Clinical Program Research Articles

FEASIBILITY, ACCEPTABILITY, AND EFFICACY OF A PILOT EXERCISE PHYSIOLOGY GROUP SERVICE FOR OLDER ADULTS WITH TYPE 2 DIABETES

INTRODUCTION & AIMS Type 2 diabetes prevalence increases with ageing, affecting over half a million older Australians. Medicare type 2 diabetes group interventions can support older adults’ diabetes management. However, Accredited Exercise Physiologist (AEP) delivered service feasibility and acceptability is yet to be assessed. This study aimed to assess feasibility, acceptability and preliminary efficacy of a Medicare type 2 diabetes group exercise and education intervention for older adults. METHODS This study was a single arm feasibility, acceptability, and preliminary efficacy trial of an AEP delivered type 2 diabetes group service for older adults. Participants attended the Diabetes Clinic once per week for 8 weeks, for a group exercise and education session. Attendance, participation, enjoyment, suitability, usefulness, and pre-post clinical health outcomes were assessed. RESULTS The intervention was feasible and acceptable, with 40 participants (71.8±4.5 years old, range 65-81 years, 45% female) attending 87% of sessions, with high treatment compliance within sessions (aerobic training: 86%; resistance training: 86%; education: 87%). Almost all participants (97%) strongly agreed that the program was enjoyable. Significant post intervention improvements (mean difference [95% CI]) were observed for right arm systolic blood pressure (SBP) (-7mmHg [-12, -2], p=0.007), left arm diastolic blood pressure (DBP) (-3mmHg [-5, -0], p=0.021), body weight (-0.7kg [-1.3, -0.0], p=0.039), waist circumference (-1.3cm [-2.2, -0.4], p=0.006), 6-minute walk test (22.8m, [9.1. 36.5], p=0.002), 5 times sit to stand (-0.8sec [-1.2, -0.5], p<0.001), short physical performance battery ordinal scale (0.3 [0.1, 0.5], p=0.009), and whole-body muscle strength (32.2kg [22.3, 42.1], p<0.001). CONCLUSION Older adults attended and enjoyed the AEP led Diabetes Clinic program, while also improving fitness and cardiometabolic health outcomes. Ways to enhance referrals and engage older adults in the programs warrant further investigation. The potential for additional sessions to achieve greater physical activity engagement and diabetes self-management should be further investigated.

Once-weekly insulin efsitora alfa: Design and rationale for the QWINT phase 3 clinical development programme.

Insulin efsitora alfa (efsitora) is a once-weekly basal insulin. This review describes the study design and rationale of the efsitora phase 3 Once Weekly (QW) Insulin Therapy (QWINT) clinical development programme, including the five trials, QWINT-1 through QWINT-5. The five trials included insulin-naïve adults (QWINT-1 and -2) with type 2 diabetes (T2D), adults with T2D previously treated with basal insulin (QWINT-3 and -4), and QWINT-5 in adults with type 1 diabetes. All five trials were designed as multicentre, randomized, controlled, open-label, treat-to-target studies to investigate the efficacy and safety of efsitora versus active once-daily basal insulin comparators (insulin glargine U100 or insulin degludec U100). The primary objective of each trial is to compare the change in HbA1c from baseline to week 26 or 52 between efsitora and the active comparator. The key secondary objectives include change in fasting glucose, insulin dose and continuous glucose monitoring variables, and patient-reported outcome questionnaires. The QWINT development programme includes a racially and geographically diverse population to provide important information regarding the efficacy and safety of efsitora and its clinical management of people with diabetes.

Addressing Sexually Transmitted Infections Due to Neisseria gonorrhoeae in the Present and Future

It was in the 1800s when the first public publications about the infection and treatment of gonorrhoea were released. However, the first prevention programmes were only published a hundred years later. In the 1940s, the concept of vaccination was introduced into clinical prevention programmes to address early sulphonamide resistance. Since then, tons of publications on Neisseria gonorrhoeae are undisputed, around 30,000 publications today. Currently, the situation seems to be just as it was in the last century, nothing has changed or improved. So, what are we doing wrong? And more importantly, what might we do? The review presented here aims to review the current situation regarding the resistance mechanisms, prevention programmes, treatments, and vaccines, with the challenge of better understanding this special pathogen. The authors have reviewed the last five years of advancements, knowledge, and perspectives for addressing the Neisseria gonorrhoeae issue, focusing on new therapeutic alternatives.

Personalization above anonymization? A role for considering the humanity and spirituality of the dead in anatomical education.

Clinical anatomy education is meant to prepare students for caring for the living, often by working with the dead. By their nature many clinical anatomy education programs privilege topographical form over the donor's humanity. This inbalance between the living and the dead generates tensions between the tangible and the spiritual insofar as semblances of the humanity of donors endure even in depictions and derivatives. This article argues that considering the relevance of spirituality, and what endures of a donor's humanity after death, would enhance contemporary anatomy education and the ethical treatment of human body donors (and derivatives). In developing this argument, we (the authors) address the historical connection between spirituality and anatomy, including the anatomical locations of the soul. This serves as a basis for examining the role of the mimetic-or imitative-potential of deceased human donors as representations of the living. We deliberate on the ways in which the depersonalization and anonymization of those donating challenge themimetic purpose of human body donorsand the extent to which such practicesare misaligned with the health care shift from a biomedical to a biopsychosocial model. Weighing up the risks and opportunities of anonymization versus personalization of human body donors, we propose curricula that could serve to enhance the personalization of human donors to support students learning topographical form. In doing so, we argue that the personalization of human donors and depictions could prevent the ill effects of digital representations going "viral," and enhance opportunities for donors to help the general public learn more about the human form.

Assisted Reproductive Technologies: A New Player in the Foetal Programming of Childhood and Adult Diseases?

Assisted reproductive technology (ART) is an emerging field in medicine that incorporates complex procedures and has profound ethical, moral, social, religious, and economic implications not just for the individuals who have access to this method but also for society. In this narrative review, we summarise multiple aspects of ART procedures and the possible consequences on the mother and newborn. Moreover, we provide an overview of the possible long-term consequences of ART procedures on the health of newborns, although longitudinal evidence is particularly scant. Users should be informed that ART procedures are not risk-free to prepare them for the possible negative outcomes that may occur in the perinatal period or even in childhood and adulthood. Indeed, risk estimates point to increased liability for major nonchromosomal birth defects; cardiovascular, musculoskeletal, and urogenital (in male newborns) defects; and any other birth defects. Less certainty is present for the risk of neuropsychiatric sequelae in children conceived through ART. Thus, its application should be accompanied by adequate counselling and psychological support, possibly integrated into specific multidisciplinary clinical programmes.

Content of medicine prescription and clinical practice training for haematology advanced practice nurses in China: A modified Delphi study

AimTo explore the scope and form of prescriptions for blood and hematopoietic drugs that future advanced practice nurses (APNs) in the Department of Haematology and to establish a medicine prescription training content in China. BackgroundBecause the increasing number of doctors cannot meet the increasing demand for medical care with the population growth, many countries have begun to explore the medical team structure and practice areas, among which nurse prescribing rights have been the most effective. However, China's higher nursing education system still lacks education and training on nurse prescription. DesignOn the basis of literature research and semi-structured interviews, a set of nursing prescription content, education, training and practice system suitable for Chinese nurses was jointly created. MethodsTwo rounds of expert consultation between 23 haematology nursing experts and clinical experts determined the training content of blood system drugs and medicine prescriptions. Additionally, on the basis of the 23 experts，13 experts engaged in clinical and education, teaching and training experts were involved. Two rounds of expert consultation with 36 experts identified a general clinical practice training program for advanced practice nurses in China. ResultsRegarding contents and forms of hematopoietic drugs, the study concluded that advanced practice nurses in haematology department can prescribe anti-anemia drugs, anti-coagulant drugs and anti-thrombotic drugs in 2 categories and 16 drugs. Of these, four kinds of drugs should be prescribed in the form of protocol prescription. One kind of drug should be prescribed in the form of extended prescription and 11 drugs should be prescribed in the form of independent/extended or agreed/extended prescription. Regarding training content, the study obtained the training content of nurses' medicine prescriptions in eight clinical circumstances and the medicine prescription training content for common diseases of the blood system. The required specifications and the medicine prescription decision skills of nurses were sorted out according to different prescription types. ConclusionsThe degrees of expert authority were both higher in consultations. Moreover, the results after consultation were reliable. It was recommended that haematology APNs could prescribe anti-anaemic drugs and anti-coagulation and anti-thrombotic drugs. Furthermore, most drugs should be prescribed in the form of independent/extended or agreed/extended prescriptions. The establishment of a medicine prescription training content for haematology APNs is expected to provide a reference for clinical practice education and training for drug prescriptive authority applicants for blood and hematopoietic system nurses in China.

P172 An integrated safety analysis of treatment-emergent fungal infections in patients with psoriasis, psoriatic arthritis, or axial spondyloarthritis treated with ixekizumab from 26 clinical studies

Abstract Background/Aims Interleukin (IL)-17 plays a role in host defense against common extracellular pathogens, including fungi. Treatment with IL-17 inhibitors has been associated with fungal infections. Ixekizumab (IXE) is an anti-IL-17A monoclonal antibody approved for the treatment of psoriasis (PsO) in adults and children, psoriatic arthritis (PsA) in adults, and axial spondyloarthritis (axSpA) in adults. This integrated post-hoc analysis investigates treatment-emergent fungal infections in IXE-treated patients across the approved indications. Methods Safety data on fungal infections were pooled from the IXE paediatric and adult clinical trial programs, comprising 26 clinical studies. Here, we describe the types of fungal infections, number of infections, recurrence (defined by at least two separate events irrespective of location), severity (defined at the investigator’s discretion), events that lead to discontinuation, and anti-fungal medications. Data are presented as frequency or incidence rate per 100 person-years (IR). Results Fungal infections were reported in patients with PsO (IR = 4.0), PsA (IR = 4.1), and axSpA (IR = 2.7). Across indications, most fungal infections were not recurrent and were classified as mild or moderate in severity. There were few severe fungal infections in patients with PsO (IR = 0.1), PsA (IR = 0.0), and axSpA (IR = 0.0). Most fungal infections in patients with PsO, PsA, and axSpA were candidiasis (IR = 1.9, IR = 2.5, IR = 1.4, respectively) and superficial dermatophytosis (IR = 1.5, IR = 1.0, IR = 1.0, respectively). No cases of subcutaneous and systemic mycosis infections were reported. The proportions of patients with PsO, PsA, and axSpA who received a topical vs systemic anti-fungal medication were 53.6% vs 1.1%, 47.8% vs 0.0%, and 45.6% vs 3.5%, respectively (Table 1). Most fungal infections did not lead to discontinuation of IXE (Table 1). Conclusion Consistent with previously disclosed IXE data, the majority of treatment-emergent fungal infections observed in patients with PsO, PsA, or axSpA treated with IXE were: (i) not recurrent; (ii) mild or moderate in severity, (iii) associated with candidiasis and superficial dermatophytosis, (iv) managed with topical anti-fungal medications or no treatment reported, and (v) not leading to drug discontinuation. Disclosure S. Schwartzman: Corporate appointments; SS reports being a board member of the National Psoriasis Foundation. Consultancies; S. Schwartzman has served as a speaker and/or consultant for AbbVie, Janssen, Eli Lilly and Company, Pfizer, UCB, Myriad, Novartis, Regeneron, Sanofi, Stelexis, Jubilant, Teijin. L. Puig: Corporate appointments; Board member of the International Psoriasis Council. Consultancies; AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Leo Pharma, Eli Lilly and Company, Novartis, Pfizer, Sandoz, Sanofi, UCB. Honoraria; Boehringer Ingelheim, Janssen, Eli Lilly and Company, Novartis, UCB, travel support from Janssen, Eli Lilly and Company, Pfizer, UCB. Grants/research support; L. Puig reports receiving grants from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Leo Pharma, Eli Lilly and Company, Novartis, Pfizer, Sanofi, UCB. A.D. Cohen: Honoraria; AbbVie, Amgen, Boehringer Ingelheim, Dexcel Pharma; Janssen, Eli Lilly and Company, Neopharm, Novartis, Perrigo, Pfizer, Rafa. Grants/research support; A. D. Cohen has served on advisory board for Samsung, and reports receiving grants from AbbVie, Janssen, Novartis, Pfizer, travel support from AbbVie. S. Khattri: Consultancies; S. Khattri reports being part of Eli Lilly and Company speaker’s bureau, receiving consulting fees and honoraria from Eli Lilly and Company, AbbVie, UCB, Janssen, BI, Regeneron, Leo Pharma. C. Jossart: Shareholder/stock ownership; C. Jossart is a stockholder of Eli Lilly and Company and was an employee of Eli Lilly and Company when this study was conducted. C. Diaz: Shareholder/stock ownership; C. Diaz is employee and stockholder of Eli Lilly and Company. A. Garrelts: Shareholder/stock ownership; A. Garrelts is employee and stockholder of Eli Lilly and Company. D. Zhu: Shareholder/stock ownership; D. Zhu is employee and stockholder of Eli Lilly and Company. N. Eberhart: Shareholder/stock ownership; N. Eberhart is employee and stockholder of Eli Lilly and Company. A. Eleftheriadi: Shareholder/stock ownership; A. Eleftheriadi is employee and stockholder of Eli Lilly and Company. N. Tangsirisap: Shareholder/stock ownership; N. Tangsirisap is employee and stockholder of Eli Lilly and Company. C. Schuster: Shareholder/stock ownership; C. Schuster is an employee and stockholder of Eli Lilly and Company. A.B. Gottlieb: Consultancies; Xbiotech (stock options for an RA project). Honoraria; Amgen, AnaptysBio, Avotres Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Dice Therapuetics, Dermavant, Lilly, Janssen, Leo, Pharma, Novartis, Pfizer, Sanofi, Sun Pharma, UCB Pharma. Grants/research support; AnaptysBio, Moonlake Immunotherapeutics, Novartis, BMS, and UCB Pharma; all funds go to the Icahn School of Medicine at Mount Sinai. M. Sheesh: Shareholder/stock ownership; MS is a full-time employee and minor share holder of Eli-Lilly and Company.

The development of a framework for clinical education programme of undergraduate nursing students in Ghana

IntroductionClinical education is an important aspect of the training of nursing students but it is faced with challenges in Ghana. The development of a framework will respond to the need for improvement in the quality of clinical nursing education. This study describes part of a larger study which culminated in the development of a framework for a clinical education programme for undergraduate nursing students in Ghana. The aim of the current study was to integrate findings from a scoping review and situational analysis to develop a framework for clinical education in nursing.MethodsA sequential multimethod design approach was used to conduct the study. A scoping review on the practices that facilitate clinical nursing education and situational analysis were first conducted. The lessons learnt from the scoping review and the situational analysis provided the data matrix that was triangulated to develop the framework. The framework was developed using the model for clinical education developed by South African Nursing Education Stakeholders in consultation with experts in nursing education. An implementation plan was developed from the framework and evaluated using a Delphi technique.FindingsThe resulting framework indicates the need for effective communication and collaboration between nursing education institution and the service setting to ensure that there is a well-structured clinical placement, formal supervision system and effective clinical assessment of students. The framework also proposes that to ensure quality clinical nursing education there is the need for Nursing Education Institutions to implement innovative and cost-effective clinical teaching methods.ConclusionThe framework spells out the functions of the various stakeholders in nursing education and how these can be integrated and implemented to enhance quality clinical nursing education. Effectiveness of the thematic areas of the framework will increase the quality of clinical nursing education.

Opinion & Special Article: Community Approach Toward Inclusion of Sex and Gender Diversity in Graduate Neurology Education.

Sex and gender diverse (SGD) neurology trainees include transgender, nonbinary, and intersex people. There has been historical exclusion of SGD trainees from participating in clinical care, medical research, and academic training programs. Therefore, neurology educators have unique opportunities to support SGD trainees and colleagues, but may lack the education to appropriately do so. Training programs and professional organizations can collaborate to create safe pathways for SGD trainees to disclose their identities in professional settings. Referral to community support and resources is important for SGD trainees considering professional disclosure. Educators should address the challenges and discrimination unique to SGD graduate trainees in neurology, such as lack of inclusion, affirming environments, supportive policies, and medical accommodations. Faculty training on sensitivity, bias, and bystander effects should be ongoing among institutions. Topics regarding sex and gender diversity are lacking in graduate medical education. Educational curricula often use outdated terminology or binary paradigms to teach about sex and gender. Health care training inequities may cause downstream harm to SGD patients; therefore, training curricula that are reflective of an accurate and affirming understanding of sex and gender may mitigate the potential for inequities. This article provides recommendations to support SGD neurology trainees and to incorporate specific training on sex and gender diversity in academic neurology curricula. Such support is critical to the career success and development of SGD neurology trainees.

SEEIIST – a new research facility for tumor treatment and biomedical investigations with proton and ion beams

Abstract Purpose A project for the establishment of an international intergovernmental scientific organization in the region of South East Europe (South East European Institute for Sustainable Technologies - SEEIIST) is currently in progress. SEEIIST is an intergovernmental effort supported by nine countries from the region (Albania, Bosnia and Herzegovina, Bulgaria, Greece, Kosovo (This designation is without prejudice to positions on status, and is in line with UNSC 1244 and the ICJ Opinion on the Kosovo Declaration of Independence.), Montenegro, North Macedonia, Serbia and Slovenia, while Switzerland is an observer). The main goals of the project are to establish a unique research infrastructure and to form a research nucleus in the region of South-East Europe, to boost the technology transfer from European laboratories like CERN and others, to promote collaboration between science, technology, and industry, to mitigate tensions between countries in the region, and to provide platforms for the development of education. Methods The research infrastructure will include a powerful next-generation accelerator that will provide proton and ion beams for tumor treatment and biomedical research. The center will comprise of three rooms for patient treatment and two large experimental halls. Results A wide pre-clinical and clinical research program in the fields of radiobiology, medical physics, medical imaging, biophysical modeling and planning of patient treatment, design and investigation of new materials, production of isotopes for diagnosis, and treatment of patients are envisaged. Conclusions This infrastructure is unique for Europe and will attract researchers from all European countries to perform their investigations.

Pegvaliase for the treatment of phenylketonuria: Final results of a long-term phase 3 clinical trial program

Phenylketonuria (PKU) is a genetic disorder caused by deficiency of the enzyme phenylalanine hydroxylase (PAH), which results in phenylalanine (Phe) accumulation in the blood and brain, and requires lifelong treatment to keep blood Phe in a safe range. Pegvaliase is an enzyme-substitution therapy approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 μmol/L) despite prior management. Aggregated results from the PRISM clinical trials demonstrated substantial and sustained reductions in blood Phe with a manageable safety profile, but also noted individual variation in time to and dose needed for a first response. This analysis reports longer-term aggregate findings and characterizes individual participant responses to pegvaliase using final data from the randomized trials PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862), and the open-label extension study 165–304 (NCT03694353). In 261 adult participants with a mean of 36.6 months of pegvaliase treatment, 71.3%, 65.1%, and 59.4% achieved clinically significant blood Phe levels of ≤600, ≤360, and ≤ 120 μmol/L, respectively. Some participants achieved blood Phe reductions with <20 mg/day pegvaliase, although most required higher doses. Based on Kaplan-Meier analysis, median (minimum, maximum) time to first achievement of a blood Phe threshold of ≤600, ≤360, or ≤ 120 μmol/L was 4.4 (0.0, 54.0), 8.0 (0.0, 57.0), and 11.6 (0.0, 66.0) months, respectively. Once achieved, blood Phe levels remained below clinical threshold in most participants. Sustained Phe response (SPR), a new method described within for measuring durability of blood Phe response, was achieved by 85.5%, 84.7%, and 78.1% of blood Phe responders at blood Phe thresholds of ≤600, ≤360, or ≤ 120 μmol/L, respectively. Longer-term safety data were consistent with previous reports, with the most common adverse events (AEs) being arthralgia, injection site reactions, headache, and injection site erythema. The incidence of most AEs, including hypersensitivity AEs, was higher during the early treatment phase (≤6 months) than later during treatment. In conclusion, using data from three key pegvaliase clinical trials, participants treated with pegvaliase were able to reach clinically significant blood Phe reductions to clinical thresholds of ≤600, ≤360, or ≤ 120 μmol/L during early treatment, with safety profiles improving from early to sustained treatment. This study also supports the use of participant-level data and new ways of looking at durable blood Phe responses to better characterize patients' individual PKU treatment journeys.

Clinical impact of an individualised clinical pharmacy programme into the memory care pathway of older people: an observational study.

In older patients, medication exposure [i.e. polypharmacy, potentially inappropriate medications (PIMs), medications with anticholinergic and/or sedative properties] is a modifiable risk factor associated with cognitive iatrogenic risk and dementia. To assess the potential clinical impact of the implementation of an individualised clinical pharmacy programme at the initiation of the Memory care pathway in older patients with a cognitive complaint. This prospective observational study included older patients with high-risk of adverse drug event (HR) admitted in a French geriatric university hospital to explore the cognitive complaint or the cognitive disorder between January and November 2021. Drug-related problems (DRPs) were identified during a medication review performed in HR patients, and pharmaceutical interventions (PIs) notified in the patient's hospitalisation report were collected. The clinical impact of PIs was assessed by an expert panel (geriatricians and clinical pharmacists) using the Clinical, Economic, and Organisational (CLEO) tool. Overall, 326 patients were eligible and 207 (63.5%) were considered as HR patients. Among HR patients, 88.9% (n = 184) were treated using at least 5 medications (polypharmacy), and 36.7% (n = 76) received at least one PIM with cognitive iatrogenic risk. During the medication review, 490 PIs were provided and their clinical impact was rated as minor for 57.3% (n = 281), moderate for 26.7% (n = 131), and major for 2.5% (n = 12). The integration of clinical pharmacist secured the Memory care pathway of older patients with a cognitive complaint by identifying an important number of DRPs and PIMs with potential cognitive iatrogenic risk.

Refining the impact of genetic evidence on clinical success.

The cost of drug discovery and development is driven primarily by failure1, with only about 10% of clinical programmes eventually receiving approval2-4. We previously estimated that human genetic evidence doubles the success rate from clinical development to approval5. In this study we leverage the growth in genetic evidence over the past decade to better understand the characteristics that distinguish clinical success and failure. We estimate the probability of success for drug mechanisms with genetic support is 2.6 times greater than those without. This relative success varies among therapy areas and development phases, and improves with increasing confidence in the causal gene, but is largely unaffected by genetic effect size, minor allele frequency or year of discovery. These results indicate we are far from reaching peak genetic insights to aid the discovery of targets for more effective drugs.

Availability and use of institutional support programs for emergency department healthcare personnel during the COVID-19 pandemic.

The COVID-19 pandemic placed health care personnel (HCP) at risk for stress, anxiety, burnout, and post-traumatic stress disorder (PTSD). To address this, hospitals developed programs to mitigate risk. The objectives of the current study were to measure the availability and use of these programs in a cohort of academic emergency departments (EDs) in the United States early in the pandemic and identify factors associated with program use. Cross-sectional survey of ED HCP in 21 academic EDs in 15 states between June and September 2020. Site investigators provided data on the availability of 28 programs grouped into 9 categories. Individual support programs included: financial, workload mitigation, individual COVID-19 testing, emotional (e.g., mental health hotline), and instrumental (e.g., childcare) Clinical work support programs included: COVID-19 team communication (e.g., debriefing critical incident), patient-family communication facilitation, patient services (e.g., social work, ethics consultation), and system-level exposure reduction. Participants provided corresponding data on whether they used the programs. We used generalized linear mixed models clustered on site to measure the association between demographic and facility characteristics and program use. We received 1,541 survey responses (96% response rate) from emergency physicians or advanced practice providers, nurses, and nonclinical staff. Program availability in each of the 9 categories was high (>95% of hospitals). Program use was variable, with clinical work support programs used more frequently (28-50% of eligible HCP across categories) than individual employee support programs (6-13% of eligible HCP across categories). Fifty-seven percent of respondents reported that the COVID-19 pandemic had affected their stress and anxiety, and 12% were at elevated risk for PTSD. Program use did not significantly differ for HCP who reported symptoms of anxiety and/or stress compared to those who did not. Early in the pandemic, support programs were widely available to ED HCP, but program use was low. Future work will focus on identifying barriers and facilitators to use and specific programs most likely to be effective during periods of highest occupational stress.

Tree-temporal scan statistics for safety signal detection in vaccine clinical trials.

The evaluation of safety is critical in all clinical trials. However, the quantitative analysis of safety data in clinical trials poses statistical difficulties because of multiple potentially overlapping endpoints. Tree-temporal scan statistic approaches address this issue and have been widely employed in other data sources, but not to date in clinical trials. We evaluated the performance of three complementary scan statistical methods for routine quantitative safety signal detection: the self-controlled tree-temporal scan (SCTTS), a tree-temporal scan based on group comparison (BGTTS), and a log-rank based tree-temporal scan (LgRTTS). Each method was evaluated using data from two phase III clinical trials, and simulated data (simulation study). In the case study, the reference set was adverse events (AEs) in the Reference Safety Information of the evaluated vaccine. The SCTTS method had higher sensitivity than other methods, and after dose 1 detected 80 true positives (TP) with a positive predictive value (PPV) of 60%. The LgRTTS detected 49 TPs with 69% PPV. The BGTTS had 90% of PPV with 38 TPs. In the simulation study, with simulated reference sets of AEs, the SCTTS method had good sensitivity to detect transient effects. The LgRTTS method showed the best performance for the detection of persistent effects, with high sensitivity and expected probability of type I error. These three methods provide complementary approaches to safety signal detection in clinical trials or across clinical development programmes. All three methods formally adjust for multiple testing of large numbers of overlapping endpoints without being excessively conservative.

Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme.

Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, oncedaily, selective sphingosine 1phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. Patients, including those with isolated proctitis (<10cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed. We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all p<0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings. Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52.

Literature Review of Pathogen Agnostic Molecular Testing of Clinical Specimens From Difficult-to-Diagnose Patients: Implications for Public Health.

To better identify emerging or reemerging pathogens in patients with difficult-to-diagnose infections, it is important to improve access to advanced molecular testing methods. This is particularly relevant for cases where conventional microbiologic testing has been unable to detect the pathogen and the patient's specimens test negative. To assess the availability and utility of such testing for human clinical specimens, a literature review of published biomedical literature was conducted. From a corpus of more than 4,000 articles, a set of 34 reports was reviewed in detail for data on where the testing was being performed, types of clinical specimens tested, pathogen agnostic techniques and methods used, and results in terms of potential pathogens identified. This review assessed the frequency of advanced molecular testing, such as metagenomic next generation sequencing that has been applied to clinical specimens for supporting clinicians in caring for difficult-to-diagnose patients. Specimen types tested were from cerebrospinal fluid, respiratory secretions, and other body tissues and fluids. Publications included case reports and series, and there were several that involved clinical trials, surveillance studies, research programs, or outbreak situations. Testing identified both known human pathogens (sometimes in new sites) and previously unknown human pathogens. During this review, there were no apparent coordinated efforts identified to develop regional or national reports on emerging or reemerging pathogens. Therefore, development of a coordinated sentinel surveillance system that applies advanced molecular methods to clinical specimens which are negative by conventional microbiological diagnostic testing would provide a foundation for systematic characterization of emerging and underdiagnosed pathogens and contribute to national biodefense strategy goals.

Cardiopulmonary rehabilitation’s influence on cognitive functions, psychological state, and sleep quality in long COVID-19 patients: A randomized controlled trial

ABSTRACT Background: Cognitive impairment, brain fog, depressive symptoms, and sleep disturbance are prevalent symptoms among individuals with long COVID, for which there currently is no treatment. Aim: To assess the effectiveness of an eight-week cardiopulmonary rehabilitation programme on cognition, psychological well-being, and sleep quality in individuals with long COVID-19. Methods: Forty participants diagnosed with long COVID-19 (26 female, 14 male participants; mean age 53 ± 11 years) were randomly assigned to a rehabilitation group or to a control group. The control group maintained their regular daily habits, while the rehabilitation group was prescribed an individualized clinical programme consisting of three sessions per week. Each session involved light to moderate aerobic exercise, resistance training, and respiratory exercises. Neuropsychological tests evaluating executive function, memory, and processing speed were administered at baseline and at study completion. Participants also completed questionnaires on their psychological state and sleep quality at both time points. Results: No difference between groups was observed for neuropsychological test performance, however significant group differences in perceived stress and depression were found post-intervention. Conclusion: Cardiopulmonary rehabilitation was shown to be effective in individuals suffering from long COVID in terms of decreasing perceived stress and depression levels but not for neuropsychological test performance. ClinicalTrials.gov NCT05035628. Trial registration: ClinicalTrials.gov identifier: NCT05035628..

Leveraging healthcare standards-based improvement initiatives to support learning and continuous improvement: lessons from implementing the Ideal Clinic programme in Cape Town, South Africa

Abstract This paper draws on the experiences of a group of health system leaders and researchers in leading and supporting, respectively, the implementation of the Ideal Clinic Realisation and Maintenance Framework (ICRMF) in Cape Town, South Africa. The ICRMF is a national standards-based quality improvement initiative that seeks to improve the quality of care in public primary healthcare (PHC) facilities. We share lessons learned on how efforts to improve healthcare standards can be leveraged for learning and meaningful system change. A three-pronged approach to improving the implementation of the ICRMF was used in 15 PHC facilities across two sub-districts. The approach included i) nurturing trust, ii) changing the ICRMF assessment strategy and iii) promoting a collaborative and collective sense-making approach to understanding performance and addressing gaps. Routine ICRMF quantitative data and qualitative feedback from both the ICRMF assessment process and routine management meetings were used to reflect on the experience of using this approach and to draw lessons. The results and conclusions were further confirmed through member-checking. We found that using the three-pronged approach, the ICRMF assessments were able to facilitate deep and reflexive conversations about everyday health system challenges facing healthcare delivery in the sub-districts, while encouraging collective sensemaking and collaboration. The ICRMF was often perceived as a compliance-driven exercise with limited value on the actual quality of care. The three-pronged approach helped shift some of these perceptions and improved the experiences of facility managers in implementing the programme. However, it became clear that leveraging the full potential of the ICRMF requires health system leaders to recognise and consider the on-the-ground realities of health system change and the micropolitics of QI. Failure to recognise these issues and intentionally tackle them can result in negative unintended consequences and undermine improvement efforts.

Safety Profile of Semaglutide in People Aged 55 Years and Over: Pooled Data from the PIONEER, SUSTAIN, and STEP Phase 3 Clinical Programmes (P11-9.014)

Safety Profile of Semaglutide in People Aged 55 Years and Over: Pooled Data from the PIONEER, SUSTAIN, and STEP Phase 3 Clinical Programmes (P11-9.014)