Ferric carboxymaltose versus standard-of-care oral iron to treat second-trimester anaemia in Malawian pregnant women: a randomised controlled trial.

BACKGROUND: Anaemia affects 46% of pregnancies in Africa; oral iron is recommended by WHO but uptake and adherence are suboptimal. We tested a single dose of a modern intravenous iron formulation, ferric carboxymaltose, for anaemia treatment in Malawian pregnant women. METHODS: In this open-label, individually randomised controlled trial, we enrolled women with a singleton pregnancy of 13-26 weeks' gestation in primary care and outpatient settings across two regions in southern Malawi. Women were eligible if they had capillary haemoglobin of less than 10·0 g/dL and negative malaria rapid diagnostic test. Participants were randomised by sealed envelope 1:1. Assessors for efficacy outcomes (laboratory parameters and birthweight) were masked to intervention; participants and study nurses were not masked. Participants were given ferric carboxymaltose up to 1000 mg (given once at enrolment in an outpatient primary care setting), or standard of care (60 mg elemental iron twice daily for 90 days), along with intermittent preventive malaria treatment. The primary maternal outcome was anaemia at 36 weeks' gestation. The primary neonatal outcome was birthweight. Analyses were performed in the intention-to-treat population for mothers and liveborn neonates, according to their randomisation group. Safety outcomes included incidence of adverse events during infusion and all adverse events from randomisation to 4 weeks' post partum. The trial is registered with ANZCTR, ACTRN12618001268235. The trial has completed follow-up. FINDINGS: Between Nov 12, 2018, and March 2, 2021, 21 258 women were screened, and 862 randomly assigned to ferric carboxymaltose (n=430) or standard of care (n=432). Ferric carboxymaltose did not reduce anaemia prevalence at 36 weeks' gestation compared with standard of care (179 [52%] of 341 in the ferric carboxymaltose group vs 189 [57%] of 333 in the standard of care group; prevalence ratio [PR] 0·92, 95% CI 0·81 to 1·06; p=0·27). Anaemia prevalence was numerically lower in mothers randomly assigned to ferric carboxymaltose compared with standard of care at all timepoints, although significance was only observed at 4 weeks' post-treatment (PR 0·91 [0·85 to 0·97]). Birthweight did not differ between groups (mean difference -3·1 g [-75·0 to 68·9, p=0·93). There were no infusion-related serious adverse events or differences in adverse events by any organ class (including malaria; ≥1 adverse event: ferric carboxymaltose 183 [43%] of 430 vs standard of care 170 [39%] of 432; risk ratio 1·08 [0·92 to 1·27]; p=0·34). INTERPRETATION: In this malaria-endemic sub-Saharan African setting, treatment of anaemic pregnant women with ferric carboxymaltose was safe but did not reduce anaemia prevalence at 36 weeks' gestation or increase birthweight. FUNDING: Bill & Melinda Gates Foundation (INV-010612).

Benefits and Risks of Iron Interventions in Infants in Rural Bangladesh.

BACKGROUND: Universal provision of iron supplements (drops or syrup) or multiple micronutrient powders to young children in low-to-middle-income countries where anemia is prevalent is recommended by the World Health Organization and widely implemented. The functional benefits and safety of these interventions are unclear. METHODS: We conducted a three-group, double-blind, double-dummy, individually randomized, placebo-controlled trial to assess the immediate and medium-term benefits and risks of 3 months of daily supplementation with iron syrup or iron-containing multiple micronutrient powders, as compared with placebo, in 8-month-old children in rural Bangladesh. The primary outcome was cognitive development, as assessed by the cognitive composite score on the Bayley Scales of Infant and Toddler Development, third edition, immediately after completion of the assigned 3-month regimen; scores range from 55 to 145, with higher scores indicating better cognitive performance. Secondary outcomes included the cognitive composite score at 9 months after completion of the assigned regimen; behavioral, language, and motor development, as well as growth and hematologic markers, immediately after completion and at 9 months after completion; and safety. RESULTS: We randomly assigned 3300 infants to receive iron syrup (1101 infants), multiple micronutrient powders (1099), or placebo (1100) daily. After completion of the assigned 3-month regimen, no apparent effect on the cognitive composite score was observed with iron syrup as compared with placebo (mean between-group difference in change in score from baseline, -0.30 points; 95% confidence interval [CI], -1.08 to 0.48) or with multiple micronutrient powders as compared with placebo (mean between-group difference in change in score from baseline, 0.23 points; 95% CI, -0.55 to 1.00). No apparent effect on any other developmental or growth outcome was observed immediately after completion of the assigned regimen or at 9 months after completion. At 9 months after completion of the assigned regimen, the prevalences of anemia, iron deficiency, and iron deficiency anemia increased in all three trial groups but remained lower among the children who received iron syrup or multiple micronutrient powders than among those who received placebo. The risk of serious adverse events and incidence of symptoms of infection were similar in the three trial groups. CONCLUSIONS: In this trial involving infants in Bangladesh, 3 months of daily supplementation with iron syrup or multiple micronutrient powders did not appear to have an effect on child development or other functional outcomes as compared with placebo. (Funded by the National Health and Medical Research Council of Australia; BRISC Australian New Zealand Clinical Trials Registry number, ACTRN12617000660381.).

Eggsurance? A randomized controlled trial of a decision aid for elective egg freezing.

STUDY QUESTION: Does a purpose-designed Decision Aid for women considering elective egg freezing (EEF) impact decisional conflict and other decision-related outcomes? SUMMARY ANSWER: The Decision Aid reduces decisional conflict, prepares women for decision-making, and does not cause distress. WHAT IS ALREADY KNOWN: Elective egg-freezing decisions are complex, with 78% of women reporting high decisional conflict. Decision Aids are used to support complex health decisions. We developed an online Decision Aid for women considering EEF and demonstrated that it was acceptable and useful in Phase 1 testing. STUDY DESIGN, SIZE, DURATION: A single-blind, two-arm parallel group randomized controlled trial was carried out. Target sample size was 286 participants. Randomization was 1:1 to the control (existing website information) or intervention (Decision Aid plus existing website information) group and stratified by Australian state/territory and prior IVF specialist consultation. Participants were recruited between September 2020 and March 2021 with outcomes recorded over 12 months. Data were collected using online surveys and data collection was completed in March 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Females aged ≥18 years, living in Australia, considering EEF, proficient in English, and with internet access were recruited using multiple methods including social media posts, Google advertising, newsletter/noticeboard posts, and fertility clinic promotion. After completing the baseline survey, participants were emailed their allocated website link(s). Follow-up surveys were sent at 6 and 12 months. Primary outcome was decisional conflict (Decisional Conflict Scale). Other outcomes included distress (Depression Anxiety and Stress Scale), knowledge about egg freezing and female age-related infertility (study-specific measure), whether a decision was made, preparedness to decide about egg freezing (Preparation for Decision-Making Scale), informed choice (Multi-Dimensional Measure of Informed Choice), and decision regret (Decision Regret Scale). MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 306 participants (mean age 30 years; SD: 5.2) were randomized (intervention n = 150, control n = 156). Decisional Conflict Scale scores were significantly lower at 12 months (mean score difference: -6.99 [95% CI: -12.96, -1.02], P = 0.022) for the intervention versus control group after adjusting for baseline decisional conflict. At 6 months, the intervention group felt significantly more prepared to decide about EEF than the control (mean score difference: 9.22 [95% CI: 2.35, 16.08], P = 0.009). At 12 months, no group differences were observed in distress (mean score difference: 0.61 [95% CI: -3.72, 4.93], P = 0.783), knowledge (mean score difference: 0.23 [95% CI: -0.21, 0.66], P = 0.309), or whether a decision was made (relative risk: 1.21 [95% CI: 0.90, 1.64], P = 0.212). No group differences were found in informed choice (relative risk: 1.00 [95% CI: 0.81, 1.25], P = 0.983) or decision regret (median score difference: -5.00 [95% CI: -15.30, 5.30], P = 0.337) amongst participants who had decided about EEF by 12 months (intervention n = 48, control n = 45). LIMITATIONS, REASONS FOR CAUTION: Unknown participant uptake and potential sampling bias due to the recruitment methods used and restrictions caused by the coronavirus disease 2019 pandemic. Some outcomes had small sample sizes limiting the inferences made. The use of study-specific or adapted validated measures may impact the reliability of some results. WIDER IMPLICATIONS OF THE FINDINGS: This is the first randomized controlled trial to evaluate a Decision Aid for EEF. The Decision Aid reduced decisional conflict and improved women's preparation for decision making. The tool will be made publicly available and can be tailored for international use. STUDY FUNDING/COMPETING INTEREST(S): The Decision Aid was developed with funding from the Royal Women's Hospital Foundation and McBain Family Trust. The study was funded by a National Health and Medical Research Council (NHMRC) Project Grant APP1163202, awarded to M. Hickey, M. Peate, R.J. Norman, and R. Hart (2019-2021). S.S., M.P., D.K., and S.B. were supported by the NHMRC Project Grant APP1163202 to perform this work. R.H. is Medical Director of Fertility Specialists of Western Australia and National Medical Director of City Fertility. He has received grants from MSD, Merck-Serono, and Ferring Pharmaceuticals unrelated to this study and is a shareholder of CHA-SMG. R.L. is Director of Women's Health Melbourne (Medical Practice), ANZSREI Executive Secretary (Honorary), RANZCOG CREI Subspecialty Committee Member (Honorary), and a Fertility Specialist at Life Fertility Clinic Melbourne and Royal Women's Hospital Public Fertility Service. R.A.A. has received grants from Ferring Pharmaceuticals unrelated to this study. M.H., K.H., and R.J.N. have no conflicts to declare. TRIAL REGISTRATION NUMBER: ACTRN12620001032943. TRIAL REGISTRATION DATE: 11 August 2020. DATE OF FIRST PATIENT'S ENROLMENT: 29 September 2020.

Application of the Estimand Framework to Anesthesia Trials.

SUMMARY: Events occurring after randomization, such as use of rescue medication, treatment discontinuation, or death, are common in randomized trials. These events can change either the existence or interpretation of the outcome of interest. However, appropriate handling of these intercurrent events is often unclear. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9(R1) addendum introduced the estimand framework, which aligns trial objectives with the design, conduct, statistical analysis, and interpretation of results. This article describes how the estimand framework can be used in anesthesia trials to precisely define the treatment effect to be estimated, key attributes of an estimand, common intercurrent events in anesthesia trials with strategies for handling them, and use of the estimand framework in a hypothetical anesthesia trial on postoperative delirium. When planning anesthesia trials, clearly defining the estimand is vital to ensure that what is being estimated is clearly understood, is clinically relevant, and helps answer the clinical questions of interest.

Breathing control training for functional seizures: A multi-site, open-label pilot study.

There are no well-validated treatments for functional seizures. While specialist psychotherapy is usually recommended, the evidence for its benefit is qualified, and it can be difficult to obtain. Given the association between hyperventilation and functional seizures we explored an alternative modality, breathing control training, in a multi-site open label pilot trial. Participants with functional seizures over the age of 16 received an hour of breathing training from a respiratory physiotherapist, with a half-hour booster session a month later. Seizure frequency and Nijmegen scores (a measure of hyperventilation) were reported at baseline and follow-up, 3-4 months later. Eighteen subjects were recruited, and 10 completed follow-up. Seven of these 10 had improved seizure frequency, and 3 did not (Wilcoxon signed rank test, p = 0.09), with seizure frequency correlating with Nijmegen score (Spearman's rank correlation = 0.75, p = 0.034). The intervention was well tolerated, with no adverse events reported. These preliminary results support a potentially new approach to treating functional seizures that should prove cost-effective and acceptable, though require confirmation by a randomised controlled trial.

On the horns of a dilemma: choosing total intravenous anaesthesia or volatile anaesthesia for cancer surgery, an enduring controversy.

Two methods for administering general anaesthesia are widely used: propofol-based total intravenous anaesthesia (propofol-TIVA) and inhalation volatile agent-based anaesthesia. Both modalities, which have been standards of care for several decades, boast a robust safety profile. Nevertheless, the potential differential effects of these anaesthetic techniques on immediate, intermediate, and extended postoperative outcomes remain a subject of inquiry. We discuss a recently published longitudinal analysis stemming from a multicentre randomised controlled trial comparing sevoflurane-based inhalation anaesthesia with propofol-TIVA in older patients with cancer, which showed a reduced incidence of emergence and postoperative delirium, comparable postoperative complication rates within 30 days after surgery, and comparable long-term survival rates. We undertake an assessment of the trial's methodological strengths and limitations, contextualise its results within the broader scientific evidence, and explore avenues for resolving the extant controversies in anaesthetic choice for cancer surgery. We aim to pave the way for the incorporation of precision medicine paradigms into the evolving landscape of perioperative care for patients with cancer.

Supplementation With Iron Syrup or Iron-Containing Multiple Micronutrient Powders Alters Resting Brain Activity in Bangladeshi Children.

BACKGROUND: Anemia and iron deficiency have been associated with poor child cognitive development. A key rationale for the prevention of anemia using supplementation with iron has been the benefits to neurodevelopment. However, little causal evidence exists for these gains. OBJECTIVES: We aimed to examine effects of supplementation with iron or multiple micronutrient powders (MNPs) on brain activity measures using resting electroencephalography (EEG). METHODS: Children included in this neurocognitive substudy were randomly selected from the Benefits and Risks of Iron Supplementation in Children study, a double-blind, double-dummy, individually randomized, parallel-group trial in Bangladesh, in which children, starting at 8 mo of age, received 3 mo of daily iron syrup, MNPs, or placebo. Resting brain activity was recorded using EEG immediately after intervention (month 3) and after a further 9-month follow-up (month 12). We derived EEG band power measures for delta, theta, alpha, and beta frequency bands. Linear regression models were used to compare the effect of each intervention with that of placebo on the outcomes. RESULTS: Data from 412 children at month 3 and 374 at month 12 were analyzed. At baseline, 43.9% were anemic and 26.7% were iron deficient. Immediately after intervention, iron syrup, but not MNPs, increased the mu alpha-band power, a measure that is associated with maturity and the production of motor actions (iron vs. placebo: mean difference = 0.30; 95% CI: 0.11, 0.50 µV2; P = 0.003; false discovery rate adjusted P = 0.015). Despite effects on hemoglobin and iron status, effects were not observed on the posterior alpha, beta, delta, and theta bands, nor were effects sustained at the 9-month follow-up. CONCLUSIONS: The effect size for immediate effects on the mu alpha-band power is comparable in magnitude with psychosocial stimulation interventions and poverty reduction strategies. However, overall, we did not find evidence for long-lasting changes in resting EEG power spectra from iron interventions in young Bangladeshi children. This trial was registered at www.anzctr.org.au as ACTRN12617000660381.

A protocol for a prospective, multicentre observational study to determine if nonanaemic iron deficiency worsens postoperative outcome in patients undergoing elective surgery for resection of colorectal cancer: The NATO study.

BACKGROUND: Preoperative absolute and functional iron deficiency anaemia is associated with poor postoperative outcomes in patients undergoing surgery for colorectal cancer. It is biologically plausible that "early", or "nonanaemic" iron deficiency may also be associated with worse postoperative outcomes in similar cohorts, albeit at lesser severity than that seen for anaemia. The evidence supporting this assertion is of low quality. METHODS: We have designed a prospective, observational study to delineate associations between preoperative non-anaemic iron deficiency and postoperative outcomes after surgery for colorectal cancer. Patients without anaemia, undergoing elective surgery for colorectal cancer will be allocated to an iron replete or an iron deficient group based on preoperative transferrin saturation. The primary outcome is days alive and at home on postoperative day 90. Secondary outcomes include days alive and at home on postoperative day 30, length of hospital stay, readmission to acute care, postoperative complications, health-related quality of life scores, quality of postoperative recovery, and requirement for allogeneic blood transfusion. The planned sample size is 422 patients, which has 80% power to detect a two-day difference in the primary outcome. The study commenced in May 2019. CONCLUSION: The results of this study will provide patients and clinicians with high-quality evidence concerning associations between nonanaemic iron deficiency and patient-centred outcomes after surgery for colorectal cancer. The study will be conducted in multiple urban and rural centres across Australia and New Zealand. The results will be highly generalisable to contemporary surgical practice and should be rapidly translated.

Feasibility and acceptability of the use of flash glucose monitoring encountered by Indigenous Australians with type 2 diabetes mellitus: initial experiences from a pilot study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is highly prevalent within the Indigenous Australian community. Novel glucose monitoring technology offers an accurate approach to glycaemic management, providing real-time information on glucose levels and trends. The acceptability and feasibilility of this technology in Indigenous Australians with T2DM has not been investigated. OBJECTIVE: This feasibility phenomenological study aims to understand the experiences of Indigenous Australians with T2DM using flash glucose monitoring (FGM). METHODS: Indigenous Australians with T2DM receiving injectable therapy (n = 8) who used FGM (Abbott Freestyle Libre) for 6-months, as part of a clinical trial, participated in semi-structured interviews. Thematic analysis of the interviews was performed using NVivo12 Plus qualitative data analysis software (QSR International). RESULTS: Six major themes emerged: 1) FGM was highly acceptable to the individual; 2) FGM's convenience was its biggest benefit; 3) data from FGM was a tool to modify lifestyle choices; 4) FGM needed to be complemented with health professional support; 5) FGM can be a tool to engage communities in diabetes management; and 6) cost of the device is a barrier to future use. CONCLUSIONS: Indigenous Australians with T2DM had positive experiences with FGM. This study highlights future steps to ensure likelihood of FGM is acceptable and effective within the wider Indigenous Australian community.

The development and phase 1 evaluation of a Decision Aid for elective egg freezing.

BACKGROUND: Elective egg freezing decisions are complex. We developed a Decision Aid for elective egg freezing and conducted a phase 1 study to evaluate its acceptability and utility for decision-making. METHODS: The online Decision Aid was developed according to International Patient Decision Aid Standards and evaluated using a pre/post survey design. Twenty-six Australian women aged 18-45 years, interested in receiving elective egg freezing information, proficient in English, and with access to the internet were recruited using social media and university newsletters. Main outcomes were: acceptability of the Decision Aid; feedback on the Decision Aid design and content; concern raised by the Decision Aid, and; utility of the Decision Aid as measured by scores on the Decisional Conflict Scale and on a study-specific scale assessing knowledge about egg freezing and age-related infertility. RESULTS: Most participants found the Decision Aid acceptable (23/25), balanced (21/26), useful for explaining their options (23/26), and for reaching a decision (18/26). Almost all reported satisfaction with the Decision Aid (25/26) and the level of guidance  it provided (25/26). No participant reported serious concerns about the Decision Aid, and most would recommend it to other women considering elective egg freezing (22/26). Median Decisional Conflict Scale score decreased from 65/100 (Interquartile range: 45-80) pre-Decision Aid to 7.5/100 (Interquartile range: 0-37.5) post-Decision Aid review (p < 0.001). Median knowledge score increased from 8.5/14 (Interquartile range: 7-11) pre-Decision Aid to 11/14 (Interquartile range: 10-12) post-Decision Aid review (p = 0.01). CONCLUSION: This elective egg freezing Decision Aid appears acceptable and useful for decision-making. It improved knowledge, reduced decisional conflict and did not raise serious concerns. The Decision Aid will be further evaluated using a prospective randomised control trial. STUDY REGISTRATION: ACTRN12618001685202 (retrospectively registered: 12 October 2018).

Information and decision support needs: A survey of women interested in receiving planned oocyte cryopreservation information.

PURPOSE: Identifying the information and decision support needs of women interested in receiving planned oocyte cryopreservation (POC) information. METHODS: An online survey of Australian women, aged 18-45, interested in receiving POC information, proficient in English, with internet access. The survey covered POC information sources, information delivery preferences, POC and age-related infertility knowledge (study-specific scale), Decisional Conflict Scale (DCS), and time spent considering POC. Target sample size (n=120) was determined using a precision-based method. RESULTS: Of 332 participants, 249 (75%) had considered POC, whilst 83 (25%) had not. Over half (54%) had searched for POC information. Fertility clinic websites were predominately used (70%). Most (73%) believed women should receive POC information between ages 19-30 years. Preferred information providers were fertility specialists (85%) and primary care physicians (81%). Other methods rated most useful to deliver POC information were online. Mean knowledge score was 8.9/14 (SD:2.3). For participants who had considered POC, mean DCS score was 57.1/100 (SD:27.2) and 78% had high decisional conflict (score >37.5). In regression, lower DCS scores were associated with every 1-point increase in knowledge score (-2.4; 95% CI [-3.9, -0.8]), consulting an IVF specialist (-17.5; [-28.0, -7.1]), and making a POC decision (-18.4; [-27.5, -9.3]). Median time to decision was 24-months (IQR: 12.0-36.0) (n=53). CONCLUSION: Women interested in receiving POC information had knowledge gaps, and wanted to be informed about the option by age 30 years from healthcare professionals and online resources. Most women who considered using POC had high decisional conflict indicating a need for decision support.

The impact of removing financial incentives and/or audit and feedback on chlamydia testing in general practice: A cluster randomised controlled trial (ACCEPt-able).

BACKGROUND: Financial incentives and audit/feedback are widely used in primary care to influence clinician behaviour and increase quality of care. While observational data suggest a decline in quality when these interventions are stopped, their removal has not been evaluated in a randomised controlled trial (RCT), to our knowledge. This trial aimed to determine whether chlamydia testing in general practice is sustained when financial incentives and/or audit/feedback are removed. METHODS AND FINDINGS: We undertook a 2 × 2 factorial cluster RCT in 60 general practices in 4 Australian states targeting 49,525 patients aged 16-29 years for annual chlamydia testing. Clinics were recruited between July 2014 and September 2015 and were followed for up to 2 years or until 31 December 2016. Clinics were eligible if they were in the intervention group of a previous cluster RCT where general practitioners (GPs) received financial incentives (AU$5-AU$8) for each chlamydia test and quarterly audit/feedback reports of their chlamydia testing rates. Clinics were randomised into 1 of 4 groups: incentives removed but audit/feedback retained (group A), audit/feedback removed but incentives retained (group B), both removed (group C), or both retained (group D). The primary outcome was the annual chlamydia testing rate among 16- to 29-year-old patients, where the numerator was the number who had at least 1 chlamydia test within 12 months and the denominator was the number who had at least 1 consultation during the same 12 months. We undertook a factorial analysis in which we investigated the effects of removal versus retention of incentives (groups A + C versus groups B + D) and the effects of removal versus retention of audit/feedback (group B + C versus groups A + D) separately. Of 60 clinics, 59 were randomised and 55 (91.7%) provided data (group A: 15 clinics, 11,196 patients; group B: 14, 11,944; group C: 13, 11,566; group D: 13, 14,819). Annual testing decreased from 20.2% to 11.7% (difference -8.8%; 95% CI -10.5% to -7.0%) in clinics with incentives removed and decreased from 20.6% to 14.3% (difference -7.1%; 95% CI -9.6% to -4.7%) where incentives were retained. The adjusted absolute difference in treatment effect was -0.9% (95% CI -3.5% to 1.7%; p = 0.2267). Annual testing decreased from 21.0% to 11.6% (difference -9.5%; 95% CI -11.7% to -7.4%) in clinics where audit/feedback was removed and decreased from 19.9% to 14.5% (difference -6.4%; 95% CI -8.6% to -4.2%) where audit/feedback was retained. The adjusted absolute difference in treatment effect was -2.6% (95% CI -5.4% to -0.1%; p = 0.0336). Study limitations included an unexpected reduction in testing across all groups impacting statistical power, loss of 4 clinics after randomisation, and inclusion of rural clinics only. CONCLUSIONS: Audit/feedback is more effective than financial incentives of AU$5-AU$8 per chlamydia test at sustaining GP chlamydia testing practices over time in Australian general practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614000595617.

Low Levels of Hepatocyte-Specific Methylation in Cell-Free DNA Are a Strong Negative Predictor for Acute T Cell-Mediated Rejection Requiring Treatment Following Liver Transplantation.

Graft-derived cell-free DNA (gdcfDNA) quantification is a promising, minimally invasive tool for detecting acute T cell-mediated rejection (ATCMR) following liver transplantation (LT). We investigated the utility of measuring hepatocyte-specific methylation in cfDNA (HS-cfDNA) to quantify gdcfDNA, examining its accuracy in detecting ATCMR in a prospective, cross-sectional study. Blood was collected from LT recipients immediately prior to graft biopsy for suspected rejection. HS-cfDNA was quantified using droplet-digital polymerase chain reaction. Prebiopsy liver function tests (LFTs) and HS-cfDNA levels were correlated with biopsy results and the primary outcome of treated biopsy-proven acute rejection (tBPAR). A total of 51 patients were recruited; 37 had evidence of rejection on biopsy and 20 required treatment. As much as 11 patients needed inpatient treatment for rejection. HS-cfDNA significantly outperformed LFTs in identifying patients with tBPAR, particularly those needing inpatient treatment (area under the curve, 73.0%; 95% confidence interval, 55.4%-90.6%; P = 0.01). At a threshold of <33.5% of the total cfDNA fraction, HS-cfDNA had a specificity of 97%, correctly excluding tBPAR in 30/31 patients. Quantifying graft-specific methylation in cfDNA has a major advantage over previous gdcfDNA techniques: it does not require genotyping/sequencing, lending it greater feasibility for translation into transplantation care. Low levels of HS-cfDNA were a strong negative predictor for tBPAR (negative predictive value, 86%) and may have a future role in triaging patients prior to invasive graft biopsies.

Intrahepatic CXCL10 is strongly associated with liver fibrosis in HIV-Hepatitis B co-infection.

In HIV-hepatitis B virus (HBV) co-infection, adverse liver outcomes including liver fibrosis occur at higher frequency than in HBV-mono-infection, even following antiretroviral therapy (ART) that suppresses both HIV and HBV replication. To determine whether liver disease was associated with intrahepatic or circulating markers of inflammation or burden of HIV or HBV, liver biopsies and blood were collected from HIV-HBV co-infected individuals (n = 39) living in Bangkok, Thailand and naïve to ART. Transient elastography (TE) was performed. Intrahepatic and circulating markers of inflammation and microbial translocation were quantified by ELISA and bead arrays and HIV and HBV infection quantified by PCR. Liver fibrosis (measured by both transient elastography and liver biopsy) was statistically significantly associated with intrahepatic mRNA for CXCL10 and CXCR3 using linear and logistic regression analyses adjusted for CD4 T-cell count. There was no evidence of a relationship between liver fibrosis and circulating HBV DNA, qHBsAg, plasma HIV RNA or circulating cell-associated HIV RNA or DNA. Using immunohistochemistry of liver biopsies from this cohort, intrahepatic CXCL10 was detected in hepatocytes associated with inflammatory liver infiltrates in the portal tracts. In an in vitro model, we infected an HBV-infected hepatocyte cell line with HIV, followed by interferon-γ stimulation. HBV-infected cells lines produced significantly more CXCL10 than uninfected cells lines and this significantly increased in the presence of an increasing multiplicity of HIV infection. Conclusion: Enhanced production of CXCL10 following co-infection of hepatocytes with both HIV and HBV may contribute to accelerated liver disease in the setting of HIV-HBV co-infection.

Intensified partner notification and repeat testing can improve the effectiveness of screening in reducing Chlamydia trachomatis prevalence: a mathematical modelling study.

BACKGROUND: The Australian Chlamydia Control Effectiveness Pilot (ACCEPt) was a cluster randomised controlled trial designed to assess the effectiveness of annual chlamydia testing through general practice in Australia. The trial showed that testing rates increased among sexually active men and women aged 16-29 years, but after 3 years the estimated chlamydia prevalence did not differ between intervention and control communities. We developed a mathematical model to estimate the potential longer-term impact of chlamydia testing on prevalence in the general population. METHODS: We developed an individual-based model to simulate the transmission of Chlamydia trachomatis in a heterosexual population, calibrated to ACCEPt data. A proportion of the modelled population were tested for chlamydia and treated annually at coverage achieved in the control and intervention arms of ACCEPt. We estimated the reduction in chlamydia prevalence achieved by increasing retesting and by treating the partners of infected individuals up to 9 years after introduction of the intervention. RESULTS: Increasing the testing coverage in the general Australian heterosexual population to the level achieved in the ACCEPt intervention arm resulted in reduction in the population-level prevalence of chlamydia from 4.6% to 2.7% in those aged 16-29 years old after 10 years (a relative reduction of 41%). The prevalence reduces to 2.2% if the proportion retested within 4 months of treatment is doubled from the rate achieved in the ACCEPt intervention arm (a relative reduction of 52%), and to 1.9% if the partner treatment rate is increased from 30%, as assumed in the base case, to 50% (a relative reduction of 59%). CONCLUSION: A reduction in C. trachomatis prevalence could be achieved if the level of testing as observed in the ACCEPt intervention arm can be maintained at a population level. More substantial reductions can be achieved with intensified case management comprising retesting of those treated and treatment of partners of infected individuals.

The role of fingernail selenium in the association between arsenic, lead and mercury and child development in rural Vietnam: a cross-sectional analysis.

As, Pb and Hg are common environmental contaminants in low- and middle-income countries. We investigated the association between child toxicant exposure and growth and development and determined if this association was mitigated by Se concentration. Toxicant concentrations in fingernail samples, anthropometry and Bayley's Scales of Infant Development, 3rd edition domains were assessed in 36-month-old children whose mothers had been part of a randomised controlled trial in rural Vietnam. Multivariable regression analyses were performed to estimate the effect of toxicant exposure on clinical outcomes with adjustments for potential confounders and interaction with fingernail Se concentration. We analysed 658 children who had data for at least one physical or developmental outcome, and at least one toxicant measurement, and each of the covariates. Fingernail As concentration was negatively associated with language (estimate per 10 % increase in As: -0·19, 95 % CI: (-0·32, -0·05)). Pb was negatively associated with cognition (estimate per 10 % increase in Pb: -0·08 (-0·15, -0·02)), language (estimate per 10 % increase in Pb: -0·18 (-0·28, -0·10)) and motor skills (estimate per 10 % increase in Pb: -0·12 (-0·24, 0·00)). Hg was negatively associated with cognition (estimate per 10 % increase in Hg: -0·48, (-0·72, -0·23)) and language (estimate per 10 % increase in Hg -0·51, (-0·88, -0·13)) when Se concentration was set at zero in the model. As Se concentration increased, the negative associations between Hg and both cognition and language scores were attenuated. There was no association between toxicant concentration and growth. As, Pb and Hg concentrations in fingernails of 3-year-old children were associated with lower child development scores. The negative association between Hg and neurological development was reduced in magnitude with increasing Se concentration. Se status should be considered when assessing heavy metal toxicants in children and their impact on neurodevelopmental outcomes.

Characterising DSCATT: A case series of Australian patients with debilitating symptom complexes attributed to ticks.

OBJECTIVES(S): To characterise the clinical profile, aetiology and treatment responsiveness of 'Australian Lyme', or Debilitating Symptom Complexes Attributed to Ticks. METHODS: Single-centre retrospective case analysis of patients referred to the Infectious Diseases Unit at Austin Health - a tertiary health service in Heidelberg, Australia - between 2014 and 2020 for investigation and treatment of suspected Debilitating Symptom Complexes Attributed to Ticks. Patients were included if they had debilitating symptoms suggested by either themselves or the referring clinician as being attributed to ticks. RESULTS: Twenty-nine Debilitating Symptom Complexes Attributed to Ticks cases were included in the analysis. Other than Lyme disease (83%), the most common prior medical diagnoses were Epstein-Barr virus (38%), chronic fatigue syndrome (28%) and fibromyalgia (24%). Prior histories of anxiety (48%) and depression (41%) were common. The most frequently reported symptoms included fatigue (83%), headache (72%) and arthralgia (69%). National Association of Testing Authorities/Royal College of Pathologists of Australasia-accredited serology was not diagnostic of acute infective causes, including Lyme disease, in any patient. Of 25 cases with available data, 23 (92%) had previously been prescribed antimicrobials, with 53% reporting benefit from them. The most common diagnoses made by our hospital were chronic fatigue syndrome (31%), migraines (28%) and fibromyalgia (21%). Only one patient's symptoms were not accounted for by other diagnoses. CONCLUSION: This is the first case series of patients with Debilitating Symptom Complexes Attributed to Ticks. They had high rates of other medically unexplained syndromes, and no evidence of acute Lyme disease, or any common organic disease process. Debilitating Symptom Complexes Attributed to Ticks remains medically unexplained, and may therefore be due to an as yet unidentified cause, or may be considered a medically unexplained syndrome similar to conditions such as chronic fatigue syndrome.

Population-level diagnosis and care cascade for chlamydia in Australia.

OBJECTIVES: Key strategies to control chlamydia include testing, treatment, partner management and re-testing. We developed a diagnosis and care cascade for chlamydia to highlight gaps in control strategies nationally and to inform efforts to optimise control programmes. METHODS: The Australian Chlamydia Cascade was organised into four steps: (1) annual number of new chlamydia infections (including re-infections); (2) annual number of chlamydia diagnoses; (3) annual number of diagnoses treated; (4) annual number of diagnoses followed by a re-test for chlamydia within 42-180 days of diagnosis. For 2016, we estimated the number of infections among young men and women aged 15-29 years in each of these steps using a combination of mathematical modelling, national notification data, sentinel surveillance data and previous research studies. RESULTS: Among young people in Australia, there were an estimated 248 580 (range, 240 690-256 470) new chlamydia infections in 2016 (96 470 in women; 152 100 in men) of which 70 164 were diagnosed (28.2% overall: women 43.4%, men 18.6%). Of the chlamydia infections diagnosed, 65 490 (range, 59 640-70 160) were treated (93.3% across all populations), but only 11 330 (range, 7660-16 285) diagnoses were followed by a re-test within 42-180 days (17.3% overall: women 20.6%, men 12.5%) of diagnosis. CONCLUSIONS: The greatest gaps in the Australian Chlamydia Cascade for young people were in the diagnosis and re-testing steps, with 72% of infections undiagnosed and 83% of those diagnosed not re-tested: both were especially low among men. Treatment rates were also lower than recommended by guidelines. Our cascade highlights the need for enhanced strategies to improve treatment and re-testing coverage such as short message service reminders, point-of-care and postal test kits.

Accuracy of the Clinical Frailty Scale for perioperative frailty screening: a prospective observational study.

PURPOSE: Perioperative frailty increases postoperative complications, mortality, and new functional dependence. Despite this, routine perioperative frailty screening is not widespread. We aimed to assess the accuracy of the Clinical Frailty Scale (CFS) as a screening tool prior to anesthesia, and to determine which health domains are affected by frailty. METHODS: In a prospective, single-centre observational study, we enrolled 218 patients aged ≥ 65 yr undergoing elective and emergency surgery. The screening performance of the CFS was compared with the Edmonton Frail Scale, including the effect in individual frailty domains, and outcomes including discharge location and mortality. RESULTS: The median [interquartile range] age of the enrolled subjects was 74 [69-80] yr and 24% of the patients were frail. The CFS and Edmonton scales were highly correlated (Spearman correlation coefficient, 0.81; 95% confidence interval [CI], 0.77 to 0.86), and in substantial agreement (kappa coefficient, 0.76; 95% CI, 0.70 to 0.81), with an area under the receiver operating characteristic curve of 0.91 (95% CI, 0.86 to 0.94) indicating excellent discrimination for the CFS in predicting frailty status based on the Edmonton scale. Frail patients had higher 30-day mortality (odds ratio, 5.26; 95% CI, 1.28 to 21.62), and were less likely to be discharged home. Frail patients had poorer health throughout frailty domains, including functional dependence (42% of frail vs 4% of non-frail patients; P < 0.001), malnutrition (48% vs 19%, P < 0.001), and poor physical performance (47% vs 7%, P < 0.001). CONCLUSION: The CFS is a valid and accurate tool to screen for perioperative frailty, which encompasses the spectrum of health-related domains.

RéSUMé: OBJECTIF: La fragilité périopératoire augmente les complications postopératoires, la mortalité et une nouvelle dépendance fonctionnelle. Le dépistage de routine de la fragilité périopératoire n'est cependant pas une pratique répandue. Nous avions pour objectif d'évaluer la précision de l'échelle de mesure de fragilité CFS (pour Clinical Frailty Scale) comme outil de dépistage préanesthésique et de déterminer quels domaines de la santé étaient affectés par la fragilité. MéTHODE: Nous avons recruté 218 patients âgés de plus de 65 ans et subissant une chirurgie non urgente ou urgente dans notre étude observationnelle prospective et monocentrique. Les résultats du dépistage de la CFS ont été comparés à l'échelle de fragilité d'Edmonton (Edmonton Frail Scale), y compris en ce qui a trait à l'effet de la fragilité sur les domaines individuels de fragilité et aux résultats tels que la destination au congé et la mortalité. RéSULTATS: L'âge médian [écart interquartile] des patients recrutés était de 74 [69­80] ans et 24 % des patients étaient fragiles. Les échelles CFS et d'Edmonton avaient une forte corrélation (coefficient de corrélation de Spearman, 0,81; intervalle de confiance [IC] 95 %, 0,77 à 0,86) et étaient en accord substantiel (coefficient kappa, 0,76; IC 95 %, 0,70 à 0,81), avec une surface sous la courbe de fonction d'efficacité de l'observateur de 0,91 (IC 95 %, 0,86 à 0,94), indiquant une discrimination excellente de la CFS pour prédire l'état de fragilité fondé sur l'échelle d'Edmonton. Les patients fragiles souffraient d'une mortalité à 30 jours plus élevée (rapport de cotes, 5,26; IC 95 %, 1,28 à 21,62) et il était moins probable qu'ils reçoivent leur congé de l'hôpital à la maison. Les patients fragiles étaient en moins bonne santé dans tous les domaines de fragilité, notamment en dépendance fonctionnelle (42 % des patients fragiles vs 4 % des patients non fragiles; P < 0,001), en malnutrition (48 % vs 19 %, P < 0,001) et en mauvaise performance physique (47 % vs 7 %, P < 0,001). CONCLUSION: L'échelle CFS constitue un outil valable et précis pour dépister la fragilité périopératoire, qui englobe l'éventail des domaines liés à la santé.

Population effectiveness of opportunistic chlamydia testing in primary care in Australia: a cluster-randomised controlled trial.

BACKGROUND: Screening young adults who are sexually active for genital Chlamydia trachomatis infection is promoted in several high-income countries, but its effectiveness at the population level is highly debated. We aimed to investigate the effects of opportunistic chlamydia testing in primary care on the estimated chlamydia prevalence in the population aged 16-29 years in Australia. METHODS: We did a cluster-randomised controlled trial. Clusters were rural towns with a minimum of 500 women and men aged 16-29 years and no more than six primary care clinics. We randomly allocated each cluster using a computer-generated minimisation algorithm to receive a multifaceted, clinic-based chlamydia testing intervention or to continue usual care. The intervention included computerised reminders to test patients, an education package, payments for chlamydia testing, and feedback on testing rates. The primary outcome was chlamydia prevalence, estimated before randomisation (survey 1) and at the end of the trial (survey 2) in patients aged 16-29 years who attended the clinics. Analyses were done by intention to treat. General practitioners and clinic staff were aware of group allocation, whereas patients and laboratory staff who performed the chlamydia tests were not. This trial was completed on Dec 31, 2015, and is registered (ACTRN12610000297022). FINDINGS: Between Dec 14, 2010, and Sept 14, 2015, 26 clusters (63 clinics) received the chlamydia testing intervention and 26 (67 clinics) continued usual care. Over a mean duration of 3·1 years (SD 0·3), 93 828 young adults attended intervention clinics and 86 527 attended control clinics. The estimated chlamydia prevalence decreased from 5·0% (95% CI 3·8 to 6·2) at survey 1 to 3·4% (2·7 to 4·1) at survey 2 in the intervention clusters (difference -1·6%, 95% CI -2·9 to -0·3) and from 4·6% (95% CI 3·5 to 5·7) at survey 1 to 3·4% (2·4 to 4·5) at survey 2 in the control clusters (difference -1·1%, -2·7 to 0·5). The unadjusted odds ratio for the difference between intervention and control clusters was 0·9 (95% CI 0·5 to 1·5). INTERPRETATION: These findings, in conjunction with evidence about the feasibility of sustained uptake of opportunistic testing in primary care, indicate that sizeable reductions in chlamydia prevalence might not be achievable. FUNDING: Australian Government Department of Health, National Health and Medical Research Council, Victorian Department of Health and Human Services, and New South Wales Ministry of Health.