Characterization of Turner Syndrome-associated diabetes mellitus.

CONTEXT: Diabetes mellitus (DM) risk factors in Turner Syndrome (TS) may include autoimmunity, obesity, beta-cell dysfunction, genetic predisposition and insulin resistance (IR). OBJECTIVE: Evaluate glucose tolerance and DM risk factors in adults with TS. DESIGN: A single centre study with two phases. To determine the prevalence of DM and to assess diabetes risk markers comparing women with TS with and without impaired glucose tolerance (IGT). SETTING: Tertiary referral center, University College Hospitals. PATIENTS: 106 Women with TS (age range 18-70 years) undergoing annual health surveillance. INTERVENTIONS: Participants underwent oral glucose tolerance tests (OGTT), with additional samples for autoimmunity and genetic analysis. MAIN OUTCOME MEASURE: Glucose tolerance, insulin, autoimmune and single nucleotide polymorphism (SNP) profile. RESULTS: OGTT screening showed that those without a previous DM diagnosis, 72.7% had normal glucose tolerance, 19.5% had IGT, and 7.6% were newly diagnosed with DM. OGTT identified more cases of DM than HbAc1 sampling alone. Women with IGT or DM were older, with higher body mass index and IR. No association was found between autoimmune markers GAD, IA-2 and ZnT8, risk karyotypes or selected SNPs and DM. In DM cases, GAD positivity was associated with requirement for insulin therapy. The median age of onset of the diagnosis of DM was 36 years (range 11-56). CONCLUSIONS: In the spectrum of DM subtypes, TS-associated DM lies between type 1 and type 2 DM with features of both. Key factors include weight and IR. Assessing C-peptide or GAD antibodies may aid future insulin requirement.

Fertility and pregnancy outcomes in women with Turner syndrome: A single centre experience.

OBJECTIVE: Many women with Turner syndrome (TS) will consider fertility options and pregnancy. We wished to examine the fertility and pregnancy outcomes in women with TS undergoing oocyte donation (OD) treatment or spontaneous pregnancy in a large single-centre cohort. General population reference data or data from those with idiopathic premature ovarian insufficiency were used as comparators. DESIGN: A retrospective single-centre cross-sectional study. PATIENTS AND MEASUREMENTS: Seventy-four women with TS underwent OD treatment with a total of 105 pregnancies, and 31 women with TS had 71 spontaneous conceptions. Fertility outcomes included clinical pregnancy and live birth rate. Pregnancy outcomes included miscarriage rate, prevalence of hypertension, gestational diabetes, lower segment caesarean section (LSCS), small for gestational age (SGA), prematurity and vertical transmission of TS. RESULTS: In those with TS, OD pregnancies were associated with increased rates of LSCS and SGA compared to spontaneous pregnancies; LSCS (OR: 4.19, 95% CI: 1.6-10.8, p = .003) and SGA (OR: 2.92, 95% CI: 1.02-8.38, p = .04). There were no recorded cardiac events but 5 (17.2%) cases of vertical transmissions of TS in daughters were identified. OD in those with TS was associated with a lower live birth rate per cycle started (OR: 0.53, 95% CI: 0.34-0.84, p = .008) and a higher rate of miscarriage compared to women with POI (40% vs. 26.2%, p = .04). CONCLUSIONS: We show that pregnancy in women with TS, whether OD or spontaneously conceived, carries obstetric risks, and therefore, women with TS, considering pregnancy, should receive comprehensive pre-pregnancy counselling and optimal obstetric care.

A conserved NR5A1-responsive enhancer regulates SRY in testis-determination.

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.

Muscularity of older trauma patients at intensive care unit admission, association with functional outcomes, and relationship with frailty: A retrospective observational study.

BACKGROUND: Older individuals are at an increased risk of delayed recovery following a traumatic injury. Measurement of muscularity and frailty at hospital admission may aid with prognostication and risk stratification. OBJECTIVE: This study aimed to describe muscularity at intensive care unit (ICU) admission in patients admitted following trauma and assess the relationship between muscularity and clinical, long-term functional outcomes and frailty at ICU admission. METHODS: This retrospective study utilised data from a prospective observational study investigating frailty in patients aged ≥50 years, admitted to the ICU following trauma. Patients were eligible if they had a Computed Tomography (CT) scan including the third lumbar vertebra at ICU admission. Specialist software was used to quantify CT-derived skeletal muscle cross-sectional area. Muscularity status was classified as normal or low using published sex-specific cut-points. Demographic data, frailty, clinical, and long-term functional outcomes (Glasgow Outcome Scale-Extended and EQ-5DL-5L Visual analogue scale and utility score) were extracted from the original study. RESULTS: One hundred patients were screened; 71 patients had a CT scan on admission with 66 scans suitable for muscle assessment. Patients with low muscularity (n = 25, 38%) were older and had a higher Acute Physiology and Chronic Health Evaluation II score and lower body mass index than patients with normal muscularity. Low muscularity was associated with frailty at admission (32% vs 5%, p = 0.005) but not with long term outcomes at 6 or 12 months. As a continuous variable, lower muscle cross-sectional area was associated with a poorer outcome on the Glasgow Outcome Scale-Extended at 6 months (mean [standard deviation]: 150 [43] and 180 [44], respectively; p = 0.014), no association was observed after adjustment for age p = 0.43). CONCLUSION: In a population of older adults hospitalised following trauma, low muscularity at ICU admission was prevalent. Low muscularity was associated with frailty but not long-term functional outcomes. Larger studies are warranted to better understand the relationship between muscularity and long-term functional outcomes.

Analysis of genetic variability in Turner syndrome linked to long-term clinical features.

Background: Women 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. Objective: We 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. Methods: Whole 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. Results: Standard 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<0.02). Conclusions: Women with TS do not have an excess of genetic variability in exome analysis. No obvious X-chromosome variants driving phenotype were found, but several possible genes/variants of interest emerged. A reported association between autosomal TIMP3 variance and congenital cardiac anomalies was replicated.

Examining the immunoepigenetic-gut microbiome axis in the context of self-esteem among Native Hawaiians and other Pacific Islanders.

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.

Aligning quality of life and guidelines for off-label psychotropic drugs in adults with intellectual disabilities and challenging behaviour.

Introduction: Adults with intellectual disabilities have an increased vulnerability to mental health problems and challenging behaviour. In addition to psychotherapeutic or psychoeducational methods, off-label pharmacotherapy, is a commonly used treatment modality. Objective: The aim of this study was to establish evidence-based guideline recommendations for the responsible prescription of off-label psychotropic drugs, in relation to Quality of Life (QoL). Method: A list of guidelines was selected, and principles were established based on international literature, guideline review and expert evaluation. The Delphi method was used to achieve consensus about guideline recommendations among a 58-member international multidisciplinary expert Delphi panel. Thirty-three statements were rated on a 5-point Likert-scale, ranging from totally disagree to totally agree, in consecutive Delphi rounds. When at least 70% of the participants agreed (score equal or higher than 4), a statement was accepted . Statements without a consensus were adjusted between consecutive Delphi rounds based on feedback from the Delphi panel. Results: Consensus was reached on 4 general:the importance of non-pharmaceutical treatments, comprehensive diagnostics and multidisciplinary treatment. Consensus was reached in 4 rounds on 29 statements. No consensus was reached on 4 statements concerning: freedom-restricting measures, the treatment plan, the evaluation of the treatment plan, and the informed consent. Conclusion: The study led to recommendations and principles for the responsible prescription - aligned with the QoL perspective - of off-label psychotropic drugs for adults with intellectual disabilities and challenging behaviour. Extensive discussion is needed regarding the issues on which there was no consensus to furthering the ongoing development of this guideline.

Retrieval of a Cook Celect inferior vena cava (IVC) filter after prolonged dwell time of 5,117 days: Factors to consider for retrieval of long-dwell IVC filters.

Inferior vena cava (IVC) filters are used in certain patients to help prevent the occurrence of pulmonary embolism (PE). IVC filters are generally recommended to be removed once PE prophylaxis is no longer required. Long-dwelling IVC filters are associated with higher complication rates (Vasa 2020; 49: 449), being more difficult to retrieve and associated with higher retrieval complications (Cardiovasc Diagn Ther 2016; 6: 632). This report describes the pre-procedural work-up and removal of an IVC filter with a prolonged dwell time of 5,117 days (14 years, 3 days) using the loop snare advanced retrieval technique. As far as the authors are aware this case is the longest-described successful retrieval of a Cook Celect IVC filter at 5,117 days.

The gender imbalance in Interventional Radiology in Australia and New Zealand.

INTRODUCTION: There are few female Interventional Radiologists worldwide and this is a significant issue for many countries. There is little known about the current status and attitudes to women in Interventional Radiology in Australia and New Zealand. The purpose of this study was to explore the gender balance, workforce challenges and perceptions towards women in Interventional Radiology in Australia and New Zealand. METHODS: An anonymised voluntary survey exploring the current demographics of Interventional Radiologists and opinions on multiple gender issues in Interventional Radiology was conducted. The survey was sent to all members of the Interventional Radiology Society of Australasia. Statistical analysis was performed using independent samples t-tests, the non-parametric Mann-Whitney U testing and proportions of binary variables using logistic regression. RESULTS: Seventy seven responses were received, 83% males and 17% females. The majority of participants worked full time (83%) and identified as an Interventional Radiologist with/without some sessions of diagnostic radiology per week (83%). There was general consensus in many issues; however, males tended to disagree more than females that female IRs are treated differently than male IRs (p < 0.037), and that male IRs are paid more than female IRs (P = 0.020). Females agreed it was harder for female IRs to gain academic or clinical promotion; however, males disagreed (P < 0.001). CONCLUSION: There is a clear gender imbalance in Interventional Radiology in Australia and New Zealand. Multiple issues should be investigated and addressed by the major stakeholders such as the Royal Australian and New Zealand College of Radiologists and the Interventional Radiology society of Australasia.

Results from the First-in-Human Study of the Caterpillar™ Arterial Embolization System.

PURPOSE: To assess occlusion success and adverse events associated with the use of a self-expanding device for peripheral artery embolization. METHODS: This prospective, single-arm, feasibility study was conducted using the Caterpillar™ Arterial Embolization Device composed of opposing nitinol fibers and a flow-occluding membrane. Twenty patients (24 embolization sites) were treated at four investigational centers in New Zealand and Australia and followed for 30 days. Embolization sites included mesenteric, accessory renal, and iliac arteries and their branches. Primary outcome measures were peri-procedural occlusion confirmed by angiography and freedom from device-related serious adverse events (SAEs) at 30 days. Secondary observations included time to occlusion and assessment of adverse events. RESULTS: Peri-procedural occlusion was 100%, and freedom from a device-related SAE was 94.7% at 30 days. One patient had abdominal bloating that required hospitalization deemed possibly related to the device or procedure. Twenty-two of 24 embolization sites were occluded with one device (91.7%). Mean procedure duration was 11.7 ± 8.6 min (device deployment time: 1.8 ± 1.0 min), and mean fluoroscopy time was 241 ± 290.7 s. All embolization sites occluded during the procedure with 62.5% occluded within three minutes and 91.6% occluded within ten minutes. No devices migrated or required re-embolization. Freedom from device- and procedure-related adverse events was 84.2%. One patient died from aortic rupture during a subsequent adjunctive abdominal aortic endovascular procedure deemed unrelated to the embolization device or procedure. CONCLUSIONS: This first-in-human study of the Caterpillar embolization device achieved peri-procedural occlusion in all patients with a 94.7% freedom from device-related SAE at 30 days. LEVEL OF EVIDENCE: Level 2b-prospective, multicenter, single-arm, first-in-human clinical study. Pre-specified endpoints were analyzed using descriptive statistics.

Ten-year incidence and treatment outcomes of closed degloving injuries (Morel-Lavallee lesions) in a level 1 trauma centre.

INTRODUCTION: Morel-Lavallée lesions (MLL), also referred to as closed degloving injuries, result from traumatic shearing forces with separation of the subcutaneous fat from the underlying fascia. The aim of this study was to determine the incidence and treatment of MLLs at a level 1 trauma centre. METHODS: Single-centre retrospective cross-sectional study of consecutive patients with an imaging diagnosis of a Morel-Lavallee lesion from 1/1/2010-31/12/2019. Demographic data, mechanism of injury, volume of lesion, management and outcome data were collated. RESULTS: Sixty-six MLLs were identified in 63 patients (64% Male) with a median age of 49.5 years (19-94 years). Mechanism of injury were road traffic accidents in the majority (66%). Median injury severity score (ISS) was 17 (range 1-33). Patients on oral anti-coagulants had significantly larger lesions (181.9 cc v 445.5 cc, P = 0.044). The most common lesion location was the thigh (60.5%). Patients that underwent imaging within 72 h of injury had significantly larger lesions than those imaged more than 72 h after the inciting trauma (65 cc v 167 cc, P < 0.05). Management data were documented in 59% of lesions (39/66) in which 66.6% (n = 26) had invasive treatment. In the 31 patients where follow-up was available, 64.5% (n = 20) were persistent but decreasing in size. There was no significant difference in follow-up size for those who had invasive compared to conservative treatment (P = 0.3). CONCLUSION: The diagnosis of MLL should be considered for soft-tissue swelling in the context of shearing trauma. A variety of management options have been employed, with good overall outcomes.

Injury patterns, management and outcomes of retroperitoneal haemorrhage caused by lower intercostal arterial bleeding at a level-1 trauma centre: A 10-year retrospective review.

OBJECTIVE: Haemorrhagic shock is a life-threatening complication of trauma, but remains a preventable cause of death. Early recognition of retroperitoneal haemorrhage (RPH) is crucial in preventing deleterious outcomes including mortality. Injury to the 9-11th intercostal arteries (i.e. arteries of the lower thoracic region) are complicit in RPH. However, the associated injuries, implications and management of such bleeds remain poorly characterised. METHODS: We performed a retrospective review of the medical records of patients diagnosed with RPH who presented to our level-1 trauma centre (2009-2019). We described the associated injuries, management and outcomes relating to RPH of the lower thoracic region (the 9-11th intercostal arteries) from this cohort to identify potential predictors and evaluate the impact of early identification and management of non-cavitary bleeds. RESULTS: Haemorrhage of the lower intercostal arteries (LIA) into the retroperitoneal space is associated with an increased number of posterior lower rib fractures and pneumothorax/haemothorax. A higher proportion of patients in the LIA group required massive transfusion, angioembolisation or surgical ligation when compared to other causes of RPH. CONCLUSION: The present study highlights the importance of injury patterns, particularly posterior lower rib fractures, as predictors for early recognition and management of RPH in the prevention of deleterious patient outcomes. RPH secondary to bleeding of the LIA may require early and aggressive management of haemorrhage through massive transfusion, and angioembolisation or surgical ligation when compared to RPH because of other causes.

A prospective cross-sectional study assessing teaching of interventional radiology across 20 Australian medical schools, endorsed by the Australian Medical Students Association.

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 < 0.001), only 12% suggested that current IR teaching was adequate, and 99% suggested that IR teaching could be improved. Only 11% of students would consider a career in IR. CONCLUSIONS: Medical student perception of exposure to IR is poor compared to diagnostic radiology. Better awareness may lead to improved referral patterns for patients and more career interest in IR.

Retia mirabilia: Protecting the cetacean brain from locomotion-generated blood pressure pulses.

Cetaceans have massive vascular plexuses (retia mirabilia) whose function is unknown. All cerebral blood flow passes through these retia, and we hypothesize that they protect cetacean brains from locomotion-generated pulsatile blood pressures. We propose that cetaceans have evolved a pulse-transfer mechanism that minimizes pulsatility in cerebral arterial-to-venous pressure differentials without dampening the pressure pulses themselves. We tested this hypothesis using a computational model based on morphology from 11 species and found that the large arterial capacitance in the retia, coupled with the small extravascular capacitance in the cranium and vertebral canal, could protect the cerebral vasculature from 97% of systemic pulsatility. Evolution of the retial complex in cetaceans-likely linked to the development of dorsoventral fluking-offers a distinctive solution to adverse locomotion-generated vascular pulsatility.

Management of a Girl With Delayed Puberty and Elevated Gonadotropins.

A girl presenting with delayed puberty and elevated gonadotropins may have a range of conditions such as Turner syndrome (TS), primary ovarian insufficiency (POI), and 46,XY disorders of sexual development (DSD). An organized and measured approach to investigation can help reach a timely diagnosis. Management of young people often requires specialist multidisciplinary input to address the endocrine and nonendocrine features of these complex conditions, as well as the psychological challenges posed by their diagnosis. Next-generation sequencing within the research setting has revealed several genetic causes of POI and 46,XY DSD, which may further facilitate an individualized approach to care of these young people in the future. Pubertal induction is required in many and the timing of this may need to be balanced with other issues specific to the condition (eg, allowing time for information-sharing in 46,XY DSD, optimizing growth in TS). Shared decision-making and sign-posting to relevant support groups from the outset can help empower young people and their families to manage these conditions. We describe 3 clinical vignettes of girls presenting with delayed puberty and hypergonadotropic amenorrhea and discuss their clinical management in the context of current literature and guidelines.