Trial Sites Research Articles

Exploring the divergence in perspectives on clinical trial operations in South Korea during the COVID-19 pandemic: a comparison of a trial site and sponsors.

During the COVID-19 pandemic, novel clinical trial methods known as decentralized clinical trials (DCTs) were rapidly introduced. The attitude toward operating clinical trials and perspectives on DCTs may differ between clinical trial sites and sponsors. The impact of the COVID-19 pandemic on clinical trials was investigated for a society of sponsors and a trial site in South Korea. The current difficulties and future perspectives on clinical trials were assessed and compared between the site and sponsors. Both the site and sponsors reported on their experiences with the challenges of conducting clinical trials during the pandemic era. While 64% of personnel from the site judged that the difficulties were solved by their own solutions, 67.6% of personnel from sponsors considered cooperation with trial sites as a key solution to overcome the difficulties. While half of the personnel from the site were skeptical of the changes in trial operation methods, the sponsors expected the institutionalization of DCT elements. In conclusion, with varying attitudes, sponsors and sites attempted to overcome the challenges of conducting clinical trials during the pandemic era. To conduct clinical trials effectively, both sponsors and sites must work closely together to find solutions with efficient communication. For the successful implementation of new tools such as DCTs, the government needs to solicit support from sponsors and sites and change regulations.

Effects of Abiotic Stress Associated with Climate Change on Potato Yield and Tuber Quality Under a Multi-environment Trial in New Zealand

In the 2018/19 growing season, a multi-environment trial in Opiki, Hastings, and Ohakune located in three different regions of the North Island of New Zealand was conducted to evaluate responses of selected potato cultivars to abiotic stress associated with climate change. Heat and drought stresses were evident with supra-optimal temperatures (> 25 °C) in Opiki and Hastings and sub-optimal rainfall (< 500 mm) in Opiki, which influenced the different morpho-physiological characteristics of the potato crop, ultimately affecting yield and tuber quality. These abiotic stresses also increased the incidence of malformation, growth cracks, and second growth in tubers reducing the total and marketable tuber yields by 43% and 45%, respectively. In addition, the genotype × environment analysis showed that Ohakune had the most favourable environmental conditions for potato production since all cultivars in this site had superior marketable tuber yields. ‘Taurus’ was the most stable and adaptable cultivar across trial sites (wide adaptation), whilst ‘Hermes’ and ‘Snowden’ were more adapted under Opiki and Hastings conditions (specific adaptation), respectively. As established in this study, heat and drought stresses have significant effects on the morpho-physiology, yield, and tuber quality of commercial potato cultivars in New Zealand.

Association between brachial-ankle pulse wave velocity and the risk of new-onset atrial fibrillation: A report from Kailuan prospective cohort study

One marker of arterial stiffness (AS) is the brachial-ankle pulse wave velocity (baPWV). We aim to investigate the predictive value of baPWV with regard to new-onset atrial fibrillation (AF). All participants without AF from 2010 to 2020 in the Kailuan cohort were included. The primary endpoint was new-onset AF. Participants were categorized into three study groups based on baPWV, with a normal baPWV group as a reference. The predictive value of baPWV was analyzed as a continuous variable. Multivariable Cox proportional hazard regression models were used to investigate the association. A total of 49,872 subjects (mean age: 47.57 years old, 74.2% male) were included with a mean follow-up of 6.17 (3.95–8.46) years. The risk of AF increased as the baseline baPWV increased, whereby the adjusted hazard ratio (aHR) of the borderline AS group and the elevated AS group were 1.82 (95% confidence interval [CI]: 1.18–2.80) and 2.08 (95% CI: 1.31–3.30), respectively. When considered as a continuous variable, each 361 cm/s increase in baseline baPWV, increased the risk of AF by 21.7% (aHR: 1.22; 95% CI: 1.08–1.37). In the subgroup analysis of non-hypertensive patients, the risks of AF were significantly higher in the borderline AS group (aHR: 3.16, 95% CI: 1.74–5.74) and elevated AS group (aHR: 2.26, 95% CI: 1.02–5.05). For patients with elevated BMI, the risk of AF in the elevated AS group was significantly higher (aHR: 1.69, 95% CI: 1.00–2.83). Baseline baPWV was associated with new-onset AF after adjustments. (Trial registration site and registration number are, respectively, http://www.chictr.org.cn/index.aspx and ChiCTR-TNRC-11001489).

Nurse-Led Strategy to Improve Blood Pressure and Cholesterol Level Among People With HIV

Despite higher atherosclerotic cardiovascular disease (ASCVD) risk, people with HIV (PWH) experience unique barriers to ASCVD prevention, such as changing models of HIV primary care. To test whether a multicomponent nurse-led strategy would improve systolic blood pressure (SBP) and non-high-density lipoprotein (HDL) cholesterol level in a diverse population of PWH receiving antiretroviral therapy (ART). This randomized clinical trial enrolled PWH at 3 academic HIV clinics in the US from September 2019 to January 2022 and conducted follow-up for 12 months until January 2023. Included patients were 18 years or older and had a confirmed HIV diagnosis, an HIV-1 viral load less than 200 copies/mL, and both hypertension and hypercholesterolemia. Participants were stratified by trial site and randomized 1:1 to either the multicomponent EXTRA-CVD (A Nurse-Led Intervention to Extend the HIV Treatment Cascade for Cardiovascular Disease Prevention) intervention group or the control group. Primary analyses were conducted according to the intention-to-treat principle. The EXTRA-CVD group received home BP monitoring guidance and BP and cholesterol management from a dedicated prevention nurse at 4 in-person visits (baseline and 4, 8, and 12 months) and frequent telephone check-ins up to every 2 weeks as needed. The control group received general prevention education sessions from the prevention nurse at each of the 4 in-person visits. Study-measured SBP was the primary outcome, and non-HDL cholesterol level was the secondary outcome. Measurements were taken over 12 months and assessed by linear mixed models. Prespecified moderators tested were sex at birth, baseline ASCVD risk, and trial site. A total of 297 PWH were randomized to the EXTRA-CVD arm (n = 149) or control arm (n = 148). Participants had a median (IQR) age of 59.0 (53.0-65.0) years and included 234 males (78.8%). Baseline mean (SD) SBP was 135.0 (18.8) mm Hg and non-HDL cholesterol level was 139.9 (44.6) mg/dL. At 12 months, participants in the EXTRA-CVD arm had a clinically significant 4.2-mm Hg (95% CI, 0.3-8.2 mm Hg; P = .04) lower SBP and 16.9-mg/dL (95% CI, 8.6-25.2 mg/dL; P < .001) lower non-HDL cholesterol level compared with participants in the control arm. There was a clinically meaningful but not statistically significant difference in SBP effect in females compared with males (11.8-mm Hg greater difference at 4 months, 9.6 mm Hg at 8 months, and 5.9 mm Hg at 12 months; overall joint test P = .06). Results of this trial indicate that the EXTRA-CVD strategy effectively reduced BP and cholesterol level over 12 months and should inform future implementation of multifaceted ASCVD prevention programs for PWH. ClinicalTrials.gov Identifier: NCT03643705.

FRAMM: Fair ranking with missing modalities for clinical trial site selection

The underrepresentation of gender, racial, and ethnic minorities in clinical trials is a problem undermining the efficacy of treatments on minorities and preventing precise estimates of the effects within these subgroups. We propose FRAMM, a deep reinforcement learning framework for fair trial site selection to help address this problem. We focus on two real-world challenges: the data modalities used to guide selection are often incomplete for many potential trial sites, and the site selection needs to simultaneously optimize for both enrollment and diversity. To address the missing data challenge, FRAMM has a modality encoder with a masked cross-attention mechanism for bypassing missing data. To make efficient trade-offs, FRAMM uses deep reinforcement learning with a reward function designed to simultaneously optimize for both enrollment and fairness. We evaluate FRAMM using real-world historical clinical trials and show that it outperforms the leading baseline in enrollment-only settings while also greatly improving diversity.

Adjunctive Brexpiprazole for Patient Life Engagement in Major Depressive Disorder: A Canadian, Phase 4, Open-Label, Interventional Study: Brexpiprazole d'appoint pour l'engagement dans la vie des patients souffrant de trouble dépressif majeur: une étude interventionnelle canadienne ouverte de phase 4.

To characterize the effects of adjunctive brexpiprazole on patient life engagement and depressive symptoms in patients with major depressive disorder (MDD) using patient-reported outcomes. An 8-week, Phase 4, open-label, interventional study was conducted at 15 Canadian trial sites between April 2021 and May 2022. Adult outpatients with MDD (at least moderately severe) and inadequate response to 1-2 antidepressants continued their current antidepressant and received oral adjunctive brexpiprazole 0.5-2 mg/day. Co-primary endpoints were change from baseline to Week 8 in Inventory of Depressive Symptomatology Self-Report (IDS-SR) 10-item Life Engagement subscale score, and IDS-SR 30-item total score. Safety was assessed by standard variables. Of 122 enrolled patients, 120 (98.4%) were treated (mean [SD] dose: 1.2 [0.4] mg/day) and analyzed, and 111 (91.0%) completed the study. Statistically significant least squares mean improvements to Week 8 were observed on IDS-SR10 Life Engagement subscale score (baseline mean [SD]: 16.1 [4.7]; change [95% confidence interval]: -8.11 [-9.34, -6.88]; p < 0.001) and IDS-SR total score (baseline mean [SD]: 41.3 [9.8]; change [95% confidence interval]: -17.38 [-20.08, -14.68]; p < 0.001). Improvements were observed from Week 2, onwards. Treatment-emergent adverse events with incidence ≥5% were fatigue (n = 13, 10.8%), headache (n = 13, 10.8%), insomnia (n = 12, 10.0%), nausea (n = 9, 7.5%), tremor (n = 8, 6.7%), and weight increase (n = 7, 5.8%). Six patients (5.0%) discontinued due to adverse events. Mean (SD) change in body weight from baseline to last visit was +1.9 (3.4) kg. Using an exploratory patient-reported outcome measure, patients with MDD and inadequate response to antidepressants who received open-label adjunctive brexpiprazole showed early and clinically meaningful improvement in patient life engagement, which should be further assessed in a prospective randomized controlled trial. Patient-rated depressive symptoms (on the validated 30-item IDS-SR) also improved. Adjunctive brexpiprazole was well tolerated, and no new safety signals were observed. ClinicalTrials.gov identifier: NCT04830215.

Decentralisation in Clinical Trials and Patient Centricity: Benefits and Challenges.

Decentralised clinical trials (DCTs) encompass various terms such as virtual, home-based, remote and siteless trials. The objectives of DCTs are to enhance the ease of participation for patients in clinical trials by minimising or removing the necessity for trial subjects to travel to the trial sites. This approach has been shown to reduce drop-out rates, increase study effectiveness and ultimately get life-altering drugs to market faster-saving sponsors billions. At the outset, DCTs deploy a wide range of digital technologies to collect safety and efficacy data from study participants, providing study treatments and performing investigations from the comfort of the patient's own home. The aim of decentralised trials includes patient centricity, enhanced efficacy in clinical trial conduct and generating real-world data. This is done by not only making it convenient for the patient to participate in the trial execution, but also involving them from the planning stage and taking their inputs during designing of trials and consenting documentation, understanding their treatment requirements and designing the studies accordingly. Various regulatory authorities have published guidelines governing DCT principles, especially after the coronavirus disease 2019 (COVID-19) experience of undertaking multicentric clinical trials. Both United States Food and Drug Administration (USFDA) and European Medicines Agency (EMA) have newer, recently updated guidelines to capture this growing reality to undertake clinical trials using patient technology or patient-centric technologies. Other regulatory agencies are accepting data generated using decentralised and patient-centric technologies and making an effort to include elements of decentralised trials in their regulatory guidelines. Decentralised trials follow a hybrid approach to have a balanced mix of remote and in-person data collection and trial procedures. Decentralised and patient-centric approaches are the future of any organisation for the conduct of clinical trials. Globally, all sponsor pharmaceutical companies must start undertaking drug development and clinical trials using a decentralised approach while keeping patient centricity in mind.

Can an educational video improve the adequacy of bowel preparation for patients undergoing their first colonoscopy? Results of the EBOPS RCT.

Background and study aims The aim of this study was to assess the effect of an educational video on the quality of bowel preparation of patients from a UK population attending for their first colonoscopy. Patients and methods A prospective, endoscopist-blinded trial with 1:1 allocation was performed. Patients referred for their first colonoscopy were recruited between February 2019 and December 2019. All participants were prescribed Moviprep and received the trial site's standard written bowel preparation instructions, with the intervention group also receiving a bespoke educational video. Adequacy of bowel preparation (defined as a Boston Bowel Preparation Scale of ≥2 in each segment of the bowel) and polyp detection rates (PDRs) were compared. Fisher's chi squared test was utilized with P <0.05 as the threshold for significance. Results A total of 509 participants completed the trial from six centers; 251 were randomized to the intervention group. The mean age was 57 years and 52.3% were female. The primary endpoint was met with an adequacy rate of 216 of 251 (86.1%) in the intervention group, compared with 205 of 259 (79.1%) in the control group ( P <0.05, odds ratio [OR] 1.626, 95% CI 1.017-2.614). The PDR was significantly higher in the intervention group (39% vs 30%, OR 1.51, 95% CI 1.04-2.19, P <0.05). Conclusions An educational video leads to improved bowel preparation for patients attending for their first colonoscopy, and is also associated with greater detection of polyps. Widespread adoption of an educational video incurs minimal investment, but would reduce the number of inadequate procedures, missed pathology, and the cost that both these incur.

The Bio-Hermes Study: Biomarker database developed to investigate blood-based and digital biomarkers in community-based, diverse populations clinically screened for Alzheimer's disease.

Alzheimer's disease (AD) trial participants are often screened for eligibility by brain amyloid positron emission tomography/cerebrospinal fluid (PET/CSF), which is inefficient as many are not amyloid positive. Use of blood-based biomarkers may reduce screen failures. We recruited 755 non-Hispanic White, 115 Hispanic, 112 non-Hispanic Black, and 19 other minority participants across groups of cognitively normal (n=417), mild cognitive impairment (n=312), or mild AD (n=272) participants. Plasma amyloid beta (Aβ)40, Aβ42, Aβ42/Aβ40, total tau, phosphorylated tau (p-tau)181, and p-tau217 were measured; amyloid PET/CSF (n=956) determined amyloid positivity. Clinical, blood biomarker, and ethnicity/race differences associated with amyloid status were evaluated. Greater impairment, older age, and carrying an apolipoprotein E (apoE) ε4 allele were associated with greater amyloid burden. Areas under the receiver operating characteristic curve for amyloid status of plasma Aβ42/Aβ40, p-tau181, and p-tau217 with amyloid positivity were ≥ 0.7117 for all ethnoracial groups (p-tau217, ≥0.8128). Age and apoE ε4 adjustments and imputation of biomarker values outside limit of quantitation provided small improvement in predictive power. Blood-based biomarkers are highly associated with amyloid PET/CSF results in diverse populations enrolled at clinical trial sites. Amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p-tau)181, and p-tau 217 blood-based biomarkers predicted brain amyloid positivity. P-tau 217 was the strongest predictor of brain amyloid positivity. Biomarkers from diverse ethnic, racial, and clinical cohorts predicted brain amyloid positivity. Community-based populations have similar Alzheimer's disease (AD) biomarker levels as other populations. A prescreen process with blood-based assays may reduce the number of AD trial screen failures.

Varying Doses of Epicutaneous Immunotherapy With Viaskin Milk vs Placebo in Children With Cow’s Milk Allergy

No approved treatment exists for allergen-specific immunoglobulin E (IgE)-mediated cow's milk allergy (CMA), a common childhood food allergy. To assess dose, efficacy, and safety of epicutaneous immunotherapy with Viaskin milk in children with IgE-mediated CMA. A phase 1/2, 2-part, randomized, double-blind, placebo-controlled dose-ranging clinical trial in children aged 2 to 17 years with IgE-mediated CMA was conducted between November 2014 through December 2017. It took place at 17 trial sites in the US and Canada. Current CMA was confirmed by double-blind, placebo-controlled food challenge at study entry. Part A assessed the short-term safety of 150 μg, 300 μg, or 500 μg of Viaskin milk; part B evaluated the efficacy and safety of the 3 doses vs placebo over 12 months of treatment. Of the 308 screened participants with physician-diagnosed CMA, 198 met eligibility criteria (including an eliciting dose 300 mg or less) and were randomized. Safety of Viaskin milk (150-μg, 300-μg, or 500-μg doses) was evaluated over a 3-week period (part A). In part B, 180 additional participants were randomized to receive Viaskin milk at doses of 150 μg, 300 μg, or 500 μg or placebo (1:1:1:1) for 12 months. The primary outcome was the proportion of treatment responders, defined as a 10-fold or more increase in the cumulative reactive dose of cow's milk protein (reaching at least 144 mg) or a cumulative reactive dose of cow's milk protein at 1444 mg or more at the month 12 double-blind, placebo-controlled food challenge. A total of 95.5% of the randomized participants (mean [SD] age, 8 [4.17] years; 124 of 198 were male [62.6%]) completed treatment. The highest response rate was observed in participants who received Viaskin milk at the 300-μg dose with 24 of 49 responders (49.0%) overall vs 16 of 53 responders (30.2%) in the placebo group (odds ratio, 2.19; 95% CI, 0.91-5.41; P = .09), highest in the 2 to 11 years age group (22 of 38 [57.9%] vs 13 of 40 [32.5%]; P = .04). Most treatment-emergent adverse events were mild or moderate application-site reactions. One participant in the 500-μg Viaskin milk dose group experienced treatment-related anaphylaxis. In this randomized clinical trial, 12 months of daily epicutaneous immunotherapy with a dose of Viaskin milk at 300 μg was associated with a statistically significant treatment response in 2- to 11-year-old children with IgE-mediated CMA. Treatment-related anaphylaxis and treatment-related discontinuation rates were low. Further research is needed to explore Viaskin milk as a viable treatment option for children with IgE-mediated CMA. ClinicalTrials.gov Identifier: NCT02223182.

A Diabetes Pregnancy Technology Roadmap: The 2023 Norbert Freinkel Award Lecture.

Norbert Freinkel emphasized the need for "more aggressive therapy with exogenous insulin" during type 1 diabetes (T1D) pregnancy. Recent advances in diabetes technology, continuous glucose monitoring (CGM), and hybrid closed-loop (HCL) insulin delivery systems allow us to revisit Freinkel's observations from a contemporary perspective. The Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT) led to international recommendations that CGM be offered to all pregnant women with T1D to help them meet their pregnancy glucose targets and improve neonatal outcomes. However, despite CGM use, only 35% of trial participants reached the pregnancy glucose targets by 35 weeks' gestation, which is too late for optimal obstetric and neonatal outcomes. The constant vigilance to CGM data and insulin dose adjustment, with perpetual worry about the impact of hyperglycemia on the developing fetal structures, leave many pregnant women feeling overwhelmed. HCL systems that can adapt to marked gestational changes in insulin sensitivity and pharmacokinetics may help to bridge the gap between the nonpregnant time in range glycemic targets (70-180 mg/dL) and the substantially more stringent pregnancy-specific targets (TIRp) (63-140 mg/dL) required for optimal obstetric and neonatal outcomes. Use of HCL (CamAPS FX system) was associated with a 10.5% higher TIRp, 10.2% less hyperglycemia, and 12.3% higher overnight TIRp. Clinical benefits were accompanied by 3.7 kg (8 lb) less gestational weight gain and consistently achieved across a representative patient population of insulin pump or injection users, across trial sites, and across maternal HbA1c categories. Working collaboratively, women, HCL technology, and health care teams achieved improved glycemia with less worry, less work, and more positive pregnancy experiences.

Yield performance of virus free sweetpotato (Ipomoea batatas) cultivars in the highlands of Papua New Guinea

ABSTRACT Sweetpotato (Ipomoea batatas (L.) Lam.) is the dominant staple food crop in the Highlands Provinces in Papua New Guinea (PNG), but productivity is constrained by pests and diseases including viral pathogens. Meristem-tip culture and thermotherapy can be used to eliminate viral pathogens in planting material, overcoming productivity constraints caused by viral infections. In this study, the performance of four PNG sweetpotato cultivars grown from virus-cleaned or farmer-sourced planting material were assessed at four production locations in PNG Highlands Provinces. Total root yields were significantly increased in three of the four cultivars by using virus-cleaned material, with root number and root weight increasing as well as root quality. A weak interaction between the origin region of a cultivar and trial site location was observed, suggesting that response to virus-cleaning may be lower when cultivars selected for tolerance to pathogens in a production region are grown in the same region after virus-cleaning. The results demonstrated that under traditional production practices in gardens frequently used for sweetpotato production, the use of virus-cleaned planting material is a viable practice for farmers aiming to transition from subsistence production to commercial production.

Effects of cultural practices on soil respiration in hazelnut orchards and a comparison with an adjacent natural oak forest.

Soil respiration (RS) is one of the largest terrestrial sources of CO2 causing global warming and may vary according to land use and vegetation type. Türkiye is in the first place in the world in terms of area of hazelnut orchards that are generally converted from natural forests. The aim of this study was the comparison of the effects of cultural practices (pruning, fertilizing, and pruning+fertilizing) on RS in hazelnut orchards and that of the adjacent natural oak forest. Every trial site had a statistically similar annual mean RS, which ranged from 0.15 to 1.55 g C m-2 day-1. The RS on the sites was different only in the spring season and was similar in the other seasons. The RS of the pruned and fertilized hazelnut orchard (Hpf) in the spring was 58% greater than the unmaintained hazelnut orchard (Hc) and oak forest and 28% greater than the only fertilized hazelnut orchard (Hf). The RS of Hpf was also greater than other sites in most monthly measurements. While the positive correlation between soil moisture and RS was on an annual basis (r = 0.44), it was higher in summer (r = 0.61) and autumn (r = 0.55) seasons. The negative correlation between soil temperature and RS in the summer and autumn seasons evolved positively in winter. The results of the study suggest that the maintenance practices applied in the hazelnut garden could increase RS in the spring when soil moisture and temperature are optimal but have no effect in other seasons or on an annual basis.

Data from the Indian drug regulator and from Clinical Trials Registry-India does not always match.

In India, regulatory trials, which require the drug regulator's permission, must be registered with the Clinical Trials Registry-India (CTRI) as of 19 March 2019. In this study, for about 300 trials, we aimed to identify the CTRI record that matched the trial for which the regulator had given permission. After identifying 'true pairs', our goal was to determine whether the sites and Principal Investigators mentioned in the permission letter were the same as those mentioned in the CTRI record. We developed a methodology to compare the regulator's permission letters with CTRI records. We manually validated 151 true pairs by comparing the titles, the drug interventions, and the indications. We then examined discrepancies in their trial sites and Principal Investigators. Our findings revealed substantial variations in the number and identity of sites and Principal Investigators between the permission letters and the CTRI records. These discrepancies raise concerns about the accuracy and transparency of regulatory trials in India. We recommend easier data extraction from regulatory documents, cross-referencing regulatory documents and CTRI records, making public the changes to approval letters, and enforcing oversight by Institutional Ethics Committees for site additions or deletions. These steps will increase transparency around regulatory trials running in India.

Multicenter assessment and longitudinal study of the prevalence of antibodies and related adaptive immune responses to AAV in adult males with hemophilia.

Adeno-associated virus (AAV) based gene therapy has demonstrated effective disease control in hemophilia. However, pre-existing immunity from wild-type AAV exposure impacts gene therapy eligibility. The aim of this multicenter epidemiologic study was to determine the prevalence and persistence of preexisting immunity against AAV2, AAV5, and AAV8, in adult participants with hemophilia A or B. Blood samples were collected at baseline and annually for ≤3 years at trial sites in Austria, France, Germany, Italy, Spain, and the United States. At baseline, AAV8, AAV2, and AAV5 neutralizing antibodies (NAbs) were present in 46.9%, 53.1%, and 53.4% of participants, respectively; these values remained stable at Years 1 and 2. Co-prevalence of NAbs to at least two serotypes and all three serotypes was present at baseline for ~40% and 38.2% of participants, respectively. For each serotype, ~10% of participants who tested negative for NAbs at baseline were seropositive at Year 1. At baseline, 38.3% of participants had detectable cell mediated immunity by ELISpot, although no correlations were observed with the humoral response. In conclusion, participants with hemophilia may have significant preexisting immunity to AAV capsids. Insights from this study may assist in understanding capsid-based immunity trends in participants considering AAV vector-based gene therapy.

Perception of health care providers on the quality of oxytocin across six E-MOTIVE Trial sites in Kenya

Background: According to the WHO, in 2020, almost 800 women died daily from preventable causes related to pregnancy and childbirth. An estimated 95% of these deaths were in low- and middle-income countries (LMICs). Postpartum hemorrhage (PPH), excessive bleeding after childbirth, is a leading cause of maternal death globally. Of the estimated 95% of maternal deaths in LMIC, an unacceptable 95% were due to PPH. A significant barrier to women receiving PPH treatment is access to quality PPH medicines, which is the basis for reducing maternal mortality. The E-MOTIVE Trial Kenyan hub conducted an online survey on September after the E-MOTIVE trial findings were released. This survey assessed the perception of health care providers’ (HCPs) of the quality of oxytocin in Augmentation of Labour, Active Management of third Third Stage of Labor (AMSTL), including PPH management. Methods: An online survey was conducted using the Survey Monkey platform in Gatundu level 4 hospital, Makindu subcounty hospital, and Vihiga, Embu, Nyeri, and Kakamega county referral hospitals. The survey targeted HCPs working within the respective maternity units. The results were analyzed in Excel. Results: 56 HCPs across the 6 health facilities participated in the survey. On augmentation of labor, Oxymed Medisel and Oxytocin Umedical were perceived to be more effective, while a score of 100% with Curtocin and Oxyt Kilitch were perceived to be very ineffective. On AMSTL, Oxymed Medisel, Syntocinin Norvatis, and Oxytocin Laborate were perceived to be very effective, whereas Curtocin and Oxyt Kilitch were perceived to be very ineffective. On PPH management, Oxytocin Umedical, Syntocinon Norvatis, and Oxytocin Laborate were perceived to be very effective, whereas Curtocin and Oxyt Kilitch were perceived to be very ineffective. Oxytocin Laborate was available across the health facilities, with other brands lacking in some facilities. Conclusion: Access to and availability of quality PPH medicines are key to effectively managing PPH and reducing maternal mortality.

Using mid-infrared spectroscopy as a tool to monitor responses of acidic soil properties to liming: case study from a dryland agricultural soil trial site in South Australia

Soil acidification is an issue for agriculture that requires effective management, typically in the form of lime (calcium carbonate, CaCO3), application. Mid infrared (MIR) spectroscopy methods offer an alternative to conventional laboratory methods, that may enable cost-effective and improved measurement of soil acidity and responses to liming, including detection of small–scale heterogeneity through the profile. Properties of an acidic soil following lime application were measured using both MIR spectroscopy with Partial Least Squares Regression (MIR-PLSR) and laboratory measurements to (a) compare the ability of each method to detect lime treatment effects on acidic soil, and (b) assess effects of the different treatments on selected soil properties. Soil properties including soil pH (in H2O and CaCl2), Aluminium (Al, exchangeable and extractable), cation exchange capacity (CEC) and organic carbon (OC) were measured at a single field trial receiving lime treatments differing in rate, source and incorporation. Model performance of MIR-PLSR prediction of the soil properties ranged from R2 = 0.582, RMSE = 2.023, RPIQ = 2.921 for Al (extractable) to R2 = 0.881, RMSE = 0.192, RPIQ = 5.729 for OC. MIR-PLSR predictions for pH (in H2O and CaCl2) were R2 = 0.739, RMSE = 0.287, RPIQ = 2.230 and R2 = 0.788, RMSE = 0.311, RPIQ = 1.897 respectively, and could detect a similar treatment effect compared to laboratory measurements. Treatment effects were not detected for MIR-PLSR-predicted values of CEC and both exchangeable and extractable Al. Findings support MIR-PLSR as a method of measuring soil pH to monitor effects of liming treatments on acidic soil to help inform precision agricultural management strategies, but suggests that some nuance and important information about treatment effects of lime on CEC and Al may be lost. Improvements to prediction model performance should be made to realise the full potential of this approach.

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial

A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

"Our desire is to make this village intestinal worm free": Identifying determinants of high coverage of community-wide mass drug administration for soil transmitted helminths in Benin, India, and Malawi.

Soil-transmitted helminth infections (STH) are associated with substantial morbidity in low-and-middle-income countries, accounting for 2.7 million disability-adjusted life years annually. Current World Health Organization guidelines recommend controlling STH-associated morbidity through periodic deworming of at-risk populations, including children and women of reproductive age (15-49 years). However, there is increasing interest in community-wide mass drug administration (cMDA) which includes deworming adults who serve as infection reservoirs as a method to improve coverage and possibly to interrupt STH transmission. We investigated determinants of cMDA coverage by comparing high-coverage clusters (HCCs) and low-coverage clusters (LCCs) receiving STH cMDA in three countries. A convergent mixed-methods design was used to analyze data from HCCs and LCCs in DeWorm3 trial sites in Benin, India, and Malawi following three rounds of cMDA. Qualitative data were collected via 48 community-level focus group discussions. Quantitative data were collected via routine activities nested within the DeWorm3 trial, including annual censuses and coverage surveys. The Consolidated Framework for Implementation Research (CFIR) guided coding, theme development and a rating process to determine the influence of each CFIR construct on cMDA coverage. Of 23 CFIR constructs evaluated, we identified 11 constructs that differentiated between HCCs and LCCs, indicating they are potential drivers of coverage. Determinants differentiating HCC and LCC include participant experiences with previous community-wide programs, communities' perceptions of directly observed therapy (DOT), perceptions about the treatment uptake behaviors of neighbors, and women's agency to make household-level treatment decisions. The convergent mixed-methods study identified barriers and facilitators that may be useful to NTD programs to improve cMDA implementation for STH, increase treatment coverage, and contribute to the successful control or elimination of STH. The parent trial was registered at clinicaltrials.gov (NCT03014167).

Survey of Neonatal Management After Amnioinfusion for Anhydramnios

This survey study reports on use of renal replacement therapy, hemodynamic support, sedation, neuroimaging, and extracorporeal membrane oxygenation at Renal Anhydramnios Fetal Therapy trial sites for neonates with either bilateral renal agenesis or fetal kidney failure.