Mechanisms of piperonyl butoxide cytotoxicity and its enhancement with imidacloprid and metals in Chinese hamster ovary cells.

The widespread use of chemicals and the presence of chemical and metal residues in various foods, beverages, and other consumables have raised concerns about the potential for enhanced toxicity. This study assessed the cytotoxic effects of Piperonyl butoxide (PBO) and its enhancement by combination with major contamination chemicals including Imidacloprid and metals, using different cytotoxic and genotoxic assays in Chinese hamster ovary (CHO) cells. PBO exhibited elevated cytotoxic effects in poly (ADP-ribose) polymerase (PARP) deficient CHO mutants but not in Glutathione S-transferase deficient CHO mutants. PBO cytotoxicity was enhanced by PARP inhibitor, Olaparib. PBO cytotoxicity was also enhanced with co-exposure to Imidacloprid, Lead Chloride, or Sodium Selenite. PBO induces γH2AX foci formation and apoptosis. The induction of DNA damage markers was elevated with PARP deficiency and co-exposure to Imidacloprid, Lead Chloride, or Sodium Selenite. Moreover, PBO triggers to form etch pits on plastic surfaces. These results revealed novel mechanisms of PBO cytotoxicity associated with PARP and synergistic effects with other environmental pollutants. The toxicological mechanisms underlying exposure to various combinations at different concentrations, including concentrations below the permitted limit of intake or the level of concern, require further study.

Estimating a Minimal Important Difference for the EQ-5D-5L Utility Index in Dialysis Patients.

OBJECTIVES: The EQ-5D-5L is a commonly used health-related quality of life instrument for evaluating interventions in patients receiving dialysis; however, the minimal important difference (MID) that constitutes a meaningful treatment effect for this population has not been established. This study aims to estimate the MID for the EQ-5D-5L utility index in dialysis patients. METHODS: 6-monthly EQ-5D-5L measurements were collected from adult dialysis patients between April 2017 and November 2020 at a renal network in Sydney, Australia. EQ-VAS and Integrated Palliative care Outcome Scale Renal symptom burden scores were collected simultaneously and used as anchors. MID estimates for the EQ-5D-5L utility index were derived using anchor-based and distribution-based methods. RESULTS: A total of 352 patients with ≥1 EQ-5D-5L observation were included, constituting 1127 observations. Mean EQ-5D-5L utility index at baseline was 0.719 (SD ± 0.267), and mean EQ-5D-5L utility decreased over time by -0.017 per year (95% CI -0.029 to -0.006, P = .004). Using cross-sectional anchor-based methods, MID estimates ranged from 0.073 to 0.107. Using longitudinal anchor-based methods, MID for improvement and deterioration ranged from 0.046 to 0.079 and -0.111 to -0.048, respectively. Using receiver operating characteristic curves, MID for improvement and deterioration ranged from 0.037 to 0.122 and -0.074 to -0.063, respectively. MID estimates from distribution-based methods were consistent with anchor-based estimates. CONCLUSIONS: Anchor-based and distribution-based approaches provided EQ-5D-5L utility index MID estimates ranging from 0.034 to 0.134. These estimates can inform the target difference or "effect size" for clinical trial design among dialysis populations.

Conservative kidney management and kidney supportive care: core components of integrated care for people with kidney failure.

Integrated kidney care requires synergistic linkage between preventative care for people at risk for chronic kidney disease and health services providing care for people with kidney disease, ensuring holistic and coordinated care as people transition between acute and chronic kidney disease and the 3 modalities of kidney failure management: conservative kidney management, transplantation, and dialysis. People with kidney failure have many supportive care needs throughout their illness, regardless of treatment modality. Kidney supportive care is therefore a vital part of this integrated framework, but is nonexistent, poorly developed, and/or poorly integrated with kidney care in many settings, especially in low- and middle-income countries. To address this, the International Society of Nephrology has (i) coordinated the development of consensus definitions of conservative kidney management and kidney supportive care to promote international understanding and awareness of these active treatments; and (ii) identified key considerations for the development and expansion of conservative kidney management and kidney supportive care programs, especially in low resource settings, where access to kidney replacement therapy is restricted or not available. This article presents the definitions for conservative kidney management and kidney supportive care; describes their core components with some illustrative examples to highlight key points; and describes some of the additional considerations for delivering conservative kidney management and kidney supportive care in low resource settings.

Preeclampsia-Associated Cardiovascular Risk Factors 6 Months and 2 Years After Pregnancy: The P4 Study.

BACKGROUND: Increased cardiovascular risk following preeclampsia is well established and there are signs of early cardiovascular aging 6 months postpartum. This study assessed whether blood pressure (BP) and other cardiovascular measures are abnormal 2 years postpartum in the same cohort to determine ongoing risk markers. METHODS: Six months and 2 years postpartum, BP was measured using sphygmomanometry, 24-hour ambulatory BP monitoring, and noninvasive central BP. Anthropometric measures, blood, and urine biochemistry were performed. Cross-sectional comparisons between preeclampsia and normotensive pregnancy (NP) groups and longitudinal comparisons within each group were made at 6 months and 2 years. RESULTS: Two years postpartum, 129 NP, and 52 preeclampsia women were studied who also had 6 months measures. At both time points, preeclampsia group had significantly higher BP (office BP 2 years, 112±12/72±8 versus 104±9/67±7 mm Hg NP; [P<0.001]; mean ambulatory BP monitoring 116±9/73±8 versus 106±8/67±6 mm Hg NP; [P<0.001]). No significant BP changes noted 6 months to 2 years within either group. Office BP thresholds of 140 mm Hg systolic and 90 mm Hg diastolic classified 2% preeclampsia and 0% NP at 2 years. American Heart Association 2017 criteria (above normal, >120/80 mm Hg) classified 25% versus 8% (P<0.002), as did our reference range threshold of 122/79 mm Hg. American Heart Association criteria classified 60% post-preeclampsia versus 16% after NP with above-normal ambulatory BP monitoring (P<0.001). Other cardiovascular risk markers more common 2 years post-preeclampsia included higher body mass index (median 26.6 versus 23.1, P=0.003) and insulin resistance. CONCLUSIONS: After preeclampsia, women have significantly higher BP 6 months and 2 years postpartum, and have higher body mass index and insulin-resistance scores, increasing their future cardiovascular risk. Regular cardiovascular risk screening should be implemented for all who have experienced preeclampsia.

The Association of Frailty and Malnutrition With Dietary Intake and Gastrointestinal Symptoms in People With Kidney Failure: 2-Year Prospective Study.

BACKGROUND: Frailty and malnutrition are both associated with worsening morbidity and mortality and become more prevalent in the elderly and as kidney function declines. Anorexia and reduced oral intake are common features of both frailty and malnutrition. However, there are sparse data evaluating the impact of other gastrointestinal (GI) symptoms, such as taste changes, on rates of frailty and malnutrition in people with kidney failure. The aim of this study is to describe the prevalence of frailty and malnutrition and their association with dietary intake and nutrition-related symptoms in people with kidney failure. METHODS: This observational study recruited people with kidney failure who were commencing Conservative Kidney Management or elderly people (aged > 75 years) newly commenced on dialysis from 3 renal units. Participants underwent assessments of frailty, nutritional status, dietary intake, and GI symptom burden when they attended clinic appointments, approximately every 6 months. RESULTS: Of the 85 participants, 57% were assessed as being frail and 33% were assessed as being malnourished. Participants assessed as frail reported more GI symptoms (3 vs. 2, P < .001) that were more severe (1.75 vs. 1.0, P < .001) compared to nonfrail participants. Being malnourished was associated with a 5 times higher chance of being frail (odds ratio 5.8; 95% confidence interval 1.5, 21.8; P = .015) and having more severe symptoms was associated with a 2 times higher chance (odds ratio 2.8; 95% CI 1.1, 7.0; P = .026) of being frail. In addition to experiencing more GI symptoms, that were more severe, participants who were malnourished consumed significantly less energy (1234 kcal vs. 1400 kcal, P = .01) and protein (51 g vs. 74 g, P < .001). CONCLUSIONS: Frailty and malnutrition are common and are associated with a higher GI symptom burden and poorer dietary intake. Future research is needed to determine effective interventions targeting frailty and malnutrition, including nutrition-related symptoms and optimal protein intake.

Childhood growth outcomes 2 years after hypertensive versus normotensive pregnancy: a P4 study.

BACKGROUND: Intrauterine exposure to hypertensive disorders of pregnancy, including gestational hypertension (GH) and preeclampsia (PE), may influence infant growth and have long-term health implications. This study aimed to compare growth outcomes of infants exposed to a normotensive pregnancy (NTP), GH, or PE from birth to 2 years. METHODS: Infants were children of women enroled in the prospective Postpartum Physiology, Psychology and Paediatric (P4) cohort study who had NTP, GH or PE. Birth, 6-month (age-corrected) and 2-year (age-corrected) weight z-scores, change in weight z-scores, rapid weight gain (≥0.67 increase in weight z-score) and conditional weight gain z-scores were calculated to assess infant growth (NTP = 240, GH = 19, PE = 66). RESULTS: Infants exposed to PE compared to NTP or GH had significantly lower birth weight and length z-scores, but there were no differences in growth outcomes at 6 months or 2 years. GH and PE-exposed infants had significantly greater weight z-score gain [95% CI] (PE = 0.93 [0.66-1.18], GH = 1.03 [0.37-1.68], NTP = 0.45 [0.31-0.58], p < 0.01) and rapid weight gain (GH = 63%, PE = 59%, NTP = 42%, p = 0.02) from birth to 2 years, which remained significant for PE-exposed infants after confounder adjustment. CONCLUSION: In this cohort, GH and PE were associated with accelerated infant weight gain that may increase future cardiometabolic disease risk. IMPACT: Preeclampsia exposed infants were smaller at birth, compared with normotensive pregnancy and gestational hypertension exposed infants, but caught up in growth by 2 years of age. Both preeclampsia and gestational hypertension exposed infants had significantly accelerated weight gain from birth to 2 years, which remained significant for preeclampsia exposed infants after adjustment for confounders including small for gestational age. Monitoring of growth patterns in infants born following exposure to a hypertensive disorder of pregnancy may be indicated to prevent accelerated weight gain trajectories and obesity.

Factors associated with quality of life in patients with kidney failure managed conservatively and with dialysis: a cross-sectional study.

BACKGROUND: Later stage chronic kidney disease (CKD) is associated with poorer self-perceived health-related quality of life (HRQOL), a major consideration for many patients. Psychological factors such as depression and anxiety have been linked with poorer HRQOL. We aimed to determine if anxiety or depressive symptoms are significantly associated with self-perceived health-related quality of life, in patients with CKD Stage 5. The secondary aim was to determine which patient-associated factors are associated with HRQOL in patients with CKD Stage 5. METHODS: This retrospective cross-sectional study included patients that attended the St George Hospital Kidney Supportive Care (KSC) clinic between 1 and 2015 and 30 June 2022 with CKD Stage 5 (either conservatively-managed or receiving dialysis). Patients completed surveys of their functional 'domains' and quality of life (EQ-5D-5L) and symptom surveys (IPOS-Renal) at their first visit. We performed multivariable linear regression analysis with the outcome of interest being HRQOL, measured using the EQ-VAS, a continuous 100-point scale, for patients undergoing conservative management or dialysis. Pre-specified variables included age, sex, eGFR (for those conservatively-managed), "feeling depressed" (IPOS-Renal), "feeling anxious" (IPOS-Renal) and "anxiety/depression" (EQ-5D-5L). RESULTS: We included 339 patients. 216 patients received conservative kidney management (CKM) and 123 patients received dialysis. Patients receiving CKM were significantly older than those on dialysis, (median age 83 years vs. 73 years, p < 0.001). For conservatively-managed patients, variables independently associated with poorer EQ-VAS were difficulty performing usual activities (EQ-5D-5L), drowsiness (IPOS-Renal) and shortness of breath (IPOS-Renal). For patients receiving dialysis, variables that were independently associated with poorer EQ-VAS were reduced ability to perform self-care (EQ-5D-5L) and lack of energy (IPOS-Renal). Anxiety and depressive symptoms were not significantly associated with poorer EQ-VAS for either group of patients. CONCLUSIONS: Symptoms associated with reduced HRQOL include shortness of breath, drowsiness and impaired functional ability. Optimization of multidisciplinary teams focusing on these issues are likely to be of benefit.

Lysine Methyltransferase SMYD1 Regulates Myogenesis via skNAC Methylation.

The SMYD family is a unique class of lysine methyltransferases (KMTases) whose catalytic SET domain is split by a MYND domain. Among these, Smyd1 was identified as a heart- and skeletal muscle-specific KMTase and is essential for cardiogenesis and skeletal muscle development. SMYD1 has been characterized as a histone methyltransferase (HMTase). Here we demonstrated that SMYD1 methylates is the Skeletal muscle-specific splice variant of the Nascent polypeptide-Associated Complex (skNAC) transcription factor. SMYD1-mediated methylation of skNAC targets K1975 within the carboxy-terminus region of skNAC. Catalysis requires physical interaction of SMYD1 and skNAC via the conserved MYND domain of SMYD1 and the PXLXP motif of skNAC. Our data indicated that skNAC methylation is required for the direct transcriptional activation of myoglobin (Mb), a heart- and skeletal muscle-specific hemoprotein that facilitates oxygen transport. Our study revealed that the skNAC, as a methylation target of SMYD1, illuminates the molecular mechanism by which SMYD1 cooperates with skNAC to regulate transcriptional activation of genes crucial for muscle functions and implicates the MYND domain of the SMYD-family KMTases as an adaptor to target substrates for methylation.

Targeting Epigenetic Changes Mediated by Members of the SMYD Family of Lysine Methyltransferases.

A comprehensive understanding of the mechanisms involved in epigenetic changes in gene expression is essential to the clinical management of diseases linked to the SMYD family of lysine methyltransferases. The five known SMYD enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine (SAM) to specific lysines on histones and non-histone substrates. SMYDs family members have distinct tissue distributions and tissue-specific functions, including regulation of development, cell differentiation, and embryogenesis. Diseases associated with SMYDs include the repressed transcription of SMYD1 genes needed for the formation of ion channels in the heart leading to heart failure, SMYD2 overexpression in esophageal squamous cell carcinoma (ESCC) or p53-related cancers, and poor prognosis associated with SMYD3 overexpression in more than 14 types of cancer including breast cancer, colon cancer, prostate cancer, lung cancer, and pancreatic cancer. Given the importance of epigenetics in various pathologies, the development of epigenetic inhibitors has attracted considerable attention from the pharmaceutical industry. The pharmacologic development of the inhibitors involves the identification of molecules regulating both functional SMYD SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domains, a process facilitated by available X-ray structures for SMYD1, SMYD2, and SMYD3. Important leads for potential pharmaceutical agents have been reported for SMYD2 and SMYD3 enzymes, and six epigenetic inhibitors have been developed for drugs used to treat myelodysplastic syndrome (Vidaza, Dacogen), cutaneous T-cell lymphoma (Zoinza, Isrodax), and peripheral T-cell lymphoma (Beleodag, Epidaza). The recently demonstrated reversal of SMYD histone methylation suggests that reversing the epigenetic effects of SMYDs in cancerous tissues may be a desirable target for pharmacological development.

Kidney failure end-of-life care: impact of advance care planning - retrospective observational study.

OBJECTIVES: Patients with kidney failure (KF) have poor prognosis yet receive aggressive medical interventions at the end of life. Advance care planning (ACP) aims to respect patients' treatment preference and facilitate good death, though whether these are achieved in KF is unknown.This study examines the utility of ACP for end-of-life care in KF patients. METHODS: A retrospective observational study of KF patients who completed an ACP document 2012-2019 and died in an Australian hospital. Medical records were reviewed to assess treatment concordance to the ACP document and quality of end-of-life care received. RESULTS: 65 KF patients (29 dialysis, 36 conservative) had a median age of 84 years and 57% males. 86% of deaths followed an emergency admission. ACP documents recorded patients' preference to avoid cardiopulmonary resuscitation (91%) and forego dialysis (86%). 95% patients received treatment concordant with ACP. One patient was resuscitated, and one conservative patient dialysed. A good quality death was achieved for most, including dialysis withdrawal (80%), palliative care referral (88%), discussion of prognosis (95%), rationalised medications (89%) and anticipatory end-of-life medications (92%). CONCLUSION: ACP documents are useful facilitating treatment concordant with KF patients' preferences. Most patients avoided aggressive medical interventions and received good quality end-of-life care.

Carbon emissions and hospital pathology stewardship: a retrospective cohort analysis.

BACKGROUND: As healthcare is responsible for 7% of Australia's carbon emissions, it was recognised that a policy implemented at St George Hospital, Sydney, to reduce non-urgent pathology testing to 2 days per week and, on other days only if essential, would also result in a reduction in carbon emissions. The aim of the study was to measure the impact of this intervention on pathology collections and associated carbon emissions and pathology costs. AIMS: To measure the impact of an intervention to reduce unnecessary testing on pathology collections and associated carbon emissions and pathology costs. METHODS: The difference in the number of pathology collections, carbon dioxide equivalents (CO2 e) for five common blood tests and pathology cost per admission were compared between a 6-month reference period and 6-month intervention period. CO2 e were estimated from published pathology CO2 e impacts. Cost was derived from pathology billing records. Outcomes were modelled using multivariable negative binomial, generalised linear and logistic regression. RESULTS: In total, 24 585 pathology collections in 5695 patients were identified. In adjusted analysis, the rate of collections was lower during the intervention period (rate ratio 0.90; 95% confidence interval (CI), 0.86-0.95; P < 0.001). This resulted in a reduction of 53 g CO2 e (95% CI, 24-83 g; P < 0.001) and $22 (95% CI, $9-$34; P = 0.001) in pathology fees per admission. The intervention was estimated to have saved 132 kg CO2 e (95% CI, 59-205 kg) and $53 573 (95% CI, 22 076-85 096). CONCLUSIONS: Reduction in unnecessary hospital pathology collections was associated with both carbon emission and cost savings. Pathology stewardship warrants further study as a potentially scalable, cost-effective and incentivising pathway to lowering healthcare associated greenhouse gas emissions.

Quality of Life in Patients with Chronic Kidney Disease Managed with or without Dialysis: An Observational Study.

Background: Emerging research suggests that quality of life (QOL) outcomes, such as maintenance of independence, rather than length of life, are the main priority for many patients with end stage kidney disease (ESKD). There is therefore a need to focus on whether QOL for older patients on dialysis differs significantly from conservative kidney management (CKM). This study aimed to describe the QOL trajectory for patients with ESKD, comparing CKM to dialysis and transplantation. Methods: This retrospective, observational study included all patients who attended the Kidney Supportive Care Clinic at St. George Hospital and had one or more EuroQOL (EQ5D5L) questionnaires between July 2014 and May 2020. Kruskal-Wallis tests compared QOL scores between groups at baseline and 12 months. Wilcoxon signed rank tests compared QOL scores from baseline to 18 months within groups. Chi-squared tests compared proportions of patients reporting problems with QOL "domains" between the groups at baseline and 12 months. McNemar's tests compared changes in proportions of patients reporting problems with QOL "domains" within groups from baseline to 12 months. Results: A total of 604 patients had an initial survey. At baseline, patients who were managed conservatively reported more problems with mobility, self-care, and ability to perform usual activities. However, pain/discomfort and anxiety/depression were no higher in the conservative population. CKM patients reported no significant decline in mobility, self-care, ability to perform their usual activities, pain/discomfort, or anxiety/depression after 12 months or in QOL scores after 18 months compared with the other groups. Conclusions: QOL scores or symptom burdens did not change significantly in patients receiving CKM compared with dialysis, suggesting that appropriately supported CKM can maintain patients' QOL.

Optimising mothers' health behaviour after hypertensive disorders of pregnancy: a qualitative study of a postnatal intervention.

BACKGROUND: Hypertensive disorders of pregnancy have longer-term implications, increasing women's lifetime cardiovascular disease risk. The Blood Pressure Postpartum study is a multi-centre randomised three-arm trial of interventions, ranging in intensity and including education and lifestyle coaching, to support women to maintain or adopt healthy eating and physical activity during the first postpartum year. This qualitative sub-study nested within the main trial aimed to investigate whether and how women adopted healthy behaviours after a pregnancy complicated by a hypertensive disorder. METHODS: Semi-structured telephone interviews were recorded, transcribed and analysed thematically, following Braun and Clarke principles. They explored behaviour change among new mothers following their hypertensive pregnancy, and the intervention's effect on their capacity and motivation to pursue healthy lifestyles. RESULTS: Thirty-four women from all three trial arms participated at 10-12 months postpartum. The three main themes were 1) Awareness of cardiovascular risk: some did not acknowledge the health risks, whereas others embraced this information. 2) Sources of motivation: while the majority were motivated to make a concerted effort to adapt their health behaviour, motivation often centred on their baby and family rather than their own needs. 3) Sustaining behaviour change with a new baby: women in the more intensive intervention arm demonstrated increased recognition of the importance of reducing cardiovascular health risks, with greater motivation and guidance to change their health behaviour. There was minimal evidence of crossover amongst groups, with women largely accepting their randomised level of intervention and not seeking additional help when randomised to minimal intervention. CONCLUSIONS: Among women participating in an early post-hypertensive disorders of pregnancy randomised controlled trial aimed at improving their cardiovascular disease risk profile, the majority recognised the future health risks and appeared motivated to improve their lifestyle, particularly women in the highest-intensity intervention group. This highlights the importance of structured support to assist women embrace healthy lifestyles especially during the challenges of new parenthood. TRIAL REGISTRATION: The Blood Pressure Postpartum study was prospectively registered as a clinical trial with the Australian New Zealand Clinical Trials Registry (anzctr.org.au) on 13 December 2018 (registration number: ACTRN12618002004246).

The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice.

All units managing hypertensive pregnant women should maintain and review uniform departmental management protocols and conduct regular audits of maternal & fetal outcomes. The cause(s) of pre-eclampsia and the optimal clinical management of the hypertensive disorders of pregnancy remain uncertain; therefore, we recommend that every hypertensive pregnant woman be offered an opportunity to participate in research, clinical trials and follow-up studies.

Growth from birth to 6 months of infants with and without intrauterine preeclampsia exposure.

Intrauterine preeclampsia exposure affects the lifelong cardiometabolic health of the child. Our study aimed to compare the growth (from birth to 6 months) of infants exposed to either a normotensive pregnancy or preeclampsia and explore the influence of being born small for gestational age (SGA). Participants were children of women participating in the Post-partum, Physiology, Psychology and Paediatric follow-up cohort study. Birth and 6-month weight and length z-scores were calculated for term and preterm (<37 weeks) babies, and change in weight z-score, rapid weight gain (≥0.67 increase in weight z-score) and conditional weight gain z-score were calculated. Compared with normotensive exposed infants (n = 298), preeclampsia exposed infants (n = 84) were more likely to be born SGA (7% versus 23%; P < 0.001), but weight gain from birth to 6 months, by any measure, did not differ between groups. Infants born SGA, irrespective of pregnancy exposure, were more likely to have rapid weight gain and had greater increases in weight z-score compared with those not born SGA. Preeclampsia exposed infants born SGA may benefit from interventions designed to prevent future cardiometabolic disease.

A Novel Clinical Tool for the Management of Taste Changes in Patients With Chronic Kidney Disease: The Chronic Kidney Disease Taste Plate.

Taste alteration is a common, but poorly understood, symptom in end-stage kidney disease. The pathophysiology of taste alteration is complex; to date, management has been largely empirical. As our understanding of pathophysiology grows so does the evidence base for its management. This article introduces a clinical tool-the CKD Taste Plate-to assist clinicians in directing management to the underlying pathophysiology of taste alterations in chronic kidney disease.