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Black women with breast cancer often present with more aggressive disease compared with other races, contributing to an increased risk of cancer mortality. Despite this inequity, Black women remain severely underrepresented in breast cancer clinical trials. We aim to characterize factors that influence a woman's decision to enroll in a clinical trial, with the goal of identifying clinical interventions to aid in the recruitment of vulnerable groups. A cross-sectional, descriptive study was conducted using a questionnaire adapted from 2 prevalidated surveys investigating factors influencing clinical trial enrollment. The survey was administered to women with curable breast cancer during a single follow-up visit at 4 different sites within a university medical system where all patients are screened for clinical trial eligibility. Chi-square tests and Mann-Whitney U tests were used to assess associations or differences between the populations. One hundred ninety-four out of 209 women completed the survey, giving a compliance rate of 93%. Twenty-six percent of women self-identified as Black, most women were located at community sites (67.1%), most women had diagnoses of early-stage disease (I: 57.7%, II: 29.4%), and 81% of women had some collegiate-level education. Black women were younger at diagnosis (P =.005) and less likely to be married (P =.012) but more often lived with family members (P =.003) and had a lower median income (P <.001). According to the survey, Black women were less likely to trust their care team (P =.032), more likely to believe that research ultimately harms minorities (P <.001), and had a stronger belief in God's will determining illness and wellness (P <.001). Recurring themes of trust in the health care team, patient education, and advancement of cancer treatments were discussed in the focus groups. Failure to offer clinical trials and mistrust in research institutions may pose the greatest hindrances to the enrollment of Black women in clinical trials. Empowering women through education and fostering trustworthy relationships can encourage greater clinical trial participation. [ABSTRACT FROM AUTHOR]

The year 2023 marked the 25th anniversary of the first detected outbreak of Nipah virus disease. Despite Nipah virus being a priority pathogen in the WHO Research and Development blueprint, the disease it causes still carries high mortality, unchanged since the first reported outbreaks. Although candidate vaccines for Nipah virus disease exist, developing new therapeutics has been underinvested. Nipah virus disease illustrates the typical market failure of medicine development for a high-consequence pathogen. The unpredictability of outbreaks and low number of infections affecting populations in low-income countries does not make an attractive business case for developing treatments for Nipah virus disease—a situation compounded by methodological challenges in clinical trial design. Nipah virus therapeutics development is not motivated by commercial interest. Therefore, we propose a regionally led, patient-centred, and public health-centred, end-to-end framework that articulates a public health vision and a roadmap for research, development, manufacturing, and access towards the goal of improving patient outcomes. This framework includes co-creating a regulatory-compliant, clinically meaningful, and context-specific clinical development plan and establishing quality standards in clinical care and research capabilities at sites where the disease occurs. The success of this approach will be measured by the availability and accessibility of improved Nipah virus treatments in affected communities and reduced mortality. [ABSTRACT FROM AUTHOR]

Nursing- and healthcare-associated pneumonia (NHCAP) constitutes most of the pneumonia in elderly patients including aspiration pneumonia in Japan. Lascufloxacin (LSFX) possesses broad antibacterial activity against respiratory pathogens, such as Streptococcus spp. And anaerobes inside the oral cavity. However, the efficacy and safety of LSFX in NHCAP treatment remains unknown. We aimed to evaluate the efficacy and safety of LSFX tablets in the treatment of patients with NHCAP. In this single-arm, open-label, uncontrolled study, LSFX was administered to patients with NHCAP at 24 facilities. The study participants were orally administered 75 mg LSFX once daily for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC). The secondary endpoints included clinical efficacy at the time of end of treatment (EOT), early clinical efficacy, microbiological efficacy, and safety analysis. During the study period, 75 patients provided written informed consent to participate and were included. Finally, 56 and 71 patients were eligible for clinical efficacy and safety analyses, respectively. The median age of the patients was significantly high at 86 years. All patients were classified as having moderate disease severity using the A-DROP scoring system. LSFX tablets demonstrated high efficacy rates of 78.6 % at TOC and 89.3 % at EOT. The risk factors for resistant bacteria or aspiration pneumonia did not affect clinical efficacy. No severe adverse events associated with the study drugs were observed. Oral LSFX is an acceptable treatment option for moderate NHCAP in elderly patients who can take oral medications. [ABSTRACT FROM AUTHOR]

The increasing development of intelligent technologies for hand hygiene (HH) compliance audit has the potential to create an alternative to direct observation (DO), which is still considered the gold standard but has disadvantages such as lack of standardized monitoring practices, Hawthorne effect, insufficient sample size, and time/resource consumption. We aimed to share our preliminary results on the impacts of intelligent monitoring technology installation (IMTI) and additional modalities on healthcare workers' (HCWs') HH compliance in a Burn Center, according to the "5 Moments of HH" concept defined by the World Health Organization (WHO). Methods: A quasi-experimental longitudinal trial was conducted over eleven months.The first phase of the three-stage study evaluated basic HH compliances obtained by DO. The system-defined HH performances, which IMTI recorded, were assessed in the second phase. Finally, the effect of IMTI and additional modalities was determined in the third stage. 15202 HH events were performed by 41 HCWs, and a total of 20095 HH opportunities were observed. Four hundred fifty-five opportunities were in the preinstallation phase, and 19640 were during the total post-installation period. IMTIdefined performance rates in both Phase 2 (71.2%) and Phase 3 (80.5%) were generally considerably higher than HH compliances obtained from DO (58.5%). Nurses, physical therapy /anesthesia technicians, and housekeeping personnel showed significant increases, which was insignificant in physicians in phase 2. Meanwhile, a sustained increase was observed regarding IMTI and additional modalities of HH compliance of all HCWs in Phase 3. IMTI has significantly increased HH performance rates. Furthermore, combining the IMTI with additional modalities as components of a multimodal strategy recommended by WHO appears to affect the sustainability of the increasing trend of HCWs' HH compliance. • Infection-prevention/-control is vital to the survival of burn patients. • The primary route of infection transmission in burn patients is through the hands of healthcare workers. • Healthcare workers' hand hygiene is critical in reducing healthcare-associated infections. • Intelligent monitoring technology installation has significantly increased hand hygiene performance rates. [ABSTRACT FROM AUTHOR]

As immunotherapy makes its way into the perioperative setting, a growing number of clinical trials are expanding the evidence base for resectable non-small cell lung cancer (NSCLC) management. Identifying the optimal treatment pattern—whether it's neoadjuvant, adjuvant, or a combination of both—is a crucial next step, particularly in pinpointing which patients benefit the most. This decision-making process requires a multi-disciplinary treatment team capable of utilizing tissue and plasma genomic testing to inform therapeutic choices. Leveraging the perioperative treatment platform, it remains pivotal to integrate circulating tumor DNA (ctDNA) monitoring into clinical trial design efficiently and provide clear guidance on treatment. [ABSTRACT FROM AUTHOR]

• Advantages and challenges of a dedicated patient registry for people with CFTR-RD. • The CFTR-RD risk for infants with a CRMS/CFSPID designation. • Peculiarities of genetic counseling in people and families with CFTR-RD. • Identification of barriers to disseminate, implement and monitor CFTR-RD management. • Feasibility of clinical trials in people with CFTR-RD. After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders. [ABSTRACT FROM AUTHOR]

Clinical trial participation continues to be low, slowing new cancer therapy development. Few strategies have been prospectively tested to address barriers to enrollment. We investigated the effectiveness of a physician audit and feedback report to improve clinical trial enrollment. We conducted a randomized quality improvement study among radiation oncologists at a multisite tertiary cancer network. Physicians in the intervention group received quarterly audit and feedback reports comparing the physician's trial enrollments with those of their peers. The primary outcome was trial enrollments. Among physicians randomized to receive the feedback report (n = 30), the median proportion of patients enrolled during the study period increased to 6.1% (IQR, 2.6%-9.3%) from 3.2% (IQR, 1.1%-10%) at baseline. Among those not receiving the feedback report (n = 29), the median proportion of patients enrolled increased to 4.1% (IQR, 1.3%-7.6%) from 1.6% (IQR, 0%-4.1%) at baseline. There was a nonsignificant change in the proportion of enrollments associated with receiving the feedback report (−0.6%; 95% CI, −3.0% to 1.8%; P =.6). Notably, there was an interaction between baseline trial accrual and receipt of feedback reports (P =.005), with enrollment declining among high accruers. There was an increase in enrollment throughout the study, regardless of study group (P =.001). In this study, a positive effect of physician audit and feedback on clinical trial enrollment was not observed. Future efforts should avoid disincentivizing high accruers and might consider pairing feedback with other patient- or physician-level strategies. The increase in trial enrollment in both groups over time highlights the importance of including a comparison group in quality improvement studies to reduce confounding from secular trends. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy. This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov , NCT02851797 , and is complete. Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1–11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17–1·37) for boys receiving givinostat and 1·48 (1·32–1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745–0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred. Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy. Italfarmaco. [ABSTRACT FROM AUTHOR]

• The Registry data are consistent with literature on genotype phenotype correlation. • The Registry data are a helpful clinical resource. • The Registry is a powerful resource to inform all areas of translational research. • The Registry can provide data collection services in response to new research needs. • Continued investment will unlock further potential to ultimately benefit patients. The Myotubular and Centronuclear Myopathy Registry is an international research database containing key longitudinal data on a diverse and growing cohort of individuals affected by this group of rare and ultra-rare neuromuscular conditions. It can inform and support all areas of translational research including epidemiological and natural history studies, clinical trial feasibility planning, recruitment for clinical trials or other research studies, stand-alone clinical studies, standards of care development, and provision of real-world evidence data. For ten years, it has also served as a valuable communications tool and provided a link between the scientific and patient communities. With the anticipated advent of disease-modifying therapies for these conditions, the registry is a key resource for the generation of post-authorisation data for regulatory decision-making, real world evidence, and patient-reported outcome measures. In this paper we present some key data from the current 444 registered individuals with the following genotype split: MTM1 n=270 , DNM2 n=42 , BIN1 n=4 , TTN n=4 , RYR1 n=12 , other n=4, unknown n=108. The data presented are consistent with the current literature and the common understanding of a strong genotype/phenotype correlations in CNM, most notably the data supports the current knowledge that XLMTM is typically the most severe form of CNM. Additionally, we outline the ways in which the registry supports research, and, more generally, the importance of continuous investment and development to maintain the relevance of registries for all stakeholders. Further information on the registry and contact details are available on the registry website at www.mtmcnmregistry.org. [ABSTRACT FROM AUTHOR]

• Although clinical trial methods and conduct are well established, efforts are needed to optimize consistent monitoring of harm outcomes of trials. • Work done in the cystic fibrosis clinical trials space have focused on rates and characteristics of adverse events. • Attribution of adverse events to the intervention is more likely in the active drug group than in the placebo group. • Females were less likely to have attribution of the adverse event to the assigned treatment highlighting the need to develop improved processes in clinical trial monitoring. Although work to date in cystic fibrosis (CF) has elucidated frequencies and characteristics of adverse events, the accuracy of attribution of relatedness to study drug by investigators has not been assessed. We aimed to determine whether there was an association of attribution by group allocation in CF clinical trials. We conducted a secondary analysis from 4 CF trials of all persons who experienced an AE. Our primary outcome was the odds of an AE related to active study drug and predictor of interest was the treatment allocation. We constructed a multivariable generalized estimating equation model allowing for repeated measures. A total of 785 subjects (47.5% female, mean age 12 years) had 11,974 AEs, of which 430 were serious. AE attribution was greater with receipt of active study drug as compared to placebo but did not reach statistical significance (OR 1.38, 95% CI 0.98–1.82). Significantly associated factors included female sex (OR 0.58, 95% 0.39–0.87), age (OR 1.24, 95% CI 1.06–1.46) and baseline lung function (per 10%, OR 1.16, 95% CI 1.05–1.28). In our large study, there was a non-significant but greater odds of AE attribution (a key element of clinical trial reporting) to active study drug based on assigned treatment to study drug or control which suggests that there is a trend in physicians to attribute blinded safety data to the active drug. Interestingly, females were less likely to have AE attribution to study drug and warrants further work in development and validation of monitoring guidelines and processes. [ABSTRACT FROM AUTHOR]

• Impaired quality of life in SLE can be of greater concern from the patient's perspective than disease activity assessed by the physician. • Adherence to EULAR-based QIs by physicians does not suffice to provide a favorable impact on the quality of life of SLE patients. • An integrated disease modification approach, based on disease activity indices and subjective patients' wellness, should be considered as primary end point in clinical trials. Quality indicators (QIs) for systemic lupus erythematosus (SLE) management based on the 2019 update of European League Against Rheumatism (EULAR) recommendations have been recently proposed. We aimed to determine whether adherence to QIs was associated with patient reported outcome (PRO). Adherence to a set of 18 EULAR-based QIs and correlation with PRO assessed by Lupus Impact Tracker (LIT) was tested in a cohort of 162 SLE patients. On average, SLE patients received 41% (33; 52.5) of recommended care. Higher adherence to monitoring-related QIs was associated with an older age, a shorter SLE disease duration and a more severe disease (i.e. Class III/IV/V nephritis). LIT demonstrated that the average impact of lupus on patients' life was of 30% (12.5;47.5). In multivariable analysis, patients of female gender (OR 0.25, 95% 0.05–0.94; p = 0.05), with lupus CNS (OR 0.33, 95%CI 0.08–1.05; p = 0.08) and skin involvements (OR 0.49, 95%CI 0.23–1.04; p = 0.07) had higher odds of experiencing a negative impact of the lupus on their life. No association were found between adherences to QIs by physicians and reported quality of life in lupus patients. Our study confirms a variable degree of clinicians' adherence to QIs for SLE and shows no clear association between QIs adherence and patient reported outcome. Adherence to QIs by physicians are not enough to impact the quality of life of patients. [ABSTRACT FROM AUTHOR]

Childhood dementias are a group of over 100 rare and ultra-rare pediatric conditions that are clinically characterized by chronic global neurocognitive decline. This decline is associated with a progressive loss of skills and shortened life expectancy. With an estimated incidence of one in 2800 births and less than 5% of the conditions having disease-modifying therapies, the impact is profound for patients and their families. Traditional research, care, and advocacy efforts have focused on individual disorders, or groups classified by molecular pathogenesis, and this has established robust foundations for further progress and collaboration. This review describes the shared and disease-specific clinical changes contributing to childhood dementia and considers these as potential indicators of underlying pathophysiologic processes. Like adult neurodegenerative syndromes, the heterogeneous phenotypes extend beyond cognitive decline and may involve changes in eating, motor function, pain, sleep, and behavior, mediated by physiological changes in neural networks. Importantly, these physiological phenotypes are associated with significant carer stress, anxiety, and challenges in care. These phenotypes are also pertinent for the development of therapeutics and optimization of best practice management. A collective approach to childhood dementia is anticipated to identify relevant biomarkers of prognosis or therapeutic efficacy, streamline the path from preclinical studies to clinical trials, increase opportunities for the development of multiple therapeutics, and refine clinical care. [ABSTRACT FROM AUTHOR]

Systematic cognitive training and aerobic exercise programs have emerged as promising interventions to improve cognitive deficits in first-episode schizophrenia, with successful outcomes closely linked with greater treatment engagement (e.g., higher attendance and homework completion rates). Unfortunately, treatment disengagement from these services remains a persistent issue. Intrinsic motivation, or the willingness to exert effort because a task is inherently interesting or meaningful, has emerged as a promising malleable personal factor to enhance treatment engagement. This study investigated whether early task-specific intrinsic motivation and its domains (e.g., interest, perceived competence, and value) predicted treatment engagement within the context of intensive cognitive training and aerobic exercise interventions over a 6-month period. Thirty-nine participants with first-episode schizophrenia were administered baseline measures of task-specific intrinsic motivation inventories, one for cognitive training and one for exercise, and completed a 6-month randomized clinical trial comparing a neuroplasticity-based cognitive training plus aerobic exercise program against the same cognitive training alone. Results indicated that higher baseline scores of intrinsic motivation for cognitive training, specifically early perceptions of task interest and value, were predictive of greater cognitive training and exercise group attendance. Scores for exercise-specific intrinsic motivation were generally unrelated to indices of exercise participation, with the exception that the gain over time in perceived choice for exercise was linked with greater exercise homework completion and a similar directional tendency for greater in-clinic exercise attendance. This study provides support for monitoring and enhancing motivation early during service delivery to maximize engagement and the likelihood of successful treatment outcomes. [ABSTRACT FROM AUTHOR]

During recent years, the burden of bureaucracy in clinical research has increased dramatically, adversely impacting the activity of investigators and clinical research teams. Although compliance with the Declaration of Helsinki, the guidelines for Good Clinical Practice (GCP), and other applicable regulations remains unquestionable, their overinterpretation and substitution by the internal operating procedures of sponsors and Contract Research Organizations (CROs) have increased the administrative burden. A survey conducted by the European Society for Medical Oncology (ESMO) Clinical Research Observatory (ECRO) among 940 investigators confirmed that they considered that the administrative burden in clinical research is excessive; that administrative procedures could be reduced without affecting the safety and the rights of the patients and the quality of the data; and that bureaucracy represents an obstacle for clinical research. A panel of physicians with extensive experience in clinical research, composed by members of the ECRO and the ESMO Scientific Medical and Public Policy divisions, analyzed clinical trial procedures related to administrative workflow, pharmacovigilance, and medical care. The panel identified situations that generate debate between investigators and sponsors/CROs and selected real clinical scenarios that exemplify such situations. The panel discussed and proposed specific recommendations for those situations, based on GCP. This initiative aspires to streamline clinical research procedures and to become a platform for discussion among all clinical trial stakeholders, with the aim of promoting the sustainability of clinical research and the care of cancer patients. • The burden of bureaucracy in clinical research is overwhelming investigators and clinical research teams. • This ESMO manuscript proposes a framework of principles to improve sponsoring and monitoring of clinical trials. • We expect this awareness call to streamline clinical research and to promote the welfare of patients. [ABSTRACT FROM AUTHOR]

1. Describe the potential benefits and harms of remote video monitoring of hospitalized palliative care patients. 2. Describe strategies that may help guide future implementation of remote video monitoring in the palliative care setting to maximize safety benefits while minimizing harm. Remote Video Monitoring (RVM) is increasingly used by hospitals for patient safety and monitoring but may come with unique risks and ethical considerations for patients receiving Palliative Care. Since COVID, the adoption of remote video monitoring (RVM) has accelerated to reduce staff infectious exposures while monitoring patient safety. While evidence supports RVM's cost-effectiveness and equivalence to a sitter in preventing falls, there remains scant implementation guidance or research on potential harms, particularly for Palliative Care patients. A 29-year-old man with familial adenomatous polyposis and desmoid fibromatosis requiring multiple treatment modalities and bulky disease in his neck requiring tracheostomy has followed with Palliative Care for complex pain requiring repeated admissions. Following the implementation of universal RVM, he expressed mistrust of his room camera, stating that it impacted his emotional well-being, ability to sleep, and led to a perception that all medication intake was being monitored. On a previous admission, the patient had a makeshift covering placed on the camera. On the present admission, the camera was disabled but not permitted to be covered per hospital policy. Despite assurances, the patient refused to leave his unmonitored bathroom, refused nursing assessments, and threatened to leave against medical advice. RVM fractured previously trusting relationships with the Palliative Care team. RVM offers potential safety benefits, but also poses risks, exemplified in this case. It may enhance safety for Palliative Care patients, who may be frail and at risk for medication side effects and delirium-related complications. RVM use in patients prone to substance use disorder may enhance safety but could further stigmatization. Thought should be given to the minimum surveillance necessary to avoid being intrusive during private moments, such as decision-making among caregivers, religious rituals, or intimate moments during end-of-life care. When feasible, consent should be explicit, and options for physical covering of the camera should be offered. Further research is needed to guide implementation, particularly as artificial intelligence technology advances. Innovative TechnologiesEthical / Legal Aspects of Care [ABSTRACT FROM AUTHOR]

In this letter, we propose a miniaturization scheme of inkjet printed ionic sensing electrodes by adding graphene into the ion-selective PVC film not only to reduce the impedance of the ionic liquid layer of the electrode but also to increase the electrode capacitance for the reduction of the response time. Based on the scheme, we present a fully inkjet-printed electrochemical ion-selective sensor comprising a working electrode and reference electrode, which are inkjet-printed Ag NPs/PEDOT:PSS-graphene/PVC -graphene and Ag/AgCl (s) /ionic liquid PVC-graphene layer structures, respectively. The printed ion-selective working electrode has been miniaturized to a size of 22,400 μm2 equivalent to a square shape of ∼150 × 150 μm2 comparable to the size of a human cell. By adding graphene to the ion selective PVC film, more than 90 % charge transfer resistance reduction can be achieved and the shunt capacitance is increased by 3.4-fold in shunt capacitance compared to the film without graphene, thereby more than 33 % reduction of the response time required to reach equilibrium. Meanwhile, the se miniaturized potassium sensors using the working electrodes with/without adding graphene have been integrated with in-lab signal-processing and wireless-transmission module to yield similar results to the one measured by commercial electrochemical workstation showing a great potential for real-time monitoring in portable clinical trials. Specifically, the proposed sensor utilizing graphene-enhanced electrodes demonstrates a linearity uncertainty of 2.9 mV, which is approximately half of the uncertainty observed in the sensors lacking graphene integration. [Display omitted] • Inkjet printed ion-selective electrodes with a size of ∼150′150 mm2 exhibit stable and rapid OCP responses. • Graphene-added ion selectivity membranes exhibit good ion selectivity. • Miniaturized K+ and Na+ electrodes with 57.5 and 57.1 mV/decade (R>99%) show potential for real-time monitoring. • Miniaturized ionic sensors show reductions of over 65% in output potential variation and over 30% in response time. [ABSTRACT FROM AUTHOR]

Clinical trial monitoring is evolving from labor-intensive to targeted approaches. The traditional 100% Source Data Monitoring (SDM) approach fails to prioritize data by significance, diverting attention from critical elements. Despite regulatory guidance on Risk-Based Monitoring (RBM), its widespread implementation has been slow. Our study teams assess the study's overall risk, document heightened and critical risks, and create a study-specific risk-based monitoring plan, integrating SDM and Central Data Monitoring (CDM). SDM combines a fixed list of pre-identified variables and a list of randomly identified variables to monitor. Identifying variables follows a two-step approach: first, a random sample of participants is selected, second, a random set of variables for each participant selected is identified. Sampling weights prioritize critical variables. Regular team meetings are held to discuss and compile significant findings into a Study Monitoring Report. We present a random SDM sample and a Study Monitoring Report. The random SDM output includes a look-up table for selected database elements. The report provides a holistic view of the study issues and overall health. The proposed random sampling method is used to monitor a representative set of critical variables, while the Study Monitoring Report is written to summarize significant monitoring findings and data trends. The report allows the sponsor to assess the current status of the study and data effectively. Communicating and sharing emerging insights facilitates timely adjustments of future monitoring activities, optimizing efficiencies, and study outcomes. [ABSTRACT FROM AUTHOR]

Computerized assessment of brain tumor identification and discrimination process from magnetic resonance imaging is of immense concern for improved investigation, growth rate prediction, treatment planning and monitoring of clinical trials. Due to extensive diversification of tumors and complex outline interactions between sub-regions, it is of a great challenge to extract significant features. The proposed approach starts with Grey Wolf Optimization based Gabor Filtering for enhancement process and spatial fuzzy c-means clustering algorithm for segmentation purpose. Following this, we apply non-sub-sampled shearlet transformation to investigate multi-scale space-frequency representation of tumor data. In order to measure the hierarchical correlation pattern of tumors, interlayer cross spectral coherence function is analyzed in terms of some significant indices such as fundamental global mean, secondary mean pair, span of secondary mean pair, percentage of samples having values greater than upper secondary mean pair and percentage of samples having values smaller than lower secondary mean pair. Additionally, topological profile of tumor getsassessed from its phase spectrum distribution pattern. Regarding this, some phase spectrum distribution-based quantifiers such as phase-sign change counter, phase change frequency, figure of merit and standard deviation of phase sign change location are introduced as the significant indices. These feature quantifiers have been fed to a deep neural network model and hybrid AdaBoost classifier to discriminate the state of benignancy/malignancy of tumors. Experimental results demonstrate that the overall accuracy attained by the proposed model are 99.67 %, 98.92 %, 96.89 %, 97.82 %, 96.98 %, 99.54 %for the datasets of Harvard University, BraTS −2018, −2019, −2020, −2021 and Kaggle respectively. Apart from this, promising sensitivity rate of the model helps us to avoid the risk of false negativity. Altogether, these qualities make the proposed model superior to the state of art techniques. [ABSTRACT FROM AUTHOR]

Background: Clozapine must be retitrated after 2 consecutive days or more of missed doses owing to the risk of severe hypotension, bradycardia, and cardiac arrest. However, other important adverse events such as somnolence, sialorrhea, or respiratory depression can occur without severe cardiovascular sequalae. These other unintended consequences are not well characterized in the literature. Three cases are reported, highlighting the concerns for continuing clozapine without retitration after periods of not taking the medication. Implications are discussed as well as how pharmacists can collaborate with other disciplines to mitigate safety risks associated with clozapine for hospitalized patients.Case Summaries: The first case highlights the importance of medication reconciliation and verifying adherence before clozapine continuation in the hospital. Waiting for collateral information and missing one dose are safer than unknowingly resuming clozapine. The second case suggests that it may be safer to consider patients with unexplained worsening psychiatric symptoms as nonadherent and even partially reduced clozapine doses after nonadherence may be unsafe. The final case demonstrates the importance assessing comedications (e.g., warfarin, phenytoin) that have available therapeutic drug monitoring to suggest nonadherence. Each case resulted in significant adverse events requiring transfer to a higher level of care or prolonged hospitalization.Practice Implications: Continuation of psychiatric medications when a patient is admitted to the hospital is important to prevent worsening of symptoms. However, assessment of clozapine adherence and confidence in that assessment is crucial to prevent clozapine intoxication, severe hypotension, and even death. Pharmacists are uniquely positioned to assess clozapine adherence and ensure patient safety. A hospital-based service was created at a 2000-bed academic medical center to improve transitions of care when patients are admitted with clozapine. The process was created in collaboration with the psychiatric consultation service. Through this process, pharmacists also complete appropriate hematologic monitoring and ongoing clinical monitoring for adverse events. [ABSTRACT FROM AUTHOR]

• Tensor electrical impedance myography reduces complex multi-frequency, multi-electrode configuration impedance data down to a single metric. • This metric captures disease progression more sensitively than other bulbar disease biomarkers, including tongue strength and the ALS-FRS-R. • Tensor electrical impedance myography improves the bulbar biomarker potential of electrical impedance measurements in ALS. Electrical impedance myography (EIM) is a promising biomarker for amyotrophic lateral sclerosis (ALS). A key issue is how best to utilise the complex high dimensional, multi-frequency data output by EIM to fully characterise the progression of disease. Muscle volume conduction properties were obtained from EIM recordings of the tongue across three electrode configurations and 14 input frequencies (76 Hz–625 kHz). Analyses of individual frequencies, averaged EIM spectra and non-negative tensor factorisation were undertaken. Longitudinal data were collected from 28 patients and 17 healthy volunteers at 3-monthly intervals for a maximum of 9 months. EIM was evaluated against the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) bulbar sub-score, tongue strength and an overall bulbar disease burden score. Longitudinal changes to individual patient EIM spectra demonstrated complex shifts in the spectral shape. At a group level, a clear pattern emerged over time, characterised by an increase in centre frequency and general shift to the right of the spectral shape. Tensor factorisation reduced the spectral data from a total of 168 data points per participant per recording to a single value which captured the complexity of the longitudinal data and which we call tensor EIM (T-EIM). The absolute change in tensor EIM significantly increased within 3 months and continued to do so over the 9-month study duration. In a hypothetical clinical trial scenario tensor EIM required fewer participants (n = 64 at 50% treatment effect), than single frequency measures (n range 87–802) or ALSFRS-R bulbar subscore (n = 298). Changes to tongue EIM spectra over time in ALS are complex. Tensor EIM captured and quantified disease progression and was more sensitive to changes than single frequency EIM measures and other biomarkers of bulbar disease. Objective biomarkers for the assessment of bulbar disease in ALS are lacking. Tensor EIM enhances the biomarker potential of EIM data and can improve bulbar symptom monitoring in clinical trials. [ABSTRACT FROM AUTHOR]

Objectives: To determine the incidence of out-of-range segesterone acetate (NES) concentrations in participants of a pharmacokinetic/pharmacodynamic trial of a continuous use contraceptive vaginal ring (CVR) releasing NES and estradiol (E2). We hypothesized that out-of-range concentrations reflect nonadherent ring use and predict ovulation risk.Study Design: We conducted a secondary analysis of data from a prospective, multi-centered, randomized, Phase IIa dose-finding trial for a CVR releasing NES and E2. Our primary outcome was the risk of ovulation associated with out-of-range NES events. We calculated the 5th and 95th percentile NES concentrations of subjects at steady state to determine high and low cutoffs. We used a Fisher's exact test to determine group differences, and calculated the relative risk of ovulation for each group.Results: We analyzed available serum NES data from cycles 2 (n = 172), 3 (n = 156) and 7 (n = 115) to determine the 5th and 95th percentile of all NES concentrations (64, 296 pg/mL). In the 443 cycles of observation, no ovulations occurred in participants with NES concentrations within the expected range. In contrast, we found ovulatory elevations of progesterone in 21 cycles with out-of-range values. Of these, 15 (71%) cycles had evidence of one or more nonadherent low and 6 (29%) one or more unexpected peak. The relative risk of ovulation increased with evidence of multiple non-adherent levels.Conclusions: We found out-of-range NES concentrations, suggestive of improper use of a CVR associated with an increased risk of ovulation, with a direct relationship between the number of out-of-range events and the relative risk.Implications: The results of this study support the use of out-of-range serum NES values as a marker of adherence in contraceptive clinical trials of continuous vaginal rings, and suggest that nonadherence occurs even in early phase clinical trials with close monitoring. [ABSTRACT FROM AUTHOR]

The association between early improvement and subsequent change in cognition is unexamined in antidementia clinical trials. We aimed to examine the consequences of early-response to antidementia medication in Alzheimer's disease. Participant-level data were analyzed from five pivotal clinical trials of donepezil for Alzheimer's disease lasting up to 24 weeks (N = 1917). Early-response was based on Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) change scores under minus four from baseline to week six, otherwise classified non-response; then subgrouped by donepezil or placebo. The primary analysis tested the group differences in ADAS-Cog change from baseline for the interval after week six up to 24, based on a three-level mixed-effects model repeated measures (MMRM) model. Four models of increasing complexity were tested, and the most parsimonious model was examined in the primary analysis. The remaining models were tested in sensitivity analysis. In the analytic sample, 32.09% (N = 396/1234) of donepezil and 24.01% (N = 164/683) of placebo participants were classified as early responders, and 67.91% donepezil (N = 838/1234), 75.99% (N = 519/683) placebo participants were not. MMRM identified a statistically significant (P < 0.05) responder group effect. Marginal means (MM) demonstrated more improvement for the early responders (donepezil: MM = −4.13, 95% CI = -5.93, −2.32; placebo MM = 1.81, 95% CI = −4.12, 0.50), compared to non-early responders (donepezil MM = 0.05, 95% CI = -1.40, 1.51; placebo MM = 2.59, 95% CI = 0.99, 4.19). Results replicated in sensitivity analysis. Our results inform clinicians regarding the extent and consequences of early improvement in cognitive functioning and potentially contribute to treatment monitoring and the design of clinical trials for Alzheimer's disease. • Examined early cognitive response to antidementia medication in Alzheimer's disease. • Used individual-participant data from five pivotal clinical trials of donepezil for Alzheimer's disease. • Early responders showed more cognitive improvement compared to non-early responders. • Early improvement is relevant to treatment monitoring and clinical trial design. [ABSTRACT FROM AUTHOR]

Our approach for GvHD prevention aims to mimic the paradigm of fetomaternal tolerance. HLA-G is an immunomodulatory molecule expressed in the placenta to protect the foetus from maternal rejection and is normally epigenetically silenced. In preclinical studies, we epigenetically modulated T cells in a clinical scale GMP protocol to produce a potent induced-Treg population enriched in HLA-G+ T-cells(iG-Tregs). We herein present the study protocol of the first-in-human phase I/II clinical trial of iG-Tregs and the monitoring assessment of the first patient(IG01) included(EUDRACT2021-006367-26). We conduct a phase I/II, dose escalation(0,1/0,5/1,5x106iG-Tregs cells/kg) study in adult patients undergoing allo-HCT from an HLA-matched sibling donor, which serves as the donor for iG-Tregs manufacturing. The primary objective is to assess the safety and the maximum tolerable dose of iG-Tregs and the secondary objective is to assess the efficacy in preventing GvHD. Patient and donor eligibility is evaluated at d+30 after allo-HCT, donor undergoes leukapheresis, and infusion is performed 4 weeks(W) later. aGVHD≥II at any time before infusion leads to exclusion. Product is released after standard QC testing and should contain≥10%HLA-G+CD3+cells. After infusion, the patient undergoes pharmacological immunosuppression tapering. Product and patient samples are also analysed for their phenotype(Cytek) and their TCR repertoire(Illumina). IG01 is a 58 y/o female with high-risk AML who underwent allo-HCT(CMV+/+) from her 51 y/o female sibling. The final iG-Tregs product contained 60x106cells, 82,3% CD3+ cells and 13,52% HLAG+CD3+ cells. iG-Tregs infusion(5,6x106 cells; 0,1x106/kg) took place on d+64 followed by cyclosporine tapering. The patient did not present infusion-related toxicities, remained GvHD-free, disease-free, without CMV reactivation with no other complications up to last follow-up(d+231). Integrated molecular and phenotypic monitoring of IG01 revealed an initial rise in HLA-G+ T-cells at W1 (baseline vs W1; 3,69% vs 4,88%), retention of 7,2% of iG-Tregs-derived TCR clonotypes at W4, and increase of CD4+CD25+CD127- nTregs at W8 post-infusion(baseline vs W8; 2,06% vs 3,56%)(Figure 1). This is the active first-in-human phase I/II study of iG-Tregs in the context of GvHD. IG01 displayed excellent clinical outcome with initial data hinting at the possible transient iG-Tregs persistence in vivo and intricate interplay within the T cell compartment. [ABSTRACT FROM AUTHOR]

Cancer is a leading cause of morbidity and mortality worldwide, and coordinated research efforts are vital to improve global outcomes. Clinical or translational research is usually planned, coordinated and executed by clinical researchers. With this survey we aimed to identify the main hurdles in front of young clinical investigators in oncology. An anonymized survey was distributed using social media between April and November 2022. Target population were health-care professionals in the field of oncology – physicians, nurses and researchers. We divided participants according to working experience (<40 vs. >40 years of age) and country of practice (Europeans vs. non-Europeans). We received 121 responses from participants practicing in 36 countries. Eighty-seven (72%) of the participants were under 40 years. Eighty-nine (74%) were from European countries and thirty-two (26%) were from non-European. Experienced and European professionals were more likely to be involved in all different aspects of clinical trials. The main source of funding – independently of geographic location – were industry grants. Investigators out of Europe have less participation in international grants. Over 50% of participants dedicate time for clinical research from their personal time and are not paid for it. Almost 50% of investigators don't have access to an experienced mentor in their institution. The majority of respondents to our survey are active clinical researchers. Our data indicate that access to education and training as well as possibilities for appropriate networking, and specifically lack of mentorship, are key limiting factors in developing clinical research by healthcare professionals. [ABSTRACT FROM AUTHOR]

1. Understand the background, context, and curricular content of a training program to teach clinical trials skills for palliative care research. 2. Describe the the impact (satisfaction, skill confidence, number of grants acquired, and total $ amount) of the palliative care Clinical Trials Intensive. A Clinical Trials Intensive (CTI) program focused on providing scientists with skills to conduct rigorous palliative care clinical trials has trained 207 investigators over 6 years. Participants reported high satisfaction and confidence in the conduct of palliative care trials and were awarded 140 extramural grants totaling $139.3 million. While a growing body of research shows benefit for palliative care interventions in the context of serious illness, large gaps in evidence remain. Currently, too few palliative care scientists have the skills to rigorously conduct the clinical trials needed to improve care. We describe: 1) the creation and 2) the impact (satisfaction, skill confidence, number of grants acquired, and total $ amount) of the palliative care Clinical Trials Intensive (CTI). Interdisciplinary senior faculty developed the program curriculum and selected participants following the NIH review model. Scholars completed a program evaluation (quantitative, 1-5 scale with 5= excellent; qualitative) on program satisfaction (content, length, organization, overall value and networking opportunities), and confidence in palliative care skills. Scholars completed annual surveys on grants acquired. We used descriptive analyses to summarize quantitative data and deductive analyses to map qualitative responses onto the satisfaction and confidence domains. The CTI components include: 1) pre-work; 2) didactics; 3) faculty consultations; and 4) small group work designing a new clinical trial building off limitations of a published study. Since 2016, we trained 207 investigators across 12 cohorts, from 122 institutions. Disciplines included nursing (69), psychology (22), social work (13), medicine (68), and others or combined degrees (35). Quantitative analyses showed high confidence and satisfaction with the program ranging from 4.2-4.9 across all domains assessed, which aligned with qualitative responses. Participation by investigators has led to 140 funded grants from 60 different fundings sources, totaling $139.3 million. The CTI increased skills and funding success in palliative care research. The CTI is an effective and efficient solution to increase number and rigor of palliative care clinical trials. Educational, training and supervision/Leadership, program development and evaluation [ABSTRACT FROM AUTHOR]

Cancer patients are often overwhelmed when being informed about clinical trials. However, there is a lack of evidence-based strategies to improve physician-patient communication in this area. This study assessed the experiences and needs of cancer patients and their support persons (SPs) during the informed consent (IC) process prior to participation in clinical trials. 17 semi-structured interviews with cancer patients and their SP were conducted and analysed using a framework analysis. Most respondents reported feeling well informed about the clinical trial. However, core aspects of the study were often not understood highlighting a dissonance between perceived and actual recall and understanding. Many participants trusted that the trial recommended was the best available care and only skimmed the consent form or did not read it at all. This is the first German study to analyse both cancer patients' and SPs' perspectives on IC processes. Although many feel well informed, our results suggest a significant gap in recall and understanding of core components of clinical trials which hinders IC. Further interventional research is required to improve the consent processes prior to clinical trials in order to provide optimal, patient-centred care. • There may be discrepancy between patients' perceived and actual understanding. • This may hinder optimal patient-centred healthcare decision making. • Our findings suggest a number of strategies to improve care in this area. • These include two shorter consultations and a protocol for the IC conversation. [ABSTRACT FROM AUTHOR]

• Phase 3, Randomized, Placebo-controlled trial of Umifenovir against COVID-19 • Unique dosage of 800mg BID was tested • Statistically significant endpoints achieved for Mild-asymptomatic patients • Umifenovir is efficacious for Mild-asymptomatic patients To test efficacy, safety and tolerability of Umifenovir in non-severe COVID-19 adult patients. We carried out randomized, double-blind, placebo-controlled, multicenter, phase III trials involving adult (18-75 years), non-severe COVID19 patients, randomized 1:1 on placebo or Umifenovir (800 mg BID, maximum 14 days) respectively along with standard-of-care. The primary endpoint for Asymptotic-mild patients was time to nasopharyngeal swab RT-PCR test negativity. For Moderate patients, the average change in the ordinal scale from the baseline scores on the eight-point WHO ordinal scale was assessed. 132 patients were recruited between 3rd October to 28th April 2021, of which 9 discontinued due to various reasons. In Mild-asymptomatic patients (n=82), we found that 73% patients in the Umifenovir arm were RT-PCR negative, while 40% patients in the placebo arm were negative (P=0.004) on day 5. However, in the moderate group (n=41), the WHO scores for the Umifenovir arm was not statistically significant (P=0.125 on day 3), while it was statistically significant in the Mild-asymptomatic group (P=0.019 on day 5). Umifenovir meets the primary and secondary endpoint criteria and exhibits statistically significant efficacy for Mild-asymptomatic patients. It is efficacious, safe and well-tolerated at the tested dosage of 800mg BID, maximum 14 days. [ABSTRACT FROM AUTHOR]

• Home spirometry can help track lung health to intervene early in pulmonary exacerbations. • The eICE trial showed no differences in FEV1 but identified health care use differences. • Outpatient visit costs were significantly higher comparing users to non-users of home spirometry. • However, overall health care costs were similar in users and non-users of home spirometry. Home spirometry with regular symptom assessment is one strategy to track lung health to intervene early in episodes of pulmonary exacerbations (PE). In a multi-center randomized controlled trial home spirometry and symptom tracking demonstrated no significant differences regarding the primary clinical endpoint, FEV 1 , compared to usual care, but did identify differences in healthcare utilization. We used data from the Early Intervention in Cystic Fibrosis Exacerbation (eICE) study to evaluate whether home monitoring of PE is a cost-minimizing intervention in the context of this randomized trial. We reviewed healthcare resource utilization of all 267 eICE participants, including outpatient visits, antibiotics and hospitalizations. Prices were identified in the IBM/Watson MarketScanⓇ Commercial Claims and Encounters Databases and averaged over the 2014-2017 period. Using total healthcare utilization costs, we generated summary statistics by intervention and protocol arm (total cost, mean cost, standard deviation). We performed Welch Two Sample t-tests to determine if total costs and cost by type of utilization differed significantly between groups. Outpatient visit costs were significantly higher by 13% in the Early Intervention (EI) than in the usual care (UC) arm ($3,345 vs. $2,966). We found no significant differences in outpatient antibiotic, hospitalization, or total health care costs between the arms. Within the context of the eICE trial, outpatient visits were significantly higher in those with experimental home spirometry care, but that did not translate into statistically significant differences of overall health care costs between the two arms. [ABSTRACT FROM AUTHOR]

Neuroinflammation has been connected to the pathophysiology of major depressive disorder (MDD) and neurochemical biomarkers of glial pathology could aid the diagnosis and might support patient stratification and monitoring in clinical trials. Our study aimed to determine the utility of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, for the differential diagnosis and monitoring of MDD. Employing Simoa technology we measured levels of GFAP in prospectively collected serum samples from 81 age-matched patients with MDD, schizophrenia (SZ), bipolar disorder (BP), and healthy controls (HC). Highest GFAP levels were determined for MDD. At a cut-off of 130 pg/ml, MDD could be discriminated with 87% sensitivity from SZ and BP (specificity 70%) and from HC (specificity 56%). GFAP levels increased with age (r = 0.5236, p = 0.0002) and with MDD severity quantified based on the Montgomery-Åsberg Depression Rating Scale (r = 0.4308, p = 0.0221). Neurofilament light chain serum levels were not different in the diagnostic groups and not associated with GFAP levels (r = 0.0911, p = 0.576) pointing to an independence of astrocyte activation on neurodegeneration. Our study provides first evidence that serum GFAP levels could improve the differential diagnosis of MDD and that depression severity could be objectively quantified using serum GFAP levels. Furthermore, serum GFAP might represent a marker to monitor astroglial pathology in the course of MDD. [ABSTRACT FROM AUTHOR]

Background: The Scale for the Assessment and Rating of Ataxia (SARA) is commonly used as the primary outcome measure in therapeutic trials. Driven by spontaneous comments from ataxia patients participating in a trial, we aimed to examine the clinical meaningfulness of the SARA from their perspective.Methods: Twenty mildly to moderately affected individuals with spinocerebellar ataxia type 3 (SARA score 11.3 ± 4.1) completed a custom-designed survey. SARA item scores were compared with self-reported complaints in everyday life. Discrepancies between SARA ratings and patients' daily life experiences were reported as "overestimation" (i.e., a SARA item score more than 0, but no corresponding complaints) or "underestimation" (i.e., a SARA item score of 0, yet accompanying complaints).Results: Patient-physician discrepancies were present in essentially all SARA items except for gait. The mean number of overestimated SARA points per patient was 3.1 ± 2.1. Underestimation occurred less frequently, but was relatively common in stance and fast alternating hand movements. Three quarters of patients marked gait as the most valuable SARA item, while the remaining 25% selected stance.Conclusion: On average, a quarter of total SARA score does not reflect meaningful impairments from a patient's perspective. Our data suggest that it is doubtful whether potential improvements at some of the items will be perceived as comparably important by mildly to moderately affected ataxia patients. These observations question the utility of delta SARA score as the most appropriate primary endpoint in clinical trials and call for the addition of outcome measures, such as the Patient Global Impression of Change scale and validated ataxia-specific patient-reported outcome measures. [ABSTRACT FROM AUTHOR]

Introduction: The diagnosis or exclusion of obstructive stable coronary artery disease (SCAD) in clinical practice is challenging and therefore clinical guidelines provide recommendations on the use of non-invasive and invasive testing. For Germany, data obtained from the OECD and health insurances indicate a potential non-adherence to guideline-recommended diagnostic pathways. However, there is a lack of prospective and reliable evidence for appropriate use of invasive coronary angiography (CA) in Germany.Objective: To provide evidence on the nature and extent of guideline non-adherence in patients undergoing CA with presumed obstructive SCAD in Germany and, to evaluate the clinical and economic consequences of potential deviations in guideline adherence.Methods: ENLIGHT-KHK is a multicentre, prospective observational study recruiting 1500 patients being admitted for CA with presumed obstructive SCAD and exclusion of acute myocardial infarction (DRKS00015638). The primary outcome measure is the adherence to clinical guidelines in the decision-making process for use of CA. Therefore, the patients' diagnostic pathways and adherence to German and European guidelines will be assessed using clinical data, health-claims data, and a patient questionnaire. The primary safety outcome is a composite of myocardial infarction, stroke and all-cause death. Secondary outcome measures are periprocedural complications and costs. Using a decision-analytic model, the clinical and economic impact of observed guideline adherence in clinical practice will be assessed. Potential barriers and facilitators of guideline-adherent decision-making will be evaluated via semi-structured interviews.Conclusions: ENLIGHT-KHK will give insights into the appropriateness of invasive CA in Germany and enable the development of concepts to improve guideline-adherence in the German health-care setting. [ABSTRACT FROM AUTHOR]

There are very rich publications devoted to group sequential design, adaptive design and trial monitoring for continuous, binary and time to event endpoints. Many authors also discuss fixed design, blinded sample size re-estimation design and group sequential design for studies with a negative binomial outcome. Nonetheless, literature is sparse in adaptive design for a trial with a negative binomial endpoint. The features of such an endpoint in a flexible trial design setting remains inadequately understood. In this research, we seek to bridge this knowledge gap by offering a thorough examination of utilizing data components from a two-stage adaptive design for unblinded conditional power calculation and corresponding sample size re-estimation. We also provide expression for calculating the probability of meeting the futility criterion to determine the appropriate timing for the interim analysis. To evaluate the performance of the design, we conduct simulations to assess its operation characteristics. Finally, we provide a helpful and illustrative example to demonstrate the practical applications of the methods. [ABSTRACT FROM AUTHOR]

Clinical trials often include interim analyses of the proportion of participants experiencing an event by a fixed time-point. A pre-specified proportion excluded from a corresponding confidence interval (CI) may lead an independent monitoring committee to recommend stopping the trial. Frequently this cumulative proportion is estimated by the Kaplan-Meier estimator with a Wald approximate CI, which may have coverage issues with small samples. We reviewed four alternative CI methods for cumulative proportions (Beta Product Confidence Procedure (BPCP), BPCP Mid P, Rothman-Wilson, Thomas-Grunkemeier) and two CI methods for simple proportions (Clopper-Pearson, Wilson). We conducted a simulation study comparing CI methods across true event proportions for 12 scenarios differentiated by sample sizes and censoring patterns. We re-analyzed interim data from A5340, a HIV cure trial considering the proportion of participants experiencing virologic failure. Our simulation study highlights the lower and upper tail error probabilities for each CI method. Across scenarios, we found differences in the performance of lower versus upper bounds. No single method is always preferred. The upper bound of a Wald approximate CI performed reasonably with some error inflation, whereas the lower bound of the BPCP Mid P method performed well. For a trial design similar to A5340, we recommend BPCP Mid P. The design of future single-arm interim analyses of event proportions should consider the most appropriate CI method based on the relevant bound, anticipated sample size and event proportion. Our paper summarizes available methods, demonstrates performance in a simulation study, and includes code for implementation. [ABSTRACT FROM AUTHOR]

Background: Bayesian methods, with the predictive probability (PredP), allow multiple interim analyses with interim posterior probability (PostP) computation, without the need to correct for multiple looks at the data. The objective of this paper was to illustrate the use of PredP by simulating a sequential analysis of a clinical trial.Methods: We used data from the Laryngobloc trial that planned to include 480 patients to demonstrate the equivalence of success between a laryngoscopy performed with the Laryngobloc® device and a control device. A crossover Bayesian design was used. The success rates of the two laryngoscopy devices were compared. Interim analyses, computed from random numbers of subjects, were simulated.Results: The PostP of equivalence rapidly reached the predefined bound of 0.95. The PredP computed with an equivalence margin of 10% reached the efficacy bound between 352 and 409 of the 480 included patients. If a frequentist analysis had been made on the basis of 217 out of 480 subjects, the study would have been prematurely stopped for equivalence. The PredP indicated that this result was nonetheless unstable and that the equivalence was, thus far, not guaranteed.Conclusions: Based on these interim analyses, we can conclude with a sufficiently high probability that the equivalence would have been met on the primary outcome before the predetermined end of this particular trial. If a Bayesian approach using PredP had been used, it would have allowed an early termination of the trial by reducing the calculated sample size by 15-20%. [ABSTRACT FROM AUTHOR]

Continuous drug monitoring is a promising alternative to current therapeutic drug monitoring strategies and has a strong potential to reshape our understanding of pharmacokinetic variability and to improve individualised therapy. This review highlights recent advances in biosensing technologies that support continuous drug monitoring in real time. We focus primarily on aptamer-based biosensors, wearable and implantable devices. Emphasis is given to the approaches employed in constructing biosensors. We pay attention to sensors' biocompatibility, calibration performance, long-term characteristics stability and measurement quality. Last, we discuss the current challenges and issues to be addressed in continuous drug monitoring to make it a promising, future tool for individualised therapy. The ongoing efforts are expected to result in fully integrated implantable drug biosensing technology. Thus, we may anticipate an era of advanced healthcare in which wearable and implantable biochips will automatically adjust drug dosing in response to patient health conditions, thus enabling the management of diseases and enhancing individualised therapy. Image 1 • The review summarizes biosensing technologies in real-time continuous drug monitoring. • The review focuses on aptamer-based sensors, wearables and implantable sensors. • The review summaries challenges and issues to address in continuous drug monitoring. [ABSTRACT FROM AUTHOR]

• Amongst AF patients with long term use (≥1 year) of mHealth technology for optimising stroke prevention, symptom control and comorbidity management, there was a reduced risk for the composite outcome of 'ischaemic stroke/systemic thromboembolism, death, and rehospitalization' in patients using App-based management based on the ABC (Atrial fibrillation Better Care) pathway. • Rates of clinical outcomes (thromboembolism, bleeding events, recurrent atrial fibrillation and its symptoms, heart failure, and rehospitalization) were lower in patients allocated to mAF App intervention, compared with usual care. • Over 70% of patients using the mAF App had adherence of approximately 70%, with the overall persistence of mAFA use being 91.7%. Background. In the mobile Atrial Fibrillation App (mAFA)-II trial, the use of mobile health (mHealth) technology, incorporating AF screening and integrated management strategy, was associated with improved short-term clinical outcomes. The aim of this study was to report adherence/persistence and long term (≥1 year) clinical outcomes of the mAFA-II trial, with mHealth-supported optimised stroke prevention, symptom control and comorbidity management. Methods. We studied an adult population screened for AF, where identified patients could enter a structured program of holistic and integrated care based on the ABC (Atrial fibrillation Better Care) pathway using mHealth with a mAFA intervention. In this cluster randomised trial, comparing mHeath intervention to usual care, the primary composite outcome was 'stroke/thromboembolism, all-cause death and rehospitalization'. Results. The 1261 subjects (mean age 67.0 years, 38.0% female) who were followed up over one year (mean follow-up 687 (standard deviation, SD 191) days) in the intervention arm, had a lower risk of the composite outcome of 'ischaemic stroke/systemic thromboembolism, death, and rehospitalization' (hazard ratio, HR 0.18, 95% confidence interval, CI: 0.13–0.25, P < 0.001), compared to usual care (1212 subjects, mean age 70.1 years, 42.1% female). Of 842 patients using their smart devices for 'Better symptom management', 70.8% had good management adherence (monitoring time/follow-up since initial monitoring ≥ 70%), with the persistence of use of 91.7%. Conclusion. Amongst AF patients with long term use (≥1 year) of mHealth technology for optimising stroke prevention, symptom control and comorbidity management, adherence/persistence was good and associated with a reduction in adverse clinical outcomes. [ABSTRACT FROM AUTHOR]

Ductal carcinoma in situ (DCIS) is an in-situ (pre-cancerous) breast malignancy whereby malignant cells are contained within the basement membrane of the breast ducts. Increasing awareness that some low-risk forms of DCIS might remain indolent for many years has led to concern about overtreatment, with at least 3 clinical trials underway internationally assessing the safety of active monitoring for low-risk DCIS. This study aimed to understand healthcare professionals' (HCPs) views on the management options for patients with DCIS. Qualitative study using semi-structured interviews with HCPs involved in the diagnosis and management of DCIS in Australia and New Zealand. Interviews were audio-recorded, transcribed and analysed thematically using Framework Analysis method. Twenty-six HCPs including 10 breast surgeons, 3 breast physicians, 6 radiation oncologists, and 7 breast care nurses participated. There was a strong overall consensus that DCIS requires active treatment. HCPs generally felt uncomfortable recommending active monitoring as a management option for low-risk DCIS as they viewed this as outside current standard care. Overall, HCPs felt that active monitoring was an unproven strategy in need of an evidence base; however, many acknowledged that active monitoring for low-risk DCIS could be appropriate for patients with significant co-morbidities or limited life expectancy. They believed that most patients would opt for surgery wherever possible. This study highlights the important need for robust randomised controlled trial data about active monitoring for women with low-risk DCIS, to provide HCPs with confidence in their management recommendations and decision-making. • First study to explore HCPs' in-depth views on active monitoring for low-risk DCIS. • HCPs generally feel uncomfortable recommending active monitoring for low-risk DCIS. • Active monitoring may be considered for patients with significant co-morbidities or limited life expectancy. • Need for robust randomised controlled trial data on active monitoring for DCIS. [ABSTRACT FROM AUTHOR]

• Direct evidence of diaphragmatic dysfunction in mitochondrial myopathies is reported. • Diaphragmatic dysfunction caused alveolar hypoventilation requiring noninvasive ventilation. • Weakness of the global inspiratory and expiratory muscles was also demonstrated. • Respiratory muscle weakness contrasted with preserved peripheral muscle strength. • Esogastric pressure measurements are useful to document diaphragmatic dysfunction. Diaphragmatic dysfunction has been reported in congenital myopathies, muscular dystrophies, and occasionally, mitochondrial respiratory chain deficiency. Using a minimally invasive procedure in 3 young girls, 1 with a heteroplasmic MT-CYB mutation and 2 with biallelic pathogenic TK2 variants, we provided functional evidence of diaphragmatic dysfunction with global respiratory muscle weakness in mitochondrial respiratory chain deficiency. Analysis of respiratory muscle performance using esogastric pressures revealed paradoxical breathing and severe global inspiratory and expiratory muscle weakness with a sniff esophageal inspiratory pressure and a gastric pressure during cough averaging 50% and 40% of predicted values, respectively. This diaphragmatic dysfunction was responsible for severe undiagnosed nocturnal hypoventilation, requiring noninvasive ventilation. Our results underline the interest of this minimally invasive procedure for the evaluation of respiratory muscle performance and its potential value for the monitoring of future clinical trials in respiratory chain deficiency. [ABSTRACT FROM AUTHOR]

• Repeater F-waves frequency is higher in ALS compared to healthy subjects. • Latency and amplitude values of repeater vs non repeater F-waves are similar in the same recordings. • F Wave Analyzer provides a fast, effortless and accurate estimation of repeater F-waves. We assessed the clinical usefulness of repeater F-waves (Freps) analysis in amyotrophic lateral sclerosis (ALS), using an automated computerized system (F Wave Analyzer). Forty consecutive F-waves were recorded from the ulnar and peroneal nerve in 52 patients with ALS and 52 healthy control subjects. Data were imported into the F Wave Analyzer which identifies Freps and groups them. Parameters of Freps and non repeater F-waves (Fnonreps) were compared. Total number of repeating neurons, Freps persistence (100xFreps/40stimuli) and Index Total Freps (100xFreps/total number of F-waves) were significantly higher in the ALS compared to the control group (P ≤ 0.005). There were no consistent differences of F-wave latency or amplitude measurements between Freps and Fnonreps for both studied groups, with the exception of prolonged Freps minimum latency in ALS. In ALS, the high numbers of Freps, reduced overall F-wave persistence and increased F-wave amplitude measurements in a relatively unaffected nerve-muscle complex reflects excitability alterations of the corresponding motor neuron pool. Overall, automatic analysis facilitates accurate and fast detection of Freps and could be useful in other clinical settings. Analysis of repeater F-waves is expected to provide new insight regarding ALS pathophysiology and utilized for monitoring in clinical drug trials. [ABSTRACT FROM AUTHOR]

Unwarranted variations in lung cancer care are widely described. Clinical Quality Indicators (CQIs) enable the systematic identification and alleviation of variations in care and other evidence-practice gaps. The aim of this review was to describe and evaluate lung cancer CQIs utilised internationally, in order to provide a substrate for the development of Australasian lung cancer CQIs and future quality improvement initiatives. A literature search was performed to identify relevant publications; references were excluded if they did not explicitly define original lung cancer-specific quality indicators, or were review or opinion articles. Ultimately, 48 publications containing 661 individual CQIs were evaluated. Although almost all references were published in the last decade, CQIs did not always reflect contemporary standards of care. For example, there were just sixteen CQIs regarding biomarker profiling, eleven CQIs regarding multidisciplinary team review, and three clinical trial enrolment CQIs. Of 307 lung cancer treatment CQIs, almost half (1 3 7) pertain to surgical resection; a treatment option available to a minority of lung cancer patients. Consumer engagement during indicator development was uncommon. In conclusion, whilst CQIs are widely measured and reported, they are not always consistent with evidence-based practice, nor do they reliably support the holistic evaluation of the lung cancer care continuum. Moving forward, Australia and New Zealand must adopt a unified, evidence-based and patient-centred approach to drive meaningful improvements in practice. [ABSTRACT FROM AUTHOR]

This study was aimed to determine the effectiveness of selected Siddha formulations and Standard of Care (Treatment group;(n = 76)) compared with only Standard of Care (Control group;(n = 78)) by assessing the accelerated recovery within seven days of treatment. We enroled mild and moderate SARS CoV2 patients and selected Siddha formulations as shown in (Supplementary Table 1) and (Supplementary Table 2) were administered for the asymptomatic and Mild COVID cases and for Moderate and Severe COVID cases respectively. The control group was treated with only the standard of care as per India's Ministry of Health and Family Welfare recommendations. Accelerated recovery was assessed by a 10-point ordinal WHO clinical progression scale. Statistical analysis between the two study groups was calculated using logistic models and expressed as Odds Ratios. In the treatment group, 81.6% had accelerated recovery within seven days, which statistically differs from 52.6% in the control group. Multivariate analysis revealed that the accelerated recovery in the treatment group has four (3.8) times higher odds than the control group after adjusting the effect of gender (Adjusted Odds Ratio [AOR] = 3.8; 95% Confidence Interval [CI] = 1.8–7.9). In the treatment group, median time for recovery is 6 days, 95%CI = 5.6–6.4 which is statistically significant from median time of control group 7 days, 95%CI = 6.4–7.6. Selected Siddha formulations along with the standard of care showed a significantly higher proportion of accelerated recovery. Clinical Trial Registry of India: CTRI/2020/06/025763. [Display omitted] [ABSTRACT FROM AUTHOR]

The Safety Pharmacology Society organized a scientific session at its annual conference in 2017 to discuss the challenges and opportunities of the Comprehensive In-Vitro Proarrhythmia Assay (CiPA) paradigm. Our intention was to raise awareness of this initiative with its members and also to gauge the extent to which safety pharmacologists have incorporated the CiPA testing strategy within the pharmaceutical industry. CiPA offers many potential opportunities including 1) a focus on proarrhythmic risk (as opposed to QTc prolongation), 2) providing scientific rationale to support the continued development of compounds that may have a poor selectivity over hERG whilst also blocking other inward currents and 3) reducing the extent of ECG monitoring in clinical trials with a greater influence of the non-clinical studies. Such opportunities may speed drug development and reduce costs. However, there are also challenges for CiPA implementation. For example, the mixed ion channel paradigm does not easily lend itself to a prospective drug discovery strategy although testing for such effects can be achieved with assays with good throughput. However, it should also be recognized that compounds with a mixed ion channel profile might also have properties that are undesirable to treat non-life threatening indications. All components of CiPA (nonclinical and clinical) require validation, particularly as a composite package to impact drug development and evaluation. One of the significant discussion points was that the existing regulatory guidance supports the use of components of CiPA through follow-up studies. A survey of the conference audience showed that the level of awareness of CiPA is quite high and that companies are already conducting some testing against a wider panel of cardiac ion channels beyond hERG. However, the adoption of other technologies (stem cell derived cardiac myocytes and in silico modeling) is less well developed. Taken together, the session demonstrated the potential advantages of CiPA, but also some significant challenges. [ABSTRACT FROM AUTHOR]

Randomised clinical trials and systematic reviews of research findings can provide high-quality evidence for decision-making in the management of patients with hepatic encephalopathy. A large number of clinical trials have been undertaken, over the last 50 years, relative to the prevention and treatment of this condition. However, changes have been made, during this time, in the classification of hepatic encephalopathy, diagnostic criteria and assessment measures. These temporally based changes and the consequent lack of standardisation make it difficult to compare interventions and to evaluate their comparative efficacy and safety. While some consensus has been reached in relation to the diagnostic evaluation, classification and monitoring of patients in clinical trials, there is less surety about the choice of clinical endpoints. These outcome measures should be universally applicable, easily measured and clinically relevant. This article reviews the current recommendations regarding outcome selection and outlines some of the potential problems and pitfalls inherent in clinical trial evaluating interventions for the management of hepatic encephalopathy. [ABSTRACT FROM AUTHOR]

Abstract Background Hypertension is a major cause of morbidity and mortality but frequently remains uncontrolled. A smartphone application that provides coaching regarding home blood pressure monitoring and other aspects of hypertension self-care and related behavior change may be a scalable way to help manage hypertension. Methods/design The Smart Hypertension Control Study is a prospective, randomized controlled trial to assess the effects of a hypertension personal control program (HPCP), which consists of an automated artificial intelligence smartphone application that provides individualized support and coaching to promote home monitoring and healthy behavior changes related to hypertension self-management. Enrolled adults with uncontrolled hypertension will be randomized in a 1:1 fashion to the HPCP with home blood pressure monitoring or to home monitoring alone. We plan to enroll 350 participants, with a target of 300 participants with complete six-month follow-up data. The primary study outcome will be systolic blood pressure at six months. Additional outcomes include measures of antihypertensive medication adherence, home blood pressure monitoring practices, self-management practices, weight, and self-reported health behaviors. Conclusion The Smart Hypertension Control Study will evaluate blood pressure and hypertension self-management behavior outcomes in participants with uncontrolled hypertension exposed to a smartphone-based hypertension health coaching application in addition to home blood pressure monitoring compared to those exposed to home blood pressure monitoring alone. [ABSTRACT FROM AUTHOR]

Background Previous studies have shown that industry funded trials are associated with pro-industry conclusions and publication bias. Less is known about the role of industry funders and their influence on trial conclusions and time to publication. Methods We identified all industry funded RCTs published in six high-impact clinical journals between 2014 and 2016 to estimate the prevalence of the role of industry funders in trial design, data collection, data analyses, data interpretation and manuscript writing. Ordinal logistic regression was used to assess the association between the role of industry funders and trial conclusions, which was classified on a five-point scale. Cox proportional-hazards were used to examine the effect of role of funder on time to publication. Results Of the 255 eligible RCTs, industry funders had a role in trial design in 179 (70.2%) trials, data collection in 160 (62.7%) trials, data analyses in 173 (67.8%) trials, data interpretation in 135 (52.9%) trials and manuscript writing in 168 (65.9%) trials. Trials with any role of industry funders had 3.6 times (95% CI 2.0–6.6) higher odds of having positive conclusions compared with those without role of industry funders. In trials with any role of industry funders, positive trials were published more rapidly than negative trials (hazard ratio = 4.3; 95% CI 2.7–6.7, P < 0.001), while for trials without role of industry funders, there was no association (hazard ratio = 1.07; 95% CI 0.57–1.99, P = 0.84) Conclusion The involvement of industry funders is common in all stages of clinical trials and was associated with more positive conclusions and more rapid publication of RCTs with positive results. [ABSTRACT FROM AUTHOR]

• Development of a comprehensive data dashboard for radiation oncology. • Tested within an international multi-center study. • Centers can compare their treatment approach with reference population. • Automatically detect implausibilities in patient, treatment, and outcome data. • Overview of the most common pitfalls and uncertainties in current radiotherapy for cervical cancer. To develop and implement a software that enables centers, treating patients with state-of-the-art radiation oncology, to compare their patient, treatment, and outcome data to a reference cohort, and to assess the quality of their treatment approach. A comprehensive data dashboard was designed, which al- lowed holistic assessment of institutional treatment approaches. The software was tested in the ongoing EMBRACE-II study for locally advanced cervical cancer. The tool created individualized dashboards and automatic analysis scripts, verified pro- tocol compliance and checked data for inconsistencies. Identified quality assurance (QA) events were analysed. A survey among users was conducted to assess usability. The survey indicated favourable feedback to the prototype and highlighted its value for internal monitoring. Overall, 2302 QA events were identified (0.4% of all collected data). 54% were due to missing or incomplete data, and 46% originated from other causes. At least one QA event was found in 519/1001 (52%) of patients. QA events related to primary study endpoints were found in 16% of patients. Sta- tistical methods demonstrated good performance in detecting anomalies, with precisions ranging from 71% to 100%. Most frequent QA event categories were Treatment Technique (27%), Patient Characteristics (22%), Dose Reporting (17%), Outcome 156 (15%), Outliers (12%), and RT Structures (8%). A software tool was developed and tested within a clinical trial in radia- tion oncology. It enabled the quantitative and qualitative comparison of institutional patient and treatment parameters with a large multi-center reference cohort. We demonstrated the value of using statistical methods to automatically detect implau- sible data points and highlighted common pitfalls and uncertainties in radiotherapy for cervical cancer. [ABSTRACT FROM AUTHOR]

Plants are the integral part of the traditional indigenous healthcare system and are becoming concrete source of new drug discovery, evident by the increasing numbers of modern drugs derived from the phytochemicals. Emblica officinalis Gaertn. or Phyllanthus emblica Linn (family Phyllanthaceae) has been explained extensively and well documented for its therapeutic efficacies in indigenous system of medicine, in India. Every part of this plant possesses high medicinal value but fruits are the most valuable part in folklore and therapeutic uses. The polyphenols found in E.officinalis , especially tannins and flavonoids are key responsible elements for major bioactivities. E.officinalis is one of the major component in various health tonics, also exerts synergistic effects in enhancing the medicinal efficacy. E.officinalis exhibits broad spectrum of pharmacological activities through various mode of actions including antioxidant, anticancer, immunomodulator, anti-inflammatory, cyto-protective properties etc. Medical practitioners across the globe also advocated its application in managing diabetes, dyslipidemia, obesity, several types of cancer, liver disorders, arthritis, gingivitis, wound healing etc. The present review analysed and summarized the pharmacological actions, experimental studies and clinical trials of E. officinalis with emphasis on its immuno-enhancer, antiinflammatory and anticancer activities and possible mechanism of actions to provide future directions in translating these findings clinically. [ABSTRACT FROM AUTHOR]