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Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. Over 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (−3.8 days [95% CI: −6.6 to −1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire–overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization −0.9 days [−0.7%] at 120 days, −2.3 days [−1.0%] at 240 days, and −4.8 days [−1.3%] at 360 days). Dapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the first year. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; NCT03036124) [Display omitted] [ABSTRACT FROM AUTHOR]

Il s'agit ici de nous saisir des modalités d'apparaître du corps créateur dans les œuvres que celui-ci met en forme. Ce sont plus particulièrement les œuvres de Judith Scott et Frida Kahlo qui intéresseront notre regard afin de rendre compte de l'incarnation et de l'existence de leur corps éprouvé par l'exploration de la création. Cette étude tente de rendre matière et environnement aux œuvres qui font l'objet de notre réflexion par le dialogue de la psychanalyse qui interroge le corps à l'œuvre et le corps de l'œuvre sous l'égide de Didier Anzieu, de la phénoménologie d'Henri Maldiney qui s'intéresse à l'apparaître de l'œuvre dans le mouvement de la Gestaltung et de l'esthétique de Georges Didi-Huberman qui s'intéresse au corps, à la chair des images. Penser le corps créateur comme un « corps-bouture » permet d'entrevoir les phénomènes de mise en présence des corps à l'œuvre et du corps de l'œuvre. Leur rencontre n'émane alors peut-être pas d'une situation de perte ou de manque originaire mais d'un accueil et d'une mise en forme de l'existant. L'approche psychanalytique ne semble pas suffire à explorer la sensorialité et les éprouvés corporels à l'œuvre dans la création. Opérer des liens avec l'esthétique et la phénoménologie permet ainsi d'ouvrir le temps et l'espace de la création aux effets de présence qui inscrivent l'œuvre et leur créatrice dans une écologie de gestes et de formes. Le corps créateur éprouvé et marqué par la douleur et le handicap, le corps créateur à l'écart d'une généalogie familiale stable et normée, fait l'épreuve de l'œuvre comme d'un « corps-bouture » qui apparaît par-là où il est coupé, se prolonge et pousse les marques de sa souffrance. The aim here is to grasp the ways in which the creative body appears in the works to which it gives form. The works of Judith Scott and Frida Kahlo will be of particular interest to us in their ability to account for the incarnation and the existence of their bodies as experienced through the exploration of creation. This study attempts to give substance and environment to the works that are the object of our reflection through the dialogue of psychoanalysis, which questions the body at work and the body of the work under the aegis of Didier Anzieu; the phenomenology of Henri Maldiney, who is interested in the emergence of the work in the movement of Gestaltung ; and the aesthetics of Georges Didi-Huberman, who is interested in the body, the flesh of images. Thinking of the creative body as a « cutting body" allows us to glimpse the phenomena of the presence of the bodies at work and the body of the work. Their encounter does not perhaps emanate from a situation of loss or original lack but from a welcoming and shaping of what exists. The psychoanalytical approach does not seem sufficient to explore the sensoriality and bodily experiences at work in creation. Making links with aesthetics and phenomenology thus makes it possible to open up the time and space of creation to the effects of presence that inscribe the work and its creator in an ecology of gestures and forms. The creative body, tested and marked by pain and disability, the creative body outside a stable and normalized family genealogy, puts the work to the test as a « cutting body" that appears where it is cut, extends itself, and pushes the marks of its suffering. [ABSTRACT FROM AUTHOR]

Multiple lifestyle-based childhood obesity interventions have been conducted to address childhood obesity, but individual's response to the universal intervention approach varied greatly. Whether gene variants related to children and adolescents' varied responses to obesity interventions remained unclear. To determine the associations of gene variants with the changes in obesity- and metabolism-related indicators after obesity interventions in children and adolescents. Ten databases and registers (including grey literature) were searched. The lifestyle-based obesity interventions in children and adolescents (≤18 years) that reported the changes in obesity- (body mass index (BMI), BMI Z-score, waist circumference (WC), waist-to-hip ratio (WHR), etc) and metabolism-related (glucose, cholesterol, etc) indicators by genotype after interventions were included. Our primary outcome was the mean difference of the changes in BMI Z-score by genotype after interventions, and secondary outcomes were changes in the remaining obesity- and metabolism-related indicators after interventions. We used the random-effects model to synthesize the results. This review included 50 studies (15,354 children and adolescents with overweight/obesity) covering 102 genes and 174 single nucleotide polymorphisms (SNPs). Approximately three-quarters of SNPs showed no evidence of association with the changes in obesity- or metabolic-related indicators after interventions. One quarter of SNPs were minorly associated with the changes in the BMI Z-score (median effect size: 0.001) with little clinical significance. Only 6 (12 %) studies focused on the accumulated effect of multiple gene variants. Gene variants that have been explored appear to play a minor role in lifestyle-based obesity interventions in children and adolescents. More high-quality studies based on the design of randomized controlled trials are needed to examine the accumulated effect of multiple gene variants in childhood obesity interventions. This systematic review and meta-analysis was registered at PROSPERO as CRD42022312177. [ABSTRACT FROM AUTHOR]

Antithrombotic treatment may improve the disease course in non-critically ill, symptomatic COVID-19 outpatients. We performed an individual patient-level analysis of the OVID and ETHIC randomized controlled trials, which compared enoxaparin thromboprophylaxis for either 14 (OVID) or 21 days (ETHIC) vs. no thromboprophylaxis for outpatients with symptomatic COVID-19 and at least one additional risk factor. The primary efficacy outcome included all-cause hospitalization and all-cause death within 30 days from randomization. Both studies were prematurely stopped for futility. Secondary efficacy outcomes were major symptomatic venous thromboembolic events, arterial cardiovascular events, or their composite occurring within 30 days from randomization. The same outcomes were assessed over a 90-day follow-up. The primary safety outcome was major bleeding (ISTH criteria). A total of 691 patients were randomized: 339 to receive enoxaparin and 352 to the control group. Over 30-day follow-up, the primary efficacy outcome occurred in 6.0 % of patients in the enoxaparin group vs. 5.8 % of controls for a risk ratio (RR) of 1.05 (95%CI 0.57–1.92). The incidence of major symptomatic venous thromboembolic events and arterial cardiovascular events was 0.9 % vs. 1.8 %, respectively (RR 0.52; 95%CI 0.13–2.06). Most cardiovascular thromboembolic events were represented by symptomatic venous thromboembolic events, occurring in 0.6 % vs. 1.5 % of patients, respectively. A similar distribution of outcomes between the treatment groups was observed over 90 days. No major bleeding occurred in the enoxaparin group vs. one (0.3 %) in the control group. We found no evidence for the clinical benefit of early administration of enoxaparin thromboprophylaxis in outpatients with symptomatic COVID-19. These results should be interpreted taking into consideration the relatively low occurrence of events. • Pooled analysis of OVID and ETHIC trials investigating enoxaparin thromboprophylaxis in COVID-19 symptomatic outpatients. • No significant difference in primary outcome (untoward hospitalization/all-cause death) between enoxaparin and standard of care group (RR 1.05, 95% CI 0.57-1.92). • Secondary outcome (arterial and venous thromboembolism) lower in enoxaparin group, not statistically significant (RR 0.52, 95% CI 0.13-2.06). • Prophylactic enoxaparin lacks clinical advantage for symptomatic, but clinically stable COVID-19 outpatients. [ABSTRACT FROM AUTHOR]

Targeted intrathecal drug delivery (TIDD) has the objective of bringing the drug(s) close to the receptors influencing pain modulation, and thus reducing the dose and the side effects. Intrathecal drug delivery knew its real start with the development of permanent implantation of intrathecal and epidural catheters, combined with internal or external ports, reservoirs, and programmable pumps. TIDD is a valuable treatment for patients with cancer suffering refractory pain. Patients suffering noncancer-related pain should only be considered for TIDD when all other options have been tested, including spinal cord stimulation. Only two drugs are approved by the US Food and Drug Administration for TIDD administration for chronic pain: morphine and ziconotide as monotherapy. In pain management, off-label use of medication and combination therapy is often reported. The specific action of the intrathecal drugs, the efficacy and safety, is described, as well as the modalities for trialing intrathecal drug delivery and the implantation methods. [ABSTRACT FROM AUTHOR]

Background: Women of reproductive age are at an increased risk of anemia and micronutrient deficiencies. Evidence supports the role of periconceptional nutrition in the development of neural tube defects (NTDs) and other pregnancy complications. Vitamin B12 deficiency is a risk factor for NTDs and may modify folate biomarkers that predict NTD risk at the population level. There is an interest in mandatory fortification with vitamin B12 and folic acid for anemia and birth defect prevention. However, there are limited population-representative data needed to inform policy and guidelines. Objectives: This randomized trial will be conducted to evaluate the efficacy of quadruple-fortified salt (QFS; iron, iodine, folic acid, vitamin B12) in 1,000 households in Southern India. Methods: Women 18 to 49 y who are not pregnant or lactating and reside within the catchment area of our community-based research site in Southern India will be screened and invited to participate in the trial. After informed consent, women and their households will be randomized to receive one of the following 4 interventions: 1) double-fortified salt (DFS; iron, iodine), 2) DFS + folic acid (iron, iodine, folic acid), 3) DFS + vitamin B12 (iron, iodine, vitamin B12), or 4) DFS + folic acid and vitamin B12 (QFS; iron, iodine, folic acid, vitamin B12) for 12 mo. Structured interviews will be conducted by trained nurse enumerators to collect sociodemographic, anthropometric, dietary, health, and reproductive history data. Biological samples will be collected at baseline, midpoint, and endpoint. Whole blood will be analyzed for hemoglobin using Coulter Counter. Total vitamin B12 will be measured by chemiluminescence; red blood cell folate and serum folate will be evaluated using the World Health Organization-recommended microbiologic assay. Conclusions: The results of this randomized trial will help to evaluate the efficacy of QFS to prevent anemia and micronutrient deficiencies. Clinical trial registration numbers: NCT03853304 and Clinical Trial Registry of India REF/2019/03/024479. [ABSTRACT FROM AUTHOR]

The CROSS trial group deserves enormous credit for completing a well-powered randomized trial that has established the CROSS strategy as a standard of care for patients with potentially resectable esophageal cancer. However, the 10-year results are rather disappointing with only 38% of all patients treated with the CROSS strategy cured compared with approximately 25% who had surgery alone. Another standard, perioperative chemotherapy has produced similar disappointing results as the CROSS strategy. Although many of us are consumed by the question as to which option is better for our patients, we conclude that both strategies produce only marginal benefits. We should have better treatment options. The timing may be opportune to reflect on how to develop novel and rational strategies rather than propagate the historical empiric approaches. [ABSTRACT FROM AUTHOR]

Worldwide, cancer pain management follows the World Health Organization (WHO) three-step analgesic ladder. Using weak opioids (e.g. codeine) at step 2 is debatable with low-dose strong opioids being potentially better, particularly in low- and middle-income countries where weak opioids are expensive. We wanted to assess the efficiency, safety and cost of omitting step 2 of the WHO ladder. We carried out an international, open-label, randomised (1 : 1) parallel group trial. Eligible patients had cancer, pain ≥4/10 on a 0-10 numerical rating scale, required at least step 1 (paracetamol) of the WHO ladder and were randomised to the control arm (weak opioid, step 2 of the WHO ladder) or the experimental arm (strong opioid, step 3). Primary outcome was time to stable pain control (3 consecutive days with pain ≤3). Secondary outcomes included distress, opioid-related side-effects and costs. The primary outcome analysis was by intention to treat and the follow-up was for 20 days. One hundred and fifty-three patients were randomised (76 control, 77 experimental). There was no statistically significant difference in time to stable pain control between the arms, P = 0.667 (log-rank test). The adjusted hazard ratio for the control arm was 1.03 (95% confidence interval 0.72-1.49). In the control arm, 38 patients (53%) needed to change to a strong opioid due to ineffective analgesia. The median time to change was day 6 (interquartile range 4-11). Compared to the control arm, patients in the experimental arm had less nausea (P = 0.009) and costs were less. This trial provides some evidence that the two-step approach is an alternative option for cancer pain management. • For decades the empirical WHO 3 step analgesic ladder has remained the keystone to cancer pain management education worldwide. • Debate has existed around the need for step 2 of the analgesic ladder which consists of weak opioids, such as codeine. • We examined pain and side-effects between the standard 3 step (weak to strong opioid) and a 2 step arm (no weak opioid). • Time to pain control equal in both arms, fewer side effects in 2 step arm, 50% in control arm needed strong opioid by day 7. • Important practical implications, particularly in LMICs where weak opioids (step 2) are expensive and switching complicated. [ABSTRACT FROM AUTHOR]

• 1. TRAIL exhibits promising anti-tumor potential but faces resistance issues. • 2. Combining TRAIL with various drugs can overcome tumor resistance. • 3. We categorized and discussed the relevant paradigms of TRAIL combination therapy. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows promising therapeutic potential in cancer treatment as it is able to trigger extrinsic apoptotic pathways by binding to the cognate death receptor, causing broad-spectrum apoptosis in cancer cells with negligible toxicity to normal cells. However, the majority of cancers display resistance to TRAIL, limiting its clinical utility. Overcoming resistance to TRAIL therapies remains a challenge in the development of effective anti-cancer strategies. To address the limitations of TRAIL therapy, a viable alternative approach involves combining TRAIL with more potent drugs compared to monotherapy. This combination strategy aims to induce synergistic effects or sensitize drug-resistant cancer cells. This review provides an overview of relevant modalities of TRAIL combination therapy, highlighting different drug classes. The findings demonstrate that combining TRAIL with other agents can effectively counteract resistance observed with TRAIL therapies in cancer. These findings lay a foundation for future advancements in TRAIL-based therapies for treating various cancers. [ABSTRACT FROM AUTHOR]

Clinical trials play a pivotal role in assessing the safety and efficacy of medical therapies. Addressing sex distribution among enrollees in clinical trials of radiologic contrast agents is essential for ensuring the generalizability of trial outcomes. Previous research has highlighted the influence of demographic factors, particularly sex, on treatment responses, emphasizing the need for equitable representation in clinical trials. Our study aim was to determine the sex distribution of enrollees in clinical trials of radiologic contrast agents. Our retrospective study included a total of 65 clinical trials conducted between 1990 and 2017 identified on clinicaltrials.gov after a comprehensive review including searching individually for all FDA approved contrast agents. Data collected included the year of FDA approval, the number of participants, sex distribution, trial location, trial phase, and study type. Inter-rater validation ensured data accuracy. Our analysis revealed fluctuations in sex distribution of trial enrollees. Enrollment of males exceeded females in most years, with a shift towards a more equitable representation in recent trials. Trials conducted in the United States had a higher rate of enrollment by females. Phase I trials had the most balanced representation, whereas Phase IV trials had the highest sex disparity. Across all trials, females made up 47.3 % of enrollees [3316 out of 7016 total enrollees]. Enrollment of males exceeded females in 44 of the 65 trials studied, females outnumbered males in 19 trials, and enrollment was equal between the sexes in 2 trials. While the sex distribution observed across all trials represents an equitable representation of enrollees, the wide variance of sex distribution at the level of individual trials has the potential to limit the generalizability of results. • Enrollment of men exceeded women in 44 of the 65 trials studied with women making up 47.3% of trial enrollees overall. • Our study revealed both an overall gender disparity and a disparity in individual trials. • Gender distribution varied considerably between trials. • Gender representation was more equitable in trials in recent years. • Phase 1 trials, randomized trials, and collaborative trials featured the most equitable gender representation. [ABSTRACT FROM AUTHOR]

• Conventional wisdom assumes evidentiary rules in criminal trials protect defendants. • Evidentiary rules may increase wrongful convictions and reduce rightful convictions. • If adjudicators are unbiased, evidentiary rules cannot improve accuracy in verdicts. • If adjudicators are biased, evidentiary rules may improve accuracy in verdicts. Evidentiary rules for criminal trials disallow various forms of probative evidence. Conventional wisdom assumes these rules benefit all defendants, whether guilty or innocent, and thus reduce wrongful convictions at the price of more wrongful acquittals. We show the conventional view only holds under stylized conditions. We further identify properties of evidence generation mechanisms under which the conventional view is backward: an evidentiary rule will harm the innocent and protect the guilty. However, if adjudicators place too much weight on the evidence, its exclusion can reduce both wrongful convictions and wrongful acquittals. [ABSTRACT FROM AUTHOR]

Background Universal provision of iron supplements or iron-containing multiple micronutrient powders (MNPs) is widely used to prevent anemia in young children in low- and middle-income countries. The BRISC (Benefits and Risks of Iron Interventions in Children) trial compared iron supplements and MNPs with placebo in children <2 y old in rural Bangladesh. Objectives We aimed to assess the cost-effectiveness of iron supplements or iron-containing MNPs among young children in rural Bangladesh. Methods We did a cost-effectiveness analysis of MNPs and iron supplements using the BRISC trial outcomes and resource use data, and programmatic data from the literature. Health care costs were assessed from a health system perspective. We calculated incremental cost-effectiveness ratios (ICERs) in terms of US$ per disability-adjusted life-year (DALY) averted. To explore uncertainty, we constructed cost-effectiveness acceptability curves using bootstrapped data over a range of cost-effectiveness thresholds. One- and 2-way sensitivity analyses tested the impact of varying key parameter values on our results. Results Provision of MNPs was estimated to avert 0.0031 (95% CI: 0.0022, 0.0041) DALYs/child, whereas iron supplements averted 0.0039 (95% CI: 0.0030, 0.0048) DALYs/child, over 1 y compared with no intervention. Incremental mean costs were $0.75 (95% CI: 0.73, 0.77) for MNPs compared with no intervention and $0.64 ($0.62, $0.67) for iron supplements compared with no intervention. Iron supplementation dominated MNPs because it was cheaper and averted more DALYs. Iron supplementation had an ICER of $1645 ($1333, $2153) per DALY averted compared with no intervention, and had a 0% probability of being the optimal strategy at cost-effectiveness thresholds of $200 (reflecting health opportunity costs in Bangladesh) and $985 [half of gross domestic product (GDP) per capita] per DALY averted. Scenario and sensitivity analyses supported the base case findings. Conclusions These findings do not support universal iron supplementation or micronutrient powders as a cost-effective intervention for young children in rural Bangladesh. This trial was registered at anzctr.org.au as ACTRN1261700066038 and trialsearch.who.int as U1111-1196-1125. [ABSTRACT FROM AUTHOR]

• This is the first-in-human trial of both FMP013 and the ALFQ adjuvant. • The vaccine evinced significant humoral and cell mediated immunogenicity. • The vaccine demonstrated an acceptable safety profile. • The results of this trial have led to an efficacy trial using CHMI. The global burden of malaria remains substantial. Circumsporozoite protein (CSP) has been demonstrated to be an effective target antigen, however, improvements that offer more efficacious and more durable protection are still needed. In support of research and development of next-generation malaria vaccines, Walter Reed Army Institute of Research (WRAIR) has developed a CSP-based antigen (FMP013) and a novel adjuvant ALFQ (Army Liposome Formulation containing QS-21). We present a single center, open-label, dose-escalation Phase 1 clinical trial to evaluate the safety and immunogenicity of the FMP013/ALFQ malaria vaccine candidate. In this first-in-human evaluation of both the antigen and adjuvant, we enrolled ten subjects; five received 20 μg FMP013 / 0.5 mL ALFQ (Low dose group), and five received 40 μg FMP013 / 1.0 mL ALFQ (High dose group) on study days 1, 29, and 57. Adverse events and immune responses were assessed during the study period. The clinical safety profile was acceptable and there were no serious adverse events. Both groups exhibited robust humoral and cellular immunological responses, and compared favorably with historical responses reported for RTS,S/AS01. Based on a lower reactogenicity profile, the 20 μg FMP013 / 0.5 mL ALFQ (Low dose) was selected for follow-on efficacy testing by controlled human malaria infection (CHMI) with a separate cohort. Trial Registration: Clinicaltrials.gov Identifier NCT04268420 (Registered February 13, 2020) [ABSTRACT FROM AUTHOR]

Objectives: Cost-effectiveness analysis (CEA) alongside randomized controlled trials often relies on self-reported multi-item questionnaires that are invariably prone to missing item-level data. The purpose of this study is to review how missing multi-item questionnaire data are handled in trial-based CEAs.Methods: We searched the National Institute for Health Research journals to identify within-trial CEAs published between January 2016 and April 2021 using multi-item instruments to collect costs and quality of life (QOL) data. Information on missing data handling and methods, with a focus on the level and type of imputation, was extracted.Results: A total of 87 trial-based CEAs were included in the review. Complete case analysis or available case analysis and multiple imputation (MI) were the most popular methods, selected by similar numbers of studies, to handle missing costs and QOL in base-case analysis. Nevertheless, complete case analysis or available case analysis dominated sensitivity analysis. Once imputation was chosen, missing costs were widely imputed at item-level via MI, whereas missing QOL was usually imputed at the more aggregated time point level during the follow-up via MI.Conclusions: Missing costs and QOL tend to be imputed at different levels of missingness in current CEAs alongside randomized controlled trials. Given the limited information provided by included studies, the impact of applying different imputation methods at different levels of aggregation on CEA decision making remains unclear. [ABSTRACT FROM AUTHOR]

• Early intervention has been the key work of the prevention of dementia. • Mindfulness has a significant effect on MCI patients with insomnia. • Mindfulness causes deep relaxation in the brain, increases self-awareness. • Mindfulness causes changes in the EEG associated with cognitive task. • Mindfulness can be primary and secondary prevention strategy to reduce costs. Current research on the effects of mindfulness therapy on MCI and insomnia has been inconsistent. It is still a hot topic of research and discussion. This study aimed to improve the sleep quality, cognition, and mental state of patients with mild cognitive impairment (MCI) with insomnia. A double-blind randomized controlled trial was conducted. Seventy-five patients who met the eligibility criteria were randomly assigned to the mindfulness (n = 38) or health education (n = 37) treatment group. The primary outcomes were sleep, measured by the Pittsburgh Sleep Quality Inventory, and cognition, measured by The Montreal Cognitive Assessment and Mini-Mental State Examination. Secondary outcomes included insomnia, measured by the Insomnia Severity Index, depression, anxiety, and perceived stress. EEG signals were collected at rest with eyes closed in the mindfulness state. The power spectrum was analyzed from these data. Cognitive function and sleep quality were significantly improved in the mindfulness group (95% confidence interval 0.04 - 0.05, 0.03 - 0.04, -5.58 - -1.55, respectively). Anxiety and perceived stress scores were significantly lower than those in the control group (95% confidence interval 0.002 - 0.004, 0.009 – 0.013, respectively). The power spectrum differences in δ, θ, β, and γ bands were significant between the rest and mindfulness states (P <.05). Good safety was achieved in both groups with no deaths or serious adverse events. Mindfulness improved sleep quality, cognitive function, and mentality of patients. Mindfulness practice caused deep relaxation in the brain and changes in electrical frequency bands associated with attention and cognitive tasks. Mindfulness learning can be performed successfully for individuals with MCI. Additionally, it is suitable for adoption in nursing homes. [ABSTRACT FROM AUTHOR]

Observational data suggest a potential for subclinical cardiac damage from intensive blood glucose or blood pressure (BP) control, particularly in adults with very low blood glucose and BP levels. However, this has not been tested in a randomized trial. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Research Controlled Evaluation (ADVANCE) study was a factorial, randomized trial designed to test the effects of intensive blood glucose (hemoglobin A1c ≤6.5% versus usual care) and intensive BP (combination of perindopril-indapamide versus placebo) control on vascular events in adults with diabetes. Using mixed effects tobit models, we determined the effect of the randomized interventions on change in subclinical cardiac injury (high sensitivity cardiac troponin T [hs-cTnT]) and strain (N-terminal b-type pro natriuretic peptide [NT-proBNP]), 1 year after randomization. Among the 682 participants, mean age was 66.1 (SD, 6.5) years; 40% were women. Mean baseline hemoglobin A1c was 7.4% (SD, 1.5) and systolic/diastolic BP was 147 (SD,21)/81 (SD,11) mmHg. After 1 year, intensive versus standard glucose control did not significantly change hs-cTnT (1.5%; 95%CI:-4.9,8.2) or NT-proBNP (−10.3%; 95%CI: −20.2%,0.9%). Intensive versus standard BP control also did not affect hs-cTnT (−2.9%; 95%CI: −8.9,3.6), but did significantly lower NT-proBNP by 21.6% (95%CI:-30.2%,-11.9%). Changes in systolic BP at 1 year (versus baseline) were strongly associated with NT-proBNP (P = 0.004), but not hs-cTnT (P = 0.95). In adults with diabetes, intensive BP control reduced NT-proBNP without increasing hs-cTnT, supporting the benefits and safety of intensive BP control in adults with diabetes. This trial is registered at clinicaltrials.gov , number: NCT00145925. • Intensive glucose control did not lower subclinical cardiac injury or strain. • Intensive blood pressure control lowered subclinical cardiac strain. • Intensive blood pressure control did not increase subclinical cardiac injury. • Intensive BP control is important and safe for adults with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Addition of placental histopathology studies to obstetric trials is likely to be cost-effective and may reveal structural changes suggestive of functional dysfunction to explain the success or failure of a clinical intervention. We share our recent experience in adding placental pathological examination to two clinical trials, retrospectively in one and at the outset in the other, so that other clinical trial investigators may benefit from it. The practical issues can be summarised as being regulatory and ethical, operational and reporting. Prospective inclusion of placental pathological examination as part of a clinical trial protocol is easier than retrospective, and is facilitated by fully-costed funding. • Adding placental histopathology into perinatal clinical trials, especially if multi-centre, can be challenging. • Issues are mainly practical and relate to meeting regulatory and ethics requirements, and operational and reporting procedures. • Fully-costed funding facilitates easier incorporation of placental histopathology into perinatal clinical trials. [ABSTRACT FROM AUTHOR]

• We designed a text message program, ASPIRE, aimed at coaching individuals to engage with peers to assist in meeting context-specific drinking limits. • Among a geographically diverse sample of non-collegiate young adults, we found high program engagement but suboptimal usability ratings. • Pilot trial results suggest the intervention reduces peer pressure and boosts peer support and goal confidence but needs to be further optimized to reduce drinking episodes. Scalable interventions attempting to nurture peer outreach to help young adults meet drinking limit goals remain under-developed. To address this gap, we developed ASPIRE, a text message intervention focused on coaching individuals to engage with close peers to assist them in meeting drinking limit goals. Non-collegiate young adults who had reported one or more heavy drinking days in the preceding month and were at least contemplating change were recruited through social media. Participants were randomly assigned to one of three 6-week text message interventions: Control, Goal Support, or ASPIRE. All groups completed baseline assessments and received weekly text message assessments on Thursdays and Sundays. Control and ASPIRE groups were prompted to complete web-based outcome assessments at 6- and 12-weeks. We enrolled 92 young adults from 31 US states (65% female; 73% White). All groups had high text response rates but intervention usability was sub-optimal. Follow-up rates were 87% at 6-weeks and 79% at 12-weeks. Compared to Control, ASPIRE participants reported significantly more peer support and less peer pressure to drink. ASPIRE exhibited higher goal confidence compared to the Goal Support group. Using multiple imputation, there were no significant differences in drinking outcomes between groups. Preliminary findings from this pilot study suggest that a text message intervention focused on nurturing peer outreach to help meet drinking limit goals holds promise in altering peer support and pressure as well as boosting drinking limit goal confidence. Design improvements are needed to reduce alcohol consumption. [ABSTRACT FROM AUTHOR]

Tuberose is widely recognized as one of the most important cut flowers in Iran and around the world. To assess the impact of triacontanol (TRIA) on various characteristics of tuberose, an experiment was conducted at the greenhouse of Gorgan University of Agricultural Sciences and Natural Resources. The experiment followed a completely randomized design with four treatments and three replicates. The treatments consisted of different levels of TRIA (0 mg/L as control, 50 mg/L, 100 mg/L, and 150 mg/L). These treatments were applied through foliar spraying three times: at 30, 45, and 60 days after planting. The results of this study indicated that foliar application of TRIA at 150 mg/L resulted in an increase in vase life, Ascorbate Peroxidase (APX) activity, and flower fresh weight. The concentration of 100 mg/L of TRIA showed greater effects on peroxidase (POD) activity, solution absorption, and photosynthetic pigments (chlorophyll a, b , and total) compared to other concentrations. Under natural conditions, P. tuberosa responded to changes in electrolyte leakage, weight, solution absorption, and antioxidant enzyme activity. Vase life changes were found to be correlated with the activity of antioxidant enzymes APX, POD, and Catalase (CAT). According to the regression coefficient, a one-unit change in APX, POD, and CAT resulted in 0.2901, 0.1143, and 0.0897 units changes in vase life, respectively. Overall, the application of TRIA as a foliar spray significantly enhanced most of the recorded traits compared to the control treatment. The findings from this study suggest that using TRIA hormone as a foliar spray can be highly beneficial in increasing the yield and biochemical properties of cut tuberose flowers. • Tuberose is an important cut flowers in many parts of the word. • Growth, yield and vase life of this plant is influenced by various physiological and biochemical traits. • Electrolyte leakage, weight changes, solution absorption, and antioxidant enzyme activity are the common influencing factors. • Foliar application of triacontanol hormone improved vase life, antioxidant enzymes, solution absorption, and photosynthetic pigments. • Triacontanol hormone as a foliar spray can be used to improve yield, vase life and biochemical properties of tuberose. [ABSTRACT FROM AUTHOR]

• Review essay discussing studies of fingerprint evidence in legal decisions. • Compares legal approaches with scientific research and advice. • Fingerprint evidence hardly ever challenged on methodological grounds. • Very little legal engagement with scientific research. • Reflects on effectiveness of adversarial trial safeguards. This article provides an overview of recent research on latent fingerprint evidence featured in reported legal decisions from England and Wales, Australia and New Zealand. The research casts doubts on the effectiveness of adversarial criminal procedure. Rather, than engage with the methodological foundations – e.g. validity and reliability – and the actual abilities of fingerprint examiners, for more than a century, challenges were based on legal considerations and the meaning of categorical identification for the specific proceedings. Lawyers challenged fingerprint evidence based on the circumstances in which reference prints were collected, whether fingerprint records were hearsay, whether relying on a fingerprint record is unfair because it suggests prior criminality, whether the jurors could make their own comparison and so forth. There is no reported consideration of the validity and reliability of fingerprint comparison, and no requirement for fingerprint examiners to qualify the significance of a match decision, even after the abandonment of point standards and the appearance of critical reports from the United States and Scotland, and advice from the Forensic Science Regulator. To the extent that they considered the admissibility and probative value of this prominent forensic science evidence, lawyers and judges relied heavily on proxies such as training, experience and long use. In consequence, the article considers how we should understand adversarial legal practice, the performance of lawyers and judges, as well as the implications for forensic scientists and their evidence. [ABSTRACT FROM AUTHOR]

Background: There are no treatments approved by the Food and Drug Administration for alopecia areata.Objective: To evaluate the efficacy and safety of baricitinib in patients with ≥50% scalp hair loss in a phase 2 study of adults with alopecia areata (BRAVE-AA1).Methods: Patients were randomized 1:1:1:1 to receive placebo or baricitinib 1 mg, 2 mg, or 4 mg once daily. Two consecutive interim analyses were performed after all patients completed weeks 12 and 36 or had discontinued treatment prior to these time points. The primary endpoint was the proportion of patients achieving a Severity of Alopecia Tool (SALT) score ≤20 at week 36. Logistic regression was used with nonresponder imputation for missing data.Results: A total of 110 patients were randomized (placebo, 28; baricitinib 1-mg, 28; 2-mg, 27; 4-mg, 27). The baricitinib 1-mg dose was dropped after the first interim analysis based on lower SALT30 response rate. At week 36, the proportion of patients achieving a SALT score of ≤20 was significantly greater in baricitinib 2-mg (33.3%, P = .016) and 4-mg (51.9%, P = .001) groups versus placebo (3.6%). Baricitinib was well tolerated with no new safety findings.Limitations: Small sample size limits generalizability of results.Conclusion: These results support the efficacy and safety of baricitinib in patients with ≥50% scalp hair loss. [ABSTRACT FROM AUTHOR]

To understand how COVID-19 pandemic has changed radiology research in Italy. A questionnaire (n = 19 questions) was sent to all members of the Italian Society of Radiology two months after the first Italian national lockdown was lifted. A total of 327 Italian radiologists took part in the survey (mean age: 49 ± 12 years). After national lockdown, the working-flow came back to normal in the vast majority of cases (285/327, 87.2%). Participants reported that a total of 462 radiological trials were recruiting patients at their institutions prior to COVID-19 outbreak, of which 332 (71.9%) were stopped during the emergency. On the other hand, 252 radiological trials have been started during the pandemic, of which 156 were non-COVID-19 trials (61.9%) and 96 were focused on COVID-19 patients (38.2%). The majority of radiologists surveyed (61.5%) do not conduct research. Of the radiologists who carried on research activities, participants reported a significant increase of the number of hours per week spent for research purposes during national lockdown (mean 4.5 ± 8.9 h during lockdown vs. 3.3 ± 6.8 h before lockdown; p =.046), followed by a significant drop after the lockdown was lifted (3.2 ± 6.5 h per week, p =.035). During national lockdown, 15.6% of participants started new review articles and completed old papers, 14.1% completed old works, and 8.9% started new review articles. Ninety-six surveyed radiologists (29.3%) declared to have submitted at least one article during COVID-19 emergency. This study shows the need to support radiology research in challenging scenarios like COVID-19 emergency. • COVID-19 outbreak drastically impacted on Italian radiological research. • Most ongoing radiological trials have been stopped during the first national lockdown. • Italian radiologists spent even more time on radiology research during the lockdown. • Many COVID-19 and non-COVID-19 trials have been pushed forward during the lockdown. [ABSTRACT FROM AUTHOR]

Renal stone disease is common and can cause emergency presentation with acute pain due to ureteric colic. International guidelines have stated the need for a multicentre randomised controlled trial (RCT) to determine whether a non-invasive outpatient (shockwave lithotripsy [SWL]) or surgical (ureteroscopy [URS]) intervention should be the first-line treatment for those needing active intervention. This has implications for shaping clinical pathways. To report a pragmatic multicentre non-inferiority RCT comparing SWL with URS. This trial tested for non-inferiority of up to two sessions of SWL compared with URS as initial treatment for ureteric stones requiring intervention. The primary outcome was whether further intervention was required to clear the stone, and secondary outcomes included quality of life assessment, severity of pain, and serious complications; these were based on questionnaires at baseline, 8 wk, and 6 mo. We included patients over 16 yr with a single ureteric stone clinically deemed to require intervention. Intention-to-treat and per-protocol analyses were planned. The study recruited between July 1, 2013 and June 30, 2017. We recruited 613 participants from a total of 1291 eligible patients, randomising 306 to SWL and 307 to URS. Sixty-seven patients (22.1%) in the SWL arm needed further treatment compared with 31 patients (10.3%) in the URS arm. The absolute risk difference was 11.7% (95% confidence interval 5.6%, 17.8%) in favour of URS, which was inside the 20% threshold we set for demonstrating noninferiority of SWL. This RCT was designed to test whether SWL is non-inferior to URS and confirmed this; although SWL is an outpatient noninvasive treatment with potential advantages both for patients and for reducing the use of inpatient health care resources, the trial showed a benefit in overall clinical outcomes with URS compared with SWL, reflecting contemporary practice. The Therapeutic Interventions for Stones of the Ureter (TISU) study provides new evidence to help guide the choice of modality for this common health condition. We present the largest trial comparing ureteroscopy versus extracorporeal shockwave lithotripsy for ureteric stones. While ureteroscopy had marginally improved outcome in terms of stone clearance, as expected, shockwave lithotripsy had better results in terms of health care costs. These results should enable patients and health care providers to optimise treatment pathways for this common urological condition. This level 1 evidence highlights only a slight difference between ureteroscopy (URS) and shockwave lithotripsy (SWL), supporting SWL as an outpatient treatment without anaesthetic or theatre requirements, particularly relevant after COVID-19. While URS had higher stone clearance, both modalities appear suitable for primary treatment choice. [ABSTRACT FROM AUTHOR]

Background: The DASH (Dietary Approaches to Stop Hypertension) diet has been determined to have beneficial effects on cardiac biomarkers. The effects of sodium reduction on cardiac biomarkers, alone or combined with the DASH diet, are unknown.Objectives: The purpose of this study was to determine the effects of sodium reduction and the DASH diet, alone or combined, on biomarkers of cardiac injury, strain, and inflammation.Methods: DASH-Sodium was a controlled feeding study in adults with systolic blood pressure (BP) 120 to 159 mm Hg and diastolic BP 80 to 95 mm Hg, randomly assigned to the DASH diet or a control diet. On their assigned diet, participants consumed each of three sodium levels for 4 weeks. Body weight was kept constant. At the 2,100 kcal level, the 3 sodium levels were low (50 mmol/day), medium (100 mmol/day), and high (150 mmol/day). Outcomes were 3 cardiac biomarkers: high-sensitivity cardiac troponin I (hs-cTnI) (measure of cardiac injury), N-terminal pro-B-type natriuretic peptide (NT-proBNP) (measure of strain), and high-sensitivity C-reactive protein (hs-CRP) (measure of inflammation), collected at baseline and at the end of each feeding period.Results: Of the original 412 participants, the mean age was 48 years; 56% were women, and 56% were Black. Mean baseline systolic/diastolic BP was 135/86 mm Hg. DASH (vs. control) reduced hs-cTnI by 18% (95% confidence interval [CI]: -27% to -7%) and hs-CRP by 13% (95% CI: -24% to -1%), but not NT-proBNP. In contrast, lowering sodium from high to low levels reduced NT-proBNP independently of diet (19%; 95% CI: -24% to -14%), but did not alter hs-cTnI and mildly increased hs-CRP (9%; 95% CI: 0.4% to 18%). Combining DASH with sodium reduction lowered hs-cTnI by 20% (95% CI: -31% to -7%) and NT-proBNP by 23% (95% CI: -32% to -12%), whereas hs-CRP was not significantly changed (-7%; 95% CI: -22% to 9%) compared with the high sodium-control diet.Conclusions: Combining a DASH dietary pattern with sodium reduction can lower 2 distinct mechanisms of subclinical cardiac damage: injury and strain, whereas DASH alone reduced inflammation. (Dietary Patterns, Sodium Intake and Blood Pressure [DASH - Sodium]; NCT00000608). [ABSTRACT FROM AUTHOR]

• Improved threshold compliance may improve outcomes from neurotrauma. • ICP threshold compliance was markedly improved with a threshold compliance tool. • A trial assessing our tool was negative, likely as a result of a delay in initiation.. Better physiologic threshold compliance holds promise for improving outcomes in neurocritical care patients. Our group developed a threshold compliance tool. This software computes and displays the proportion of values out of range in real time. We captured intracranial pressure (ICP) measures in our patients before and after implementation of this technology. Ten months after the threshold compliance tool was introduced we initiated a randomized controlled trial involving acute traumatic brain injury (TBI) patients to assess whether the tool was effective at reducing out-of-range ICP values. A total of 54 patients with ICP monitors were included in our analysis, 42 of whom sustained a TBI. Implementation of the threshold compliance tool was associated with an 85.3% reduction in ICP values exceeding 22 mmHg in neurocritical care patients (p = 0.004) and a 76.8% reduction in patients with TBI (p = 0.043). Out-of-range values in an area-under-the-curve analysis were reduced by 78.8% in all patients (p = 0.009) and in TBI patients by 77.9% (p = 0.051). Out-of-range values were not further reduced during our randomized controlled trial examining the threshold compliance tool, and a difference between treatment groups was not suggested. Implementation of a threshold compliance tool was associated with a marked and significant reduction in out-of-range ICP values. Benefit was, however, not evident in a randomized controlled trial. Our analysis provides a unique perspective on our failure to detect an apparent true difference and may provide insights into other neurotrauma trial failures. [ABSTRACT FROM AUTHOR]

Depersonalisation/derealisation symptoms are prevalent in psychosis patients, are associated with increased impairment, and may maintain psychosis symptoms. We aimed to establish the feasibility and acceptability of a brief, six session therapy protocol adapted from a Cognitive-Behavioural model of Depersonalisation-Derealisation Disorder (DDD) in participants with psychotic symptoms. A single-blind, randomised controlled trial was conducted with a treatment-as-usual control condition. Feasibility and acceptability estimates included rates of referral, acceptance, eligibility, consent, satisfaction and improved skills/knowledge to manage depersonalisation. Twenty-one individuals were recruited to the trial. Results suggest that the intervention was feasible and acceptable to participants and there is some signal of effect on clinical outcomes. There were some challenges in recruitment. Recruitment feasibility estimates from the research register used may not be informative for future trials recruiting directly from teams. Overall, the results suggest that further investigations would be of interest and recommendations for this are made. • First trial to target Depersonalisation/Derealisation in psychosis using CBT. • Intervention was feasible and acceptable to participants. • Promising preliminary clinical data. • Further investigations are required and recommendations are made. [ABSTRACT FROM AUTHOR]

• There are 1779 physical activity trials in the physiotherapy evidence database (PEDro). • The mean (SD) PEDro score was 5.3 (1.5) points out of 10, reflecting 'fair to poor' quality. • Journal impact factor is weakly correlated with trial quality (0.21, p < 0.001). • We make five recommendations to improve future trial quality. Observing trends in research publications helps to identify the quantity and quality of research produced, as well as reveal evidence gaps. No comprehensive review of the quality and quantity of physical activity intervention trials has been conducted. We aimed to investigate i) the volume and quality (and changes in these over time) of randomized controlled trials evaluating physical activity interventions, and ii) the association between journal ranking and trial quality. We searched the Physiotherapy Evidence Database (PEDro) for trials investigating physical activity interventions (no restrictions for population, comparison, or language). Descriptive statistics were used to describe the volume and quality of trials. The association between journal ranking (Journal Impact Factor) and trial quality (PEDro Scale) was examined using Spearman's rho correlation. We identified 1779 trials, of which 40% (n = 710) were published between 2016 and 2020. The mean (SD) total PEDro score was 5.3 (1.5) points out of 10, increasing over time from 2.5 (0.7) points in 1975–1980 to 5.6 (1.4) points in 2016–2020. Quality criteria that were least reported included blinding of intervention deliverers (therapists) (n = 3, 0.2%), participants (n = 21, 1.2%), or assessors (n = 541, 31%); concealed allocation to groups (n = 526, 30%); and intention to treat analysis (n = 764, 43%). There was a small correlation between trial quality and Journal Impact Factor (0.21, p < 0.001). A large volume of trials has investigated physical activity interventions. The quality of these trial reports is suboptimal but improving over time. Journal ranking should not be used for selecting high quality trials. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) has affected more than 96 million people worldwide, leading the World Health Organization (WHO) to declare a pandemic in March 2020. Although an optimal medical treatment of COVID-19 remains uncertain, an unprecedented global effort to develop an effective vaccine hopes to restore pre-pandemic conditions. Since cancer patients as a group have been shown to be at a higher risk of severe COVID-19, the development of safe and effective vaccines is crucial. However, cancer patients may be underrepresented in ongoing phase 3 randomised clinical trials investigating COVID-19 vaccines. Therefore, we encourage stakeholders to provide real-time data about the characteristics of recruited participants, including clearly identifiable subgroups, like cancer patients, with sample sizes large enough to determine safety and efficacy. Moreover, we envisage a prompt implementation of suitable registries for pharmacovigilance reporting, in order to monitor the effects of COVID-19 vaccines and immunisation rates in patients with cancer. That said, data extrapolation from other vaccine trials (e.g. anti-influenza virus) showed a favourable safety and efficacy profile for cancer patients. On the basis of the evidence discussed, we believe that the benefits of the vaccination outweigh the risks. Consequently, healthcare authorities should prioritise vaccinations for cancer patients, with the time-point of administration agreed on a case-by-case basis. In this regard, the American Society of Clinical Oncology and the European Society of Medical Oncology are advocating for cancer patients a high priority status, in the hope of attenuating the consequences of the pandemic in this particularly vulnerable population. • COVID-19 has affected more than 96 million people. WHO declared a pandemic in March 2020. • Cancer patients as a group have been shown to be at a higher risk of severe COVID-19. • Evidence from ongoing vaccine RCTs is currently lacking for cancer patients. • Data extrapolation from other vaccines showed a favourable safety and efficacy profile. • Cancer patients need vaccination prioritisation and tailored administration time-point. [ABSTRACT FROM AUTHOR]

Purpose: Relapse after complicated intra-abdominal infection (cIAI) remains common after treatment. The optimal antibiotic treatment duration for cIAIs is uncertain, especially in cases where source control is not achieved. We hypothesised that in patients with cIAIs, regardless of source control intervention, there would be a lower relapse rate with long-course antibiotics (28 days) compared with short course (≤ 10 days). We piloted a trial comparing ≤ 10-day with 28-day antibiotic treatment for cIAI. Methods: A randomised controlled unblinded feasibility trial was conducted. Eligible participants were adult patients with a cIAI that were diagnosed ≤ 6 days prior to screening. Randomisation was to long-course (28 days) or short-course (≤10 days) antibiotic therapy. Choice of antibiotics was determined by the clinical team. Participants were followed up for 90 days. Primary outcomes were willingness of participants to be randomised and feasibility of trial procedures. Results: In total, 172 patients were screened, 84/172 (48.8%) were eligible, and 31/84 (36.9%) were randomised. Patients were assigned to either the short-course arm (18/31, 58.0%) or the long-course arm (13/31, 41.9%). One patient in the short-course arm withdrew after randomisation. In the short-course arm, 4/17 (23.5%) were treated for a cIAI relapse vs 0/13 (0.0%) relapses in the long-course arm. Protocol violations included deviations from protocol-assigned antibiotic duration and interruptions to antibiotic therapy. Conclusions: This feasibility study identified opportunities to increase recruitment in a full trial. This study demonstrates completion of a randomised controlled trial to further evaluate if the optimum antibiotic duration for cIAIs is feasible. Trial Registration: ClinicalTrials.gov Identifier: NCT03265834 [ABSTRACT FROM AUTHOR]

Wilms tumour (WT) accounts for about 6% of all childhood cancers and overall survival of WT is about 90% in international protocols. However, for WT subgroups with much poorer prognoses, i.e. typically high-risk (unfavorable) histology and/or relapse, there is an unmet need to better understand the biology of WT and to translate biological findings into clinics through early phase clinical trials that evaluate innovative therapies. The main challenges are the small numbers of children suitable for early phase trials, the genetic heterogeneity of WT and the low number of somatic mutations that are currently considered 'druggable'. Accordingly, a joint meeting between clinical and biology experts from the international cooperative groups of the Renal Tumour Study Group of the International Society of Paediatric Oncology, the Renal Tumour Committee of the Children's Oncology Group and the European Innovative Therapies for Children with Cancer consortium and parents representatives was organised during the first SIOPE meeting in Prague, 2019. We reviewed WT molecular features, ongoing/planned early phase trials and explored available knowledge on organoid technology. The key messages were: (1) relapsed WT should undergo whenever possible thorough molecular characterization and be enrolled in protocols or trials with systematic data collecting and reporting; (2) WT displays few known 'actionable' targets and currently no novel agent has appeared promising; (3) we need to improve the enrolment rate of WT candidates in early phase trials especially for the relatively small subgroup of relapses with an adverse prognostic signature; (4) despite some agnostic early phase trials existing, development of WT-focused trials are warranted; (5) growing organoids with parallel testing of drug panels seems feasible and may direct individual treatment and encourage clinical researchers to incorporate the most promising agents into early phase trials. • A meeting at the first SIOPE identified the unmet needs for relapsed Wilms tumour (WT). • WT displays few known actionable targets and no novel agent seems promising. • Improvement of the enrolment rate for WT candidates in early phase trials needed. • Models like organoids with parallel testing help to improve theory suggestions. [ABSTRACT FROM AUTHOR]

Objective: To examine the factors associated with iatrogenic ureteral injury litigation and outcomes.Methods: The Westlaw legal database was queried for all iatrogenic ureteral injury cases. Variables extracted included available clinical factors, method of settlement, and litigation outcomes. Linear regression analysis was conducted to examine factors associated with award amount.Results: A total of 522 cases from 1961 to 2019 were included in the study. The most common specialty named was gynecology (353/512, 68.9%), followed by urology (89/512, 17.4%). The most common claim was intraoperative negligence (474/522 cases, 90.8%). Fifty two cases were settled or arbitrated and 470 went to trial. Settlement or arbitration was more likely in cases involving institution-only defendant (15.4% vs 7.3%, P< .01), academic institution (19.7% vs 7.1%, P < .01), and patient death (42.9% vs 10.7%; P < .001). Of cases that went to trial, the verdict favored the defendant in 339/470 cases (72.1%). The median award was $552,822.96 (interquartile range 187,007-1,063,603). Duration of temporary drainage ($5050/day, P = .02), delayed repair (P = .03), claim of inadequate workup (P = .03), and claim of failure to supervise trainee (P < .001) were significantly associated with increasing award amount.Conclusion: The majority of ureteral injury litigation ruled in favor of the defendant. However, when awarded, the amount was substantial and correlated with drainage duration, delayed repair, claim of inadequate workup, and failure to supervise trainee. These findings highlight factors perceived to be associated with significant distress and reflect trends in medicolegal decision-making. [ABSTRACT FROM AUTHOR]

Background: Neutralizing (buffering) lidocaine 1%/epinephrine 1:100,000 solution (Lido/Epi) with sodium hydrogen carbonate (NaHCO3) (also called sodium bicarbonate) is widely used to reduce burning sensations during infiltration of Lido/Epi. Optimal mixing ratios have not been systematically investigated.Objectives: To determine whether a Lido/Epi:NaHCO3 mixing ratio of 3:1 (investigational medicinal product 1) causes less pain during infiltration than a mixing ratio of 9:1 (IMP2) or unbuffered Lido/Epi (IMP3).Methods: Double-blind, randomized, placebo-controlled, crossover trial (n = 2 × 24) with 4 investigational medicinal products (IMP1-4).Results: The 3:1 mixing ratio was significantly less painful than the 9:1 ratio (P = .044). Unbuffered Lido/Epi was more painful than the buffered Lido/Epi (P = .001 vs IMP1; P = .033 vs IMP2). IMP4 (NaCl 0.9% [placebo]) was more painful than any of the anesthetic solutions (P = .001 vs IMP1; P = .001 vs IMP2; P = .016 vs IMP3). In all cases, the anesthesia was effective for at least 3 hours.Limitations: Results of this trial cannot be generalized to other local anesthetics such as prilocaine, bupivacaine, or ropivacaine, which precipitate with NaHCO3 admixtures.Conclusions: Lido/Epi-NaHCO3 mixtures effectively reduce burning pain during infiltration. The 3:1 mixing ratio is significantly less painful than the 9:1 ratio. Reported findings are of high practical relevance, given the extensive use of local anesthesia today. [ABSTRACT FROM AUTHOR]

Purpose: Although sorafenib as a standard of care for advanced hepatocellular carcinoma (HCC) prolongs overall survival (OS), its efficacy is limited owing to its unsatisfactory objective response and marginal survival benefit. To counter these limitations, we designed a single-arm, phase II trial with liver-directed concurrent chemoradiotherapy (LD-CCRT) and sequential sorafenib treatment in patients with advanced HCC.Methods and Materials: We enrolled advanced HCC patients diagnosed between 2014 and 2017 who were ineligible for curative treatment. During the first and last 5 days of 5-week radiation therapy, concurrent hepatic arterial infusion with 5-fluorouracil (500 mg/d) and leucovorin (50 mg/d) through an implanted port was administered 4 weeks after initiation of LD-CCRT and sequential sorafenib treatment (400 mg, twice daily). The primary endpoint was OS. This trial has been registered at clinicaltrials.gov.Results: Among the enrolled patients (n = 47), objective response rates 4 weeks after LD-CCRT and during/up to sorafenib maintenance were 44.7% and 53.2%, respectively. Overall, 9 patients (19.1%) underwent curative resection or transplantation after down staging. The median radiation dose was 60 Gy. The median OS was 24.6 months for the entire cohort and 13.0 months for the subgroup with tumor invasion into the main portal trunk or its first branch, whereas the median progression-free survival for the cohort and subgroup was 6.8 and 5.6 months, respectively. The most frequent treatment-related adverse events were diarrhea (36.2%) and hand-foot skin reaction (34%), which were manageable with conservative treatment.Conclusions: LD-CCRT and sequential sorafenib treatment provided favorable OS and progression-free survival with good tolerability. Tumor reduction using an initial LD-CCRT enabled down staging, subsequent curative treatment, and long-term survival in about 20% of the patients with advanced HCC. However, further randomized trials are required to confirm these results. [ABSTRACT FROM AUTHOR]

Young people, not in formal employment or education, face exceedingly high levels of intimate partner violence (IPV). We evaluated whether Stepping Stones and Creating Futures, compared with a wait-list control, can reduce IPV and strengthen livelihoods. A cluster randomized controlled trial with 34 clusters in urban informal settlements in eThekwini Municipality, South Africa. Participant inclusion criteria were aged 18–30 years, resident in the informal settlement, and not working or in education. A total of 676 women and 646 men were recruited from September 2015 to September 2016. At recruitment, participants were not blinded to study arm. Endline data were collected from March to October 2018 (24 months postenrollment). Analyses were by intention-to-treat and separate for men and women. No clusters withdrew; endline retention was 74.9% (n = 505) men and 80.6% (n = 545) women. At endline in the intervention arm, men's self-reported past year IPV perpetration was lower (physical IPV [adjusted odds ratio [aOR]:.71, 95% confidence interval [CI]:.51–.97], severe IPV [aOR:.70, 95% CI:.52–.94], and sexual IPV [aOR:.74, 95% CI:.54–1.03]). There was no difference in men's controlling behaviors (β =.06, 95% CI: −.51 to.63) or past month earnings (β =.21, 95% CI: −.42 to.83). For women, earnings were significantly higher in the intervention arm (β =.97, 95% CI:.43–1.51), but there were no differences for past year IPV experience (physical IPV [aOR:.92, 95% CI:.62–1.37]; sexual IPV [aOR:.90, 95% CI:.64–1.28], severe IPV [aOR:.93, 95% CI:.66–1.31]) or controlling behaviors (β = −.01, 95% CI: −.88 to.86). Stepping Stones and Creating Futures is effective in reducing men's self-reported perpetration of IPV and strengthening women's livelihoods, but not women's experiences of IPV. NCT03022370. Registered January 13, 2017. [ABSTRACT FROM AUTHOR]

Tranexamic acid reduces blood loss and transfusion requirements with no significant thrombotic adverse effects. Postoperative seizures have been seen in cardiac surgical patients in association with patient (advanced age, underlying neurologic disease, chronic kidney disease); surgical (open cardiac procedures, long bypass times); and drug (high tranexamic acid dose) risk factors. Tranexamic acid dosing regimens should be decreased in patients with chronic kidney dysfunction secondary to reduced clearance and drug accumulation. Optimal dosing for cardiac surgical patients has been recommended. Additional research is required to determine dosing regimens in major noncardiac surgery and plasma concentration levels associated with inducing seizures. [ABSTRACT FROM AUTHOR]

Objective: To provide an insightful summary of studies on biochemical markers for osteoarthritis (OA).Design: Two investigators systematically searched the electronic PubMed database for clinical studies into soluble biochemical markers for OA in humans that were published between 01-03-2018 and 01-03-2019. Data from selected publications were systematically extracted and tabulated and were summarized in a narrative review.Results: Out of 1,279 publications, 124 fulfilled all selection criteria and were selected for data extraction. The majority were around knee OA, cross-sectional in design, relatively small, and/or focused on one or a few biochemical markers. Among the intervention studies, relatively many were on non-pharmacological interventions, used clinical outcomes and/or were rather short. Some leads that were provided by this year's studies pertained to less conventional inflammatory mediators, oxidative stress, acidosis, angiogenesis and/or autoantibody formation.Conclusions: This year's biochemical marker studies did provide potential leads for therapeutic targets or other biochemical marker applications that require robust and strategic follow-up research to be validated. [ABSTRACT FROM AUTHOR]

• Randomised controlled trial testing positive-emotional and norm-based safer gambling messages. • Positive-emotional messages were rated most helpful and easily understood. • The highest-rated message was "only bet what you can afford" Effective gambling messages should curb time and money spent on gambling, since these are the behaviours proximal to gambling-related harm. Studies that aim to find what messages best achieve these objectives are scarce, and most focus on electronic gaming machine (EGM) gambling rather than sports and race betting. The present study aimed to gather longitudinal evidence on previously identified messaging strategies. In an experiment, two types of messages, positive-emotional and norm-based, were contrasted against a control condition with generic messages (e.g., gamble responsibly). By stratified random assignment, participants (N = 2,074, 36% female), were exposed to 3 unique messages in each of 3 weeks, exclusive of pre- and post-surveys in weeks 1 and 5, respectively. There were no significant differences by condition in amounts-bet commercially on sports or race betting, time spent gambling, gambling-harm experienced, gambling-urges nor risk-related gambling beliefs. However, there was a significant decrease in all these outcomes over weeks 1 through 5. The messages may not have been the factor that contributed to the decrease in outcomes over time, as participating in the study may have also prompted self-reflection on gambling expenditure. Positive-emotional messages were rated most helpful and easily understood, and the highest-rated message was the control message, "only bet what you can afford." Despite no differences found between the conditions, the present study provided evidence that self-reflection on gambling expenditure is well-rated by gamblers as being helpful. Future experiments should be conducted to gauge the robustness of this finding. [ABSTRACT FROM AUTHOR]

Metastatic HER2 -positive breast cancer remains a significant clinical challenge with a poor prognosis. The introduction of anti- HER2 therapies has significantly improved survival in early and advanced stages. However, patients with metastatic HER2 -positive breast cancer eventually experience progression due to de novo or acquired resistance. This review article comprehensively analyzes the current management of metastatic HER2 -positive breast cancer, addressing the complexities in determining the optimal HER2 -targeted therapy sequence. Discussion of selected peer-reviewed articles and expert opinion. We explore the actual standard of care and the emerging therapeutic options that hold promise for further improving patient care and survival in this aggressive breast cancer subtype. This article highlights vital toxicities linked to anti- HER2 therapies, emphasizing their recognition across treatments as interstitial lung disease, diarrhea, or left ventricular dysfunction. Oncology nurses have a key role to play in detecting potential adverse effects of anti- HER2 therapies. The development of new drugs, as antibody–drug conjugates, with a distinct toxicity profile makes it necessary for us to be updated on the management of these new toxicities. [ABSTRACT FROM AUTHOR]

The fragility index (FI) measures the robustness of statistically significant findings in randomized controlled trials (RCTs) by quantifying the minimum number of event conversions required to reverse a dichotomous outcome's statistical significance. In vascular surgery, many clinical guidelines and critical decision-making points are informed by a handful of key RCTs, especially regarding open surgical versus endovascular treatment. The objective of this study is to evaluate the FI of RCTs with statistically significant primary outcomes that compared open vs endovascular surgery in vascular surgery. In this meta-epidemiological study and systematic review, MEDLINE, Embase, and CENTRAL were searched for RCTs comparing open versus endovascular treatments for abdominal aortic aneurysms, carotid artery stenosis, and peripheral arterial disease to December 2022. RCTs with statistically significant primary outcomes were included. Data screening and extraction were conducted in duplicate. The FI was calculated by adding an event to the group with the smaller number of events while subtracting a nonevent to the same group until Fisher's exact test produced a nonstatistically significant result. The primary outcome was the FI and proportion of outcomes where the loss to follow-up was greater than the FI. The secondary outcomes assessed the relationship of the FI to disease state, presence of commercial funding, and study design. Overall, 5133 articles were captured in the initial search with 21 RCTs reporting 23 different primary outcomes being included in the final analysis. The median FI (first quartile, third quartile) was 3 (3, 20) with 16 outcomes (70%) reporting a loss to follow-up greater than its FI. Mann-Whitney U test revealed that commercially funded RCTs and composite outcomes had greater FIs (median, 20.0 [5.5, 24.5] vs median, 3.0 [2.0, 5.5], P =.035; median, 21 [8, 38] vs median, 3.0 [2.0, 8.5], P =.01, respectively). The FI did not vary between disease states (P =.285) or between index and follow-up trials (P =.147). There were significant correlations between the FI and P values (Pearson r = 0.90; 95% confidence interval, 0.77-0.96), and the number of events (r = 0.82; 95% confidence interval, 0.48-0.97). A small number of event conversions (median, 3) are needed to alter the statistical significance of primary outcomes in vascular surgery RCTs evaluating open surgical and endovascular treatments. Most studies had loss to follow-up greater than its FI, which can call into question trial results, and commercially funded studies had a greater FI. The FI and these findings should be considered in future trial design in vascular surgery. [ABSTRACT FROM AUTHOR]

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Recent years have witnessed an expanded use of single-photon emission CT and PET for a wide range of clinical applications, including imaging of brain abnormalities. As a result, molecular brain imaging is now being more extensively utilized in criminal cases, in particular in the sentencing phase of a trial. This perspective aims to provide a brief overview for the practicing radiologist of this expanded use of single-photon emission CT and PET in criminal cases and will discuss the role of radiology in this field. [ABSTRACT FROM AUTHOR]

The European Randomized study of Screening for Prostate Cancer (ERSPC) has shown a 20% relative reduction in prostate cancer mortality after 16 yr [rate ratio (RR) 0.80], but centers varied by attendance, screen interval, biopsy compliance, contamination in the control arm, and treatments. We used a microsimulation model, calibrated to the ERSPC individual-level data, to predict influence of study features on the results. The relative reduction in prostate cancer mortality would have been somewhat larger with improved study features: increased attendance (90% attendance in all volunteer-based and 70% in all population-based centers, resulting in RR 0.77), a 2-yr screen interval (RR 0.75), and an 80% biopsy compliance (RR 0.79). The RR would have been substantially lower with a 30% attendance (RR 0.92), 40% biopsy compliance (RR 0.90), or 100% contamination (RR 0.85). The variations in results by trial center may reflect differences in study design and performance and results of our simulations highlight the effect of quality indicators in prostate-specific antigen screening in different settings. We evaluated the effect of various features of prostate-specific antigen (PSA) screening on its effectiveness. The compliance to PSA testing and those having a biopsy after an elevated PSA substantially influence the prostate cancer mortality. The prostate cancer mortality reduction found in the European Randomized study of Screening for Prostate Cancer (ERSPC) is close to what would have been expected when all centers would have performed as the best performing center. [ABSTRACT FROM AUTHOR]

Background: Antenatal multiple micronutrient (MM) supplementation improves birth outcomes relative to iron-folic acid (IFA) in developing countries, but limited data exist on its impact on pregnancy micronutrient status.Objective: We assessed the efficacy of a daily MM (15 nutrients) compared with IFA supplement, each providing approximately 1 RDA of nutrients and given beginning at pregnancy ascertainment, on late pregnancy micronutrient status of women in rural Bangladesh. Secondarily, we explored other contributors to pregnancy micronutrient status.Methods: Within a double-masked trial (JiVitA-3) among 44,500 pregnant women, micronutrient status indicators were assessed in n = 1526 women, allocated by cluster to receive daily MM (n = 749) or IFA (n = 777), at 10 wk (baseline: before supplementation) and 32 wk (during supplementation) gestation. Efficacy of MM supplementation on micronutrient status indicators at 32 wk was assessed, controlling for baseline status and other covariates (e.g., inflammation and season), in regression models.Results: Baseline status was comparable by intervention. Prevalence of deficiency among all participants was as follows: anemia, 20.6%; iron by ferritin, 4.0%; iron by transferrin receptor, 4.7%; folate, 2.5%; vitamin B-12, 35.4%; vitamin A, 6.7%; vitamin E, 57.7%; vitamin D, 64.0%; zinc, 13.4%; and iodine, 2.6%. At 32 wk gestation, vitamin B-12, A, and D and zinc status indicators were 3.7-13.7% higher, and ferritin, γ-tocopherol, and thyroglobulin indicators were 8.7-16.6% lower, for the MM group compared with the IFA group, with a 15-38% lower prevalence of deficiencies of vitamins B-12, A, and D and zinc (all P < 0.05). However, indicators typically suggested worsening status during pregnancy, even with supplementation, and baseline status or other covariates were more strongly associated with late pregnancy indicators than was MM supplementation.Conclusions: Rural Bangladeshi women commonly entered pregnancy deficient in micronutrients other than iron and folic acid. Supplementation with MM improved micronutrient status, although deficiencies persisted. Preconception supplementation or higher nutrient doses may be warranted to support nutritional demands of pregnancy in undernourished populations. This trial was registered at clinicaltrials.gov as NCT00860470. [ABSTRACT FROM AUTHOR]

Prospects for recovery after traumatic brain injury (TBI) are often underestimated, potentially leading to withdrawal of care in the comatose TBI patient who may ultimately have a favorable outcome with aggressive care. Outcomes and trajectories of recovery in a large series of patients with TBI were evaluated at 30, 90, and 180 days postinjury. A secondary analysis of the phase 3 Citicoline Brain Injury Treatment (COBRIT) trial was performed analyzing recovery trajectories and long-term outcomes at 30, 90, and 180 days postinjury. A Glasgow Outcome Scale-Extended (GOS-E) score of 5 or higher was considered favorable. Pearson χ2 analysis was used, and a P value of 0.05 was considered significant. A locally weighted, polynomial regression model was used to model recovery trajectories in a nonlinear fashion. Subjects with TBI in the COBRIT trial had high rates of favorable outcome (57% of severe TBI, 86% of moderate TBI, and 93% of complicated mild TBI) at 6-month follow-up. These favorable outcomes often converted from high rates of unfavorable outcome at initial 1-month follow-up (85% of severe TBI, 57% of moderate TBI, and 21% of complicated mild TBI). Recovery trajectories had not plateaued at 6 months, suggesting that further improvement occurs beyond 6 months postinjury. In this secondary analysis of the COBRIT trial, most patients had favorable outcomes by the GOS-E at 6 months postinjury in all complicated mild and moderate TBI groups, with over half of patients with severe TBI achieving a favorable outcome as well. Of subjects in a vegetative state (GOS-E score 2) at 1 month postinjury, 18% improved to a favorable outcome by 6 months postinjury. There was substantial improvement in all groups from 1 to 6 months, and this improvement may continue beyond 6 months. Clinical trials in TBI should consider recovery curves with repeated measures to assess outcomes because arbitrary single-moment outcome determination likely underestimates treatment effect in TBI care. [ABSTRACT FROM AUTHOR]

Highlights • A randomized trial in painful diabetic neuropathy comparing capsaicin to placebo for 8 weeks. • The efficacy of 0.075% capsaicin lotion was similar to placebo. • Capsaicin lotion was well tolerated but local skin reactions were common. Abstract Objective A randomized, double-blinded, crossover, placebo controlled trial was conducted to evaluate the efficacy and safety of 0.075% capsaicin lotion for treating painful diabetic neuropathy (PDN). Patients and methods PDN subjects were randomized to receive 0.075% capsaicin/placebo for 8 weeks, then crossing over to the other treatment after a 4-weeks washout period. Primary endpoint was the change in visual analog scale score of pain severity. Secondary outcomes were score changes in Neuropathic Pain Scale, short-form McGill Pain Questionnaires, and proportions of patients with pain score reductions of 30% and 50%, and adverse events. Results A total of 42 subjects were enrolled, 27 completed at least an 8-week treatment period. Intention-to-treat analysis showed no significant improvement in pain control with capsaicin lotion compared with placebo for all pain measures and proportion of patients who had 30% or 50% pain relief, respectively. Per protocol analysis were consistent. Capsaicin lotion was well tolerated but local skin reactions were common. Conclusion In patients with PDN, the efficacy of 0.075% capsaicin lotion was similar to placebo but was well tolerated. More work is needed to assess different capsaicin formulations. [ABSTRACT FROM AUTHOR]

Abstract Introduction Shortages of vaccine supplies repeatedly occur, limiting our abilities to prevent influenza. Therefore, increasing production volume remains a priority. The presently licensed seasonal influenza vaccines contain 15 µg of viral hemagglutinin per strain in adult, and up to 60 µg in elderly patients. Decreasing the amount of viral parts while maintaining efficacy is one way of increasing production capacity. Methods This was multicenter, stratified (18–60 years and >60 years of age), prospective, randomized, double-blind, active-controlled, parallel-arm, non-inferiority clinical trial, conducted in the European Union, involving 1206 patients. We used hemagglutination inhibition assay to assess the immunogenicity of a newly developed, whole virion, seasonal trivalent influenza vaccine, containing 6 µg hemagglutinin per strain (FluArt, Hungary) and to assess whether it is non-inferior to the presently licensed vaccine containing 15 µg hemagglutinin per strain. Safety and tolerability of both vaccines were assessed based on EMEA guidelines. Results The reduced dose vaccine containing 6 µg of hemagglutinin per strain was safe and non-inferior to the currently licensed 15 µg vaccine, not only in adult, but also in elderly patients, according to the immunogenicity criteria by the FDA and EMEA (seroconversion, seroprotection and post/pre vaccination GMT ratios), and it fulfilled all applicable licensing requirements for both age groups. Conclusions Based on the results, the reduced dose vaccine was licensed in the EU member state Hungary and safely administered in over 1.5 million cases so far. The amount of viral hemagglutinin needed can be reduced by using a whole virion vaccine with aluminum phosphate adjuvants. Registration This study was registered by the European Clinical Trials Database, EudraCT, number: 2011-003314-16. [ABSTRACT FROM AUTHOR]