GABA, ADX71943 increased the potency and efficacy of agonists and showed selectivity at the GABA(B) receptor. ADX71943 reduced pain-associated behaviours in AAW; an effect blocked by GABA(B) receptor antagonist CGP63360. ADX71943 reduced pain in the FT in mice and rats, but was inactive in the MB and EPM despite reaching high concentrations in plasma. ADX71943 had no effect on BT, rotarod and sLMA. CONCLUSIONS AND IMPLICATIONS: ADX71943 showed consistent and target-related efficacy in tests of disorders that have a significant peripheral component (acute and chronic pain), while having no effect in those associated with centrally-mediated anxiety-like reactivity and side effects. Thus, ADX71943 is a useful pharmacological tool for delineation of peripherally- versus centrally-mediated effects of GABA(B) receptor activation.

A French collaborative survey of 272 fetuses with 22q11.2 deletion: ultrasound findings, fetal autopsies and pregnancy outcomes.

OBJECTIVE: The 22q11.2 deletion (del22q11.2) is one of the most common microdeletions. We performed a collaborative, retrospective analysis in France of prenatal diagnoses and outcomes of fetuses carrying the del22q11.2. METHODS: A total of 272 fetuses were included. Data on prenatal diagnosis, ultrasound findings, pathological features, outcomes and inheritance were analyzed. RESULTS: The mean time of prenatal diagnosis was 25.6 ± 6 weeks of gestation. Most of the diagnoses (86.8%) were prompted by abnormal ultrasound findings [heart defects (HDs), in 83.8% of cases]. On fetal autopsy, HDs were again the most common disease feature, but thymus, kidney abnormalities and facial dysmorphism were also described. The deletion was inherited in 27% of cases. Termination of pregnancy (TOP) occurred in 68.9% of cases and did not appear to depend on the inheritance status. However, early diagnosis was associated with a higher TOP rate. CONCLUSION: This is the largest cohort of prenatal del22q11.2 diagnoses. As in postnatally diagnosed cases, HDs were the most frequently observed abnormalities. However, thymus and kidney abnormalities and polyhydramnios should also be screened for in the prenatal diagnosis of del22q11.2. Only the time of diagnosis appeared to be strongly associated with the pregnancy outcome: the earlier the diagnosis, the higher the TOP rate.

NMR metabolomics profiling of blood plasma mimics shows that medium- and long-chain fatty acids differently release metabolites from human serum albumin.

Metabolite profiling by NMR of body fluids is increasingly used to successfully differentiate patients from healthy individuals. Metabolites and their concentrations are direct reporters of body biochemistry. However, in blood plasma the NMR-detected free-metabolite concentrations are also strongly affected by interactions with the abundant plasma proteins, which have as of yet not been considered much in metabolic profiling. We previously reported that many of the common NMR-detected metabolites in blood plasma bind to human serum albumin (HSA) and many are released by fatty acids present in fatted HSA. HSA is the most abundant plasma protein and main transporter of endogenous and exogenous metabolites. Here, we show by NMR how the two most common fatty acids (FAs) in blood plasma - the long-chain FA, stearate (C18:0) and medium-chain FA, myristate (C14:0) - affect metabolite-HSA interaction. Of the set of 18 common NMR-detected metabolites, many are released by stearate and/or myristate, lactate appearing the most strongly affected. Myristate, but not stearate, reduces HSA-binding of phenylalanine and pyruvate. Citrate signals were NMR invisible in the presence of HSA. Only at high myristate-HSA mole ratios 11:1, is citrate sufficiently released to be detected. Finally, we find that limited dilution of blood-plasma mimics releases HSA-bound metabolites, a finding confirmed in real blood plasma samples. Based on these findings, we provide recommendations for NMR experiments for quantitative metabolite profiling.