In men with obesity and IGT, serum testosterone (T) is inversely associated with incident T2D. Hypothesizing that T treatment prevents or reverses T2D beyond the effects of a lifestyle program alone, ...we conducted a multi-center, double-blinded placebo-controlled trial. Men (N=1007), aged 50-74 yrs., waist circumference (WC)>95cm, serum T≤14nmol/L (chemiluminescent assay), and IGT or newly diagnosed T2D, established by an OGTT, were randomized to receive, on a 1:1 basis, either IM T undecanoate (Reandron, Bayer) (1000mg/4ml) or vehicle (V) at baseline, 6 weeks and then 3-monthly for 2 yrs. All participants were enrolled in a lifestyle program (Weight Watchers® (WW)). Co-primary 2-yr outcomes: (1) OGTT 2-hr glucose ≥11 mmol/L: 55/443 (12.4%) in the T and 87/413 (21.1%) in V groups; RR (95% CI) 0.59 (0.43-0.80), P<0.001; and (2) mean change from baseline in 2-hr glucose: -1.70 mmol/L and -0.95 mmol/L in the T and V groups, respectively (mean difference -0.75 (95% CI -1.10 to -0.40) P<0.001). The treatment effect was independent of baseline serum T. Secondary 2-year outcomes: Greater decreases from baseline in fasting glucose by 0.17 mmol/L, WC by 2.1 cm, total fat mass by 2.7kg, and abdominal fat mass by 2.3%, and greater increases in total muscle mass by 1.7kg, arm muscle mass by 0.36kg and hand grip strength by 2.2kg, occurred in the T vs. V group (all P<0.004). Compliance with the WW program was similar in the T (30%) vs. V (28%) groups (P=0.89). Safety: Hematocrit ≥ 0.54: 106/491 (21.6%) vs. 6/484 (1.2%) in the T vs. V groups (P<0.001). SAEs in T vs. V groups (total events 55 vs. 42): Arrythmias (8 vs. 3), IHD (7 vs. 13), cerebrovascular disease (4 vs. 3), BPH (8 vs. 3), prostate cancer (4 vs. 5), other cancers (10 vs. 4), depression (1 vs. 3). There were 2 deaths in each group. Beyond a lifestyle program, T treatment reduced the RR of T2D by ∼40% at least partially mediated by favorable changes in body composition. Clinical Trial Registration: ACTRN12612000287831.
Disclosure
G.A. Wittert: Research Support; Self; Bayer Inc., Lawley Pharmaceuticals, Lilly, Weight Watchers International, Inc. Speaker’s Bureau; Self; Besins. K.P. Robledo: None. M. Grossmann: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Novartis Pharmaceuticals Canada Inc., Otsuka Pharmaceutical Co., Ltd., Weight Watchers International, Inc. Speaker’s Bureau; Self; Besins Healthcare, Otsuka Pharmaceutical Co., Ltd. K. Bracken: None. B.B. Yeap: Advisory Panel; Self; Sanofi. Research Support; Self; Bayer AG, Lawley Pharmaceuticals. Speaker’s Bureau; Self; Besins, Sanofi. B.G.A. Stuckey: None. R.I. McLachlan: None. D.J. Handelsman: None. C. Allan: Advisory Panel; Self; Ferring Pharmaceuticals. Speaker’s Bureau; Self; Besins. W. Inder: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc. Speaker’s Bureau; Self; Amgen, Novo Nordisk Inc., Pfizer Inc. D. Jesudason: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. A.C. Keech: Advisory Panel; Self; Amgen, Kowa Research Institute, Inc. Consultant; Self; Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Amgen. A. Jenkins: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Sanofi-Aventis. M. Ng Tang Fui: None. M. Daniel: None.
Funding
National Health and Medical Council of Australia (1030123); Eli Lilly and Company; Bayer AG; Weight Watchers; University of Adelaide
Background/Objectives
Organ transplant recipients (OTR) have an increased risk of skin cancers compared with the general population.
Methods
A prospective study of renal (RTR) and liver transplant ...recipients (LTR) was conducted in a single New South Wales tertiary referral centre over 60 months. Initial and subsequent visit data were recorded in our transplant database. Only patients with a minimum of 11 months follow up were included.
Results
Altogether 142 RTR and 88 LTR were included in the analysis. Compared with RTR, the median age of liver transplant recipients was higher (64 vs 57 years), more men were patients (73 vs 60%) and there were higher rates of high‐risk skin types (54 vs 33%) and heavy sun exposure (43 vs 30%). RTR developed 304 non‐melanoma skin cancers (NMSC) with a squamous cell carcinoma:basal cell carcinoma ratio of 1.7:1. LTR developed 205 NMSC with a squamous cell carcinoma:basal cell carcinoma ratio of 1.6:1. The odds ratio of developing NMSC in LTR:RTR was 1.8:1 (95% CI: 1.02–3.11, P = 0.044) on univariate analysis but there was no difference on multivariate analysis. A previous history of NMSC, age, time from transplant from first visit, skin phenotype and previous sun exposure were significant risk factors for developing NMSC.
Conclusions
Liver transplant recipients are not at a lower risk of NMSC than RTR. Our study supports routine and regular post‐transplant skin surveillance of all LTR, like other OTR.
Incomplete revascularisation is common and prognostically important. The degree to which incomplete revascularisation (IR) is associated with adverse cardiac outcomes in patients with diabetes and ...ST-elevation myocardial infarction (STEMI) is unknown.
Late outcomes (3.6 years) were evaluated in 589 consecutive STEMI patients treated with percutaneous coronary intervention in this observational study. Associations between incomplete revascularisation, and diabetes were assessed. A residual SYNergy Between Percutaneous Coronary Intervention With TAXus and Cardiac Surgery (SYNTAX) Score (rSS) >8 defined IR. The primary endpoint studied was cardiac death, myocardial infarction or cerebrovascular accident.
Incomplete revascularisation occurred in 36% of patients with diabetes (46/127) and 32% of patients without diabetes (147/462); p=0.329. The primary endpoint occurred in 27% of patients with diabetes compared to 18% of patients without diabetes (p=0.042); and in 28% with a rSS>8 compared to 16% of patients with a rSS≤8 (p<0.001). The primary endpoint occurred in 35% of patients with both diabetes and a rSS>8, 27% without diabetes with a rSS>8, 22% with diabetes and a rSS≤8, and 14% of with patients neither factor (p<0.001), with cardiac death rates respectively of 22%, 9%, 6%, 2% (p<0.001). Patients with both IR and diabetes accounted for only 8% of STEMI patients but 30% of all cardiac deaths. On multivariable analyses diabetes and IR were independently associated with cardiac death, myocardial infarction and cerebrovascular accident; both p<0.05.
Diabetes and IR contribute independently to late outcomes in STEMI patients. The prognostic impact of diabetes was not due to IR alone. Diabetes acts synergistically with incomplete revascularisation to worsen prognosis.
Introduction
People with a family history of chronic lymphocytic leukemia (F-CLL) have an increased risk of monoclonal B lymphocytosis (F-MBL), which is found in up to 18% of first-degree relatives ...of patients compared to 5% of the total population. This may indicate that the presence of an F-MBL in the relative of a F-CLL patient is due to genetic susceptibility. In this study, we hypothesized that progressive changes in gene expression result in malignant transformation of B lymphocytes to F-MBL, and subsequent alterations in gene expression occur before overt F-CLL develops. The aim of this study of affected and unaffected individuals from a family with multiple CLL cases was to compare mRNA expression levels in control B-lymphocytes, pre-malignant F-MBL and malignant F-CLL cells.
Methods
To identify inherited changes in gene expression, a high-resolution DNA microarray was used to identify differentially abundant mRNAs in age-matched cases of F-MBL (
n
= 4), F-CLL (
n
= 2) and unaffected family relatives (F-Controls,
n
= 3) within one family. These were then compared to non-kindred controls (NK-Controls,
n
= 3) and sporadic CLL (S-CLL) cases (
n
= 6).
Results
Seven differentially abundant mRNAs were identified against similar genetic backgrounds of the family:
GRASP
and
AC016745.3
were decreased in F-MBL and further decreased in F-CLL compared to F-Controls, whereas
C11orf80
and
METTL8
were progressively increased.
PARP3
was increased in F-MBL compared to F-Controls but was decreased in F-CLL compared to F-MBL. Compared to F-Controls, levels of
ROR1
and
LEF1
were similarly increased in F-MBL and F-CLL. For six of the genes, there were no differences in mRNA levels between S-CLL and F-CLL; however
PARP3
was higher in S-CLL.
Conclusion
These results are consistent with the hypothesis that changes in expression of specific genes contribute to transformation from normal lymphocytes to MBL and CLL.
Background/aims:
Participant recruitment to diabetes prevention randomised controlled trials is challenging and expensive. The T4DM study, a multicentre, Australia-based, Phase IIIb randomised ...controlled trial of testosterone to prevent Type 2 diabetes in men aged 50–74 years, faced the challenge of screening a large number of prospective participants at a small number of sites, with few staff, and a limited budget for screening activities. This article evaluates a high-volume, low-cost, semi-automated approach to screen and enrol T4DM study participants.
Methods:
We developed a sequential multi-step screening process: (1) web-based pre-screening, (2) laboratory screening through a network of third-party pathology centres, and (3) final on-site screening, using online data collection, computer-driven eligibility checking, and automated, email-based communication with prospective participants. Phone- and mail-based data collection and communication options were available to participants at their request. The screening process was administered by the central coordinating centre through a central data management system.
Results:
Screening activities required staffing of approximately 1.6 full-time equivalents over 4 years. Of 19,022 participants pre-screened, 13,108 attended a third-party pathology collection centre for laboratory screening, 1217 received final, on-site screening, and 1007 were randomised. In total, 95% of the participants opted for online pre-screening over phone-based pre-screening. Screening costs, including both direct and staffing costs, totalled AUD1,420,909 (AUD75 per subject screened and AUD1411 per randomised participant).
Conclusion:
A multi-step, semi-automated screening process with web-based pre-screening facilitated low-cost, high-volume participant enrolment to this large, multicentre randomised controlled trial. Centralisation and automation of screening activities resulted in substantial savings compared to previous, similar studies. Our screening approach could be adapted to other randomised controlled trial settings to minimise the cost of screening large numbers of participants.
BackgroundNeonates, particularly if born preterm or with congenital anomalies, are among the pediatric patients most likely to need blood transfusion. However, they are also particularly vulnerable ...to adverse consequences of blood transfusion. Aiming to clamp the umbilical cord for at least a minute after birth is a simple safe procedure that is being increasingly adopted worldwide, although may be associated with increased rates of polycythemia and jaundice. It may also reduce the proportion of preterm babies who need a blood transfusion. The mechanisms for this are not fully understood. Potential mechanisms could include an increased volume of blood transfusion from the placenta to the baby after birth, and an overall reduction in the severity of illness in the first weeks after birth, which could lead to fewer blood tests and greater tolerance of anemia, or enhanced erythropoiesis.ObjectivesTo investigate the mechanism behind the reduced need for blood transfusions after deferral of cord clamping.MethodologyThis protocol outlines the methods and data analysis plan for a study using nested retrospective data from a large randomized trial combined with additional data collected from patient medical and pathology records. The additional data items to be collected all relate to the receipt of transfusion and the factors that affect the risk for transfusion in preterm babies. The analysis will include all randomized babies from Australia and New Zealand for whom data are available. Causal mediation analysis is planned to estimate the effects of mediators on the relationship between the timing of cord clamping and the need for blood transfusion. The analysis is designed to discern whether initial severity of illness or the magnitude of placental transfusion mediates red blood cell transfusion dependence.Anticipated outcomes and disseminationWe expect the study will identify potential strategies for reducing blood transfusions and associated negative outcomes in preterm infants. This will be relevant to researchers, clinicians, and parents. The results will be disseminated through publications, presentations, and inclusion in evidence-based guidelines.
Most unresectable metastatic colon cancer remains incurable, with a median survival of less than 3 years. Molecularly targeted therapies have recently been developed; in particular, monoclonal ...antibodies against the epidermal growth factor receptor, which are efficacious in 40% to 60% of chemotherapy-resistant patients with wild-type KRAS. This study shows that cetuximab plus irinotecan, compared with cetuximab alone, increases the response rate and delays progression in irinotecan-resistant RAS wild-type colorectal cancer.
The Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation (ICECREAM) study assessed the efficacy of cetuximab monotherapy compared with cetuximab combined with chemotherapy for quadruple wild-type (KRAS, NRAS, BRAF, or P13KCA exon 20) metastatic colorectal cancer.
Patients were enrolled in an open-label, multicenter, phase II trial and randomly assigned to cetuximab 400 mg/m2, then 250 mg/m2 cetuximab weekly, with or without irinotecan 180 mg/m2 every 2 weeks. The primary endpoint was 6-month progression-free survival; secondary endpoints were response rate, overall survival, toxicity, and quality of life.
From 2012 to 2016, 48 patients were recruited. Two were ineligible, and 2 were not evaluable for response. Characteristics were balanced, except gender (male, 62% vs. 72%) and primary sidedness (left, 95% vs. 68%). For cetuximab compared with cetuximab-irinotecan, progression-free survival was 14% versus 41% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P = .008); response rate was 10% (2 partial responses) versus 38% (1 complete, 8 partial); P = .04. Grade 3 to 4 toxicities were less with cetuximab monotherapy (23% vs. 50%); global and specific quality of life scores did not differ.
In comparison with cetuximab alone, cetuximab plus irinotecan increases the response rate and delays progression in irinotecan-resistant RAS wild-type colorectal cancer. This echoes data from molecularly unselected patients.
Deferred (also known as delayed) cord clamping can improve survival of infants born preterm (before 37 weeks of gestation), but the optimal duration of deferral remains unclear. We conducted a ...systematic review and individual participant data network meta-analysis with the aim of comparing the effectiveness of umbilical cord clamping strategies with different timings of clamping or with cord milking for preterm infants.
We searched medical databases and trial registries from inception until Feb 24, 2022 (updated June 6, 2023) for randomised controlled trials comparing cord clamping strategies for preterm infants. Individual participant data were harmonised and assessed for risk of bias and quality. Interventions were grouped into immediate clamping, short deferral (≥15 s to <45 s), medium deferral (≥45 s to <120 s), long deferral (≥120 s), and intact cord milking. The primary outcome was death before hospital discharge. We calculated one-stage, intention-to-treat Bayesian random-effects individual participant data network meta-analysis. This study was registered with PROSPERO, CRD42019136640.
We included individual participant data from 47 trials with 6094 participants. Of all interventions, long deferral reduced death before discharge the most (compared with immediate clamping; odds ratio 0·31 95% credibility interval 0·11-0·80; moderate certainty). The risk of bias was low for 10 (33%) of 30 trials, 14 (47%) had some concerns, and 6 (20%) were rated as having a high risk of bias. Heterogeneity was low, with no indication of inconsistency.
This study found that long deferral of clamping leads to reduced odds of death before discharge in preterm infants. In infants assessed as requiring immediate resuscitation, this finding might only be generalisable if there are provisions for such care with the cord intact. These results are based on thoroughly cleaned and checked individual participant data and can inform future guidelines and practice.
Australian National Health and Medical Research Council.
Umbilical cord clamping strategies at preterm birth have the potential to affect important health outcomes. The aim of this study was to compare the effectiveness of deferred cord clamping, umbilical ...cord milking, and immediate cord clamping in reducing neonatal mortality and morbidity at preterm birth.
We conducted a systematic review and individual participant data meta-analysis. We searched medical databases and trial registries (from database inception until Feb 24, 2022; updated June 6, 2023) for randomised controlled trials comparing deferred (also known as delayed) cord clamping, cord milking, and immediate cord clamping for preterm births (<37 weeks' gestation). Quasi-randomised or cluster-randomised trials were excluded. Authors of eligible studies were invited to join the iCOMP collaboration and share individual participant data. All data were checked, harmonised, re-coded, and assessed for risk of bias following prespecified criteria. The primary outcome was death before hospital discharge. We performed intention-to-treat one-stage individual participant data meta-analyses accounting for heterogeneity to examine treatment effects overall and in prespecified subgroup analyses. Certainty of evidence was assessed with Grading of Recommendations Assessment, Development, and Evaluation. This study is registered with PROSPERO, CRD42019136640.
We identified 2369 records, of which 48 randomised trials provided individual participant data and were eligible for our primary analysis. We included individual participant data on 6367 infants (3303 55% male, 2667 45% female, two intersex, and 395 missing data). Deferred cord clamping, compared with immediate cord clamping, reduced death before discharge (odds ratio OR 0·68 95% CI 0·51-0·91, high-certainty evidence, 20 studies, n=3260, 232 deaths). For umbilical cord milking compared with immediate cord clamping, no clear evidence was found of a difference in death before discharge (OR 0·73 0·44-1·20, low certainty, 18 studies, n=1561, 74 deaths). Similarly, for umbilical cord milking compared with deferred cord clamping, no clear evidence was found of a difference in death before discharge (0·95 0·59-1·53, low certainty, 12 studies, n=1303, 93 deaths). We found no evidence of subgroup differences for the primary outcome, including by gestational age, type of delivery, multiple birth, study year, and perinatal mortality.
This study provides high-certainty evidence that deferred cord clamping, compared with immediate cord clamping, reduces death before discharge in preterm infants. This effect appears to be consistent across several participant-level and trial-level subgroups. These results will inform international treatment recommendations.
Australian National Health and Medical Research Council.
To investigate the extent to which multivessel disease, incomplete revascularisation and prescribing differences contribute to sex-based outcome disparities in patients with ST-elevation MI (STEMI) ...and establish whether differences in cardiac death and MI (CDMI) rates persist at long-term follow-up.
This observational study evaluates sex-based outcome differences (median follow-up 3.6 years; IQR 2.4-5.4) in a consecutive cohort of patients (n=2,083) presenting with STEMI undergoing percutaneous coronary intervention). Of the studied patients 20.3% (423/2,083) were women and 38.3% (810/2,083) had multivessel disease (MVD). Incomplete revascularisation was common. The median residual SYNTAX score (rSS) was 5.0 (IQR 0-9) in women and 5.0 (IQR 1-11) in men (p=0.369), and in patients with MVD it was 9 (IQR 6-17) in women and 10 (IQR 6-15) in men (p=0.838). The primary endpoint CDMI occurred in 20.3% of women (86/423) and in 13.2% of men (219/1,660) (p=0.028). Differences persisted following multivariable risk adjustment: female sex was independently associated with CDMI (aHR 1.33; IQR 1.02-1.74). Women with MVD had CDMI more often than all other groups (p<0.001 for all). Significant sex-based prescribing differences were evident: women were less likely to receive guideline-recommended potent P2Y12 inhibitors than men (31% versus 43%; p=0.012), and differences were particularly evident in patients with MVD (25% in women versus 45% in men, p=0.011).
: Sex-based differences in STEMI patient outcome persist at long-term follow-up. Poor outcomes were disproportionately found in women with MVD and those with rSS>8. Observed differences in P2Y
prescribing practices may contribute to poor outcomes for women with MVD and incomplete revascularisation.
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