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1.
Baseline characteristics of participants in the NAVKIDS2 trial: a patient navigator program in children with chronic kidney disease.
Guha, C, Khalid, R, van Zwieten, A, Francis, A, Hawley, CM, Jauré, A, Teixeira-Pinto, A, Mallard, AR, Bernier-Jean, A, Johnson, DW, et al
Pediatric nephrology (Berlin, Germany). 2023;(5):1577-1590
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Abstract
BACKGROUND Children with chronic kidney disease (CKD) require multidisciplinary care to meet their complex healthcare needs. Patient navigators are trained non-medical personnel who assist patients and caregivers to overcome barriers to accessing health services through care coordination. This trial aims to determine the effectiveness of a patient navigator program in children with CKD. METHODS The NAVKIDS2 trial is a multi-center, waitlisted, randomized controlled trial of patient navigators in children with CKD conducted at five sites across Australia. Children (0-16 years) with CKD from low socioeconomic status rural or remote areas were randomized to an intervention group or a waitlisted control group (to receive intervention after 6 months). The study primary and secondary endpoints include the self-rated health (SRH) (primary), and utility-based quality of life, progression of kidney dysfunction of the child, SRH, and satisfaction with healthcare of the caregiver at 6 months post-randomization. RESULTS The trial completed recruitment in October 2021 with expected completion of follow-up by October 2022. There were 162 patients enrolled with 80 and 82 patients randomized to the immediate intervention and waitlisted groups, respectively. Fifty-eight (36%) participants were from regional/remote areas, with a median (IQR) age of 9.5 (5.0, 13.0) years, 46% were of European Australian ethnicity, and 65% were male. A total of 109 children (67%) had CKD stages 1-5, 42 (26%) were transplant recipients, and 11 (7%) were receiving dialysis. CONCLUSION The NAVKIDS2 trial is designed to evaluate the effectiveness of patient navigation in children with CKD from families experiencing socioeconomic disadvantage. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Prothrombotic states in portal vein thrombosis and Budd-Chiari syndrome in India: A systematic review and meta-analysis.
Giri, S, Angadi, S, Varghese, J, Sundaram, S, Bhrugumalla, S
Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology. 2023;(5):629-641
Abstract
BACKGROUND Both Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT) have been linked to various prothrombotic (PT) conditions. The PT profile in Asians is different from the west and there are no nationwide epidemiological surveys from India. Hence, the present meta-analysis was aimed at analyzing the prevalence of acquired and hereditary thrombophilia among Indian patients with non-cirrhotic PVT and BCS. METHODS A comprehensive literature search of Embase, Medline and Scopus was conducted from January 2000 to February 2022 for studies evaluating the prevalence of various PT conditions in Indian patients with PVT and BCS. Pooled prevalence rates across studies were expressed with summative statistics. RESULTS Thirty-five studies with 1005 PVT patients and 1391 BCS patients were included in the meta-analysis. At least one PT condition was seen in 46.2% (28.7-63.7) of the PVT patients and 44.9% (37.3-60.7) of the BCS patients. Multiple PT conditions were seen in 13.0% (4.2-21.8) of the PVT patients and 7.9% (3.5-12.4) of the BCS patients. Among PVT patients, hyperhomocysteinemia was the commonest prothrombotic condition (21.6%) followed by protein C (PC) deficiency (10.7%), Janus kinase 2 (JAK-2) mutation (8.5%) and antiphospholipid antibodies (APLA) (7.5%). Among patients with BCS, PC deficiency was the commonest prothrombotic condition (10.6%) followed by methylenetetrahydrofolate reductase (MTHFR) mutation (9.8%), APLA (9.7%) and JAK-2 mutation (9.1%). CONCLUSION The PT profile in Indian patients with abdominal vein thrombosis is different from that of the western data with a lower prevalence of PT conditions in patients with BCS.
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Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial.
Collins, MG, Fahim, MA, Pascoe, EM, Hawley, CM, Johnson, DW, Varghese, J, Hickey, LE, Clayton, PA, Dansie, KB, McConnochie, RC, et al
Lancet (London, England). 2023;(10396):105-117
Abstract
BACKGROUND Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. METHODS BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). FINDINGS Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48). INTERPRETATION Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. FUNDING Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.
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Growth of late preterm infants fed nutrient-enriched formula to 120 days corrected age-A randomized controlled trial.
Best, KP, Yelland, LN, Collins, CT, McPhee, AJ, Rogers, GB, Choo, J, Gibson, RA, Murguia-Peniche, T, Varghese, J, Cooper, TR, et al
Frontiers in pediatrics. 2023;:1146089
Abstract
OBJECTIVES We aimed to compare the effects of nutrient-enriched formula with standard term formula on rate of body weight gain of late preterm infants appropriately grown for gestational age. STUDY DESIGN A multi-center, randomized, controlled trial. Late preterm infants (34-37 weeks' gestation), with weight appropriate for gestational age (AGA), were randomized to nutrient enriched formula (NEF) with increased calories (22 kcal/30 ml) from protein, added bovine milk fat globule membrane, vitamin D and butyrate or standard term formula 20 kcal/30 ml (STF). Breastfed term infants were enrolled as an observational reference group (BFR). Primary outcome was rate of body weight gain from enrollment to 120 days corrected age (d/CA). Planned sample size was 100 infants per group. Secondary outcomes included body composition, weight, head circumference and length gain, and medically confirmed adverse events to 365 d/CA. RESULTS The trial was terminated early due to recruitment challenges and sample size was substantially reduced. 40 infants were randomized to NEF (n = 22) and STF (n = 18). 39 infants were enrolled in the BFR group. At 120 d/CA there was no evidence of a difference in weight gain between randomized groups (mean difference 1.77 g/day, 95% CI, -1.63 to 5.18, P = 0.31). Secondary outcomes showed a significant reduction in risk of infectious illness in the NEF group at 120 d/CA [relative risk 0.37 (95% CI, 0.16-0.85), P = 0.02]. CONCLUSION We saw no difference in rate of body weight gain between AGA late preterm infants fed NEF compared to STF. Results should be interpreted with caution due to small sample size. CLINICAL TRIAL REGISTRATION The Australia New Zealand Clinical Trials Registry (ACTRN 12618000092291). "mailto:maria.makrides@sahmri.com" maria.makrides@sahmri.com.
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NAVKIDS2 trial: a multi-centre, waitlisted randomised controlled trial of a patient navigator intervention in children with chronic kidney disease - statistical analysis plan and update to the protocol.
van Zwieten, A, Ryan, EG, Caldwell, P, Howard, K, Tong, A, Craig, JC, Alexander, SI, Howell, M, Teixeira-Pinto, A, Hawley, CM, et al
Trials. 2022;(1):824
Abstract
BACKGROUND This update summarises key changes made to the protocol since the publication of the original protocol for the NAVKIDS2 trial of patient navigators for children with chronic kidney disease (CKD) experiencing social disadvantage and provides the statistical analysis plan (SAP) which has not previously been published. METHODS/DESIGN The original protocol was published in BMC Nephrology ( https://doi.org/10.1186/s12882-019-1325-y ) prior to the commencement of trial recruitment. During the course of the trial, some key methodological changes needed to be made including changes to eligibility criteria (addition of patients with CKD stages 1-2, broadening of financial status eligibility criterion, addition of patients living in rural/remote areas, modification of age eligibility to 0-16 years, addition of limits related to the language spoken by family, guidance regarding families with multiple eligible children), changes to sites, reduction of sample size, addition of virtual options for consent and study procedures in response to the COVID-19 pandemic, removal of staggered recruitment across sites, addition of outcomes, and changes to the timing and number of assessments. This update summarises the changes made and their rationale and provides the detailed plan for statistical analysis of the trial. These changes have been finalised prior to the completion of study follow-up and the commencement of data analysis. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618001152213 . Prospectively registered on 12 July 2018.
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Baseline Characteristics and Representativeness of Participants in the BEST-Fluids Trial: A Randomized Trial of Balanced Crystalloid Solution Versus Saline in Deceased Donor Kidney Transplantation.
Collins, MG, Fahim, MA, Pascoe, EM, Hawley, CM, Johnson, DW, Varghese, J, Hickey, LE, Clayton, PA, Gill, JS, Dansie, KB, et al
Transplantation direct. 2022;(12):e1399
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Abstract
UNLABELLED Delayed graft function (DGF) is a major complication of deceased donor kidney transplantation. Saline (0.9% sodium chloride) is a commonly used intravenous fluid in transplantation but may increase the risk of DGF because of its high chloride content. Better Evidence for Selecting Transplant Fluids (BEST-Fluids), a pragmatic, registry-based, double-blind, randomized trial, sought to determine whether using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce DGF. We sought to evaluate the generalizability of the trial cohort by reporting the baseline characteristics and representativeness of the trial participants in detail. METHODS We compared the characteristics of BEST-Fluids participants with those of a contemporary cohort of deceased donor kidney transplant recipients in Australia and New Zealand using data from the Australia and New Zealand Dialysis and Transplant Registry. To explore potential international differences, we compared trial participants with a cohort of transplant recipients in the United States using data from the Scientific Registry of Transplant Recipients. RESULTS During the trial recruitment period, 2373 deceased donor kidney transplants were performed in Australia and New Zealand; 2178 were eligible' and 808 were enrolled in BEST-Fluids. Overall, trial participants and nonparticipants were similar at baseline. Trial participants had more coronary artery disease (standardized difference [d] = 0.09; P = 0.03), longer dialysis duration (d = 0.18, P < 0.001), and fewer hypertensive (d = -0.11, P = 0.03) and circulatory death (d = -0.14, P < 0.01) donors than nonparticipants. Most key characteristics were similar between trial participants and US recipients, with moderate differences (|d| ≥ 0.2; all P < 0.001) in kidney failure cause, diabetes, dialysis duration, ischemic time, and several donor risk predictors, likely reflecting underlying population differences. CONCLUSIONS BEST-Fluids participants had more comorbidities and received slightly fewer high-risk deceased donor kidneys but were otherwise representative of Australian and New Zealand transplant recipients and were generally similar to US recipients. The trial results should be broadly applicable to deceased donor kidney transplantation practice worldwide.
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T2 mapping in myocardial disease: a comprehensive review.
O'Brien, AT, Gil, KE, Varghese, J, Simonetti, OP, Zareba, KM
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance. 2022;(1):33
Abstract
Cardiovascular magnetic resonance (CMR) is considered the gold standard imaging modality for myocardial tissue characterization. Elevated transverse relaxation time (T2) is specific for increased myocardial water content, increased free water, and is used as an index of myocardial edema. The strengths of quantitative T2 mapping lie in the accurate characterization of myocardial edema, and the early detection of reversible myocardial disease without the use of contrast agents or ionizing radiation. Quantitative T2 mapping overcomes the limitations of T2-weighted imaging for reliable assessment of diffuse myocardial edema and can be used to diagnose, stage, and monitor myocardial injury. Strong evidence supports the clinical use of T2 mapping in acute myocardial infarction, myocarditis, heart transplant rejection, and dilated cardiomyopathy. Accumulating data support the utility of T2 mapping for the assessment of other cardiomyopathies, rheumatologic conditions with cardiac involvement, and monitoring for cancer therapy-related cardiac injury. Importantly, elevated T2 relaxation time may be the first sign of myocardial injury in many diseases and oftentimes precedes symptoms, changes in ejection fraction, and irreversible myocardial remodeling. This comprehensive review discusses the technical considerations and clinical roles of myocardial T2 mapping with an emphasis on expanding the impact of this unique, noninvasive tissue parameter.
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New Directions in Treatment of Metastatic or Advanced Pheochromocytomas and Sympathetic Paragangliomas: an American, Contemporary, Pragmatic Approach.
Jimenez, C, Xu, G, Varghese, J, Graham, PH, Campbell, MT, Lu, Y
Current oncology reports. 2022;(1):89-98
Abstract
PURPOSE OF REVIEW Multiple therapies with novel mechanisms have been explored in clinical trials for the treatment of metastatic pheochromocytomas and paragangliomas. We review current and future therapies for this disease and provide guidance on how and when to prescribe them based on tumor progression, clinical manifestations, molecular features, and social factors. RECENT FINDINGS Approximately 60-70% of metastatic pheochromocytomas and paragangliomas express the noradrenaline transporter in their cell membranes. High specific activity iodine-131 metaiodobenzylguanidine has been recently approved by the US Food and Drug Administration for the treatment of metastatic pheochromocytomas and paragangliomas that express the noradrenaline transporter, in patients aged ≥ 12 years. More than 90% of patients treated with this medication exhibit clinical benefits. However, other therapies with novel mechanisms of action are needed to help all patients with this disease. Treatment of metastatic pheochromocytomas and paragangliomas is recommended based on the severity of symptoms, the progression of the disease, and the patient's performance status. Currently available therapies include surgery; systemic chemotherapy with cyclophosphamide, vincristine, and dacarbazine, or with temozolomide; high specific activity iodine-131 metaiodobenzylguanidine; peptide receptor radionuclide therapy; immunotherapy; tyrosine kinase inhibitors; and hypoxia-inducible factor 2 alpha inhibitors. Financial and social factors such as health insurance coverage and disparities also impact current clinical practice in the USA.
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Role of Biomaterials Used for Periodontal Tissue Regeneration-A Concise Evidence-Based Review.
Varghese, J, Rajagopal, A, Shanmugasundaram, S
Polymers. 2022;(15)
Abstract
Periodontal infections are noncommunicable chronic inflammatory diseases of multifactorial origin that can induce destruction of both soft and hard tissues of the periodontium. The standard remedial modalities for periodontal regeneration include nonsurgical followed by surgical therapy with the adjunctive use of various biomaterials to achieve restoration of the lost tissues. Lately, there has been substantial development in the field of biomaterial, which includes the sole or combined use of osseous grafts, barrier membranes, growth factors and autogenic substitutes to achieve tissue and bone regeneration. Of these, bone replacement grafts have been widely explored for their osteogenic potential with varied outcomes. Osseous grafts are derived from either human, bovine or synthetic sources. Though the biologic response from autogenic biomaterials may be better, the use of bone replacement synthetic substitutes could be practical for clinical practice. This comprehensive review focuses initially on bone graft replacement substitutes, namely ceramic-based (calcium phosphate derivatives, bioactive glass) and autologous platelet concentrates, which assist in alveolar bone regeneration. Further literature compilations emphasize the innovations of biomaterials used as bone substitutes, barrier membranes and complex scaffold fabrication techniques that can mimic the histologically vital tissues required for the regeneration of periodontal apparatus.
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Adverse events associated with bone-directed therapies in patients with cancer.
Jara, MA, Varghese, J, Hu, MI
Bone. 2022;:115901
Abstract
Bone metastatic disease may lead to serious adverse events in patients with cancer. Bone-directed therapies, including bisphosphonates such as pamidronate and zoledronic acid and the human monoclonal antibody denosumab, are currently approved for the prevention of bone-related adverse events. However, despite the benefits of these drugs, they may cause side effects that are mostly associated with dosages and treatment durations. These side effects range from more frequent, mostly mild, and generally self-limited side effects-such as fever, myalgias, arthralgias, and electrolyte imbalances-to less frequent and more severe side effects such as medication-related osteonecrosis of the jaw and atypical femoral fractures. The purpose of this review is to familiarize clinicians with the literature regarding adverse events associated with bone-directed therapies in patients with cancer. It is important to be aware of these possible adverse events and to educate patients about the predisposing factors associated with side effects from bone-directed therapies and the preventive measures necessary to decrease the risk of occurrence.