ß3-adrenergic agonist counters oxidative stress and Na+-K+ pump inhibitory S-glutathionylation of placental cells: Implications for preeclampsia.

Oxidative stress from placental ischemia/reperfusion and hypoxia/reoxygenation (H/R) in preeclampsia is accompanied by Na+-K+ pump inhibition and S-glutathionylation of its ß1 subunit (GSS-ß1), a modification that inhibits the pump. ß3-adrenergic receptor (ß3-AR) agonists can reverse GSS-ß1. We examined effects of the agonist CL316,243 on GSS-ß1 and sources of H/R-induced oxidative stress in immortalized first trimester human trophoblast (HTR-8/SVneo) and freshly isolated placental explants from normal term pregnancies. H/R increased GSS-ß1 and, reflecting compromised α1/ß1 subunit interaction, it reduced α1/ß1 pump subunit co-immunoprecipitation. H/R increased p47phox/p22phox NADPH oxidase subunit co-immunoprecipitation reflecting membrane translocation of cytosolic p47phox that is needed to activate NADPH oxidase. Fluorescence of O2•--sensitive dihydroethidium increased in parallel. H/R increased S-glutathionylation of endothelial nitric oxide synthase (GSS-eNOS) that uncouples NO synthesis towards synthesis of O2•- and reduced trophoblast migration. Oxidative stress induced by tumor necrosis factor α (TNF-α) increased soluble fms-like tyrosine kinase receptor 1 (sFlt-1) trophoblast release, a marker of preeclampsia, and reduced trophoblast integration into endothelial cellular networks. CL316,243 eliminated H/R-induced GSS-ß1 and decreases of α1/ß1 subunit coimmunoprecipitation, eliminated NADPH oxidase activation and increases in GSS-eNOS, restored trophoblast migration, eliminated increased sFlt-1 release and restored trophoblast integration in endothelial cell networks. H/R induced GSS-ß1, α1/ß1 subunit co-immunoprecipitation and NADPH oxidase activation of placental explants reflected effects of H/R for trophoblasts and CL316,243 eliminated these changes. We conclude a ß3-AR agonist counters key pathophysiological features of preeclampsia in vitro. ß3 agonists already in human use for another purpose are potential candidates for re-purposing to treat preeclampsia.

A summary of the 2023 Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) hypertension in pregnancy guideline.

INTRODUCTION: Hypertensive disorders of pregnancy (HDP) affect up to 10% of all pregnancies annually and are associated with an increased risk of maternal and fetal morbidity and mortality. This guideline represents an update of the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) guidelines for the management of hypertensive disorders of pregnancy 2014 and has been approved by the National Health and Medical Research Council (NHMRC) under section 14A of the National Health and Medical Research Council Act 1992. In approving the guideline recommendations, NHMRC considers that the guideline meets NHMRC's standard for clinical practice guidelines. MAIN RECOMMENDATIONS: A total of 39 recommendations on screening, preventing, diagnosing and managing HDP, especially preeclampsia, are presented in this guideline. Recommendations are presented as either evidence-based recommendations or practice points. Evidence-based recommendations are presented with the strength of recommendation and quality of evidence. Practice points were generated where there was inadequate evidence to develop specific recommendations and are based on the expertise of the working group. CHANGES IN MANAGEMENT RESULTING FROM THE GUIDELINE: This version of the SOMANZ guideline was developed in an academically robust and rigorous manner and includes recommendations on the use of combined first trimester screening to identify women at risk of developing preeclampsia, 14 pharmacological and two non-pharmacological preventive interventions, clinical use of angiogenic biomarkers and the long term care of women who experience HDP. The guideline also includes six multilingual patient infographics which can be accessed through the main website of the guideline. All measures were taken to ensure that this guideline is applicable and relevant to clinicians and multicultural women in regional and metropolitan settings in Australia and New Zealand.

Validation of the Apnealink Air for diagnosis of obstructive sleep apnoea (OSA) in pregnant women in early-mid gestation.

PURPOSE: The detection of obstructive sleep apnoea (OSA) in pregnant women in early-mid gestation is logistically difficult. Accurate alternates to polysomnography (PSG) in early pregnancy are not well identified. We compared the agreement between Apnealink Air (AL) and existing screening questionnaires to PSG in pregnant women ≤ 24-week gestation. METHODS: Pregnant women (≤ 24-week gestation) underwent AL at home plus attended PSG in any order, completed within 7 days where practicable. AL was manually scored (AL(M)) and automatically scored (AL(A)). An apnoea-hypopnea index (AHI) ≥ 5 was considered diagnostic of OSA and an AHI ≥ 15 considered at least moderate OSA. Diagnostic analysis was undertaken (sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)) by generating receiver operating characteristic (ROC) curves and an area under the curve (AUC) (95% CI). Bland-Altman plots were used to plot agreement. Screening questionnaires (Epworth sleepiness score (ESS), STOP-BANG, calculated pregnancy-specific screening tool) were compared to PSG. RESULTS: A total of 49 participants successfully completed both tests at around 14-weeks gestation (IQR 12.9, 17.1). The time interval between AL and PSG was a median of 2 days (IQR 1, 5 (range 1-11)). A total of 14 (29%) participants had OSA. The median AHI of AL(A) (3.1(IQR 0.85,4.6)) and AL(M) (IQR2.4(0.65,4.8)) did not differ from PSG (1.7(IQR1.0,6.1)). AL(A) and AL(M) compared to PSG demonstrated diagnostic test accuracy (area under curve (ROC)) of 0.94(95% CI 0.87-1.0) and 0.92(95% CI 0.85-1.0) respectively. Apnealink Air outperformed screening questionnaires tested. CONCLUSION: The findings suggest that Apnealink may provide a substitute to attended PSG identification of OSA in pregnant women in early-mid gestation using both manual and auto-scoring methods.

Patient preference of level I, II and III sleep diagnostic tests to diagnose obstructive sleep apnoea among pregnant women in early to mid-gestation.

PURPOSE: There is a paucity of data on preferences for obstructive sleep apnoea (OSA) diagnostic tests during pregnancy. Simple test completion rates fail to capture patient preference or experience of completing sleep diagnostic tests. We assessed preference, ease of use, convenience, and the repeatability of level I, II and III sleep diagnostic tests, using questionnaires, in pregnant women in early to mid-gestation. METHODS: Pregnant women with signs or symptoms of OSA, or at high risk of cardiometabolic disorders of pregnancy completed level I, II and III sleep studies by 24 weeks gestation. Participants then completed a questionnaire to rank test preference. Additional questionnaires assessed ease of use, convenience, and acceptability to repeat test, using 5-point Likert scale questions, yes/no response and optional linked text fields. RESULTS: Of fifty-two consented participants, 43 completed any questionnaire (mean age 32.7 ± 5.4 years, BMI 32.7 ± 5.4, median gestation at Level I polysomnography (PSG) of 14.2 weeks (interquartile range (IQR) 13.5-17.6)). Of the 29 respondents who completed test ranking questionnaire, level III was the preferred test ((n = 21 / 29, 75%)), followed by level 1 (n = 6 / 29, 20.7%) and level II (n = 2 / 29, 7.1%) (p for diff < 0.001). Level III was reported the easiest test (very easy to complete) (n = 16, 51.6%), followed by level I(n = 10, 33.3%), and level II (n = 9, 9.1%) (p for diff < 0.001)). Level III was reported most convenient test (very convenient to complete) (n = 16, 51.6%), followed by level I (n = 4, 13.3%) and level II (n = 4, 13.3%) (p for diff < 0.001)). Level III was reported most acceptable to repeat (very acceptable to repeat) (n = 13, 41.9%), followed by level I (n = 3, 10.0%) and level II (n = 3, 10.0%) (p for diff < 0.001)). CONCLUSION: Pregnant women being assessed for OSA by 24 weeks gestation preferred to undertake level III sleep studies and found level III easier to use, more convenient and most acceptable to repeat than Level I and II studies. Given autonomy is an important principle, patient preference of sleep diagnostic tests should be taken into consideration in sleep clinical services and research involving pregnant women.

Validation of self-applied unattended polysomnography using Somte V2 PSG (Somte) for diagnosis of obstructive sleep apnoea (OSA) in pregnant women in early to mid-gestation.

PURPOSE: Polysomnography (PSG) may be completed in the home environment (unattended), and when self-applied, allow the collection of data with minimal healthcare worker intervention. Self-applied, unattended PSG in the home environment using Somte PSG V2 (Somte) has not been validated in pregnant women in early to mid-gestation. We undertook a study to evaluate the accuracy of Somte compared to attended PSG. The agreement between apnoea hypopnea index (AHI) and respiratory disturbance index (RDI) scores in Somte and PSG in early to mid-gestation were assessed. METHODS: Pregnant women (≤ 24 weeks gestation) were scheduled for PSG and Somte within a 7-day window, in any order. Somte were self-applied and completed in the home. Somte were scored blinded to PSG result. AHI was the primary outcome of interest, though an AHI ≥ 5 or RDI ≥ 5 on PSG was considered diagnostic of Obstructive Sleep Apnoea (OSA). AHI, RDI, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) was calculated and receiver operating characteristic (ROC) curves were produced. Bland-Altman plots were used to determine agreement. Technical issues occurring during tests were explored. RESULTS: Twenty-four participants successfully completed both tests between March 2021 and January 2023. PSG were completed at around 14.1 weeks' gestation (IQR 13.4, 15.7). The time interval between Somte and PSG was a median of 4 days (IQR 2, 7 (range 1-12)). Five (20.8%) women had OSA on PSG at AHI ≥ 5 and 10 (41.6%) women had OSA on PSG at RDI ≥ 5. Somte and PSG did not differ in the measurement of AHI ((1.8, 1.6, p = 0.09) or RDI (3.3, 3.5), p = 0.73). At AHI ≥ 5, diagnostic test accuracy (area under the ROC curve) of Somte was 0.94, sensitivity 80.0%, specificity 94.7%, PPV and NPV were 80.0% and 94.7% respectively. At RDI ≥ 5, diagnostic test accuracy (area under the ROC curve) was 0.95, sensitivity 60.0%, specificity 93.0% and PPV and NPV were 85.7% and 76.4% respectively. The confidence limits of Bland-Altman plots were 6.37 to - 8.89 at cut off AHI ≥ 5 and 8.89 to - 10.43 at cut off RDI ≥ 5. Somte failed to start in four tests. Technical issues were reported in both Somte (n = 13, 54.2%) and PSG (n = 6, 25.0%). CONCLUSION: Self-applied, unattended Somte may provide an acceptable substitute to attended PSG in the identification of OSA in pregnant women in early to mid-gestation in this small sample but may fail to detect cases of OSA, particularly when using RDI as the diagnostic marker.

A prospective observational cohort study of covid-19 epidemiology and vaccine seroconversion in South Western Sydney, Australia, during the 2021-2022 pandemic period.

BACKGROUND: It is known that COVID-19 disproportionally adversely affects the immunocompromised, including kidney transplant recipients (KTR), as compared to the general population. Risk factors for adverse outcomes and vaccine seroconversion patterns are not fully understood. Australia was uniquely positioned to reduce initial case numbers during the 2021-2022 pandemic period due to its relative isolation and several significant public health interventions. South-Western Sydney Local Heath District was one of the predominant regions affected. METHODS: A single centre, prospective cohort study of prevalent renal transplant recipients was conducted between 25th July 2021 and 1st May 2022. Baseline characteristics, COVID-19 vaccination status, COVID-19 diagnosis and outcomes were determined from the electronic medical record, Australian vaccination register and Australian and New Zealand Dialysis and Transplant Registry. Assessment of vaccine-induced seroconversion was assessed with ELISA in a subpopulation. Analysis was performed using SPSS v.28. RESULTS: We identified 444 prevalent transplant recipients (60% male, 50% diabetic, median age 58 years (Interquartile range (IQR)21.0) and eGFR 56 ml/min/1.73m2 (IQR 21.9). COVID-19 was identified in 32% (n = 142) of patients, of which 38% (n = 54) required hospitalisation and 7% (n = 10) died. At least one COVID-19 vaccination was received by 95% (n = 423) with 17 (4%) patients remaining unvaccinated throughout the study period. Seroconversion after 2 and 3 doses of vaccine was 22% and 48% respectively. Increased COVID-19 related deaths were associated with older age (aOR 1.1, 95% CI 1.004-1.192, p = 0.040), smoking exposure (aOR 8.2, 05% CI 1.020-65.649, p = 0.048) and respiratory disease (aOR 14.2, 95%CI:1.825-110.930, p = 0.011) on multi-variable regression analysis. Receipt of three doses of vaccination was protective against acquiring COVID-19 (aOR 0.48, 95% CI 0.287-0.796, p = 0.005) and death (aOR 0.6, 95% CI: 0.007-0.523, p = 0.011), but not against hospitalisation (p = 0.32). Seroconversion was protective for acquiring COVID-19 on multi-variable regression independent of vaccination dose (aOR 0.1, 95%CI: 0.0025-0.523, p = 0.011). CONCLUSIONS: COVID-19 was associated with a high mortality rate. Older age, respiratory disease and prior smoking exposure may be risk factors for increased mortality. Vaccination of 3 doses is protective against acquiring COVID-19 and death, however not hospitalisation. Antibody response is protective for acquiring COVID-19, however seroconversion rates are low.

Significant kidney disease in pregnancy: Feasibility and outcomes of a national population-based study using the Australasian Maternity Outcomes Surveillance System.

BACKGROUND: Current understanding of clinical practice and care for maternal kidney disease in pregnancy in Australia is hampered by limitations in available renal-specific datasets. AIMS: To capture the epidemiology, management, and outcomes of women with significant kidney disease in pregnancy and demonstrate feasibility of a national cohort study approach. MATERIALS AND METHODS: An Australian prospective study (2017-2018) using a new kidney disease-specific survey within the Australasian Maternity Outcomes Surveillance System (AMOSS). Women who gave birth with acute kidney injury (AKI), advanced chronic kidney disease (CKD), dialysis dependence or a kidney transplant were included. Demographic data, renal and obstetric management, and perinatal outcomes were collected. RESULTS: Among 58 case notifications from 12 hospitals in five states, we included 23 cases with kidney transplant (n = 12), pre-existing CKD (n = 8), newly diagnosed CKD (n = 2) and dialysis (n = 1). No cases of AKI were reported. Reporting rates were better in states with study investigators and, overall, cases were likely under-reported. Nearly 35% of women had a non-delivery-related antenatal admission. Nephrology involvement was 78.3% during pregnancy and 91% post-partum. Adverse events were increased, including pre-eclampsia (21.7%), and preterm birth (60.9%). Women had high rates of aspirin (82.6%) and antihypertensive (73.9%) use, indwelling catheter for labour/delivery (65.2%), caesarean delivery (60.9%), and blood transfusion (21.7%). CONCLUSIONS: This first-ever Australian prospective study of significant kidney diseases in pregnancy provided novel insights into renal-specific clinical patterns and practices. However, under-reporting was likely. Future studies need to overcome the challenges of case identification and data collection burden.

SOMANZ position statement for the investigation and management of sepsis in pregnancy 2023.

BACKGROUND: The Society of Australia and New Zealand (SOMANZ) published its first sepsis in pregnancy and the postpartum period guideline in 2017 (Aust N Z J Obstet Gynaecol, 57, 2017, 540). In the intervening 6 years, maternal mortality from sepsis has remained static. AIMS: To update clinical practice with a review of the subsequent literature. In particular, to review the definition and screening tools for the diagnosis of sepsis. MATERIALS AND METHODS: A multi-disciplinary group of clinicians with experience in all aspects of the care of pregnant women analysed the clinical evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system following searches of Cochrane, Medline and EMBASE. Where there were conflicting views, the authors reviewed the topic and came to a consensus. All authors reviewed the final position statement. RESULTS: This position statement has abandoned the use of the quick Sequential Organ Failure Assessment score (qSOFA) score to diagnose sepsis due to its poor performance in clinical practice. Whilst New Zealand has a national maternity observation chart, in Australia maternity early warning system charts and vital sign cut-offs differ between states. Rapid recognition, early antimicrobials and involvement of senior staff remain essential factors to improving outcomes. CONCLUSION: Ongoing research is required to discover and validate tools to recognize and diagnose sepsis in pregnancy. Australia should follow New Zealand and have a single national maternity early warning system observation chart.

Clinical characteristics and sequelae of intrapartum hypertension - a retrospective cohort study.

BACKGROUND: In a significant proportion of pregnant women, elevated blood pressure may first present during the intrapartum period. This phenomenon, intrapartum hypertension, is often overlooked as blood pressure during delivery is attributed to labour pain, analgesic agents and haemodynamic changes. Thus the true prevalence and clinical significance of intrapartum hypertension remains unknown. This study sought to define the prevalence of intrapartum hypertension in previously normotensive women, identify associated clinical characteristics, and its impact on maternal and fetal outcomes. METHODS: In this single-center retrospective cohort study, all available partograms were reviewed over a 1-month period at an outer metropolitan hospital in Sydney (Campbelltown Hospital). Women with diagnosed hypertensive disorders of pregnancy during the incident pregnancy were excluded. A total of 229 deliveries were included in the final analysis. Intrapatum hypertension (IH) was defined as two or more systolic blood pressure (SBP)⩾140 mmHg or diastolic blood pressure (DBP)⩾90 mmHg during the intrapartum. Demographic data at the time of the first antenatal visit for the incident pregnancy as well as final maternal outcomes (intrapartum and post-partum) and fetal outcomes were collected. Statistical analyses were carried out using SPSSv27 with adjustments for baseline variables. RESULTS: Amongst 229 deliveries, 32 women (14%) had intrapartum hypertension. Older maternal age (p = 0.02), higher body mass index (p < 0.01) and higher diastolic blood pressure at the first antenatal visit (p = 0.03) were associated with intrapartum hypertension. A longer second stage of labour (p = 0.03), intrapartum non-steroidal anti-inflammatory medications (p < 0.01) and epidural anaesthesia (p = 0.03) were associated with intrapartum hypertension, while IV syntocin for labour induction was not. Women with intrapartum hypertension had a longer inpatient admission following delivery (p < 0.01), and elevated postpartum BP (p = 0.02) with discharge on antihypertensive medications (p < 0.01). Intrapartum hypertension was not associated with poor fetal outcomes, though subgroup analyses showed that women who had at least a single elevated blood pressure reading during the intrapartum experienced poorer fetal outcomes. CONCLUSION: In previously normotensive women, 14% developed intrapartum hypertension during delivery. This was associated with postpartum hypertension, longer maternal admission and discharge with antihypertensive medications. There was no difference in fetal outcomes.

Intrahepatic cholestasis of pregnancy - Diagnosis and management: A consensus statement of the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ): Executive summary.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy liver disease, characterised by pruritus and increased total serum bile acids (TSBA), Australian incidence 0.6-0.7%. ICP is diagnosed by non-fasting TSBA ≥19 µmol/L in a pregnant woman with pruritus without rash without a known pre-existing liver disorder. Peak TSBA ≥40 and ≥100 µmol/L identify severe and very severe disease respectively, associated with spontaneous preterm birth when severe, and with stillbirth, when very severe. Benefit-vs-risk for iatrogenic preterm birth in ICP remains uncertain. Ursodeoxycholic acid remains the best pharmacotherapy preterm, improving perinatal outcome and reducing pruritus, although it has not been shown to reduce stillbirth.

Diet in the management of non-dialysis dependent chronic kidney disease: perceptions and practices of health professionals.

BACKGROUND: Therapeutic strategies, including dietary intervention, to target non-dialysis dependent Chronic Kidney Disease (CKD) progression have been at the forefront of recent renal research. Nephrologists and other renal health professionals are key stakeholders in the dietary management of patients with non-dialysis dependent CKD and referrals to dietetic services. The aims of this study were to explore (i) health professional perceptions regarding the role of diet in managing non-dialysis dependent CKD, and (ii) health professional practices regarding the provision of dietary advice and referrals to dietetic services. METHODS: A 31-item online survey was emailed to members of professional renal networks and associations in Australia and New Zealand. Data was analysed descriptively. Categorical variables were assessed to determine associations between referral frequency, demographic variables, health professional role (non-dietetic versus dietetic) and perceptions of the role of diet. RESULTS: Overall, 189 health professionals completed the survey. Nephrologists (42%), renal nurses (29%) and renal dietitians (24%) were the most common respondents. Non-dietetic health professionals rated the importance of diet in the management of non-dialysis dependent CKD significantly lower than renal dietitians (73% versus 98% ranked as very-extremely important, p = 0.002). Fifty percent of non-dietetic health professionals referred patients to renal dietetic services never or 0-25% of the time. Reasons for not referring included perceptions there is a lack of evidence that diet reduces CKD progression, perceptions that patients will not adhere to dietary recommendations, and a desire to reduce visit burden for patients. Barriers to accessing dietetic services were perceived to be significant and include lengthy wait times and inadequate dietetic staffing. CONCLUSION: Inconsistencies exist between non-dietetic health professionals and dietitians regarding the importance of diet in non-dialysis dependent CKD. Referral practices appear to be influenced by beliefs about the evidence base and perceptions regarding the ability of dietitians to meet referral demand. Raising awareness for non-dietetic health professionals working in nephrology regarding the evidence on diet and CKD progression is needed. An improved understanding of this evidence base may improve knowledge and referral patterns. Further, an increase in renal dietetic staffing is recommended to enhance patient access to services.

Health Service Costs for a Predialysis Dietetic Clinic: A Retrospective Cost Analysis Study.

OBJECTIVES: Effect of dietetic consultation (DC) on clinical outcomes is an under-researched component of predialysis education. Predialysis DC has been associated with a 7.5-month delay in requiring dialysis commencement, having potential cost implications for health services. Limited studies have evaluated the possible impact of predialysis DC on health service costs. This study aimed to investigate the hospital health service costs associated for patients attending a predialysis dietetic clinic. METHODS: A cost analysis comparing hospital health service costs over 4 years in a cohort of predialysis patients with and without DC. Retrospective study data were used (n = 246) along with outpatient renal clinic visits, hospital admissions records to estimate total hospital service costs. A generalized linear model evaluated associations between total cost and the marginal effects of DC and other variables on total costs. RESULTS: Mean total cost for patients (outpatient visits, admissions, and dialysis) was AUD$178,913 (95% confidence interval = $158,735-$199,090) or $185/day (95% confidence interval = $12-$161). The DC group total costs/day were lower than the no-DC group with a mean difference of $51/day ($155 vs. $206; P = .03). Patients in the DC group had less admissions compared to the no-DC group (6.32 vs. 8.06; P = .02). The highest marginal costs estimated for the entire cohort were lower estimated glomerular filtration rate at admission ($123,511, P = .001), inpatient admissions ($189,333, P < .001), commencing dialysis ($581,812, P < .001), having diabetes ($94,590, P = .014), and cerebrovascular disease ($177,080, P = .01). DC advice did not influence total costs. CONCLUSIONS: Patients who received DC had lower total health services costs/day compared to those who did not receive DC. Marginal cost analysis indicates the cost difference to be attributed to less time on dialysis and fewer hospital admissions in this retrospective observational cohort. An assessment of dietetic staffing in predialysis renal services is warranted.

Comparison of Sampling Methods for International Normalized Ratio Monitoring in Haemodialysis Patients (INRHaemo Study).

BACKGROUND: Haemorrhagic and thrombotic complications are common in dialysis patients on warfarin; thus, accurate international normalized ratio (INR) monitoring is critical. For expediency and patient comfort, blood sampling from the haemodialysis access or circuit is commonly performed. Point-of-care (POC) INR machines allow both peripheral vein preservation and rapid results, yet are not validated in the haemodialysis population. METHODS: A prospective cohort study in haemodialysis patients taking warfarin was undertaken. Three paired samples were drawn over a single session: peripheral blood INR, POC INR, and dialysis INR. Agreement using Bland-Altman analysis and correlation coefficients between the peripheral blood INR, haemodialysis INR, and POC INR were calculated. Inappropriate dosing decisions based on haemodialysis or POC INR were quantified. RESULTS: Amongst 34 patients, agreement between the dialysis INR and peripheral blood INR was high, with the haemodialysis INR differing from the peripheral INR by <±0.2, 85.2% of the time. Correlation between the 2 methods was high (r = 0.914; p < 0.001). POC INR differed from peripheral INR values by <±0.2, 67.6% of the time, with less agreement at higher INR values. Dosing decisions were incongruent between the dialysis and peripheral INR in 6%, whilst the POC and peripheral INR disagreed in 26%. CONCLUSIONS: There was good agreement and correlation between the peripheral blood, haemodialysis access/circuit, and POC INR values. POC INR was less reliable at higher values, and dosing decisions differed from the peripheral INR in a quarter of cases.

A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised trial.

BACKGROUND: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. METHODS: We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. DISCUSSION: Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. TRIAL IDENTIFIERS: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

Renal supportive care programs: An observational study assessing impact on hospitalization and survival outcomes.

AIM: Renal supportive care (RSC) programs are used to manage non-dialysis end-stage kidney disease (ESKD) patients. The aim of this study was to analyse the impact of RSC programs on hospitalization and survival outcomes in these patients. METHODS: A retrospective, single-centre observational cohort study of non-dialysis ESKD patients was undertaken. Hospitalizations and survival from eGFR≤15 ml/min was compared between patients managed in an RSC program (RSC group) and patients receiving standard conservative therapy (non-RSC group). Local databases, physician letters and electronic medical records were used for data collection. Prevalent patients from 2013 to 2017 with eGFR ≤15 ml/min were included. Cox proportion hazard testing and generalized linear modelling was undertaken to adjust for confounders. RESULTS: A total of 172 patients were included (95 RSC; 75 non-RSC). The median age was 82 years [IQR 78-85], 46% were male, the median Charlson-comorbidity Index was 5 [IQR 4-7]. The RSC group had significantly lowered haemoglobin level (102 g/L vs. 111 g/L) and fewer English-speakers (34% vs. 44%). RSC was associated with the decreased number of days in hospital per year (estimated means 46.6 days [95% CI 21-67] vs. 83.2 days [95%CI 60.5-105.8]; p = .01) and decreased number of hospital admissions per year (estimated means 5.4 [95%CI 2.1-8.8] vs. 12.3 [95%CI 8.2-16.4]; p = .01) compared with non-RSC. Median overall survival from eGFR≤15 in the entire cohort was 735 days, with no significant difference between RSC and non-RSC groups (p = .9), both unadjusted and adjusted for confounders. CONCLUSION: RSC programs can significantly decrease the number and length of hospitalizations in conservatively managed ESKD patients.

Update on pulmonary embolism in pregnancy and post-partum: The Society of Obstetric Medicine of Australia and New Zealand Position Statement on Pulmonary Embolism in Pregnancy and Post-partum.

In this clinical review we highlight aspects of the diagnosis and management of pulmonary embolism (PE) in pregnancy and post-partum and how this may impact on antenatal and postnatal management. Investigation for PE in pregnancy is challenging and includes appropriate patient selection and knowledge of the risks and benefits of pulmonary imaging modalities. The complete Society of Obstetric Medicine of Australia and New Zealand Position Statement on Pulmonary Embolism in Pregnancy and Post-Partum comprehensively reviews all aspects of diagnosis, investigation and management and is accessible at https://www.somanz.org/guidelines.asp. It includes a summary of all recommendations and a guide to developing a management plan for birth in women on anticoagulation.

The Learning Curves for Transradial and Ultrasound-Guided Arterial Access: An Analysis of the SURF Trial.

INTRODUCTION: Historically, coronary angiography and percutaneous coronary intervention involved accessing the femoral artery via palpation. However, recently there has been a trend towards using a transradial approach and ultrasound guidance for arterial access. Studies have shown that these techniques respectively improve major bleeding rates and access outcomes. There have been no studies conducted that assess the time it takes to train operators to attain proficiency. This sub-analysis of the Standard versus Ultrasound-guided Radial and Femoral access in coronary angiography and intervention (SURF) trial aims to assess the number of procedures required to attain proficiency in ultrasound-guided transradial and transfemoral access. METHODS: The SURF trial randomised 1,388 patients undergoing coronary angiography and/or percutaneous coronary intervention into standard or ultrasound-guidance and radial or femoral access in a 2×2 factorial design. Operators who participated in this trial were required to have performed at least 50 standard and 10 ultrasound-guided punctures for each of transradial and transfemoral access. Cases were then chronologically ordered and stratified into groups of five, from which the primary endpoint measured was a progression in mean access time and first-pass success rates. RESULTS: Across all operators, there was a reduction in mean access time between procedures one to five and six to 10 with ultrasound-guided femoral punctures (60.5 secs-51.5 secs, p=0.029) and between procedures 11 to 15 and 16 to 20 ultrasound-guided radial punctures (74s to 62.5 secs, p=0.082). This trend was more obvious in trainees, with significant reductions in mean access time between procedures one to five and six to 10 from 73.5 to 53.5 seconds (p<0.001) for ultrasound-guided femoral access and from 99.5 seconds to 60 seconds (p=0.024) for ultrasound-guided radial access. There were no trends with standard transradial access. CONCLUSION: The numbers required to attain competency in ultrasound-guided femoral and radial access are 15 and 25 punctures, respectively. Fifty (50) punctures appear adequate for proficiency in a standard transradial approach. These numbers are useful in incorporating into training program for advanced trainees and interventionalists.

Effect of placental growth factor in models of experimental pre-eclampsia and trophoblast invasion.

Placental growth factor (PlGF) is decreased in early gestation of pregnant women who subsequently develop pre-eclampsia. In this study, pre-emptive treatment with PlGF to prevent pre-eclampsia was evaluated in an in vivo rodent model of experimental pre-eclampsia (EPE) induced by TNF-α and in an in vitro model of human first-trimester trophoblast invasion. Pregnant C57/BL6 mice were treated with recombinant mouse placental growth factor-2 (rmPlGF-2) 100 µg/kg/day IP from gestational day (gd) 10. Animals had EPE induced by continuous TNF-α infusion on gd 13 and were subject to either continuous blood pressure monitoring by radiotelemetry throughout pregnancy or live placenta T2 -weighted magnetic resonance imaging (MRI) to demonstrate placental function on gd 17. There was no difference in BP (P > .99), proteinuria (P = .9) or T2 values on MRI (P = .9) between control and rmPlGF-2-treated animals. On gd 13, animals treated with rmPlGF-2 demonstrated increased placenta PlGF (P = .01) and Toll-like receptor-3 (P = .03) mRNA expression as compared with controls. Fluorescent-labelled human uterine microvascular endothelial cells and HTR8/SVNeo cells were co-cultured on Matrigel™ and treated with recombinant human PlGF (rhPlGF) (10 ng/mL) and/or TNF-α (0.5 ng/mL). Trophoblast integration into endothelial networks was reduced by added TNF-α (P = .006), as was rhPlGF concentration in conditioned media (P < .0001). Cell integration was not ameliorated by addition of rhPlGF (P > .9). Although TNF-α-induced EPE was not reversed with pre-emptive rmPlGF-2, a further trial of pre-emptive rhPlGF in vivo is required to determine whether the absence of effect of rhPlGF demonstrated in vitro precludes PlGF as a preventative therapy for pre-eclampsia.

The association between dietetic consultation and time to dialysis for patients attending a pre-dialysis clinic: A retrospective cohort study.

AIM: A multidisciplinary approach, including dietetics, is considered the optimal model of care for dialysis preparation. Dietetic consultation (DC) focuses on symptom management and dietary changes to delay time to dialysis. Evidence of the effectiveness of DC on time to dialysis is limited. This study aimed to investigate the impact of DC on time to dialysis for patients attending a pre-dialysis clinic. METHODS: A retrospective cohort study was designed to include all patients attending outpatient pre-dialysis clinics at a large metropolitan renal service between January 2014 and March 2018. Time to dialysis (days) was compared between patients that received DC and those who did not. Cox proportional hazards analysis allowing for adjustment of differences and confounders was undertaken. RESULTS: A cohort of 246 patients was identified. Median estimated glomerular filtration rate was 16mL/min per 1.73 m2 (interquartile range = 13-20) at initial pre-dialysis clinic visit and 63% commenced dialysis during the study period. Only 41% of patients received dietetic consultation. Significantly fewer patients needed to commence dialysis in the DC group compared to the no-DC group (hazards ratio 0.63; 95% confidence interval (CI) 0.45-0.89; P = 0.008 Cox proportion hazard). The DC group commenced dialysis significantly later than the no-DC group; 933 days (95% CI 832-1034) versus 710 days (95% CI 630-790) respectively, after the initial pre-dialysis clinic visit; log-rank 0.005. CONCLUSION: DC provided to patients attending a pre-dialysis clinic was associated with a delayed time to dialysis. Standardised referral pathways to improve patient access to renal dietetic services are recommended to optimise care.

A pharmacokinetic assessment of optimal dosing, preparation, and chronotherapy of aspirin in pregnancy.

BACKGROUND: The benefit of aspirin in preventing preeclampsia is well established; however, studies over the years have demonstrated variability in outcomes with its use. Potential contributing factors to this variation in efficacy include dosing, time of dosing, and preparation of aspirin. OBJECTIVE: We aimed to compare the difference in pharmacokinetics of aspirin, through its major active metabolite, salicylic acid, in pregnant women and nonpregnant women, and to examine the effect of dose (100 mg vs 150 mg), preparation (enteric coated vs non-enteric-coated), and chronotherapy of aspirin (morning vs evening) between the 2 groups. MATERIALS AND METHODS: Twelve high-risk pregnant women and 3 nonpregnant women were enrolled in this study. Pregnant women were in 1 of 4 groups (100 mg enteric coated, 100 mg non-enteric-coated, 150 mg non-enteric-coated morning dosing, and 150 mg non-enteric-coated evening dosing), whereas nonpregnant women undertook each of the 4 dosing schedules with at least a 30-day washout period. Blood samples were collected at baseline (before ingestion) and at 1, 2, 4, 6, 12, and 24 hours after ingestion of aspirin. Plasma obtained was analyzed for salicylic acid levels by means of liquid chromatography-mass spectrometry. Pharmacokinetic values of area under the curve from time point 0 to 24 hours point of maximum concentration, time of maximum concentration, volume of distribution, clearance, and elimination half-life were analyzed for statistical significance with SPSS v25 software. RESULTS: Pregnant women had a 40% ± 4% reduction in area under the curve from time point 0 to 24 hours (P < .01) and 29% ± 3% reduction in point of maximum concentration (P < .01) with a 44% ± 8% increase in clearance (P < .01) in comparison to that in nonpregnant women when 100 mg aspirin was administered. The reduction in the area under the curve from time point 0 to 24 hours, however, was minimized with the use of 150 mg aspirin in pregnant women, with which the area under the curve from time point 0 to 24 hours was closer to that achieved with the use of 100 mg aspirin in nonpregnant women. There was a 4-hour delay (P < .01) in the time of maximum concentration, a 47% ± 3% reduction in point of maximum concentration (P < .01) and a 48% ± 1% increase in volume of distribution (P < .01) with the use of 100 mg enteric-coated aspirin compared to non-enteric-coated aspirin, with no difference in the overall area under the curve. There was no difference in the pharmacokinetics of aspirin between morning and evening dosing. CONCLUSION: There is a reduction in the total drug metabolite concentration of aspirin in pregnancy, and therefore a dose adjustment is potentially required in pregnant women. This is likely due to the altered pharmacokinetics of aspirin in pregnancy, with an increase in clearance. There was no difference in the total drug metabolite concentration of aspirin between enteric-coated and non-enteric-coated aspirin and between morning and evening dosing of aspirin. Further pharmacodynamic and clinical studies are required to examine the clinical relevance of these pharmacokinetic findings.