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Abstract Laterally directed explosive eruptions are responsible for multiple fatalities over the past decade and are an increasingly important volcanology problem. To understand the energy dynamics for these events, we collected field-scale explosion data from nine acoustic sensors surrounding a tiltable cannon as part of an exploratory experimental design. For each cannon discharge, the blast direction was varied systematically at 0°, 12°, and 24° from vertical, capturing acoustic wavefield directivity related to the tilt angle. While each event was similar in energy discharge potential, the resulting acoustic signal features were variable event-to-event, producing non-repetitious waveforms and spectra. Systematic features were observed in a subset of individual events for vertical and lateral discharges. For vertical discharges, the acoustic energy had a uniform radiation pattern. The lateral discharges showed an asymmetric radiation pattern with higher frequencies in the direction of the blast and depletion of those frequencies behind the cannon. Results suggest that, in natural volcanic systems, near-field blast directionality may be elucidated from acoustic sensors in absence of visual data, with implications for volcano monitoring and hazard assessment. Graphical Abstract

Abstract Volcanic tremor is a crucial indicator for assessing the state and hazard potential of volcanic systems. At Whakaari (White Island volcano, Aotearoa New Zealand), a pulsed tremor signal emerged after a hydrothermal explosion in August 2012. The tremor accompanied the extrusion of a lava dome, before gradually disappearing prior to the onset of renewed hydrothermal activity in January 2013. We interpret this seismic signal to represent discrete gas transfers from a magmatic intrusion toward a permeable cap—possibly a hydrothermal seal—in the upper layers of Whakaari's hydrothermal system. Such tremor may thus be associated with heightened potential for hazardous explosive activity but is difficult to detect using conventional seismic monitoring parameters. To highlight the emergence of subtle periodic signals, we experiment with Lomb‐Scargle periodograms (LS). LS detect the tremor 5 days before it becomes visible in seismograms, thus facilitating the recognition of such elusive seismic patterns.

Abstract Whakaari/White Island has been the most active New Zealand volcano in the 21st century, producing small phreatic and phreatomagmatic eruptions, which are hard to predict. The most recent eruption occurred in 2019, tragically claiming the lives of 22 individuals and causing numerous injuries. We employed shear‐wave splitting analyses to investigate variations in anisotropy between 2018 and 2020, during quiescence, unrest, and the eruption. We examined spatial and temporal variations in 3,499 shear‐wave splitting and 2,656 Vp/Vs ratio measurements. Comparing shear‐wave splitting parameters from similar earthquake paths across different times indicates that the observed temporal changes are unlikely to result from variations in earthquake paths through media with spatial variability. Instead, these changes may stem from variations in anisotropy over time, likely caused by changes in crack alignment due to stress or varying fluid content.

Introduction: Systemic sclerosis (SSc) is a rare autoimmune disease currently classified into two subgroups based on skin extension. The aim of this study was to determine in a large cohort whether the determination of autoantibody (AAb) profile among a full antinuclear AAbs panel including nine specificities had a higher impact than skin phenotype on stratifying the risk of organ involvement and mortality in SSc., Methods: Data for patients with SSc followed in seven French university hospitals were retrospectively analysed in terms of skin phenotype, AAbs (anti-topoisomerase I (ATA), anticentromere (ACA), anti-RNA polymerase III (anti-RNAPIII), anti-U1RNP, anti-U3RNP, anti-Pm/Scl, anti-Ku, anti-Th/To, anti-NOR90), organ involvement and mortality. Multivariate analyses were performed to identify independent factors associated with organ involvement and mortality., Results: We included 1605 patients with SSc (367 with diffuse cutaneous SSc). On multivariate analysis, ATAs were associated with interstitial lung disease and mortality (OR=3.27 (95% CI 2.42 to 4.42); HR=1.9 (95% CI 1.01 to 3.58)), anti-RNAPIII with scleroderma renal crisis and mortality (OR=7.05 (95% CI 2.98 to 16.72); HR=2.35 (95% CI 1.12 to 4.93)), anti-U1RNP with arthritis (OR=3.79 (95% CI 2.16 to 6.67)), anti-Pm/Scl and anti-Ku with myositis (OR=7.09 (95% CI 3.87 to 12.98) and 7.99 (95% CI 2.41 to 26.46)). The skin phenotype was not associated with survival or organ involvement on multivariate analysis without stepwise selection., Conclusion: This study unravels, by contrast with skin phenotype, a strong association between AAbs specificities, organ involvement and outcome in SSc and suggests that patients' classification based on only skin extension is not sufficient for defining prognosis and phenotype., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Radiolabeling is critical in complex chemical reactions involving positron emission tomography (PET) radiotracer production. The process is now automated within a synthesis module to enhance efficiency and reduce radiation exposure. The key to this automation is the use of radiation detectors to monitor radioactivity transfer and ensure the progression of reactions. However, the high cost of these detectors has motivated the need for a more affordable alternative., Purpose: This study aimed to develop a compact and cost-efficient detector using scintillating fibers and silicon photomultipliers (SiPMs) to track radioactivity throughout PET radiotracer production., Methods: Monte Carlo simulations were performed with the Geant4-based M-TAG software for four detector geometries (single fiber, single fiber with bolus, 16-fiber bundle, and spiral) to optimize the detector construction for better detection efficiency. The simulations scored the energy deposited into the scintillating fibers per simulated particle, which was used to estimate the expected voltage pulse height from the SiPM considering the total light collection efficiency. Based on the simulation results, two detector configurations (16-fiber bundle and spiral fiber) were constructed using plastic scintillating fibers, optical fibers, a 6 mm × $\times$ 6 mm SiPM, and commonly available electronic components. The detectors were calibrated using a Fluorine-18 ( 18 F $^{18}{\rm F}$ ) source with typical activity levels used in radiotracer production. Detector performances were subsequently evaluated through linearity tests and measurement uncertainty assessments. Errors up to ± 5 % $\pm 5\%$ were considered acceptable for troubleshooting purposes., Results: The calibration curves showed a linear response with changing activity for both detectors. The calibrated detectors offered real-time activity measurements ranging from 0.10 to 49.41 GBq, with a 3-s refresh rate. In the activity range above 0.145 GBq, the uncertainties were less than 5 % $5\%$ for both the 16-fiber and spiral configurations. The spiral detector recorded a signal with a half-life of 105.88 ± 0.40 $105.88 \pm 0.40$ min, closely aligning with the reference half-life of 18 F $^{18}{\rm F}$ ., Conclusions: Cost-efficient plastic scintillation fiber detectors were developed to facilitate the troubleshooting of automated synthesis of PET radiotracers., (© 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Introduction: Body mass index (BMI) is often used in surgical settings to determine patients' risk of complications. In the context of gender-affirming care, BMI requirements for surgery can limit access to necessary care for larger-bodied people. There is a critical need to understand the association between BMI and postoperative outcomes for this population., Methods: A retrospective chart review was conducted using the first 250 consecutive gender-affirming masculinizing chest reconstructions performed between 2017 and 2021 at a large academic medical institution. The relationships between BMI, preoperative factors, and common postsurgical outcomes were assessed., Results: Average BMI at surgery was 27.5 ± 6.7 kg/m 2 . Increases in BMI were associated with longer drain stays, larger volume of tissue resected, higher likelihood of nipple grafts, and lower likelihood of periareolar surgery (all P < 0.0001). Simple logistic regression revealed that BMI increases were significantly related to the likelihood of experiencing dog ears in the intermediate term (P = 0.002). Multivariate logistic regression adjusted for common covariates (age, ethnicity, smoking status, asthma, autoimmune disorders, cardiovascular conditions, and mental health disorders) did not reveal any significant relationships between BMI and the likelihood of experiencing complications at any study point., Conclusions: Masculinizing chest reconstruction is safe and satisfactory for young adult patients across the range of BMI, with significant differences in outcomes found only for esthetic complications (i.e., dog ears). Surgeons should inform patients with higher BMIs about what outcomes to expect but higher BMI should not preclude surgery access., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: No competing financial interests exist.

The field of behavioral neuroendocrinology has only begun to explore the lived experiences of transgender and gender diverse (TGD) people exposed to stigma. In light of escalating attacks and legislation targeting TGD people in the United States, it is crucial to examine the physiological pathways through which gender minority stressors become embodied, impact health, and contribute to health inequities. The Trans Resilience and Health Study included baseline data collection from fall 2019 to spring 2020 from a sample of 124 TGD people, reflecting a diversity of gender identities (e.g., trans masculine, trans feminine, and nonbinary) and ages (range = 19-70 years old; M = 34.10), living in Michigan, Nebraska, Oregon, and Tennessee. These analyses examine experiences of gender-related enacted stigma in association with hypothalamic-pituitary-adrenal (HPA)-axis functioning. Among those experiencing the highest levels of enacted stigma, findings show a blunted cortisol awakening response and sluggish daily decline that resulted in elevated concentrations at bedtime compared to those experiencing less enacted stigma. These results of flattened diurnal activity are consistent with an emergent literature on discrimination as a social determinant of potential stress pathophysiology. In contrast, community connectedness was associated with a larger, more dynamic cortisol awakening response. These findings emphasize the importance of incorporating gender-minority stress and resilience measures when studying HPA-axis functioning among TGD people., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This study sought to prospectively examine the effects of gender-affirming chest reconstruction on gender congruence and chest dysphoria in transmasculine and nonbinary adolescents and young adults., Methods: Individuals between the ages of 15-35 who were seeking gender-affirming chest surgery were enrolled as part of a broader, longitudinal study of transgender surgical experiences. Their chest dysphoria and gender congruence were measured at baseline, six months, and one year, using the Transgender Congruence and Chest Dysphoria scales. Repeated measures analysis of variance were used to detect differences in scores across assessment points. Where there were significant differences indicated, Tukey's honestly significant difference test was used to determine which differences in mean scores were significant between assessment points, as well as how results differed by demographic factors., Results: The analytical sample consisted of 153 individuals who had completed both the baseline and at least one follow-up assessment - 36 (24%) endorsing a nonbinary gender and 59 (38%) under the age of 18. Repeated measures analysis of variance indicated significant differences in gender congruence, appearance congruence, and chest dysphoria between at least two assessment points for the total sample and each subgroup (binary/non-binary and adult/minor). Honestly significant difference tests indicated no significant differences between the postoperative assessments by age or binary gender., Discusson: Gender-affirming chest reconstruction improves gender and appearance congruence and reduces chest dysphoria in both non-binary and binary populations of adolescents and young adults. These data support the need to improve access to gender-affirming chest reconstruction for adolescents and young adults and to remove legislative and other barriers to care., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine if and how race impacts the 30-day outcomes of gender-affirming chest surgeries., Background: Little is currently known about how race may affect the outcomes of gender-affirming surgeries., Methods: We analyzed data from the National Surgical Quality Improvement Program (NSQIP) database of 30-day complications of gender-affirming chest surgeries from 2005 to 2019. All participants had a postoperative diagnosis code for gender dysphoria and at least one procedure code for bilateral mastectomy, bilateral breast reduction, or bilateral augmentation mammoplasty. Differences by racial group were analyzed through Pearson χ 2 and multivariate logistic regression., Results: There were no racial differences in the all-complication rates for both transmasculine and transfeminine individuals undergoing gender-affirming chest surgeries. Black patients undergoing masculinizing procedures were significantly more likely to experience mild systemic [adjusted odds ratio (aOR): 2.17, 95% confidence interval (CI): 1.02-4.65] and severe complications (aOR: 5.63, 95% CI: 1.99-15.98) when compared with White patients. Patients of unknown race had increased odds of experiencing severe complications for masculinizing procedures compared with White patients (aOR: 3.77, 95% CI: 1.39-10.24). Transmasculine individuals whose race was unknown were 1.98 times more likely (95% CI: 1.03-3.81) to experience an unplanned reoperation compared with White individuals. Black transfeminine individuals were 10.50 times more likely to experience an unplanned reoperation (95% CI: 1.15-95.51) than their White peers., Conclusions: Although overall complications are uncommon, there is evidence to suggest that there are racial disparities in certain 30-day outcomes of gender-affirming chest surgeries., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

While masculinizing gender-affirming genital surgeries may include scrotoplasty, there has been limited research on the safety and outcomes of scrotoplasty among transgender men. We compared scrotoplasty complication rates between cisgender and transgender patients using data from the American College of Surgeon's National Surgical Quality Improvement Program (NSQIP) database. Data was queried between 2013 and 2019 for all patients with procedure codes for scrotoplasty. Transgender patients were identified through a gender dysphoria diagnosis code. T-tests and Fisher's exact test were used to identify any differences in demographics, operative characteristics, and outcomes. The primary outcomes of interest were demographic factors, operative details, and surgical outcomes. A total of 234 patients were identified between 2013 and 2019. Fifty were transgender and 184 were cisgender. Age and BMI were significantly different between the two cohorts, such that the cisgender cohort was older ( M trans  = 38 years (SD:14), M cis  = 53 years (SD: 15)) and had higher BMI than the transgender cohort ( M trans  = 26.9 (SD: 5.5), M cis  = 35.2 (SD: 11.2)). Cisgender patients also had poorer overall health ( p  = 0.001), and were more likely to have hypertension ( p  = 0.001) and diabetes ( p  = 0.001). Race and ethnicity did not vary significantly between the cohorts. Operative details differed significantly between cohorts, such that transgender patients had a longer operating time ( M trans  = 303 min (SD: 155), M cis  = 147 min (SD: 107)) and fewer transgender patients had a simple scrotoplasty ( p  = 0.02). The majority of gender-affirming scrotoplasties were performed by plastic surgeons (62%) whereas the majority of cisgender scrotoplasties were performed by urologists (76%). Despite these demographic and pre-operative differences, the number of patients who underwent complex scrotoplasty experiencing any of the tested complications did not differ by gender. Our results support scrotoplasty as a safe procedure for transgender patients, with no significant differences in outcomes between transgender and cisgender patients., Competing Interests: None., (© 2023 The Author(s).)

Objective: This study aimed to assess the transcultural adaptation and psychometric properties of the French-language version of the Xerostomia Inventory (XI-Fr)., Methods: In total, 65 patients aged 65 years or older were recruited from three departments of a single French hospital. Patients had to have a Mini Mental State Examination score of 10 or more and be able to read and write French. The XI-Fr was administered to all patients after transcultural adaptation, at the start of the study, and again at 7 days after inclusion. We assessed reliability, acceptability, validity, internal consistency and reproducibility of the instrument in its French-language version., Results: The XI-Fr showed good internal consistency (Cronbach's alpha 0.79) and good reliability (intra-class correlation 0.83) at 7 days. Convergent validity showed no relation between salivary flow and XI-Fr score, as with the original instrument. Discriminant validity showed a positive correlation between the XI-Fr and the GOHAI, but no difference for the MNA or miniGDS scores., Conclusion: The XI-Fr is a valid and reliable measure of xerostomia in French, with psychometric properties comparable to those of the original English-language version., (© 2022 Gerodontology Association and John Wiley & Sons Ltd.)

Introduction: Transgender men interested in achieving penetration after phalloplasty are currently limited to internal devices and makeshift supports. More options are needed to support sexual penetration after phalloplasty., Aim: This study was designed to assess the feasibility of an external erectile prosthesis (the Elator) for transgender men who have undergone phalloplasty and wish to use their neophallus for sexual penetration, assess how the device affected the sexual experiences of men and their partners, and identify any side effects and concerns., Methods: Transgender men and their partners were provided with an erectile device to use for one month. They were surveyed at 4 time points: enrollment, measurement, receipt, and after using the device, using a combination of pre-existing and device-specific measures., Main Outcome Measure: The primary outcome was whether men found it feasible to use an external penile prosthesis for sexual penetration after phalloplasty - defined as interest in, and willingness to, use the device more than once over the study period; intention to continue using the device on the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS); and no decrease in relationship satisfaction on the Gay and Lesbian Relationship Satisfaction Scale (GLRSS). The secondary outcome was an increase in sexual or relationship satisfaction with use of the device, defined as a statistically significant increase on either the Quality of Sexual Experience Scale (QSE) or the GLRSS., Results: Fifteen couples enrolled in the pilot study. Of the 10 who completed the study, only 3 found device use feasible and endorsed strongly positive experiences, while the remaining 7 found it unusable. There were no changes in QSE or GLRSS scores. Most device issues were related to proper fit., Conclusion: There is a great deal of interest in non-surgical options for achieving penetration after phalloplasty. The tested external erectile device can work well, but its utility is limited to individuals with very specific post-phalloplasty anatomy. Most individuals and couples found the device unsuitable for the neophallus and/or that it could not be used comfortably. Boskey ER, Jolly D, Mehra G, et al. Feasibility of an External Erectile Prosthesis for Transgender Men Who have Undergone Phalloplasty. Sex Med 2022;10:100560., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The potential effects of breast cancer (BC) on health-related quality of life (HRQoL) should be considered in clinical and policy decision-making, as the economic burden of BC management is currently assessed. In the last decades, time-to-HRQoL score deterioration (TTD) has been proposed as an approach to the analysis of longitudinal HRQoL in oncology. The main objectives of the current study were to investigate the evolution of the utility values in BC patients after diagnosis and during follow-ups and to evaluate the TTD in utility values among women in all stages of BC., Methods: Health-state utility values (HSUV) were assessed using the EuroQol 5-Dimension 3-Level at diagnosis, at the end of the first hospitalization and 3 and 6 months after the first hospitalization. For a given baseline score, HSUV was considered to have deteriorated if this score decreased by ≥ 0.08 points of the EQ-5D utility index score and ≥ 7 points of the EQ visual analogue scale. TTD curves were calculated using the Kaplan-Meier estimation method., Results: Overall 381 patients were enrolled between February 2006 and February 2008. The highest proportions of respondents at the baseline and all follow-ups reporting some and extreme problems were in pain discomfort and anxiety/depression dimensions; more than 80% of patients experienced a deterioration in EQ-5D utility index score and EQ VAS score with a median TTD of 3.15 months and 6.24 Months, respectively., Conclusions: BC patients undergoing therapy need psychological support to cope with their discomfort, pain, depression, anxiety, and fear during the process of diagnosis and treatment to improve their QoL., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

As gender-affirming surgeries are being performed, new techniques have been developed to meet patient desires, including recent reports of several gender-affirming procedures being combined into a single operative encounter. Such a development may provide several advantages to both patients and providers. However, it is less clear whether combining these procedures affects patient safety and surgical case planning factors. To address this, we compared the complication rates and the length of hospital stay and operative time for standalone and combined gender-affirming procedures (e.g., hysterectomy and bilateral mastectomy, breast augmentation, and vaginoplasty) performed between 2005 and 2019 in the National Surgical Quality Improvement Program database. There were 1857 standalone mastectomies, 826 standalone hysterectomies, and 30 cases where they were combined. There were 379 vaginoplasties, 648 breast augmentations, and 31 cases where they were combined. There was no evidence of differences in overall health status between those undergoing combined and standalone procedures. Two-sample proportion testing did not find significant differences in any of the complications experienced between standalone and combined procedures. Similarly, two-sample t-tests did not find significant differences in the length of the hospital stays nor in the length of the operative encounter between standalone and combined masculinizing surgeries. Combining breast augmentation and vaginoplasty, however, saved an average of 97.86 min (p = .000) of operating time. These results suggest that combining gender-affirming procedures may be a safe and viable option for individuals who desire multiple gender-affirming procedures and may even be an advantageous option for patients and practitioners alike., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Objective: Since the expiry of the patents on originator anti-TNF agents in Europe, France has authorized the sale of biosimilars. The penetration rate of anti-TNF agents and their biosimilars, and the cost savings driven by the introduction of biosimilars appears to vary widely. This study aimed to describe the market share of anti-TNFs and their biosimilars, and the cost savings generated by the introduction of biosimilars in French hospitals 5 years ago., Methods: The pharmaceutical component of the French national uniform hospital discharge data set database (PMSI) was used to study sales of infliximab, etanercept and adalimumab originators and biosimilars, and to estimate cost savings generated by the introduction of biosimilars onto the market, using the historical tariffs of the originators., Results: The penetration rate of anti-TNF biosimilars in France in 76% for infliximab, 74% for etanercept and 77% for adalimumab. In 2020, Inflectra® (41%) was the Remicade® biosimilar with the highest sales volume, while Erelzi® (57%) and Amgevita® (64%) were the most widely sold biosimilars of Enbrel® and Humira® respectively. In terms of cost savings since the launch of biosimilars, overall, for all biosimilars taken together, over the 5-year period, a total of 824 million Euro was saved, in relation to the historical tariffs of the originators., Conclusions: This study shows firstly that the penetration rate of anti-TNF biosimilars in France 5 years after their launch is close to 80%. Secondly, we show that the cost savings generated by the use of biosimilars to anti-TNF agents exceed 820 million Euro over 5 years., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background : Data describing patients hospitalized in medical rehabilitation wards after the acute phase of COVID-19 could help to better understand the rehabilitation needs in the current pandemic situation. Methods : Cohort including all patients with COVID-19 hospitalized in a single, large university hospital in Northeast France from 25 February to 30 April 2020. Results : 479 patients were admitted with COVID-19 during the study period, of whom 128 died (26.7%). Among the 351 survivors, 111 were referred to rehabilitation units, including 63 (17.9%) referred to physical and rehabilitation medicine (PRM) units. The median age of patients referred to rehabilitation units was 72 years. Patients who had been in intensive care, or who had had a long hospital stay, required referral to PRM units. Two biomarkers were associated with referral to rehabilitation units, namely, elevated troponin ( p = 0.03) and impaired renal function ( p = 0.03). Age was associated with referral to PRM units ( p = 0.001). Conclusions : Almost one-third of COVID-19 patients required post-acute care, but only one-fifth had access to PRM units. The optimal strategy for post-acute management of COVID-19 patients remains to be determined. The need for rehabilitation wards during a pandemic is a primary concern in enabling the long-term functioning of infected patients.

Background: The SARS-COV2 pandemic has been ongoing worldwide since at least 2 years. In severe cases, this infection triggers acute respiratory distress syndrome and quasi-systemic damage with a wide range of symptoms. Long-term physical and psychological consequences of this infection are therefore naturally present among these patients. The aim of this study was to describe the state of health of these patients at 6 (M6) and 12 months (M12) after infection onset, and compare quality-of-life (QOL) and fatigue at these time-points., Methods: A prospective cohort study was set up at Reims University Hospital. Patients were clinically assessed at M6 and M12. Three scores were calculated to describe patient's status: the modified Medical Research Council score (mMRC) used to determine dyspnoea state, the Fatigue Severity Scale (FSS) and the Short Form 12 (SF12) that was carried out to determine the QOL both mentally and physically (MCS12 and PCS12). Descriptive analysis and comparison of scores between M6 and M12 were made., Results: 120 patients completed both follow-up consultations. Overall, about 40% of the patients presented dyspnoea symptoms. The median mMRC score was 1 Interquartile ranges (IQR) = [0-2] at the two assessment. Concerning FSS scores, 35% and 44% of patients experienced fatigue at both follow-ups. The two scores of SF12 were lower than the general population standard scores. The mean PCS12 score was 42.85 (95% confidence interval (95% CI [41.05-44.65])) and mean MCS12 score of 46.70 (95% CI [45.34-48.06]) at 6 months. At 12 months, the mean PCS12 score was 42.18 (95% confidence interval (95% CI [40.46-43.89])) and mean MCS12 score of 47.13 (95% CI [45.98-48.28]). No difference was found between SF12 scores at 6 and 12 months., Conclusions: This study pinpoints the persistence of fatigue and a low mental and physical QOL compared to population norms even after 1 year following infection. It also supports the claims of mental or psychological alterations due to infection by this new virus, hence a lower overall QOL in patients., (© 2022. The Author(s).)

Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [ 11 C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug-occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [ 11 C]martinostat using [ 11 C]methyl triflate in ethanol, as opposed to the originally described synthesis using [ 11 C]methyl iodide and DMSO. [ 11 C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 μl), reacted at ambient temperature for 5 min and purified by high-performance liquid chromatography; 1.5-1.8 GBq (41-48 mCi; n = 3) of formulated [ 11 C]martinostat was obtained from solid-phase extraction using a hydrophilic-lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [ 11 C]MeI), with a molar activity of 369 ± 53 GBq/μmol (9.97 ± 1.3 Ci/μmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [ 11 C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre-release quality control testing., (© 2022 John Wiley & Sons, Ltd.)

Melatonin is a neurohormone that modulates several physiological functions in mammals through the activation of melatonin receptor type 1 and 2 (MT 1 and MT 2 ). The melatonergic system is an emerging therapeutic target for new pharmacological interventions in the treatment of sleep and mood disorders; thus, imaging tools to further investigate its role in the brain are highly sought-after. We aimed to develop selective radiotracers for in vivo imaging of both MT 1 and MT 2 by positron emission tomography (PET). We identified four previously reported MT ligands with picomolar affinities to the target based on different scaffolds which were also amenable for radiolabeling with either carbon-11 or fluorine-18. [ 11 C]UCM765, [ 11 C]UCM1014, [ 18 F]3-fluoroagomelatine ([ 18 F]3FAGM), and [ 18 F]fluoroacetamidoagomelatine ([ 18 F]FAAGM) have been synthesized in high radiochemical purity and evaluated in wild-type rats. All four tracers showed moderate to high brain permeability in rats with maximum standardized uptake values (SUV max of 2.53, 1.75, 3.25, and 4.47, respectively) achieved 1-2 min after tracer administration, followed by a rapid washout from the brain. Several melatonin ligands failed to block the binding of any of the PET tracer candidates, while in some cases, homologous blocking surprisingly resulted in increased brain retention. Two 18 F-labeled agomelatine derivatives were brought forward to PET scans in non-human primates and autoradiography on human brain tissues. No specific binding has been detected in blocking studies. To further investigate pharmacokinetic properties of the putative tracers, microsomal stability, plasma protein binding, log D , and membrane bidirectional permeability assays have been conducted. Based on the results, we conclude that the fast first pass metabolism by the enzymes in liver microsomes is the likely reason of the failure of our PET tracer candidates. Nevertheless, we showed that PET imaging can serve as a valuable tool to investigate the brain permeability of new therapeutic compounds targeting the melatonergic system.

Background: Severe forms of SARS-CoV-2 infections are associated with high rates of thromboembolic complications. Professional societies and expert consensus reports have recommended anticoagulants for COVID-19 hospitalized patients. Our study aimed to compare the effect of therapeutic, intermediate and prophylactic doses of heparin on 6-week survival in patients hospitalized for COVID-19., Methods: The study sample is a French cohort of COVID-19 patients hospitalized between Feb 25th and Apr 30th 2020. Patients were assigned to one of 3 anticoagulation dose groups based on the maximum dose they received for at least three days (prophylactic, intermediate or therapeutic). The main outcome was survival up to 42 days after hospital admission. Multivariate Cox regression models were performed to adjust analyses for confounding factors., Results: A total of 323 patients were included. The mean age of the study sample was 71.6 ± 15 years, and 56.3% were men. Treatment with the intermediate versus prophylactic dose of anticoagulation (HR = 0.50, 95%CI = [0.26; 0.99], p = 0.047) and with therapeutic versus prophylactic dose (HR = 0.58 95%CI = [0.34; 0.98], p = 0.044) was associated with a significant reduction in 6-week mortality, after adjustment for potential confounding factors. Comparison of therapeutic versus intermediate doses showed no significant difference in survival., Conclusions: Our results reported a significant positive effect of intermediate and therapeutic doses of heparin on 6-week survival for hospitalized COVID-19 patients compared with a prophylactic dose., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Evidence-Based Answer: Yes. Compared to the use of a transcervical balloon alone, combined cervical ripening with a balloon catheter and oxytocin shortens the time to overall delivery by 3 hours and the time to vaginal delivery by 4 hours, without altering the rate of cesarean section (strength of recommendation [SOR]: A, network meta-analysis). The effect is more pronounced in nulliparous patients (SOR: A, meta-analysis).When combined therapy is used, 6 hours of balloon time may result in faster delivery than 12 hours (SOR: B, single randomized controlled trial [RCT]). Fixed-dose oxytocin and titrated oxytocin appear to have similar effect when combined with a cervical ripening balloon (SOR: C, underpowered RCT).