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Abstract The Y-linked SRY gene initiates mammalian testis-determination. However, how the expression of SRY is regulated remains elusive. Here, we demonstrate that a conserved steroidogenic factor-1 (SF-1)/NR5A1 binding enhancer is required for appropriate SRY expression to initiate testis-determination in humans. Comparative sequence analysis of SRY 5’ regions in mammals identified an evolutionary conserved SF-1/NR5A1-binding motif within a 250 bp region of open chromatin located 5 kilobases upstream of the SRY transcription start site. Genomic analysis of 46,XY individuals with disrupted testis-determination, including a large multigenerational family, identified unique single-base substitutions of highly conserved residues within the SF-1/NR5A1-binding element. In silico modelling and in vitro assays demonstrate the enhancer properties of the NR5A1 motif. Deletion of this hemizygous element by genome-editing, in a novel in vitro cellular model recapitulating human Sertoli cell formation, resulted in a significant reduction in expression of SRY. Therefore, human NR5A1 acts as a regulatory switch between testis and ovary development by upregulating SRY expression, a role that may predate the eutherian radiation. We show that disruption of an enhancer can phenocopy variants in the coding regions of SRY that cause human testis dysgenesis. Since disease causing variants in enhancers are currently rare, the regulation of gene expression in testis-determination offers a paradigm to define enhancer activity in a key developmental process.

Summary: Background: Chronic cough is a common respiratory symptom with an impact on daily activities and quality of life. Global prevalence data are scarce and derive mainly from European and Asian countries and studies with outcomes other than chronic cough. In this study, we aimed to estimate the prevalence of chronic cough across a large number of study sites as well as to identify its main risk factors using a standardised protocol and definition. Methods: We analysed cross-sectional data from 33,983 adults (≥40 years), recruited between Jan 2, 2003 and Dec 26, 2016, in 41 sites (34 countries) from the Burden of Obstructive Lung Disease (BOLD) study. We estimated the prevalence of chronic cough for each site accounting for sampling design. To identify risk factors, we conducted multivariable logistic regression analysis within each site and then pooled estimates using random-effects meta-analysis. We also calculated the population attributable risk (PAR) associated with each of the identifed risk factors. Findings: The prevalence of chronic cough varied from 3% in India (rural Pune) to 24% in the United States of America (Lexington,KY). Chronic cough was more common among females, both current and passive smokers, those working in a dusty job, those with a history of tuberculosis, those who were obese, those with a low level of education and those with hypertension or airflow limitation. The most influential risk factors were current smoking and working in a dusty job. Interpretation: Our findings suggested that the prevalence of chronic cough varies widely across sites in different world regions. Cigarette smoking and exposure to dust in the workplace are its major risk factors. Funding: Wellcome Trust.

Lithium (Li) metal serving as an anode has the potential to double or triple stored energies in rechargeable Li batteries. However, they typically have short cycling lifetimes due to parasitic reactions between the Li metal and electrolyte. It is critically required to develop early fault-detection methods for different failure mechanisms and quick lifetime-prediction methods to ensure rapid development. Prior efforts to determine the dominant failure mechanisms have typically required destructive cell disassembly. In this study, non-destructive diagnostic method based on rest voltages and coulombic efficiency are used to easily distinguish the different failure mechanisms-from loss of Li inventory, electrolyte depletion, and increased cell impedance-which are deeply understood and well validated by experiments and modeling. Using this new diagnostic method, the maximum lifetime of a Li metal cell can be quickly predicted from tests of corresponding anode-free cells, which is important for the screenings of electrolytes, anode stabilization, optimization of operating conditions, and rational battery design.

BackgroundWomen with Turner syndrome (TS) (45,X and related karyotypes) have an increased prevalence of conditions such as diabetes mellitus, obesity, hypothyroidism, autoimmunity, hypertension, and congenital cardiovascular anomalies (CCA). Whilst the risk of developing these co-morbidities may be partly related to haploinsufficiency of key genes on the X chromosome, other mechanisms may be involved. Improving our understanding of underlying processes is important to develop personalized approaches to management.ObjectiveWe investigated whether: 1) global genetic variability differs in women with TS, which might contribute to co-morbidities; 2) common variants in X genes - on the background of haploinsufficiency - are associated with phenotype (a “two-hit” hypothesis); 3) the previously reported association of autosomal TIMP3 variants with CCA can be replicated.MethodsWhole exome sequencing was undertaken in leukocyte DNA from 134 adult women with TS and compared to 46,XX controls (n=23), 46,XX women with primary ovarian insufficiency (n=101), and 46,XY controls (n=11). 1) Variability in autosomal and X chromosome genes was analyzed for all individuals; 2) the relation between common X chromosome variants and the long-term phenotypes listed above was investigated in a subgroup of women with monosomy X; 3) TIMP3 variance was investigated in relation to CCA.ResultsStandard filtering identified 6,457,085 autosomal variants and 126,335 X chromosome variants for the entire cohort, whereas a somatic variant pipeline identified 16,223 autosomal and 477 X chromosome changes. 1) Overall exome variability of autosomal genes was similar in women with TS and control/comparison groups, whereas X chromosome variants were proportionate to the complement of X chromosome material; 2) when adjusted for multiple comparisons, no X chromosome gene/variants were strongly enriched in monosomy X women with key phenotypes compared to monosomy X women without these conditions, although several variants of interest emerged; 3) an association between TIMP3 22:32857305:C-T and CCA was found (CCA 13.6%; non-CCA 3.4%, p

While powder diffraction methods are routinely utilized to optimize structural models for compounds whose crystal structures are known, the determination of unknown structures is far more challenging. When the unknown structure is large, structure solution can become a virtually intractable problem using standard structure solution methodologies, especially when the space group cannot be unambiguously resolved. One such system is the promising Na-ion battery cathode material Na3V2(PO4)2F3, whose high-temperature and room-temperature structures were previously solved, but whose more complex low-temperature structure could not be determined. Here, a novel materials genomic approach is demonstrated for the solution of the unknown 100 K structure of Na3V2(PO4)2F3 in which enumeration methods are first used to generate a large number (∼3000) of trial structures based on plausible orderings of Na ions and then automated Rietveld refinements are carried out to optimize each of these trial structures. Based on both the analysis of the ensemble of optimized trial structures and the density functional theory energy minimization of selected trial structures, the 100 K structure of Na3V2(PO4)2F3 is best described as belonging to the space group A21am with unit cell dimensions of a = 9.01928(4), b = 27.1379(1), and c = 10.73307(5). The 100 K unit cell has a large volume of 2627.07(2) Å3 with Z = 12 and 33 independent crystallographic sites (9 Na, 3 V, 3 P, 12 O, and 6 F) that is 3× and 6× larger than the room- and high-temperature polymorphs of this phase, respectively. The novel methods described here will be generally applicable for the solution of the complex cation-ordered structures that commonly occur for battery materials.

Abstract Background Existing literature from around the world has shown that teaching of Interventional Radiology (IR) to medical students remains suboptimal. Despite calls for improvement at a “grass-roots” level, most IRs find that junior doctors have limited or no knowledge of IR, and thus reduced awareness of potential IR treatments for their patients or contemplating IR as a future career. The aim of this study was to survey current medical students to assess perception of whether a wider variety of medical schools are integrating IR into their curriculum, from universities all across Australia. This was a prospective cross-sectional study of members of the Australian Medical Students Association (AMSA) from across Australia. Students were given a 14-question survey of current university teaching and students’ knowledge of the discipline of IR. The primary outcome was perception of current teaching and knowledge of IR. Secondary outcomes include awareness of technical, clinical, and other duties of IRs. Results Surveys were sent in a newsletter and posted on the AMSA Facebook page to their members. 82 responses were received via students from 20 out of 23 Australian medical schools. 61% of students described poor or no knowledge of IR. Teaching of IR was significantly worse than diagnostic radiology (p

Two species of Anacaena Thomson, 1859, A. angatbuhay sp. nov. and A. auxilium sp. nov., are described from Northern Luzon, Philippines. The new species can be distinguished through colour, body shape, surface puncturation and characteristic aedeagi. Descriptions are provided and complemented with habitus photographs and drawings of the aedeagi. Data on genus distribution in the Philippines are reviewed and an updated Philippine checklist is provided.

Introduction: Native Hawaiian and other Pacific Islander (NHPI) populations experience higher rates of immunometabolic diseases compared to other racial-ethnic groups in Hawaii. As annual NHPI mortality rates for suicide and type 2 diabetes mellitus (T2DM) exceed those of the state as a whole, understanding the social and biological mechanisms underlying these disparities are urgently needed to enable preventive strategies.Methods: A community-based approach was used to investigate the immunoepigenetic-gut microbiome axis in an NHPI-enriched cohort of Oahu residents (N = 68). Self-esteem (SE) data was collected using a modified Rosenberg self-esteem (SE) assessment as a proxy measure for mental wellbeing in consideration for cultural competency. T2DM status was evaluated using point-of-care A1c (%) tests. Stool samples were collected for 16s-based metagenomic sequencing analyses. Plasma from blood samples were isolated by density-gradient centrifugation. Peripheral blood mononuclear cells (PBMCs) were collected from the same samples and enriched for monocytes using negative selection techniques. Flow-cytometry was used for immunoprofiling assays. Monocyte DNA was extracted for Illumina EPIC array-based methylation analysis.Results: Compared to individuals with normal SE (NSE), those with low SE (LSE) exhibited significantly higher plasma concentrations (pg/ml) of proinflammatory cytokines IL-8 (p = 0.051) and TNF-α (p = 0.011). Metagenomic analysis revealed that the relative abundance (%) of specific gut bacteria significantly differed between SE groups - some of which directly correlated with SE scores. Gene ontology analysis revealed that 104 significantly differentially methylated loci (DML) between SE groups were preferentially located at genes involved in immunometabolic processes. Horvath clock analyses indicated epigenetic age (Epi-Age) deceleration in individuals with LSE and acceleration in individuals with NSE (p = 0.042), yet was not reproduced by other clocks.Discussion: These data reveal novel differences in the immunoepigenetic-gut microbiome axis with respect to SE, warranting further investigation into its relationship to brain activity and mental health in NHPI. Unexpected results from Epi-Age analyses warrant further investigation into the relationship between biological age and disparate health outcomes among the NHPI population. The modifiable component of epigenetic processes and the gut microbiome makes this axis an attractive target for potential therapeutics, biomarker discovery, and novel prevention strategies.

In education, the stories of LGBTQIA+ students are one of the most powerful tales of hardship. It uncovers a wide range of experiences, much like opening a box full of obstacles and successes. This study primarily aimed to delve into and provide a comprehensive understanding of the struggles and successes of LGBTQIA+ students at Morong National High School. The researchers used self-reported data from in-depth semi-structured interviews involving 20 students, five per grade level, from Grades 7 to 10 as the main instrument and were interpreted using Interpretative Phenomenological Analysis (IPA) to identify patterns or themes within the qualitative data. The student-respondents were selected through purposive sampling ensuring representation from diverse backgrounds. As the respondents shared their stories, the researchers found that some LGBTQIA+ students experience gradual teasing from their fellow learners. Even though they faced such challenges, they succeeded in breaking stereotypes and excelled academically. They also demonstrated their skills and abilities in sports, leadership, and other extracurricular pursuits. As a coping mechanism, the respondents mentioned that they seek support from friends and other support groups. Their hobbies and engagement in various activities help divert their attention from gender-based discrimination. Therefore, the results indicate that we need to work together in schools and communities to make everyone feel included. This research tells us that we must create safe places for LGBTQIA+ students so they don't face discrimination or bullying. Schools should let students talk about their experiences and feel like they belong. If schools show understanding and help with education, they can help LGBTQIA+ students do well. [ABSTRACT FROM AUTHOR]

Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo‐pituitary disorders, whether organic or functional. [ABSTRACT FROM AUTHOR]

Introduction: It is estimated that 8% of hospitalised patients require treatment from Interventional Radiology (IR). However, little is known about the potential impact of IR on regional and remote Australians, including Indigenous patients. This study aimed to assess treatments performed by IRs on regional/remote patients to predict future IR workforce and governance needs. Methods: Single‐centre cross‐sectional study at a tertiary Victorian hospital. Patients were identified when they had an advanced IR treatment between 1 January 2022 and 2024. Basic procedures such as biopsy and drain insertion were not included. The primary outcome was the type and volume of IR treatments performed on patients who were transferred from a regional or remote home location for treatment. Results: Of 3485 advanced IR interventions, 908 procedures (26.0%) from patients who lived in a regional or remote location were included with 36.5% female, of mean age 55.6 years (SD 17.9). 1.4% identified as Indigenous which is similar to the Indigenous population incidence in Victoria of 1.0%. Of this group, 350 (38.5%) were either a day procedure, overnight elective admission, or simple inpatient procedure which could have been performed in a regional centre, which included 1.1% Indigenous patients. Conclusion: There is an unmet need for IR services in regional and remote Australia, with many patients being transferred to our metropolitan centre for treatment that could be performed in regional IR hubs. This data will be important to drive government and hospital planning including capital infrastructure, workforce modelling and future recognition of IR as a new specialty in Australia. [ABSTRACT FROM AUTHOR]

Although the determination of site occupancies is often a major goal in Rietveld refinement studies, the accurate refinement of site occupancies is exceptionally challenging due to many correlations and systematic errors that have a hidden impact on the final refined occupancy parameters. Through the comparison of results independently obtained from neutron and synchrotron powder diffraction, improved approaches capable of detecting occupancy defects with an exceptional sensitivity of 0.1% (absolute) in the class of layered NMC (Li[NixMnyCoz]O2) Li-ion battery cathode materials have been developed. A new method of visualizing the diffraction parameter space associated with crystallographic site scattering power through the use of f* diagrams is described, and this method is broadly applicable to ternary compounds. The f* diagrams allow the global minimum fit to be easily identified and also permit a robust determination of the number and types of occupancy defects within a structure. Through a comparison of neutron and X-ray diffraction results, a systematic error in the synchrotron results was identified using f* diagrams for a series of NMC compounds. Using neutron diffraction data as a reference, this error was shown to specifically result from problems associated with the neutral oxygen X-ray atomic form factor and could be eliminated by using the ionic O2- form factor for this anion while retaining the neutral form factors for cationic species. The f* diagram method offers a new opportunity to experimentally assess the quality of atomic form factors through powder diffraction studies on chemically related multi-component compounds.

ZrW2O8 (ZrO2•2WO3) and HfW2O8 (HfO2•2WO3) have been the focus of thermal expansion studies due to their isotropic negative thermal expansion (NTE) measured previously at temperatures below 775°C. This work presents measurements of these materials at their thermodynamically stable temperature ranges of 1105 and 1257°C for ZrW2O8 and 1105–1276°C for HfW2O8, where they were characterized with in situ, powder X‐ray diffraction. The linear coefficients of thermal expansion were measured to be −5.52 × 10−6 and −4.87 × 10−6°C−1 for ZrW2O8 and HfW2O8, respectively. The mechanism leading to this NTE is discussed. Powder samples were synthesized by a solution‐based process called the organic–inorganic steric entrapment method. In situ characterization in air was carried out at the National Synchrotron Light Source II using a hexapole lamp, optical furnace and the Advanced Photon Source using a quadrupole lamp, optical furnace to achieve elevated temperatures. [ABSTRACT FROM AUTHOR]

Introduction Long-term percutaneous enteral nutrition forms an important part of treatment for patients with an inability to meet nutrient requirements orally. Radiologically inserted gastrostomy (RIG) is an alternative to the traditionally performed percutaneous endoscopic gastrostomy technique. However, there is marked heterogeneity in the way that RIG is performed. In addition, the role for antibiotic prophylaxis during RIG insertion is not clearly established. This study aimed to assess the safety of RIG insertion using our technique including the role of antibiotics in RIG insertion. Method Retrospective study over 5 years at a tertiary teaching hospital. Periprocedural or early complications within the first 2 weeks of the procedure were collected and correlated with the use of prophylactic antibiotics. Results A total of 116 patients met the inclusion criteria. 18-French tube was used in 96.6%. Note that 58.6% of procedures were done with intravenous sedation. Prophylactic 1 g cefazolin was used in 70 patients with 1 case of infection. Procedures were performed without antibiotics in 46 patients with 3 infections, p = 0.20. There were two major complications (1.7%) consisting of right gastric artery injury requiring embolization and gastric wall injury requiring laparotomy. There were 12 minor complications (10.3%) including 4 cases of infection, 3 of severe pain, 1 of minor bleeding, 2 of early dislodgement, and 2 of leak/bypass of gastric contents around the tube. Conclusion The technique used for RIG insertion at our institution results in a low complication rate. In addition, this study shows no significant difference in early peristomal infection rate with the use of antibiotic prophylaxis.

Abstract Background As an adjunct to non-operative management, splenic artery embolization (SAE) has been increasingly utilized throughout the world and is now the standard of care for hemodynamically stable patients. This study aimed to retrospectively assess the rate of splenic salvage and complications after SAE for blunt trauma at a level 1 trauma center using the 2018 update to the AAST criteria, and further sub-stratify the role of angiography in AAST grade III injuries with significant hemoperitoneum. All patients between 1 January 2009 and 1 January 2019 who underwent blunt trauma and proceeded to embolization were included. Data was collected concerning initial injury grade, location of embolization, type of embolic material used, complications, and need for subsequent splenectomy. Technical success was defined as successful angiographic occlusion of the target artery at the conclusion of embolization. Clinical success was defined as splenic salvage at discharge. Vascular lesions were characterized including those with active bleeding, pseudoaneurysm, and arterio-venous fistula. Results Two hundred thirty-two patients were included in the study. Treatments were performed at a median of 0 days (range 0–28 days) and the median AAST grade was IV (range III-V). Technical success was achieved in all patients. There were 13 complications (5.6%) consisting of re-bleed (9, 3.9%), infarction (3, 1.3%), and access site haematoma (1, 0.43%). Clinical success was achieved in 97% of patients with 7 patients requiring splenectomy after SAE (3.0%) at a median time of 4 days (range 0–17 days). Angiography in patients with grade III injuries identified 18 occult vascular injuries not identified at initial CT (p

Primary ovarian insufficiency (POI) affects 1% of women and carries significant medical and psychosocial sequelae. Approximately 10% of POI has a defined genetic cause, with most implicated genes relating to biological processes involved in early fetal ovary development and function. Recently, Ythdc2, an RNA helicase and N6-methyladenosine reader, has emerged as a regulator of meiosis in mice. Here, we describe homozygous pathogenic variants in YTHDC2 in 3 women with early-onset POI from 2 families: c. 2567C>G, p.P856R in the helicase-associated (HA2) domain and c.1129G>T, p.E377*. We demonstrated that YTHDC2 is expressed in the developing human fetal ovary and is upregulated in meiotic germ cells, together with related meiosis-associated factors. The p.P856R variant resulted in a less flexible protein that likely disrupted downstream conformational kinetics of the HA2 domain, whereas the p.E377* variant truncated the helicase core. Taken together, our results reveal that YTHDC2 is a key regulator of meiosis in humans and pathogenic variants within this gene are associated with POI.

We aimed to discuss and evaluate the technical success and efficacy of the ArtVentive endoluminal occlusion system (EOS) device for splenic embolization. A retrospective review was undertaken for all patients in whom the EOS device was deployed for the purpose of splenic embolization. Data was collected by a search of splenic artery embolization procedures in the hospital computer database. Data was reviewed for all patients in whom an EOS plug was deployed. Patient demographics, technical aspects of the procedure and follow-up at one month were reviewed. We review the technical success and efficacy of this occlusion device. Six patients underwent splenic embolization with the EOS plug. There were 5 male and 1 female patients; age range was 24–88 years. Five 8 mm and one 5 mm EOS plugs were deployed for the occlusion of the splenic artery. The technical success rate was 100% occurring in all 6 splenic arteries. One patient underwent a second angiogram and subsequent splenectomy for persistent splenic hemorrhage. One patient had a subsequent splenectomy for bacteremia with the spleen as the suspected source. This early data supports the efficacy of the EOS plug for the embolization of the proximal splenic artery.

Concerns have been raised in the literature, regarding the risk of venous thromboembolic events associated with the use of thermoregulatory catheters. Inferior vena cava (IVC) filters are commonly used to prevent venous thromboembolic events. We demonstrate the usefulness of IVC filter placement prior to the removal of thermoregulatory warming catheters. The management of thermoregulatory warming catheter associated venous thromboembolism is outlined through a retrospective case series of three patients. In one case IVC thrombus was incidentally detected at ultrasonography one-week post removal. The second case describes the occurrence of pulseless electrical activity arrest secondary to massive pulmonary embolism immediately post removal of the thermoregulatory catheter, and subsequent interventional radiology management including pulmonary thrombectomy and caval filter placement. The third case is of a patient in whom the removal of the warming catheter was performed in the angiography suite, with placement of IVC filter prior to removal. Venography displayed a large thrombus burden within the IVC filter. There is limited data in the literature regarding the use of IVC filters as prophylaxis in patients with thermoregulatory catheters, particularly warming catheters. We advocate the placement of an IVC filter prior to the removal of warming catheters. We raise awareness regarding the potential risks of venous thromboembolism in this population and the key role interventional radiology has in the management of these patients.

The three-dimensional UnTRIM San Francisco Bay–Delta model was applied to simulate tidal hydrodynamics and salinity in the San Francisco Estuary (estuary) using an unstructured grid. We compared model predictions to observations of water level, tidal flow, current speed, and salinity collected at 137 locations throughout the estuary. A quantitative approach based on multiple model assessment metrics was used to evaluate the model's accuracy for each comparison. These comparisons demonstrate that the model accurately predicted water level, tidal flow, and salinity during a 3-year simulation period that spanned a large range of flow and salinity conditions. The model is therefore suitable for detailed investigation of circulation patterns and salinity distributions in the estuary.The model was used to investigate the location, and spatial and temporal extent of the low-salinity zone (LSZ), defined by salinity between 0.5 and 6 psu. We calculated X2, the distance up the axis of the estuary to the daily-averaged 2-psu near-bed salinity, and the spatial extent of the LSZ for each day during the 3-year simulation. The location, area, volume, and average depth of the low-salinity zone varied with X2; however this variation was not monotonic and was largely controlled by the geometry of the estuary.We used predicted daily X2 values and the corresponding daily Delta outflow for each day during the 3-year simulation to develop a new equation to relate X2 to Delta outflow. This equation provides a conceptual improvement over previous equations by allowing the time constant for daily changes in X2 to vary with flow conditions. This improvement resulted in a smaller average error in X2 prediction than previous equations. These analyses demonstrate that a well-calibrated three-dimensional (3-D) hydrodynamic model is a valuable tool for investigating the salinity distributions in the estuary, and their influence on the distribution and abundance of physical habitat.