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This study demonstrated the impact of formic acid (FAc), a common reactive impurity in pharmaceutical excipients, on the stability of mirabegron (MB). The investigation of MB‐excipient compatibility tests revealed the formation of a new degradation product, FAc‐DP, at 0.2% after 7 days of isothermal stress at 55°C. FAc‐DP was synthesized and characterized as N‐formyl MB using liquid chromatography–mass spectrometry (LC‐MS) and both 1D and 2D nuclear magnetic resonance spectroscopy (NMR). [ABSTRACT FROM AUTHOR]

Background: Intracerebellar schwannoma is an extremely rare disease entity with only 21 case reports described in the literature. Case Description: A 68‐year‐old male presented with chronic headaches, dizziness, gait imbalance, and incoordination. Previous MRI had revealed a cystic lesion in the right cerebellum; however, patient was lost to follow‐up. Updated MRI revealed dramatic enlargement of the lesion in addition to worsening clinical status. The patient underwent successful surgical resection. Conclusion: Intracerebellar schwannoma can be challenging to diagnose preoperatively due to its rare occurrence; however, it should be included in the differential diagnosis of cystic lesions in the cerebellum, and most cases can be successfully treated with complete surgical resection. Pathological examination revealed a spindle cell neoplasm with other typical histopathological features of schwannoma. [ABSTRACT FROM AUTHOR]

Genetic counseling (GC) following abnormal Down syndrome (DS) screening tests aims to ensure learning of complex medical concepts and discussion of counselees' personal desires. Pre‐GC use of electronic learning tools (e‐learning tools) can facilitate GC sessions by allowing more time for dialogue rather than learning medical and genetic concepts, enabling greater focus on the counselee's decisional, psychological, and personal needs. Few studies have investigated such tools for DS screening tests and those who have focused on screening uptake rather than abnormal results and implications. This study evaluated prenatal GC outcomes following implementation of an e‐learning tool utilizing an educational animated movie for couples of varied ethnic backgrounds in northern Israel, with abnormal DS screening tests. E‐learning tool impact was assessed as knowledge level, informed choices, satisfaction with the intervention and GC process, the state of anxiety and duration of the GC meeting. The 321 study participants were randomized to three groups: animation movie, booklet, and control. All participants had been asked to complete pre‐ and post‐counseling questionnaires. Outcome scores were compared between the research groups. Results showed increased knowledge level in general among participants in the animation group; among minority participants, the highest knowledge level was in the animation group. Anxiety levels and informed choices were not statistically different among the groups. However, watching the animation, Jewish ethnicity, good level of genetic literacy, and academic degree were significant predictors of informed choice, and those who watched the animation were three times more likely to make an informed choice than the control group. Our findings suggest that this e‐learning tool is efficient and acceptable for the general population. Special attention is needed for minorities with lower genetic literacy and education. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the psychometric properties of Cultural Intelligence Scale (CQS), based on item response theory (IRT) using the graded response model (GRM). The study calibration sample included 400, while the study sample included 1000, male and female Saudi participants, aged between 18 and 62 years. IRT‐GRM results supported the quality of the psychometric properties of CQS, and its appropriateness to measure cultural intelligence (CQ) for the majority of individuals. CQS well‐distinguished people at different ability levels along the CQ latent trait, particularly with middle and low abilities. However, CQS full scale and subscales had less accurate measurement precision at high levels of CQ, and some subscales had more precision at low level abilities. CQS items had medium ability to differentiate among subjects, and they provided more information in evaluating individuals with medium CQ. Therefore, CQS might be more suitable for identification and development purposes, where low to med‐levels of CQ are expected. Additional assessment procedures need to be added, for selection or promotion purposes to increase the measurement precision. Confirmatory factor analysis results confirmed the multidimensional construct of CQS with four specific‐related factors at the first level, and an aggregate factor at the second level. This model provided better model fit using IRT‐GRM approach, and it was supported by classical test theory analysis results. Therefore, it is important to rely on subscale scores, besides the total score to interpret CQ for individuals. The study stressed the importance of examining CQS item parameters and information based on the country it is adapted for, to investigate how they interact with country culture; and to take into account ability level, when selecting optimal measures. Practitioner points: The results of confirmatory factor analysis (CFA) and item response theory (IRT) graded response model (GRM) supported the multidimensional construct of Cultural Intelligence Scale (CQS) with four specific‐related factors at the first level, and an aggregate factor at the second level, that was proposed by the CQS theory, compared to other models.IRT‐GRM analysis results in this study indicated that CQS has good psychometric properties and indicated that it appears to be a valid and moderately reliable instrument in detecting Cultural intelligence (CQ). These results were supported by CTT analysis results.IRT‐GRM analysis results showed that CQS well‐distinguished people at different ability levels along the CQ latent trait, particularly with middle and low abilities. However, CQS full scale and subscales had less accurate measurement precision at high levels of CQ, and some subscales had more precision at low level abilities.The study suggested that it is important to examine the CQS model fit, item parameters, information functions for the full scale and subscales based on the country it is adapted for, before considering it. It is important also to rely on the subscale scores to interpret CQ for individuals, and to identify their strengths, rather than relying on the total score alone.The study results suggested that CQS suites better CQ identification and development purposes. For selection or promotion purposes, it is suggested to add additional assessment procedures to increase the measurement precision. [ABSTRACT FROM AUTHOR]

Sea turtles are vulnerable to climate change since their reproductive output is influenced by incubating temperatures, with warmer temperatures causing lower hatching success and increased feminization of embryos. Their ability to cope with projected increases in ambient temperatures will depend on their capacity to adapt to shifts in climatic regimes. Here, we assessed the extent to which phenological shifts could mitigate impacts from increases in ambient temperatures (from 1.5 to 3°C in air temperatures and from 1.4 to 2.3°C in sea surface temperatures by 2100 at our sites) on four species of sea turtles, under a "middle of the road" scenario (SSP2‐4.5). Sand temperatures at sea turtle nesting sites are projected to increase from 0.58 to 4.17°C by 2100 and expected shifts in nesting of 26–43 days earlier will not be sufficient to maintain current incubation temperatures at 7 (29%) of our sites, hatching success rates at 10 (42%) of our sites, with current trends in hatchling sex ratio being able to be maintained at half of the sites. We also calculated the phenological shifts that would be required (both backward for an earlier shift in nesting and forward for a later shift) to keep up with present‐day incubation temperatures, hatching success rates, and sex ratios. The required shifts backward in nesting for incubation temperatures ranged from −20 to −191 days, whereas the required shifts forward ranged from +54 to +180 days. However, for half of the sites, no matter the shift the median incubation temperature will always be warmer than the 75th percentile of current ranges. Given that phenological shifts will not be able to ameliorate predicted changes in temperature, hatching success and sex ratio at most sites, turtles may need to use other adaptive responses and/or there is the need to enhance sea turtle resilience to climate warming. [ABSTRACT FROM AUTHOR]

Designing kinase inhibitors that bind to the substrate site of oncogenic kinases in a promising, albeit less explored, approach to kinase inhibition as it was sought to avoid the issue of untoward off‐target modulations. Our previously identified compound KAC‐12 with a meta‐chlorophenyl substitution was an example of this approach. While it showed confirmed inhibitory activity against cancer cells, this substitution shifted the profile of affected targets away from Src/tubulin which were seen with the parent KX‐01. In this paper, we synthesized compounds with ortho‐substitutions, and we investigated the effect of such substitutions on their cellular and subcellular activities. The compound N‐(4‐(2‐(benzylamino)‐2‐oxoethyl)phenyl)‐2‐(morpholine‐4‐carbonyl)benzamide (4) exhibited substantial activities against cell lines such HCT116 (IC50 of 0.97 μM) and IC50 HL60 (2.84 μM). Kinase profiling showed that compound 4 trended consistently with KAC‐12 as it did not affect Src, but it had more impact on members of the Src family of kinases (SFK) such as Yes, Hck, Fyn, Lck, and Lyn. Both compounds exhibited profound downregulation effects on Erk1/2 but differed on others such as GSK3α/β and C‐Jun. Collectively, this study further support to the hypothesis that small structural changes might bring higher changes in their kinome profile. [ABSTRACT FROM AUTHOR]

AMP‐activated Protein Kinase (AMPK) has conflicting roles in solid tumor progression as it shows anticarcinogenic activities in healthy cells while it may help the existing cancer cells to survive through certain stress conditions such as metastasis, hypoxia, and dormancy. These cells are usually present in the core of the solid tumors. To explore AMPK inhibitors and their anticancer activities, three compounds related to N‐benzyl‐[4‐(phenylamino)aryl]acetamide scaffold demonstrated high potency as α1/β1/γ2 AMPK allosteric inhibitors (IC50 range 7.77–13.75 nM). As an example, the compound N‐(6‐(2‐(benzylamino)‐2‐oxoethyl)pyridin‐3‐yl)‐3‐methoxybenzamide (MAK‐11) inhibited cancer growth at IC50 values 0.148 μM (MCF7, monolayer), 0.097 μM (T47D, monolayer), 19.58 μM (MCF7, spheroids) and 3.72 μM (T47D, spheroids). It was also found that MAK‐11 caused increases in spheroid model dead cells (36.5 % and 32.1 %), induced mitochondrial depolarization (34.0 % and 36.8 %), and elevated ROS levels (24.6 %% and 32.1 %) for MCF7 and T47D, respectively. We also profiled the drug‐likeness of compounds and confirmed that they do not inhibit HSF (non‐cancerous cell lines). It was noticed that monolayer (2D) assay results are not parallel to the spheroid (3D) results as MAK‐11 was 97 times lower than MAK‐6 in T47D 2D assay, while it was twice as potent as the same compound in the 3D assay. Therefore, we propose that AMPK inhibitors should be tested on 3D tumor models that are similar to the environment with the core of tumor cells. [ABSTRACT FROM AUTHOR]

Purpose. To synthesize new isoindole-1,3(2H)-dione derivatives by molecular hybridization of gabapentin and pregabalin with phthalic anhydride derivatives and to evaluate their biological activity as promising antioxidant, antimicrobial, and anticancer agents. Method. Molecular hybridization was successfully achieved by two procedures; synthesized compounds were characterized using analytical and spectral methods. The free radical scavenging properties of synthesized compounds were evaluated using the DPPH method. The antibacterial activity of synthesized compounds and parent compounds was evaluated against two microbial Gram-positive and Gram-negative strains by the well diffusion method. Furthermore, we have studied the effect of compounds on proliferation, cell cycle, and cell death in two human cancer cell lines (Caco-2 and HCT-116). Results. Compounds 1, 3, and 4 exhibited a good free radical scavenging effect, and compound 3 is the most effective with IC50 value of 2.525 μmol/mL. All compounds showed antibacterial activity against Escherichia coli and Staphylococcus aureus related to concentration, while parent drugs did not exhibit any antibacterial effect. Compounds 1 and 2 showed a good zone of inhibition against E. coli at micromolar concentrations, and they are more effective than Gentamicin Sulfate. Treatment with the studied compounds suppresses proliferation, arrests progress throughout the cell cycle, and induces apoptosis in Caco-2 and HCT-116 cancer cells. Compound 2 is highly effective against Caco-2 cells and more effective than thalidomide, with IC50 value less than 1 μmol/L. Conclusion. Our results showed that molecular hybridization of gabapentin and pregabalin in the isoindole-1,3(2H)-dione moiety results in promising anticancer and antimicrobial molecules. Results of this preliminary study show that halogenation of the isoindole-1,3(2H)-dione moiety improves antimicrobial and anticancer activity and that tetra-brominated derivatives are comparable to or more effective than related tetra-chlorinated derivatives. [ABSTRACT FROM AUTHOR]

In this study, we have established promising drug candidates with approved antimicrobial, antioxidant, antileishmanial, and anticancer activities. We hereby report drug likeliness, ADME prediction, synthesis, characterization, and in vitro biological evaluation of isoindole-1,3-(2H) dione derivatives. Synthesized compounds showed a free radical scavenging effect, with compound 1 being the most effective (IC50 value 1.174 μmol/mL). The antibacterial activity of compounds was studied against two microbial Gram-positive and Gram-negative strains by well diffusion method. The inhibition zone of compound 3 is comparable with the inhibition zone of gentamycin at the same concentration. The compounds are highly effective against Leishmania tropica with compound 3 being the most effective one (IC50 0.0478 μmol/mL). The compounds are highly potential for the treatment of Leishmania tropica, and they are more effective than the first-line treatment, Glucantime. Compounds showed good antiproliferative activity against two human cancer cell lines (Caco-2 and HCT-116). Treatment with studied compounds arrests progress throughout the cell cycle and induces apoptosis in cancer cells. Data from structure-activity relationship (SAR) analysis revealed that lipophilic properties of compounds might enhance their activity as antimicrobial, antileishmanial, and antiproliferative activity. The halogenation of isoindole-1,3 (2H) dione moiety increases antimicrobial, antileishmanial, and anticancer activities. Tetra-brominated derivatives are more effective than tetra-chlorinated derivatives. [ABSTRACT FROM AUTHOR]

Introduction: Recent guidelines for von Willebrand Disease (VWD) highlighted the challenges in diagnosis and management. Identifying the number of persons with VWD (PwVWD) internationally will help target support to aid diagnosis of PwVWD. Aim: To examine international registration rates of PwVWD, the influence of income status, geographical region and the age and sex profile. Cumulatively, these data will be used to inform future strategy from the World Federation of Haemophilia (WFH) to address unmet clinical and research needs. Methods: Data from the 2018/2019 WFH Annual Global Survey (AGS) were analysed, providing a global perspective on VWD registration. Results: Registration rates are lowest in South Asia (0.6/million population) and highest in Europe/Central Asia (50.9/million population, 0.005%), but below the expected prevalence rate (0.1%). National economic status impacted VWD registration rates, reflecting variation in access to optimal healthcare infrastructure. Females represented the majority of PwVWD globally, however, in low‐income countries (LIC) males predominated. Age profile varied, with markedly higher rates of paediatric registrations in North America, Middle East and North Africa and South Asia. Rates of type 3 VWD registrations were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings. Conclusion: Significant variation in registration rates of PwVWD exist internationally and is influenced by income status and the presence of HTC networks. Improved understanding of registration rates will enable targeting of advocacy to improve awareness, diagnosis and support for PwVWD internationally. Key points: Registration rates of People with Von Willebrand Disease (PwVWD) vary internationally and are influenced by national income statusAlthough females represent the majority of PwVWD globally, in low income countries (LIC) males predominated, possibly related to stigma surrounding gynaecological bleeding.Rates of type 3 VWD registration were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings. [ABSTRACT FROM AUTHOR]

We use near‐infrared spectra returned from the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) aboard the Mars Reconnaissance Orbiter (MRO) to provide retrievals of the column‐integrated optical depth of water ice aerosols for more than 5 Martian years between Mars Year (MY) 28 at Ls = 112° (27 September 2006) and MY 33 at Ls = 213° (30 August 2016). We have developed a radiative transfer model for this purpose that retrieves aerosol opacity from the water ice aerosol feature near 3.3 μm using CRISM hyperspectral observations for the first time. The resulting retrievals well depict the main features in the water ice aerosol climatology with repeatable patterns every Martian year. The aphelion cloud belt (ACB) is observed between 10°S and 30°N, with peak optical depth around Ls = 90°. Apart from the global dust storm during MY 28, modest interannual variability in the water ice aerosol optical depth is observed in the ACB. The north polar hood is observed at latitudes poleward of 45°N throughout northern spring and summer seasons and reappears in northern winter. The south polar hood is observed in early to mid‐southern autumn, reaching latitudes around 60°S, and re‐emerging during southern winter between 45°S and 60°S. A lack of water ice aerosols is repeatedly seen in the southern hemisphere throughout southern spring and summer. High optical depth in the ACB is observed over the volcanoes of Olympus Mons, Elysium, and the Tharsis bulge, as well as over Hellas Basin. Plain Language Summary: The atmosphere of Mars can hold water ice crystals when the right temperature and pressure conditions are met. We use observations from an instrument onboard the Mars Reconnaissance Orbiter to track the presence and evolution of water ice in the atmosphere based on how much the ice crystals absorb and scatter sunlight. The observations extend for 5 Martian years (∼10 Earth years) and cover all the Martian seasons. We show that there is a concentration of clouds around the equator of the planet, forming during spring and summer seasons, particularly over the volcanoes on Mars. Water ice clouds are also observed at high latitudes near the poles in the form of polar hoods, showing up in the north during northern spring, summer and winter, and in the south during southern autumn and winter. The main features in the retrieved cloud climatology in this study are repeated every Martian year. The amount of absorption caused by the water ice clouds is similar between the equatorial cloud belt, the north and south polar hoods. Key Points: Retrievals using Mars Reconnaissance Orbiter/Compact Reconnaissance Imaging Spectrometer for Mars near‐infrared spectra of the atmosphere of Mars provide the water ice aerosol climatology for 5 Martian yearsThe aphelion cloud belt is observed every Mars Year (MY) between mid‐northern spring and mid‐northern summer in the latitudinal range 10°S–30°NThe north polar hood is observed every MY. It covers the entirety of northern spring and summer seasons and reappears in winter [ABSTRACT FROM AUTHOR]

This paper proposes a zero‐sum dynamic game (ZSDG) design to mitigate frequency deviations in the secondary control layer of islanded AC microgrids. By defining a min‐max optimization problem, where the control input minimizes the frequency deviations while the external disturbances maximizes the cost function, a robust control law is designed. The outcome leads to setting the frequency to its desired value and at the same time effects of disturbances are attenuated by applying the H∞$H_{\infty }$ optimal controller in the secondary control level of AC microgrids. Since the basic ZSDG controller cannot eliminate adverse effects of external disturbances on the system frequency, an extended‐ZSDG (EZSDG) method is introduced to design an effective H∞$H_{\infty }$ controller. Due to the lack of access to the state variables of the microgrids, a full‐order observer is designed to estimate these variables based on the measured output. In simulation results, the validity of the proposed EZSDG is investigated by considering uncertainties in both the communication and physical layers. [ABSTRACT FROM AUTHOR]

The NOMAD‐UVIS instrument on board the ExoMars Trace Gas Orbiter has been investigating the Martian atmosphere with the occultation technique since April 2018. Here, we analyze almost two Mars Years of ozone vertical distributions acquired at the day‐night terminator. The ozone retrievals proved more difficult than expected due to spurious detections of ozone caused by instrumental effects, high dust content, and very low values of ozone. This led us to compare the results from three different retrieval approaches: (a) an onion peeling method, (b) a full occultation Optimal Estimation Method, and (c) a direct onion peeling method. The three methods produce consistently similar results, especially where ozone densities are higher. The main challenge was to find reliable criteria to exclude spurious detections of O3, and we finally adopted two criteria for filtering: (a) a detection limit, and (b) the Δχ2 criterion. Both criteria exclude spurious O3 values especially near the perihelion (180° < Ls < 340°), where up to 98% of ozone detections are filtered out, in agreement with general circulation models, that expect very low values of ozone in this season. Our agrees well with published analysis of the NOMAD‐UVIS data set, as we confirm the main features observed previously, that is, the high‐altitude ozone peak around 40 km at high latitudes. The filtering approaches are in good agreement with those implemented for the SPICAM/MEx observations and underline the need to evaluate carefully the quality of ozone retrievals in occultations. Key Points: We compare three different retrieval codes and different criteria to filter spurious detection of ozone on MarsThe filtering criteria demonstrate the ozone detection in perihelion season is mostly spurious in both yearsThe three retrieval methods produce consistent results with a maximum percentage difference of ∼30% for large ozone densities below 50 km [ABSTRACT FROM AUTHOR]

Xia‐Gibbs syndrome (XGS; MIM# 615829) is a rare mendelian disorder characterized by Development Delay (DD), intellectual disability (ID), and hypotonia. Individuals with XGS typically harbor de novo protein‐truncating mutations in the AT‐Hook DNA binding motif containing 1 (AHDC1) gene, although some missense mutations can also cause XGS. Large de novo heterozygous deletions that encompass the AHDC1 gene have also been ascribed as diagnostic for the disorder, without substantial evidence to support their pathogenicity. We analyzed 19 individuals with large contiguous deletions involving AHDC1, along with other genes. One individual bore the smallest known contiguous AHDC1 deletion (∼350 Kb), encompassing eight other genes within chr1p36.11 (Feline Gardner‐Rasheed, IFI6, FAM76A, STX12, PPP1R8, THEMIS2, RPA2, SMPDL3B) and terminating within the first intron of AHDC1. The breakpoint junctions and phase of the deletion were identified using both short and long read sequencing (Oxford Nanopore). Quantification of RNA expression patterns in whole blood revealed that AHDC1 exhibited a mono‐allelic expression pattern with no deficiency in overall AHDC1 expression levels, in contrast to the other deleted genes, which exhibited a 50% reduction in mRNA expression. These results suggest that AHDC1 expression in this individual is compensated by a novel regulatory mechanism and advances understanding of mutational and regulatory mechanisms in neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Inherited epidermolysis bullosa (EB) simplex is a heterogeneous group of skin fragility disorders caused by mutations in genes encoding cell‐cell or cell‐matrix adhesion proteins. A recently identified, rare subtype of EB simplex is due to bi‐allelic mutations in the EXPH5 gene, which encodes exophilin5, an effector protein of the Rab27B GTPase involved in intracellular vesicle trafficking and exosome secretion. The EXPH5 EB subtype is characterized by early‐onset skin blisters and scars, mainly on extremities, and varying degrees of pigmentary alterations. Here, we present a 31‐year‐old female with diffuse guttate hypopigmentation on the trunk and extremities since early childhood, with no apparent blisters or scars. We employed whole exome sequencing of germline DNA extracted from the patient's leukocytes to determine the genetic aetiology of the phenotype. A novel homozygous variant in EXPH5, c.1153C>T causing a premature stop codon at amino acid Glutamine 385, was identified. Histologic examination after skin pricking disclosed focal keratinocyte detachment typical to EB. Additionally, we identified a deleterious‐predicted variant in ENPP1, a gene associated with disturbed transfer of melanosomes to keratinocytes in Cole disease. Our report expands the clinical spectrum of inherited EB simplex with a possible di‐genic synergism contributing to co‐presentation with guttate leukoderma. [ABSTRACT FROM AUTHOR]

Introduction: Congenital afibrinogenaemia and hypofibrinogenaemia are rare coagulation disorders where clotting is impaired due to a lack of fibrinogen. Consequent bleeding episodes (BEs) are treated using human fibrinogen concentrate (HFC). Aim: This post‐hoc analysis compared HFC pharmacokinetics (PK) and dosing between patient age groups and defined the in vivo recovery (IVR) for children with a‐ and hypofibrinogenaemia. Methods: The analysis used data from the FORMA‐01 (Phase 2), FORMA‐02 and FORMA‐04 (Phase 3) multinational, prospective, open‐label studies in patients with a‐ and hypofibrinogenaemia. HFC PK in adults/adolescents (≥12 years; FORMA‐01) and children (<12 years; FORMA‐04) was examined. Haemostatic efficacy in BE treatment and perioperative prophylaxis was examined in FORMA‐02 and FORMA‐04 using an objective 4‐point scale, with success defined as excellent/good. Results: Median (range) age was 23 years for FORMA‐01 (12–53; n = 22), 26.5 years for FORMA‐02 (12–54; n = 25), and 6 years for FORMA‐04 (1–10; n = 13). Mean PK parameters were lower for children (AUC, Cmax, IVR; p =.02), while clearance was higher. Median (range) total dose of HFC for all BEs was 59.41 mg/kg (32.12–273.80) in adults/adolescents and was 24% higher (ns) in children at 73.91 mg/kg (47.45–262.50). Treatment was successful in 98.9% of the 89 BEs in adults/adolescents and in 100% of the 10 BEs in children, with comparable results for perioperative prophylaxis. Conclusion: As expected, HFC PK differed between adults/adolescents and children. However, with the higher doses given to children, HFC showed similar efficacy across age groups. Dose adaptation based on age groups appears recommendable. [ABSTRACT FROM AUTHOR]

Background: Congenital fibrinogen deficiency (CFD) is a rare coagulation disorder placing patients at increased bleeding risk. Human fibrinogen concentrate (HFC) represents current standard of care for fibrinogen replacement in CFD, however, limited data are available on HFC for prophylactic administration before/during surgery. Here, we report results and dosing considerations for HFC treatment in perioperative bleeding management in adult, adolescent, and pediatric patients with CFD.Study Design and Methods: FORMA-02/FORMA-04 were multinational, prospective, open-label, uncontrolled Phase 3 HFC efficacy/safety studies for surgical bleeding prophylaxis in adult/adolescent (≥12 years) and pediatric patients (<12 years) respectively. HFC dosing was calculated to achieve pre-established target fibrinogen plasma levels. Overall hemostatic efficacy was assessed as success/failure by an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) according to objective criteria.Results: Twelve patients (≥12 years, N = 9; <12 years, N = 3) received HFC for surgical prophylaxis (15 surgeries; 13 minor, 2 major). Eleven minor surgeries in patients aged ≥12 years required a median of 1 infusion (range; 1-5), with a mean (±SD) dose of 93.50 mg/kg [±41.43] and two minor surgeries in patients <12 years required 1 infusion (91.55 mg/kg [±23.40]). The major surgery in an adult patient required eight infusions (225.3 mg/kg total dose). The major surgery in a pediatric patient required six infusions (450.4 mg/kg). All surgeries were rated successful by the IDMEAC.Discussion: In adults/adolescents and pediatric patients with fibrinogen deficiency, HFC treatment for hemostatic management during/after minor and major surgery was successful, with efficacy comparable across the different age groups. [ABSTRACT FROM AUTHOR]

Objective: Polygenic risk scores (PRS) allow risk stratification using common single‐nucleotide polymorphisms (SNPs), and clinical applications are currently explored for several diseases. This study was undertaken to assess the risk of hip and knee osteoarthritis (OA) using PRS. Methods: We analyzed 12,732 individuals from a population‐based cohort from the Rotterdam Study (n = 11,496), a clinical cohort (Cohort Hip and Cohort Knee [CHECK] study; n = 908), and a high‐risk cohort of overweight women (Prevention of Knee OA in Overweight Females [PROOF] study; n = 328), for the association of the PRS with prevalence/incidence of radiographic OA, of clinical OA, and of total hip replacement (THR) or total knee replacement (TKR). The hip PRS and knee PRS contained 44 and 24 independent SNPs, respectively, and were derived from a recent genome‐wide association study meta‐analysis. Standardized PRS (with Z transformation) were used in all analyses. Results: We found a stronger association of the PRS for clinically defined OA compared to radiographic OA phenotypes, and we observed the highest PRS risk stratification for TKR/THR. The odds ratio (OR) per SD was 1.3 for incident THR (95% confidence interval [95% CI] 1.1–1.5) and 1.6 (95% CI 1.3–1.9) for incident TKR in the Rotterdam Study. The knee PRS was associated with incident clinical knee OA in the CHECK study (OR 1.3 [95% CI 1.1–1.5]), but not for the PROOF study (OR 1.2 [95% CI 0.8–1.7]). The OR for OA increased gradually across the PRS distribution, up to 2.1 (95% CI 1.4–3.2) for individuals with the 10% highest PRS compared to the middle 50% of the PRS distribution. Conclusion: Our findings validated the association of PRS across OA definitions. Since OA is becoming frequent and primary prevention is not commonly applicable, PRS‐based risk assessment could play a role in OA prevention. However, the utility of PRS is dependent on the setting. Further studies are needed to test the integration of genetic risk assessment in diverse health care settings. [ABSTRACT FROM AUTHOR]

Objective: During the political transition, people lose their confidence in their leaders, faith in the so‐called "democratic" elections, and no longer trust their political institutions. The issue of trust in institutions is highly regarded in social sciences research, as it reflects people's perceptions and valuation of how well their institutions are functioning. Therefore, the main objective of this article is to investigate the case of the Middle East and North African Region following the Arab Spring uprisings that began in 2011. Specifically, the relationship between youth self‐perception identity and confidence in various institutions is examined in the post‐Arab Spring era. Method: We use a microlevel data set extracted from the SAHWA Youth Survey conducted in 2016. The sample consists of around 10,000 randomly and nationally representative youth aged 15 to 29 years. The survey includes 2000 observations from Lebanon, 1970 observations from Egypt, 2000 from Tunisia, and 2036 and 1854 from Algeria and Morocco, respectively. The empirical analysis is carried out through the ordered probit model. Results: Controlling for a comprehensive set of socioeconomic characteristics, we find that religious associations are not confined to people who belong to an Arab, global, national, or even religious identity. Young people who identify with citizens of the world only seem to confide in the police. Additionally, Arab identity is correlated with absolute positive confidence in the elections. Coherent with previous literature, we note that a nationalistic identity increases politicians' and administrations' confidence despite the domestic turmoil. We also find that religious identity is negatively correlated with all institutions except elections, including religious associations. Conclusion: This research highlights that policies that are up‐to‐date and secure gender equality may create a modernist atmosphere that allows people to retrieve trust and confidence in the institutions and administrations in the countries. [ABSTRACT FROM AUTHOR]

The growing interest in foods that can be beneficial to human health is bringing into focus some products that have been used locally for centuries but have recently gained worldwide attention. One of these foods is pumpkin seed oil, which has been used in culinary and traditional medicine, but recent data also show its use in the pharmaceutical and cosmetic industries. In addition, some sources refer to it as a potential functional food, mainly because it is obtained from pumpkin seeds, which contain many functional components. However, the production process of the oil may affect the content of these components and consequently the biological activity of the oil. In this review, we have focused on summarizing scientific data that explore the potential of pumpkin seed oil as a functional food ingredient. We provide a comprehensive overview of pumpkin seed oil chemical composition, phytochemical content, biological activity, and safety, as well as the overview of production processes and contemporary use. The main phytochemicals in pumpkin seed oil with health‐related properties are polyphenols, phytoestrogens, and fatty acids, but carotenoids, squalene, tocopherols, and minerals may also contribute to health benefits. Most studies have been conducted in vitro and support the claim that pumpkin seed oil has antioxidant and antimicrobial activities. Clinical studies have shown that pumpkin seed oil may be beneficial in the treatment of cardiovascular problems of menopausal women and ailments associated with imbalance of sex hormones. [ABSTRACT FROM AUTHOR]

In this retrospective multicenter case series study, the predictive value of initial findings of confirm COVID‐19 cases in determining outcome of the disease was assessed. Patients were divided into two groups based on the outcome: low risk (hospitalization in the infectious disease ward and discharge) and high risk (hospitalization in ICU or death). A total of 164 patients with positive PCR‐RT were enrolled in this study. About 36 patients (22%) were in the high‐risk group and 128 (78%) were in the low‐risk group. Results of statistical analysis revealed a significant relationship between age, fatigue, history of cerebrovascular disease, organ failure, white blood cells (WBC), neutrophil‐to‐lymphocyte ratio (NLR), and derived neutrophil‐to‐lymphocyte ratio (dNLR) with increased risk of disease. The artificial neural network (ANN) could predict the high‐risk group with an accuracy of 87.2%. Preliminary findings of COVID‐19 patients can be used in predicting their outcome and ANN can determine the outcome of patients with appropriate accuracy (87.2%). Most treatment in Covid‐19 are supportive and depend on the severity of the disease and its complications. The first step in treatment is to determine the severity of the disease. This study can improve the treatment of patients by predicting the severity of the disease using the initial finding of patients and improve the management of disease with differentiating high‐risk from low‐risk groups. [ABSTRACT FROM AUTHOR]

The Nadir and Occultation for MArs Discovery (NOMAD)/UV‐visible (UVIS) spectrometer on the ExoMars Trace Gas Orbiter provided observations of ozone (O3) and water vapor in the global dust storm of 2018. Here we show in detail, using advanced data filtering and chemical modeling, how Martian O3 in the middle atmosphere was destroyed during the dust storm. In data taken exactly 1 year later when no dust storm occurred, the normal situation had been reestablished. The model simulates how water vapor is transported to high altitudes and latitudes in the storm, where it photolyzes to form odd hydrogen species that catalyze O3. O3 destruction is simulated at all latitudes and up to 100 km, except near the surface where it increases. The simulations also predict a strong increase in the photochemical production of atomic hydrogen in the middle atmosphere, consistent with the enhanced hydrogen escape observed in the upper atmosphere during global dust storms. Plain Language Summary: Global dust storms are rare but impactful events on Mars, occurring about once in a decade. Previous investigations found how water vapor is redistributed throughout the entire atmosphere in a dust storm. Photolysis of water vapor by sunlight produces highly reactive species that destroy ozone (O3). Here we present O3 measurements taken by the NOMAD/UVIS instrument on the ExoMars Trace Gas Orbiter in the 2018 global dust storm. After advanced data filtering, they demonstrate how O3 in the middle atmosphere was much reduced compared to one Mars year later when no dust storm occurred. 3D atmospheric model simulations of atmospheric chemistry in the global dust storm confirm this planet‐wide O3 destruction, and help to understand the involved processes. The simulations also predict a strong increase in production of atomic hydrogen in the middle atmosphere, that can explain the observed increased hydrogen atmospheric escape during global dust storms. Key Points: NOMAD ozone (O3) data filtering during the 2018 global dust storm shows strong O3 destruction compared to one year later with no dust storm3D simulations of atmospheric chemistry in the 2018 global dust storm are presented to understand impact on odd hydrogen and odd oxygenThe model confirms middle‐atmospheric O3 destruction in the dust storm and predicts increased photochemical production of hydrogen [ABSTRACT FROM AUTHOR]

Neurofibromatosis 1 (NF1) is caused by germline mutations in the NF1 gene and manifests as proliferation of various tissues, including plexiform neurofibromas. The plexiform neurofibroma phenotype varies from indolent to locally aggressive, suggesting contributions of other modifiers in addition to somatic loss of NF1. In this study, we investigated a life‐threatening plexiform neurofibroma in a 9‐month‐old female infant with NF1. Germline mutations in two RASopathy‐associated genes were identified using whole‐exome sequencing—a de novo pathogenic variant in the NF1 gene, and a known pathogenic variant in the LZTR1 gene. Somatic analysis of the plexiform neurofibroma revealed NF1 loss of heterozygosity and a variant in GNAZ, a gene encoding a G protein‐coupled receptor. Cells expressing mutant GNAZ exhibited increased ERK 1/2 activation compared to those expressing wild‐type GNAZ. Taken together, we suggest the variants in NF1, LZRT1 and GNAZ act synergistically in our patient, leading to MAPK pathway activation and contributing to the severity of the patient's plexiform neurofibromatosis. After treatment with the MEK inhibitor, trametinib, a prominent clinical improvement was observed in this patient. This case study contributes to the knowledge of germline and somatic non‐NF1 variants affecting the NF1 clinical phenotype and supports use of personalized, targeted therapy. [ABSTRACT FROM AUTHOR]

Maternal obesity and excessive gestational weight gain (EGWG) may have persistent effects on offspring obesity and be risk factors for both mother and child. Studies have reported that asprosin concentration is associated with metabolism and weight changes during pregnancy. This study therefore evaluated the association of maternal and newborn asprosin with normal weight gain and EGWG and nutritional intake in pregnancy. The study included 30 pregnant women with normal weight gain and 30 women with EGWG referred to Ali ibn Abi Talib Hospital in Zahedan, Iran, September 2020 to June 2021. A demographic questionnaire and neonatal complications checklist were completed. Asprosin concentrations at the time of delivery in maternal venous blood samples and umbilical vein blood samples were measured by ELISA technique. Macronutrient and energy intake were assessed by a 24‐h dietary recall questionnaire and compared with standard Recommended Dietary Allowance (RDA) and Dietary References Intake (DRI) values. Asprosin levels were significantly higher in the EGWG group's umbilical cord blood than in the control group but there was no difference in maternal asprosin concentrations between the two groups. The Appearance, Pulse, Grimace, Activity and Respiration (Apgar) score was significantly lower in the EGWG group than in the control group, although there was no difference in birthweight between the groups. Weight gain during pregnancy, energy intake and protein and carbohydrate consumption were significantly higher in the EGWG group than in the control group (p < 0.05). It seems that differences in asprosin secretion do not mediate an imbalance in energy intake and other macronutrients during pregnancy that affect pregnancy weight gain and birthweight. However, excessive gestational weight gain was associated with neonatal asprosin levels and newborn Apgar scores. [ABSTRACT FROM AUTHOR]

Ichthyosis and deafness syndrome is a group of devastating genodermatoses caused by heterozygous mutations in GJB2, encoding the gap junction protein connexin 26. These syndromes are characterized by severe skin disease, hearing loss, recurrent infections, and cutaneous neoplasms. Cutaneous somatic mutations in the same gene are associated with porokeratotic eccrine ostial dermal duct nevus. Here we report a family in which a parent presented with localized epidermal nevus and his child suffered with hystrix‐like ichthyosis with deafness. Histologic examination of the parent's cutaneous lesion revealed verrucous epidermal nevus without features of porokeratotic eccrine ostial dermal duct nevus. Genetic analysis identified the same pathogenic variant, GJB2 c.148G>A (p.D50N), in DNA extracted from the parent's cutaneous lesion and the child's leukocytes, but not in the parent's leukocytes. This study expands the phenotypic heterogeneity of GJB2 mosaic variants in addition to porokeratotic eccrine ostial dermal duct nevus, and emphasizes the importance of molecular diagnosis of mosaic skin diseases considering the risk of severe inherited diseases in the offspring. [ABSTRACT FROM AUTHOR]

To develop chemosensors for biomolecule recognition, a multi stimuli responsive supramolecular gelator, [(E)‐4‐((4‐(benzyloxy)phenyl)diazenyl)benzaldehyde], comprised of azo and formyl units, was designed and synthesized from readily available starting materials. The gelator was found to be capable of forming gels in light alcohols and alcohol/water mixtures at low concentrations (0.7–1.5 g/100 mL). The gel rheological analyses showed the dominance of storage modulus (G′) values (ca 5000 Pa) within the range of analysis, confirming the gel stiffness. The xerogel scanning electron microscopy (SEM) studies showed a flake‐like pattern of thin sheets. Our investigations on the gelator sensing abilities revealed that, in addition to the photo‐responsive function due to the presence of azo moiety, its ethanol/water gel exhibited excellent ability to detect l‐arginine among 19 various amino acids, via gel to sol transition and colour change. Furthermore, the gelator could successfully recognize l‐cysteine among 19 amino acids, through macroscopic sol to gel transition and colour change of its alkaline methanolic solution. Moreover, the photo‐ and chemo‐responsive functions of the gelator were demonstrated as two combinational logic gates. [ABSTRACT FROM AUTHOR]

Chronic Hepatitis C is a global health threat and a silent killer. Regardless of the profound progress in preventing and treating this disease, research continues to discover new direct antiviral agents (DAAs), especially against novel targets. Our research has been directed to leverage the NS4A binding site to develop peptidomimetic inhibitors of the hepatitis C virus (HCV) NS3 protease. In previous reports, we could provide evidence of tunability of this site by peptide and nonpeptide NS3/4A inhibitors. In this report, we used structure-based techniques to design 1,2,3,4-tetrahydro-1,7-naphthyridine derivative as NS4A core mimics that cover the region between residues Ile-25′ to Arg-28′. The synthetic plan featured the Povarov reaction as an efficient strategy to construct the 1,7-naphthyridine core. Although this reaction has been reported in many literatures, critical assessments for its scope and limitations are scarce. In our work, we found that Povarov was extremely sensitive to alkene and aldehyde reactants. Moreover, using pyridine amines was not as successful as anilines. The most striking results were the lack of stability of compounds during purification and storage. The four compounds that survived the stability problems (1a-1d) did not show significant binding potency with NS3, because their structures were too simple to resemble the originally planned compounds. [ABSTRACT FROM AUTHOR]

The vertical profiles of water vapor and its semi‐heavy hydrogen isotope HDO provided by instruments on ExoMars Trace Gas Orbiter constitute a unique new data set to understand the Martian water cycle including its isotopic composition. As water vapor undergoes hydrogen isotopic fractionation upon deposition (but not sublimation), the D/H isotopic ratio in water is a tracer of phase transitions, and a key quantity to understand the long‐term history of water on Mars. Here, we present 3D global simulations of D/H in water vapor and compare them to the vertically resolved observations of D/H and water ice clouds taken by NOMAD during the second half of Mars year 34. D/H is predicted to be constant with height up to the main cloud level, above which it drops because of strong fractionation, explaining the upper cut‐off in the NOMAD observations when HDO drops below detectability. During the global and regional dust storms of 2018/2019, we find that HDO ascends with H2O, and that the D/H ratio is constant and detectable up to larger heights. The simulations are within the provided observational uncertainties over wide ranges in season, latitude and height. Our work provides evidence that the variability of the D/H ratio in the lower and middle atmosphere of Mars is controlled by fractionation on water ice clouds, and thus modulated by diurnally and seasonally varying cloud formation. We find no evidence of other processes or reservoirs that would have a significant impact on the D/H ratio in water vapor. Plain Language Summary: The isotopic composition of atmospheric water on Mars provides insights about the phase transitions in the water cycle, because the light (H2O) and semi‐heavy (HDO) form of water vapor deposit at different saturation pressures. Knowing the isotopic composition of atmospheric water also provides insights on the long‐term evolution of water on Mars. The NOMAD instrument on ExoMars Trace Gas Orbiter provided the first vertical profiles of the D/H ratio in water vapor on Mars. The data set shows a large variability with season and latitude. To understand this behavior, a general circulation model is required. We provide detailed simulations of the D/H ratio in Martian water vapor and compare them with the NOMAD observations. The model predicts that the D/H ratio is constant in the lower atmosphere and decreases across a layer of strong cloud formation that varies with season. During the global dust storm of 2018, this cloud layer was severely lifted. The simulations compare well to the observations, both out and in the dust storm, and explain their upper cut‐off by this predicted decrease in D/H. No other processes than cloud formation, nor special surface ice reservoirs with strongly different D/H values, were needed to reproduce the observations. Key Points: Hydrogen fractionation by clouds in Mars water vapor is simulated and evaluated with NOMAD D/H observations in and out of dust stormsThe model D/H ratio is constant and drops when clouds form, explaining the upper cut‐off in the NOMAD profiles as HDO becomes undetectableNOMAD water ice observations provide evidence that fractionation by clouds is the main factor controlling the HDO distribution on Mars [ABSTRACT FROM AUTHOR]

Acral peeling skin syndrome (APSS) is a heterogenous group of genodermatoses, manifested by peeling of palmo‐plantar skin and occasionally associated with erythema and epidermal thickening. A subset of APSS is caused by mutations in protease inhibitor encoding genes, resulting in unopposed protease activity and desmosomal degradation and/or mis‐localization, leading to enhanced epidermal desquamation. We investigated two Arab‐Muslim siblings with mild keratoderma and prominent APSS since infancy. Genetic analysis disclosed a homozygous mutation in SERPINB7, c.796C > T, which is the founder mutation in Nagashima type palmo‐plantar keratosis (NPPK). Although not previously formally reported, APSS was found in other patients with NPPK. We hypothesized that loss of SERPINB7 function might contribute to the peeling phenotype through impairment of keratinocyte adhesion, similar to other protease inhibitor mutations that cause APSS. Mis‐localization of desmosomal components was observed in a patient plantar biopsy compared with a biopsy from an age‐ and gender‐matched healthy control. Silencing of SERPINB7 in normal human epidermal keratinocytes led to increased cell sheet fragmentation upon mechanical stress. Immunostaining showed reduced expression of desmoglein 1 and desmocollin 1. This study shows that in addition to stratum corneum perturbation, loss of SERPINB7 disrupts desmosomal components, which could lead to desquamation, manifested by skin peeling. [ABSTRACT FROM AUTHOR]

Objective: To evaluate if high-dose letrozole can be used successfully to stimulate poor responders for in vitro fertilization (IVF).Methods: This was a retrospective study conducted at a university hospital reproductive center. The analysis included women who were up to 42 years of age and were Rotterdam Consensus poor responders. A total of 247 patients received gonadotropins (300-450 IU daily) and 62 patients were stimulated with letrozole (20 mg daily) as part of an antagonist IVF protocol.Results: The use of 20 mg of letrozole decreased the total dose of gonadotropins used (645 ± 175 IU vs. 5360 ± 1028 IU, P = 0.001) and resulted in lower costs of stimulation medications ($ 555.56 ± $ 150 vs. $ 4616 ± $ 885 Canadian Dollars; P = 0.001). Pregnancy per cycle (14.5%) and per transfer (16%) rates were legitimate for this low prognosis group and may have been better than or similar to those with high-dose gonadotropins. The rate of cycle cancellation may have been reduced in the letrozole versus gonadotropin group (11% vs. 38%; P = 0.001).Conclusion: Letrozole (20 mg daily) may be used to reduce the cost of ovarian stimulation in ultra-poor responders, significantly reducing the cost of the IVF cycle with probably at least similar outcomes to high-dose gonadotropins. [ABSTRACT FROM AUTHOR]

As a result of the preference for consanguineous/endogamous marriages, the Israeli Arab population is composed of isolated communities with relatively frequent autosomal recessive (AR) conditions in each community. Clinical diagnosis of affected individuals has uncovered the pathogenic variants throughout the years. We investigated the diversity of pathogenic AR variants in a single village in northern Israel by exome analysis of 50 random, healthy adults descendants of the founders. Only likely pathogenic and pathogenic variants in known AR genes were selected. In this study 48 AR variants were found, of which 12 had been previously diagnosed in patients from this village, and for 11 with a frequency compatible with the frequency already known. Among the other 36 variants, 12 had been previously diagnosed in affected individuals in other Arab communities in Israel and 24 variants had not been previously characterized in this population. Of the 35 variants associated with conditions of moderate–severe medical consequences, only eight were known previously in this village. These findings emphasize the importance to better delineate the conditions at risk in a defined community, in particular for the development of preventive measures such as screening tests for reproductive couples, and for genetic counseling. [ABSTRACT FROM AUTHOR]

Objective: Commercial gene panels identify pathogenic variants in as low as 27% of patients suspected to have MODY, suggesting the role of yet unidentified pathogenic variants. We sought to identify novel gene variants associated with MODY. Research Design and Methods: We recruited 10 children with a clinical suspicion of MODY but non‐diagnostic commercial MODY gene panels. We performed exome sequencing (ES) in them and their parents. Results: Mean age at diabetes diagnosis was 10 (± 3.8) years. Six were females; 4 were non‐Hispanic white, 5 Hispanic, and 1 Asian. Our variant prioritization analysis identified a pathogenic, de novo variant in INS (c.94G > A, p.Gly32Ser), confirmed by Sanger sequencing, in a proband who was previously diagnosed with "autoantibody‐negative type 1 diabetes (T1D)" at 3 y/o. This rare variant, absent in the general population (gnomAD database), has been reported previously in neonatal diabetes. We also identified a frameshift deletion (c.2650delC, p.Gln884AsnfsTer57) in RFX6 in a child with a previous diagnosis of "autoantibody‐negative T1D" at 12 y/o. The variant was inherited from the mother, who was diagnosed with "thin type 2 diabetes" at 25 y/o. Heterozygous protein‐truncating variants in RFX6 gene have been recently reported in individuals with MODY. Conclusions: We diagnosed two patients with MODY using ES in children initially classified as "T1D". One has a likely pathogenic novel gene variant not previously associated with MODY. We demonstrate the clinical utility of ES in patients with clinical suspicion of MODY. [ABSTRACT FROM AUTHOR]

Aims/Introduction: This study aimed to investigate whether insulin resistance (IR) in individuals with type 2 diabetes undergoing intensive glycemic control determines the extent of improvement in neuropathy. Materials and Methods: This was an exploratory substudy of an open‐label, randomized controlled trial of individuals with poorly controlled type 2 diabetes treated with exenatide and pioglitazone or insulin to achieve a glycated hemoglobin <7.0% (<53 mmol/mol). Baseline IR was defined using homeostasis model assessment of IR, and change in neuropathy was assessed using corneal confocal microscopy. Results: A total of 38 individuals with type 2 diabetes aged 50.2 ± 8.5 years with (n = 25, 66%) and without (n = 13, 34%) IR were studied. There was a significant decrease in glycated hemoglobin (P < 0.0001), diastolic blood pressure (P < 0.0001), total cholesterol (P < 0.01) and low‐density lipoprotein (P = 0.05), and an increase in bodyweight (P < 0.0001) with treatment. Individuals with homeostasis model assessment of IR <1.9 showed a significant increase in corneal nerve fiber density (P ≤ 0.01), length (P ≤ 0.01) and branch density (P ≤ 0.01), whereas individuals with homeostasis model assessment of IR ≥1.9 showed no change. IR was negatively associated with change in corneal nerve fiber density after adjusting for change in bodyweight (P < 0.05). Conclusions: Nerve regeneration might be limited in individuals with type 2 diabetes and IR undergoing treatment with pioglitazone plus exenatide or insulin to improve glycemic control. [ABSTRACT FROM AUTHOR]

We present ∼1.5 Mars Years (MY) of ozone vertical profiles, covering LS = 163° in MY34 to LS = 320° in MY35, a period which includes the 2018 global dust storm. Since April 2018, the Ultraviolet and Visible Spectrometer channel of the Nadir and Occultation for Mars Discovery (NOMAD) instrument aboard the ExoMars Trace Gas Orbiter has observed the vertical, latitudinal and seasonal distributions of ozone. Around perihelion, the relative abundance of both ozone and water (from coincident NOMAD measurements) increases with decreasing altitude below ∼40 km. Around aphelion, localized decreases in ozone abundance exist between 25 and 35 km coincident with the location of modeled peak water abundances. High‐latitude (>±55°), high altitude (40–55 km) equinoctial ozone enhancements are observed in both hemispheres (LS ∼350°–40°) and discussed in the companion article to this work (Khayat et al., 2021). The descending branch of the main Hadley cell shapes the observed ozone distribution at LS = 40°–60°, with the possible signature of a northern hemisphere thermally indirect cell identifiable from LS = 40°–80°. Morning terminator observations show elevated ozone abundances with respect to evening observations, with average ozone abundances between 20 and 40 km an order of magnitude higher at sunrise compared to sunset, attributed to diurnal photochemical partitioning along the line of sight between ozone and O or fluctuations in water abundance. The ozone retrievals presented here provide the most complete global description of Mars ozone vertical distributions to date as a function of season and latitude. Plain Language Summary: We present over two years of new observations of the vertical distribution of ozone in the atmosphere of Mars. The ExoMars Trace Gas Orbiter spacecraft has been recording observations of the Martian atmosphere since 2018 to map the presence and changes in abundance of gases such as ozone by using the "Nadir and Occultation for Mars Discovery (NOMAD)" instrument. NOMAD continually observes the change in ozone abundance (among other gases) at different heights across much of the planet. These abundance profiles have revealed the presence of distinct layers of ozone enhancement at high altitudes in the atmosphere of Mars toward the polar regions and between spring and autumn in the southern hemisphere of Mars, discussed in detail in the companion article. We observe broad periods where often the abundance of ozone follows the abundance of water from ∼10 km altitude up to ∼50 km altitude, and other times when the two appear to be opposite in their variation with height. Our retrievals of ozone from NOMAD data provide the first coincident observations of ozone and water and provide previously unavailable information on the photochemistry of Mars. Key Points: The annual Martian O3 distribution has been measured at a vertical resolution up to 0.2 km and for the first time alongside H2O profilesO3 and H2O show strong vertical anti‐correlation around aphelion as expected, contrasted with vertical correlation toward perihelionO3 abundances between altitudes of 20–40 km are an order of magnitude higher at sunrise than at sunset between LS = 40°–50° [ABSTRACT FROM AUTHOR]

Solar occultations performed by the Nadir and Occultation for MArs Discovery (NOMAD) ultraviolet and visible spectrometer (UVIS) onboard the ExoMars Trace Gas Orbiter (TGO) have provided a comprehensive mapping of atmospheric ozone density. The observations here extend over a full Mars year (MY) between April 21, 2018 at the beginning of the TGO science operations during late northern summer on Mars (MY 34, Ls = 163°) and March 9, 2020 (MY 35). UVIS provided transmittance spectra of the Martian atmosphere allowing measurements of the vertical distribution of ozone density using its Hartley absorption band (200–300 nm). The overall comparison to water vapor is found in the companion paper to this work (Patel et al., 2021, https://doi.org/10.1029/2021JE006837). Our findings indicate the presence of (a) a high‐altitude peak of ozone between 40 and 60 km in altitude over the north polar latitudes for at least 45% of the Martian year during midnorthern spring, late northern summer‐early southern spring, and late southern summer, and (b) a second, but more prominent, high‐altitude ozone peak in the south polar latitudes, lasting for at least 60% of the year including the southern autumn and winter seasons. When present, both high‐altitude peaks are observed in the sunrise and sunset occultations, suggesting that the layers could persist during the day. Results from the Mars general circulation models predict the general behavior of these peaks of ozone and are used in an attempt to further our understanding of the chemical processes controlling high‐altitude ozone on Mars. Plain Language Summary: The presence of ozone in the Martian atmosphere has been observed since it was first detected by the 1969 and 1971 Mariner flyby missions. Mars is known to have a permanent ozone layer below 30 km. Solar occultations performed by the ultraviolet and visible spectrometer onboard the ExoMars Trace Gas Orbiter have provided a comprehensive mapping of the vertical distribution of ozone in the atmosphere of Mars for an entire Mars year, describing the seasonal, spatial, and local time distribution of ozone in detail. This analysis indicates the presence of a previously undetected high‐altitude peak of ozone between 40 and 60 km in altitude over the north polar latitudes for approximately half of the Martian year. It also confirms the presence of a second, but more prominent, high‐altitude ozone peak in the south polar latitudes. When they are present, both high‐altitude peaks are observed in the sunrise and sunset occultations, indicating that the layers could persist during the day. Key Points: We provide the first detection of a high‐altitude peak of ozone between 40 and 60 km in altitude over the north polar latitudes of MarsWe confirm the presence of a previously detected, more prominent high‐altitude ozone peak in the south polar latitudesBoth high‐altitude peaks are observed in the sunrise and sunset occultations, indicating that the layers could persist during the day [ABSTRACT FROM AUTHOR]

Background/aims: Traumatic dental injuries (TDI) are prevalent among soccer players. In Kuwait, no studies of TDI among soccer players have been carried out. The aim of this study was to investigate the prevalence, type and causes of soccer-related traumatic dental injuries among 7-18-year-old amateur soccer players.Methods: All amateur soccer players who were registered in the 14 sports clubs in the country were invited to participate in this screening study. Players who were present in the club on the assigned examination day were included. The players were examined by two trained and calibrated paediatric dentists for signs of injury to the oral tissues. Injury diagnosis was made according to the Andreasen (2007) epidemiological dental injury classification. The history of any dental injury present at the time of examination was recorded. The timing and nature of any dental advice or treatment sought was also noted.Results: Six hundred sixty-seven (48% inclusion rate) male players were included (mean age of 13.4 ± 2.6 years). In total, 213 injured teeth were observed among 169 (25%) players. The prevalence of soccer-related injuries was 11%, and a greater number of injuries were observed in older players. Maxillary central incisors were the most frequently injured teeth (91%), and enamel-only fractures represented 60% of all injured teeth. Slightly more TDIs were soccer-related (44%) compared to non-soccer-related injuries (39%), and a large number of TDIs (39%) occurred inside the sports clubs. The prevalence of reported soft-tissue injuries was 18%. The majority of the players (75%) did not receive dental care for their injuries.Conclusions: A significant number of young Kuwaiti amateur soccer players suffered TDIs. In addition, a high percentage of traumatic injuries were not treated, and there was a lack of the use of protective mouthguards. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Painful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control. Materials and Methods: This exploratory substudy of an open‐label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal–bolus insulin at baseline and 1‐year follow up, and 18 controls at baseline only. Results: Participants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P < 0.0001) and weight gain (P < 0.005), irrespective of therapy. Participants with pDPN showed a significant increase in corneal nerve fiber density (P < 0.05), length (P < 0.0001) and branch density (P < 0.005), and a decrease in the Douleur Neuropathique en 4 score (P < 0.01), but no change in electrochemical skin conductance or vibration perception threshold. Participants without pDPN showed a significant increase in corneal nerve branch density (P < 0.01) and no change in any other neuropathy measures. A change in the severity of painful symptoms was not associated with corneal nerve regeneration and medication for pain. Conclusions: This study showed that intensive glycemic control is associated with greater corneal nerve regeneration and an improvement in the severity of pain in patients with painful diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Objectives. The level of evidence (LOE) of Saudi dental research from 2000 to 2020 was evaluated, and factors associated with the LOE were determined. Methods. This study was a systematic review. PubMed, Web of Science, and Medline databases were utilized to retrieve available dental articles published in English between January 2000 and May 2020. The inclusion criteria consisted of clinical studies conducted in Saudi Arabia with at least one Saudi dental affiliation. The retrieved eligible articles were evaluated independently by two reviewers using a modified Oxford LOE scale. The LOE of the studies was compared between the last two decades. Results. Of the 7237 articles identified, 1557 articles met the inclusion criteria. Approximately 78% of the published articles reported Level IV evidence. A higher trend toward Level I, II, and III publications has occurred in recent years (i.e., 2010–2020). However, no statistically significant difference existed in LOE proportions between the two decades. The presence of international collaboration and high journals' impact factor was significantly associated with a higher LOE. Conclusion. Most published dental research studies were low LOE studies (i.e., Level IV). National and international collaboration is highly encouraged as this is a factor, according to our findings, that would be a positive addition toward publishing dental research of a higher LOE in Saudi Arabia. [ABSTRACT FROM AUTHOR]

Surface pressure measurements on Mars have revealed a wide variety of atmospheric phenomena. The Mars Science Laboratory Rover Environmental Monitoring Station pressure sensor data set is now the longest duration record of surface pressure on Mars. We use the first 2580 Martian sols, nearly 4 Mars years, of measurements to identify atmospheric pressure waves with periods of tens of minutes to hours using wavelet analysis on residual pressure after the tidal harmonics are removed. We find these waves have a clear diurnal cycle with strongest activity in the early morning and late evening and a seasonal cycle with the strongest waves in the second half of the martian year (Ls = 180–360°). The strongest such waves of the entire mission occurred during the Mars Year 34 global dust storm. Comparable atmospheric waves are identified using atmospheric modeling with the MarsWRF general circulation model in a "nested" high spatial resolution mode. With the support of the modeling, we find these waves best fit the expected properties of inertia‐gravity waves with horizontal wavelengths of O(100s) of km. Plain Language Summary: Measuring air pressure from the surface of Mars has revealed a wide variety of atmospheric phenomena. The Curiosity rover's record or surface air pressure is now the longest yet made on Mars. We use the first ∼8 years of Curiosity's pressure observations to look for atmospheric waves with periods of tens of minutes to hours. We find these waves have a clear pattern in their daily behavior with the strongest activity in the early morning and late evening and a seasonal cycle with the strongest waves in the second half of the Martian year (Northern hemisphere fall and winter). The strongest of such waves occurred in 2018 during a global dust storm. We find comparable waves in atmospheric modeling. With the support of modeling, we find these waves best fit the expected properties of buoyancy waves forced by airflow over topography with horizontal wavelengths of 100–1,000 km. Key Points: We detect atmospheric pressure waves with periods of tens of minutes to 3 h with Mars Science Laboratory Rover Environmental Monitoring Station observationsWe find comparable waves in mesoscale atmospheric simulations with the MarsWRF general circulation modelBased on their characteristics, we interpret waves with periods greater than 1 h as topographically forced inertia‐gravity waves [ABSTRACT FROM AUTHOR]

Elevated dopamine (DA) levels in the reward system underlie various drug-related behaviors, including addiction. As a major DA source in the reward system, the ventral tegmental area (VTA) is highly regulated by GABAergic inputs projected from different brain regions. It was previously shown that cocaine exposure reduces GABAA -mediated inhibitory postsynaptic currents (IPSCs) in VTA DA neurons; however, the specific GABAergic input underlying this inhibitory effect remains unknown. Here, using optogenetics, we separately activate and characterize different GABAergic afferents innervating the VTA, focusing on the rostromedial tegmental nucleus (RMTg) and the nucleus accumbens (NAc). GABAA -mediated IPSCs were recorded from VTA DA neurons, and the effect of DA-induced inhibition was measured in an afferent-specific manner. In addition, to examine the effect of enhanced GABAergic tone on the rewarding properties of cocaine, we exogenously activated the different GABAergic inputs during the acquisition phase of cocaine conditioned place preference (CPP). We found that acute cocaine exposure strongly attenuates GABAA -mediated IPSCs in VTA DA neurons from both inhibitory sources. Furthermore, exogenous light activation of both RMTg and NAc afferents in the VTA during the acquisition of cocaine-CPP significantly reduced the rewarding properties of cocaine. This behavioral observation was correlated with the reduction in the neuronal activity of VTA DA neurons as measured by the expression of c-fos. Together, these results emphasize the critical role of these GABAergic inputs to the VTA in modulating and potentially interrupting cocaine reward. [ABSTRACT FROM AUTHOR]

Xia–Gibbs syndrome (XGS) is a rare Mendelian disease typically caused by de novo stop‐gain or frameshift mutations in the AT‐hook DNA binding motif containing 1 (AHDC1) gene. Patients usually present in early infancy with hypotonia and developmental delay and later exhibit intellectual disability (ID). The overall presentation is variable, however, and the emerging clinical picture is still evolving. A detailed phenotypic analysis of 34 XGS individuals revealed five core phenotypes (delayed motor milestones, speech delay, low muscle tone, ID, and hypotonia) in more than 80% of individuals and an additional 12 features that occurred more variably. Seizures and scoliosis were more frequently associated with truncations that arise before the midpoint of the protein although the occurrence of most features could not be predicted by the mutation position. Transient expression of wild type and different patient truncated AHDC1 protein forms in human cell lines revealed abnormal patterns of nuclear localization including a diffuse distribution of a short truncated form and nucleolar aggregation in mid‐protein truncated forms. Overall, both the occurrence of variable phenotypes and the different distribution of the expressed protein reflect the heterogeneity of this syndrome. [ABSTRACT FROM AUTHOR]

Background: Congenital fibrinogen deficiency (CFD) is a rare, inherited disorder affecting normal blood clotting function, where patients can experience severe and/or frequent bleeding episodes (BEs). Treatment with human fibrinogen concentrate (HFC) can prevent/arrest bleeding. There is a need for more data on the efficacy, pharmacokinetics (PK) and safety of HFC treatment in paediatric patients with CFD. Methods: Haemostatic efficacy of HFC (Fibryga®, Octapharma AG) for on‐demand treatment of bleeding and surgical prophylaxis in patients <12 years old was assessed by investigators and an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) based on an objective 4‐point efficacy scale. Maximum clot firmness (MCF; surrogate marker of haemostatic efficacy), single‐dose PK and safety were also assessed. Results: Of 14 patients receiving HFC (median [range] age 6.0 years [1.0–10.0]), eight received HFC for 10 BEs, three for surgical prophylaxis and 13 for PK. The IDMEAC rated haemostatic efficacy as 100% successful for on‐demand BE treatment (95% CI 69.15–100.00) and surgical prophylaxis (95% CI 29.24–100.00). After a mean first dose of 70.78 mg/kg for BEs, mean (±SD) MCF significantly increased from pre‐treatment to 1‐hour post‐infusion (3.3 mm [±1.77]; P = 0.0002), coinciding with haemostatic efficacy. PK parameters were favourable. Two possibly related adverse events occurred, including one serious (portal vein thrombosis). No allergic/hypersensitivity reactions or deaths were observed. Conclusion: HFC treatment for on‐demand treatment of BEs and surgical prophylaxis was efficacious for this ultra‐rare paediatric population with congenital afibrinogenaemia and showed a favourable PK and safety profile. [ABSTRACT FROM AUTHOR]

We consider the inverse problem of recovering the missing flux and concentration on some part of a boundary of an aquifer using overspecified measurements available on some accessible part. The aquifer is under the action of point‐forces located inside the domain and governed by the advection‐diffusion equation. The method used is based on a fictitious domain decomposition. Numerical tests are done attesting the performance of the identification process. [ABSTRACT FROM AUTHOR]

Oxycodone (Oxy) conditioned place preference (CPP) in Sprague Dawley rats results in sex‐specific alterations in hippocampal opioid circuits in a manner that facilitates opioid‐associative learning processes, particularly in females. Here, we examined if Oxy (3 mg/kg, I.P.) or saline (Sal) injections not paired with behavioral testing similarly affect the hippocampal opioid system. Sal‐injected females compared to Sal‐injected males had: (1) higher densities of cytoplasmic delta opioid receptors (DOR) in GABAergic hilar dendrites suggesting higher baseline reserve DOR pools and (2) elevated phosphorylated DOR levels, but lower phosphorylated mu opioid receptor (MOR) levels in CA3a suggesting that the baseline pools of activated opioid receptors vary in females and males. In contrast to CPP studies, Oxy‐injections in the absence of behavioral tests resulted in few changes in the hippocampal opioid system in either females or males. Specifically, Oxy‐injected males compared to Sal‐injected males had fewer DORs near the plasma membrane of CA3 pyramidal cell dendrites and in CA3 dendritic spines contacted by mossy fibers, and lower pMOR levels in CA3a. Oxy‐injected females compared to Sal‐injected females had higher total DORs in GABAergic dendrites and lower total MORs in parvalbumin‐containing dendrites. Thus, unlike Oxy CPP, Oxy‐injections redistributed opioid receptors in hippocampal neurons in a manner that would either decrease (males) or not alter (females) excitability and plasticity processes. These results indicate that the majority of changes within hippocampal opioid circuits that would promote opioid‐associative learning processes in both females and males do not occur with Oxy administration alone, and instead must be paired with CPP. [ABSTRACT FROM AUTHOR]

KIF1A is a molecular motor for membrane‐bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in‐frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A‐associated phenotypes to include hip subluxation and dystonia as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus. [ABSTRACT FROM AUTHOR]