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BackgroundLeadership skills are essential for middle-level healthcare manager efficacy. Capacity-building efforts may attempt behavioural change by filling 'knowledge gaps' while neglecting a sustainable application of that knowledge. Sustainable application of that knowledge, or implementation know-how, must resonate with local cultural patterns. When it is neglected, root issues like unclear decision-making space and local authority to interpret policy during implementation remain unaddressed. Particularly in decentralized healthcare systems, the impact can appear in implementation challenges, subjective decision-making, poor teamwork, and an absence of disseminating best practices.ObjectivesThe SEARCH-IPT trial led a series of mini-collaborative meetings, which provided business leadership and management training for an intervention group of mid-level healthcare system managers in rural Eastern, East-Central, and Southwestern Uganda to see whether this would increase uptake of isoniazid-prevention therapy (IPT) for people living with HIV (PLHIV) in intervention districts. IPT is known to reduce active tuberculosis (TB), a leading cause of death among PLHIV, by 40-60%.MethodsWe performed a thematic analysis of six focus-group discussions from this intervention (held in May 2019, January 2020, September 2021) and 23 key informant interviews with control group participants (between February and August 2019 and September and December 2020).ResultsAnalysis revealed five implementation skill sets District Health Officers (DHOs) and District Tuberculosis and Leprosy Supervisors (DTLSs) deployed to achieve sustainable implementation and realize their decision-making space. The five practices were as follows: data-based decision-making, root-cause analysis, quality assurance, evidence-based empowerment, and sharing best practices with colleagues.ConclusionThese practices reached beyond outcome measures to address root problems around the DHO's range of authority and elicit buy-in from district health workers. For successful capacity building at the mid-manager level, focusing on core practices as part of competency is objectively implementable and measurable at the system level and does not rely on DHO self-assessments.

Illness narratives invite practitioners to understand how biomedical and traditional health information is incorporated, integrated, or otherwise internalized into a patient's own sense of self and social identity. Such narratives also reveal cultural values, underlying patterns in society, and the overall life context of the narrator. Most illness narratives have been examined from the perspective of European-derived genres and literary theory, even though theorists from other parts of the globe have developed locally relevant literary theories. Further, illness narratives typically examine only the experience of illness through acute or chronic suffering (and potential recovery). The advent of biomedical disease prevention methods like post- and pre-exposure prophylaxis (PEP and PrEP) for HIV, which require daily pill consumption or regular injections, complicates the notion of an illness narrative by including illness prevention in narrative accounts. This paper has two aims. First, we aim to rectify the Eurocentrism of existing illness narrative theory by incorporating insights from African literary theorists; second, we complicate the category by examining prevention narratives as a subset of illness narratives. We do this by investigating several narratives of HIV prevention from informants enrolled in an HIV prevention trial in Kenya and Uganda in 2022.

Abundant research has tried to understand how games can be designed and used effectively to improve the learning process and to examine the correlations between digital learning games and student motivation, engagement, and knowledge retention. The current study examined the correlation between learning through digital game-based learning (DGBL) and students' achievements, their sense of involvement, and motivation for learning. Using a quantitative approach, data was drawn from questionnaires and exams in two subjects: literature and language. Participants were 320 male and female students aged 12-14 attending a single middle school participated in the study. The students were randomly divided into three groups, each group was given a unique teaching and learning method. Group 1 studied and practiced using the traditional method (a teacher who teaches in the classroom and worksheets for practice), Group 2 studied with the traditional method but practiced with a digital game and Group 3 learned and practiced using a digital game. The findings showed that the students' attained significantly higher achievements in the group that was taught traditionally but practiced with a digital game. It was also found that when digital learning games are integrated into teaching and learning, the students' motivation and involvement in the class increased.

Despite recent work linking mixed phenotype acute leukemia (MPAL) to certain genetic lesions, specific driver mutations remain undefined for a significant proportion of patients and no genetic subtype is predictive of clinical outcomes. Moreover, therapeutic strategy for MPAL remains unclear, and prognosis is overall poor. We performed multiomic single cell profiling of 14 newly diagnosed adult MPAL patients to characterize the inter- and intra-tumoral transcriptional, immunophenotypic, and genetic landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. Despite this, we find that MPAL blasts express a shared stem cell-like transcriptional profile indicative of high differentiation potential. Patients with the highest differentiation potential demonstrate inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in the most stem-like MPAL cells, is applicable to bulk RNA sequencing data and is predictive of survival in an independent patient cohort, suggesting a potential strategy for clinical risk stratification.

Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss-of-function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells also demonstrated sensitivity of SH2B3-mutated hematopoietic progenitor cells to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.

IntroductionIdentifying the optimal approaches to offering HIV prevention to meet the needs of those at risk is a high priority, particularly given the expanding toolkit of biomedical HIV prevention options. An ongoing study in rural East African communities evaluated the uptake of choices in product, testing mode and location of care delivery through a structured patient-centred HIV prevention delivery model. In this qualitative study, we sought to understand clients' experiences of this "dynamic choice prevention model" (DCP) and highlight pathways of action to inform HIV prevention delivery models.MethodsIn-depth semi-structured interviews were conducted from November 2021 through March 2022 with a purposively selected sample of n = 56 participants in DCP trials (across outpatient departments, antenatal clinics and community settings), and n = 21 healthcare providers (total n = 77). A seven-person multi-regional team translated and inductively coded transcript data. We used a framework analysis approach to identify emergent themes.ResultsIndividuals taking up HIV pre-exposure prophylaxis (PrEP) reported feelings of relief, liberation from fears of acquiring HIV and satisfaction with being able to take action despite partners' behaviours. Couples used a range of approaches afforded by the study to persuade partners to get tested and opt for PrEP. Post-exposure prophylaxis (PEP) use was less common, although women welcomed it in the event of sexual coercion or assault. Participants discussed switching from PEP to PrEP after familiarizing themselves with usage and ascertaining ongoing risk. Participants felt respected by providers, trusted them and appreciated being able to contact them directly for telephone support. Prevention uptake was hindered by stigma, limited experience with and knowledge of prevention methods, gendered and generational power dynamics within intimate partnerships and families, and negative perceptions of methods due to the products themselves. Participants anticipated long-acting injectable PrEP could solve their challenges regarding pill size, daily pill burden and the likelihood of unwanted disclosure.ConclusionsDiverse preferences and barriers to uptake of prevention require a choice of HIV prevention options, locations and delivery modalities-but in addition, flexible, competent and friendly care provision is crucial to promote uptake. Helping clients feel valued, and addressing their unique needs and challenges, enables their agency to prioritize their health.

BACKGROUND: Across sub-Saharan Africa, mid-level healthcare managers oversee implementation of national guidelines. It remains unclear whether leadership and management training can improve population health outcomes. METHODS: We sought to evaluate leadership/management skills among district-level health managers in Uganda participating in the SEARCH-IPT randomised trial to promote isoniazid preventive therapy (IPT) for persons with HIV (PWH). The intervention, which led to higher IPT rates, included annual leadership/management training of managers. We conducted a cross-sectional survey assessing leadership/management skills among managers at trial completion. The survey evaluated self-reported use of leadership/management tools and general leadership/management. We conducted a survey among a sample of providers to understand the interventions impact. Targeted minimum loss-based estimation (TMLE) was used to compare responses between trial arms. RESULTS: Of 163 managers participating in the SEARCH-IPT trial, 119 (73%) completed the survey. Intervention managers reported more frequent use of leadership/management tools taught in the intervention curriculum than control managers (+3.64, 95% CI 1.98-5.30, P < 0.001). There were no significant differences in self-reported leadership skills in the intervention as compared to the control group. Among providers, the average reported quality of guidance and supervision was significantly higher in intervention vs control districts (+1.08, 95% CI 0.63-1.53, P = 0.001). CONCLUSIONS: A leadership and management training intervention increased the use of leadership/management tools among mid-level managers and resulted in higher perceived quality of supervision among providers in intervention vs control districts in Uganda. These findings suggest improved leadership/management among managers contributed to increased IPT use among PWH in the intervention districts of the SEARCH-IPT trial.

Contribution: Model-based learning improves systems thinking (ST) based on students' prior knowledge and gender. Relations were found between textual, visual, and mixed question types and student achievements. Background: ST is essential to judicious decision-making and problem-solving. Undergraduate students can be taught to apply better ST, and analysis of their online systems modeling processes can improve their ST. Research Questions: 1) What is the effect, if any, of online learning on the ST and conceptual modeling skill levels of undergraduate engineering students? 2) What differences are there, if any, between students' ST, conceptual modeling, and scores in textual, visual, and mixed question types based on their prior knowledge levels? and 3) Are there any gender differences in student performance, and if so, what are they? Methodology: The research participants were 157 undergraduate engineering students who took part in a mandatory second-year course, during which data were collected and analyzed quantitatively. Findings: Students with disparate prior knowledge differed significantly from each other in their overall ST mean score and in the mean scores of the various question types. Gender differences in ST and its relative improvement were also found.

There is social and collaborative value in a diverse student body, faculty, and staff. Despite this, universities are slow to establish evidence-based fiscal initiatives to increase representation and retention. We review inequitable financial practices in American higher education, including in endowments, tuition and annual giving, athletics, and research and innovation. We discuss fiscal initiatives that promote diversity, equity, justice, and inclusion (DEJI) while maintaining or increasing return on investment. Historical inequities are discussed in the context of institutional standards and methods of restructuring for DEJI success. A case-study of two Very High Research Activity Institutions in Alabama is used to demonstrate areas of improvement. Restructuring for an equitable, fiscally responsible, sustainable university system is feasible but requires changes to current standards.

Polygamy is the practice of marriage to multiple partners. Approximately 6-11% of households in Uganda and 4-11% of households in Kenya are polygamous. The complex families produced by polygamous marriage customs give rise to additional considerations for healthcare providers and public health messaging around HIV care. Using 27 in-depth, semi-structured qualitative interviews with participants in two studies in rural Kenya and Uganda, we analysed challenges and opportunities that polygamous families presented in the diagnosis, treatment and prevention of HIV, and provider roles in improving HIV outcomes in these families. Overall, prevention methods seemed more justifiable to families where co-wives live far apart than when all members live in the same household. In treatment, diagnosis of one member did not always lead to disclosure to other members, creating an adverse home environment; but sometimes diagnosis of one wife led not only to diagnosis of the other, but also to greater household support.

Understanding risk perception and risk-taking among youth can inform targeted prevention efforts. Using a health beliefs model-informed framework, we analysed 8 semi-structured, gender-specific focus group discussions with 93 youth 15-24 years old (48% male, 52% female), drawn from the SEARCH trial in rural Kenya and Uganda in 2017-2018, coinciding with the widespread introduction of PrEP. Highly connected social networks and widespread uptake of antiretrovirals shaped youth HIV risk perception. Amid conflicting information about HIV prevention methods, youth felt exposed to multiple HIV risk factors like the high prevalence of HIV, belief that people with HIV(PWH) purposefully infect others, dislike of condoms, and doubts about PrEP efficacy. Young women also reported minimal sexual autonomy in the context of economic disadvantages, the ubiquity of intergenerational and transactional sex, and peer pressure from other women to have many boyfriends. Young men likewise reported vulnerability to intergenerational sex, but also adopted a sexual conquest mentality. Comprehensive sexuality education and economic empowerment, through credible and trusted sources, may moderate risk-taking. Messaging should leverage youth's social networks to spread fact-based, gender- and age-appropriate information. PrEP should be offered alongside other reproductive health services to address both pregnancy concerns and reduce HIV risk.

Training district-level health officers and other mid-level health system managers revealed multiple contextual factors across political, administrative, and social axes affecting tuberculosis (TB) and TB control in Uganda. Individual relationships between local health, political, and media leaders affect efforts to inform the public and provide services, yet greater administrative coordination between national-level logistics, implementing partner funding, and local needs is required. Social challenges to TB control include high population mobility, local industries, poverty with high-density living and social venues, and misinformation about TB. Capitalizing on implementation knowledge and sharing data can overcome social geographic challenges to TB-prevention planning through strategic healthcare capacity-building at the district level.

BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.MethodsWe generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.ResultsIn the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).ConclusionsExtant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Striking weight biases emerge early in development, yet cognitive-developmental research has largely ignored weight as a social characteristic of interest. How do children conceive of weight? In particular, do children hold essentialist views of weight (i.e. do they view weight as natural, stable, inductively meaningful, and reflective of people's insides) as they do of so many other social characteristics? We conducted an exploratory investigation of children's weight essentialism across two studies. In total, 356 participants (280 4- to 11-year-old children and 76 adults from the United States, mostly White and from middle- to high-income families) participated in three tasks, respectively assessing three dimensions of essentialism of social categories: Beliefs about weight stability, heritability, and inductive potential despite transformation. Results revealed that children viewed weight as stable (similarly so to race) and informative of someone's food choices, but they did not view it as biologically- or genetically-determined. Thus, children may not view weight as reflecting people's biological nature (biological essentialism), but they may view weight as reflecting people's stable personal character (moral essentialism) - a view which is also highly compatible with weight bias, unlike biological essentialism. Children also demonstrated stronger essentialist views of lightness than heaviness across tasks, though essentialism of heaviness increased over development. Findings are discussed as they relate to early conceptions of weight and weight bias. Implications for conceptualizations and measurement of essentialism are also discussed.

Mutations in the receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although selective FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report the pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that pharmacologic SHP2 inhibition unveils an Achilles' heel of RTK-driven AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.

Current single-cell RNA-sequencing approaches have limitations that stem from the microfluidic devices or fluid handling steps required for sample processing. We develop a method that does not require specialized microfluidic devices, expertise or hardware. Our approach is based on particle-templated emulsification, which allows single-cell encapsulation and barcoding of cDNA in uniform droplet emulsions with only a vortexer. Particle-templated instant partition sequencing (PIP-seq) accommodates a wide range of emulsification formats, including microwell plates and large-volume conical tubes, enabling thousands of samples or millions of cells to be processed in minutes. We demonstrate that PIP-seq produces high-purity transcriptomes in mouse-human mixing studies, is compatible with multiomics measurements and can accurately characterize cell types in human breast tissue compared to a commercial microfluidic platform. Single-cell transcriptional profiling of mixed phenotype acute leukemia using PIP-seq reveals the emergence of heterogeneity within chemotherapy-resistant cell subsets that were hidden by standard immunophenotyping. PIP-seq is a simple, flexible and scalable next-generation workflow that extends single-cell sequencing to new applications.

ABSTRACT This study compared the performance of molecular vs stool culture assays for gastrointestinal infection (GII) detection, with focus on defining cycle threshold (Ct) cut-off values for positive culture results. A total of 6,000 records of patients with suspected GII between October 2022 and February 2023 and registered at Clalit HealthCare Services in Haifa, Israel, were reviewed. Stool samples were collected from all patients with suspected GII. PCR was performed with the Seegene Allplex GI-Bacteria (I) assay kit. PCR-positive samples were cultured on bacteria-specific agar media. Out of 356 PCR-positive samples, 196 (55.1%) were culture-positive. Significant differences were noted between the mean Ct of culture-positive vs culture-negative samples for Shigella spp. (P < 0.0001), E. coli O157 (P = 0.0001), and Campylobacter spp. (P = 0.004). Shigella had the lowest Ct cutoff (27.14). Negative culture results for PCR-positive samples may result from low bacterial load. At the same time, false-positive PCR results may exist. Thus, PCR result should be considered along with clinical presentation and with Ct value consideration.IMPORTANCEGII diagnostic procedures have shifted from traditional- to molecular-based assays, which may increase missdiagnosis due to the high PCR sensitivity and false positives. This study suggests to consider a Ct threshold for each pathogen in order to reduce inaccurate diagnosis. Alternatively, culture should be performed for PCR-positive samples.

Background Chronic obstructive pulmonary disease (COPD) is a common treatable disease often diagnosed in patients with risk factors after a prolonged period with suggestive symptoms. Our qualitative study aimed to identify barriers to establishing diagnosis in the natural history of this condition.Methods An inductive thematic analysis was performed on structured interviews with patients, general practitioners (GPs) and pulmonologists in France. Inclusion depended on criteria to generate two purposive samples (patients and physicians). Recruitment occurred online. Data collection proceeded until 15 patients and 15 physicians (eight pulmonologists, seven GPs) were interviewed. Data saturation was checked and achieved. The interviews were transcribed and coded in NVivo and triangulated between two researchers. The article respects the consolidated criteria for reporting qualitative research guidelines.Results Three phases in the patients’ clinical pathway to diagnosis and 12 barriers were found: Phase 1 (symptoms before consultation; n=4), lack of COPD knowledge, symptom denial, fear of lung cancer, and delayed general practice consultations; Phase 2 (primary care; n=3), letting bronchitis become chronic, priority to diseases with similar symptoms and/or more serious diseases, lack of COPD screening devices, time and curative treatments; Phase 3 (specialised medicine; n=5), treatment before diagnosis, late referral to pulmonologists, difficulty in accessing specialists and examination results, patient’s reluctance to undergo further examinations, and need for additional tests to confirm a diagnosis.Conclusion People unaware of their COPD condition can encounter up to 12 barriers, which may combine before obtaining a formal diagnosis. Patients, GPs, pulmonologists and the state health authorities share responsibility for addressing these barriers and enhancing the care pathway.

In 2025, it will be 30 years since the initial clinical approval of pegylated liposomal doxorubicin (PLD) by the Food and Drug Administration. PLD predated the field of nanomedicine and became a model nanomedicine setting key pharmacological principles (prolonged circulation, slow drug release and the enhanced permeability and retention (EPR) effect) for clinical application of other nano-drugs in cancer therapy. The impressive reduction of cardiotoxicity conferred by PLD is the most valuable clinical asset. While PLD has gained a strong foothold in relapsed ovarian cancer and metastatic breast cancer, it has not been extensively tested in primary (neoadjuvant) and adjuvant therapy and has not fulfilled the expectations from the results in animal models efficacy-wise. This discrepancy may be due to the large dose gap between mice and humans and the apparent variability of the EPR effect in human cancer. PLD is a complex product and we are still in a learning curve regarding a number of factors such as its interaction with the complement system and its immune modulatory properties, as well as its integration in multimodality therapy that may potentiate its value and role in cancer therapy.

Background Leadership skills are essential for middle-level healthcare manager efficacy. Capacity-building efforts may attempt behavioural change by filling ‘knowledge gaps’ while neglecting a sustainable application of that knowledge. Sustainable application of that knowledge, or implementation know-how, must resonate with local cultural patterns. When it is neglected, root issues like unclear decision-making space and local authority to interpret policy during implementation remain unaddressed. Particularly in decentralized healthcare systems, the impact can appear in implementation challenges, subjective decision-making, poor teamwork, and an absence of disseminating best practices. Objectives The SEARCH-IPT trial led a series of mini-collaborative meetings, which provided business leadership and management training for an intervention group of mid-level healthcare system managers in rural Eastern, East-Central, and Southwestern Uganda to see whether this would increase uptake of isoniazid-prevention therapy (IPT) for people living with HIV (PLHIV) in intervention districts. IPT is known to reduce active tuberculosis (TB), a leading cause of death among PLHIV, by 40–60%. Methods We performed a thematic analysis of six focus-group discussions from this intervention (held in May 2019, January 2020, September 2021) and 23 key informant interviews with control group participants (between February and August 2019 and September and December 2020). Results Analysis revealed five implementation skill sets District Health Officers (DHOs) and District Tuberculosis and Leprosy Supervisors (DTLSs) deployed to achieve sustainable implementation and realize their decision-making space. The five practices were as follows: data-based decision-making, root-cause analysis, quality assurance, evidence-based empowerment, and sharing best practices with colleagues. Conclusion These practices reached beyond outcome measures to address root problems around the DHO’s range of authority and elicit buy-in from district health workers. For successful capacity building at the mid-manager level, focusing on core practices as part of competency is objectively implementable and measurable at the system level and does not rely on DHO self-assessments.

Objectives: Trivalent inactivated influenza vaccine effectiveness was low in a prospective cohort of healthcare personnel (HCP) in Israel from 2016 to 2019. We conducted a randomised immunogenicity trial of quadrivalent recombinant influenza vaccine (RIV4) and standard-dose inactivated influenza vaccine (IIV4) among frequently and infrequently vaccinated previous cohort participants. Methods: From October 2019 to January 2020, we enrolled and randomly allocated HCP from two Israeli hospitals to receive IIV4 or RIV4. Hemagglutination inhibition (HAI) antibody titres against 2019-2020 vaccine reference influenza viruses were compared between vaccine groups using geometric mean titre (GMT) ratios from sera collected one-month post-vaccination and by frequency of vaccination in the past 5 years (>2 vs ≤2). Results: Among 415 HCP, the GMT ratio comparing RIV4 to IIV4 was 2.0 (95% confidence interval [CI] 1.7-2.7) for A(H1N1)pdm09, 1.6 (95% CI: 1.3-1.9) for A(H3N2), 1.8 (95% CI: 1.4-2.2) for B(Yamagata), and 1.1 (95% CI: 0.9-1.4) for B(Victoria). Similarly, RIV4 elicited higher HAI titres than IIV4 against all 2019-2020 vaccine reference viruses except B(Victoria) among infrequently and frequently vaccinated HCP (lower bound of GMT ratio 95% CIs ≥1.0). Conclusion: RIV4 had improved immunogenicity for influenza vaccine strains among both infrequent and frequent vaccinees compared to standard-dose IIV4. Clinical trials registration: NCT04523324