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Abstract Infections caused by Gram-negative bacteria are leading causes of mortality worldwide. Due to the rise in antibiotic resistant strains, there is a desperate need for alternative strategies to control infections caused by these organisms. One such approach is the prevention of infection through vaccination. While live attenuated and heat-killed bacterial vaccines are effective, they can lead to adverse reactions. Newer vaccine technologies focus on utilizing polysaccharide or protein subunits for safer and more targeted vaccination approaches. One promising avenue in this regard is the use of proteins released by the Type 5 secretion system (T5SS). This system is the most prevalent secretion system in Gram-negative bacteria. These proteins are compelling vaccine candidates due to their demonstrated protective role in current licensed vaccines. Notably, Pertactin, FHA, and NadA are integral components of licensed vaccines designed to prevent infections caused by Bordetella pertussis or Neisseria meningitidis. In this review, we delve into the significance of incorporating T5SS proteins into licensed vaccines, their contributions to virulence, conserved structural motifs, and the protective immune responses elicited by these proteins.

Abstract Nipah virus (NiV) is a zoonotic emergent paramyxovirus that can cause severe encephalitis and respiratory infections in humans, with a high fatality rate ranging from 40% to 75%. Currently, there are no approved human vaccines or antiviral drugs against NiV. Here, we designed a ferritin-based self-assembling nanoparticle displaying the NiV G head domain on the surface (NiV G-ferritin) and assessed immune responses elicited by the soluble NiV G head domain (NiV sG) or NiV G-ferritin. Immunization with NiV G-ferritin or NiV sG conferred complete protection against lethal NiV challenge without detection of viral RNA in Syrian golden hamsters. Compared to NiV sG, NiV G-ferritin induced significantly faster, broader, and higher serum neutralizing responses against three pathogenic henipaviruses (NiV-Malaysia, NiV-Bangladesh, and Hendra virus). Moreover, NiV G-ferritin induced a durable neutralizing immunity in mice as antisera potently inhibited NiV infection even after six months of the third immunization. Additionally, we isolated a panel of 27 NiV G-binding monoclonal antibodies (mAbs) from NiV G-ferritin immunized mice and found that these mAbs targeted four distinct antigenic sites on NiV G head domain with two sites that have not been defined previously. Notably, 25 isolated mAbs have potent neutralizing activity with 50% inhibitory concentrations less than 10 ng/mL against NiV pseudovirus. Collectively, these findings provide new insights into the immunogenicity of NiV G protein and reveal that NiV G-ferritin is a safe and highly effective vaccine candidate against Nipah virus infection.

Abstract The global population is increasingly reliant on vaccines to maintain population health with billions of doses used annually in immunisation programmes. Substandard and falsified vaccines are becoming more prevalent, caused by both the degradation of authentic vaccines but also deliberately falsified vaccine products. These threaten public health, and the increase in vaccine falsification is now a major concern. There is currently no coordinated global infrastructure or screening methods to monitor vaccine supply chains. In this study, we developed and validated a matrix-assisted laser desorption/ionisation-mass spectrometry (MALDI-MS) workflow that used open-source machine learning and statistical analysis to distinguish authentic and falsified vaccines. We validated the method on two different MALDI-MS instruments used worldwide for clinical applications. Our results show that multivariate data modelling and diagnostic mass spectra can be used to distinguish authentic and falsified vaccines providing proof-of-concept that MALDI-MS can be used as a screening tool to monitor vaccine supply chains.

Abstract Hybrid immunity against SARS-CoV-2 has not been well studied in pregnancy. We conducted a comprehensive analysis of neutralizing antibodies (nAb) and binding antibodies in pregnant individuals who received mRNA vaccination, natural infection, or both. A third vaccine dose augmented nAb levels compared to the two-dose regimen or natural infection alone; this effect was more pronounced in hybrid immunity. There was reduced anti-Omicron nAb, but the maternal-fetal transfer efficiency remained comparable to that of other variants. Vaccine-induced nAbs were transferred more efficiently than infection-induced nAbs. Anti-spike receptor binding domain (RBD) IgG was associated with nAb against wild-type (Wuhan-Hu-1) following breakthrough infection. Both vaccination and infection-induced anti-RBD IgA, which was more durable than anti-nucleocapsid IgA. IgA response was attenuated in pregnancy compared to non-pregnant controls. These data provide additional evidence of augmentation of humoral immune responses in hybrid immunity in pregnancy.

Abstract At the start of the Zika virus (ZIKV) epidemic in 2015, ZIKV spread across South and Central America, and reached parts of the southern United States placing pregnant women at risk for fetal microcephaly, fetal loss, and other adverse pregnancy outcomes associated with congenital ZIKA syndrome (CZS). For this reason, testing of a safe and efficacious ZIKV vaccine remains a global health priority. Here we report that a single immunization with Ad26.M.Env ZIKV vaccine, when administered prior to conception, fully protects pregnant rhesus macaques from ZIKV viral RNA in blood and tissues with no adverse effects in dams and fetuses. Furthermore, vaccination prevents ZIKV distribution to fetal tissues including the brain. ZIKV associated neuropathology was absent in offspring of Ad26.M.Env vaccinated dams, although pathology was limited in fetuses from non-immunized, challenged dams. Vaccine efficacy is associated with induction of ZIKV neutralizing antibodies in pregnant rhesus macaques. These data suggest the feasibility of vaccine prevention of CZS in humans.

Abstract Background Sepsis is a life-threatening condition triggered by uncontrolled immune responses to infection, leading to widespread inflammation, tissue damage, organ dysfunction, and potentially death. The liver plays a crucial role in the immune response during sepsis, serving as a major site for immune cell activation and cytokine production. Liver type 1 innate lymphoid cells (ILCs) consist of NK cells and ILC1s. They maintain the local immune microenvironment by directly eliminating target cells and secreting cytokines. However, the specific roles and pathological changes of liver-resident NK cells and ILC1s during sepsis remain poorly understood. Results This study aims to investigate the pathological changes of NK cells and ILC1s, which might contribute the dysfunction of liver. Sepsis mouse model was established by cecal ligation and puncture (CLP). Mouse immune cells from liver were isolated, and the surface makers, gene expression profiles, cytokine response and secretion, and mitochondrial function of NK (Natural Killer) cells and ILC1s (Innate Lymphoid Cell 1) were analyzed. A significant decrease in the number of mature NK cells was observed in the liver after CLP. Furthermore, the secretion of interferon-gamma (IFN-γ) was found to be reduced in spleen and liver NK cells when stimulated by IL-18. Mitochondrial activities in both liver NK cells and ILC1 were found to be increased during sepsis, suggesting an enhanced metabolic response in these cells to combat the infection. However, despite this heightened activity, liver NK cells exhibited a decreased level of cytotoxicity, which might impact their ability to target infected cells effectively. RNA sequencing supported and provided the potential mechanisms for the proinflammatory effects and exhaustion like phenotypes of liver NK cells. Conclusions Sepsis induces dysfunction and exhaustion-like phenotypes in liver NK cells and ILC1, which might further impair other immune cells and represent a potential therapeutic target for sepsis.

Abstract PF-06817024 is a humanized antibody against interleukin-33 that has the potential to inhibit type 2 inflammation. An exploratory analysis of the pharmacodynamics and clinical effects of single and repeat doses of PF-06817024 was assessed in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and patients with moderate-to-severe atopic dermatitis (AD), respectively, as part of a Phase 1, first-in-human study. Rhinosinusitis symptoms were improved, and nasal polyps were decreased in size following treatment with PF-06817024 in patients with CRSwNP. In patients with AD, PF-06817024, in aggregate, reduced disease severity and improved symptoms, as demonstrated by greater percentage decrease from baseline in Eczema Area and Severity Index (EASI) scores and reduced pruritus numerical rating scores, compared with placebo. The efficacy in AD appeared to be bimodal with a sub-group of participants exhibiting high levels of improvement (EASI75 and EASI90) for a sustained period of time after dosing. In patients with CRSwNP, a consistent trend of decrease in eosinophil levels was observed in the PF-06817024 group, compared with placebo. Further research would be needed to confirm the clinical benefit and safety of PF-06817024 as a treatment for allergic diseases. Trial registration ClinicalTrials.gov, NCT02743871. Registered 15 April 2016, https://clinicaltrials.gov/study/NCT02743871?term=NCT02743871&rank=1 .

Abstract Background Aging is a complex biological process characterized by obesity and immunosenescence throughout the organism. Immunosenescence involves a decline in immune function and the increase in chronic-low grade inflammation, called inflammaging. Adipose tissue expansion, particularly that of visceral adipose tissue (VAT), is associated with an increase in pro-inflammatory macrophages that play an important role in modulating immune responses and producing inflammatory cytokines. The leukotriene B4 receptor 1 (BLT1) is a regulator of obesity-induced inflammation. Its ligand, LTB4, acts as a chemoattractant for immune cells and induces inflammation. Studies have shown that BLT1 is crucial for cytokine production during lipopolysaccharide (LPS) endotoxemia challenge in younger organisms. However, the expression patterns and function of BLT1 in older organisms remains unknown. Results In this study, we investigated BLT1 expression in immune cell subsets within the VAT of aged male and female mice. Moreover, we examined how antagonizing BLT1 signaling could alter the inflammatory response to LPS in aged mice. Our results demonstrate that aged mice exhibit increased adiposity and inflammation, characterized by elevated frequencies of B and T cells, along with pro-inflammatory macrophages in VAT. BLT1 expression is the highest in VAT macrophages. LPS and LTB4 treatment result in increased BLT1 in young and aged bone marrow-derived macrophages (BMDMs). However, LTB4 treatment resulted in amplified Il6 from aged, but not young BMDMs. Treatment of aged mice with the BLT1 antagonist, U75302, followed by LPS-induced endotoxemia resulted in an increase in anti-inflammatory macrophages, reduced phosphorylated NFκB and reduced Il6. Conclusions This study provides valuable insights into the age- and sex- specific changes in BLT1 expression on immune cell subsets within VAT. This study offers support for the potential of BLT1 in modulating inflammation in aging.

Abstract Background The provision of professional counseling services for persons living with human immunodeficiency virus (PLHIV) is crucial in the prevention and treatment continuum of the disease. However, for counselors of people infected with the human immunodeficiency virus (HIV) leading to acquired immune deficiency syndrome (AIDS) to give their best, their motivations to become counselors and the challenges they face in their line of duty need to be contextually understood and addressed. We ascertained the roles, motivations, and experiences of HIV/AIDS counselors in the Volta Region of Ghana to inform HIV/AIDS counseling decision-making in the region and the country. Methods A phenomenological study conducted among sixteen (16) HIV/AIDS counselors from five HIV/AIDS sentinel sites in the Volta region of Ghana, recruited through a purposive sampling approach and interviewed to ascertain their HIV/AIDS counseling-related experiences. The data were thematically analyzed using the Atlas. ti software, and sub-themes supported with verbatim quotes. Results Five motives for becoming an HIV/AIDS counselor were found. These include being randomly assigned to the unit, developing interest in the job, because of the status of a relative, witnessing bad attitudes of healthcare providers, and seeing HIV- clients lacking knowledge of the condition. The study found that these counselors performed six core roles: providing nutritional counseling, educating clients on HIV, treatment, and medication provision, conducting testing and comprehensive counseling of clients, providing social support to clients, and offering financial support to clients. The experiences these counselors had were boosting clients’ health status, counseling clients back to a normal mental state, cooperation from clients, participants gaining knowledge on HIV through counseling, counseling clients to accept their status, and when a client delivered an HIV-negative baby. Their negative experiences included clients denying their HIV status, clients defaulting on their treatment, uncooperative clients, death of clients due to fear of breach of confidentiality, self-stigmatization among clients, and the myths some people hold towards HIV/AIDS. Conclusion By organizing capacity-building training programs for HIV/AIDS counselors in the Volta region and addressing the negative experiences they encounter, they could be empowered to provide effective counseling, curative, and social services to people living with HIV in the region, leading to improved health outcomes.

Abstract Introduction People living with HIV (PLHIV) have a 20-fold risk of tuberculosis (TB) disease compared to HIV-negative people. In 2021, the uptake of TB preventive treatment among the children and adolescents living with HIV at the Baylor-Uganda HIV clinic was 45%, which was below the national target of 90%. Minimal evidence documents the enablers and barriers to TB preventive treatment (TPT) initiation and completion among children and adolescents living with HIV(CALHIV). We explored the facilitators and barriers to TPT initiation and completion among CALHIV among adolescents aged 10-19years and caretakers of children below 18years. Methods We conducted a qualitative study from February 2022 to March 2023, at three paediatric and adolescent HIV treatment centers in Uganda. In-depth interviews were conducted at TPT initiation and after completion for purposively selected health workers, adolescents aged 10–19 years living with HIV, and caretakers of children aged below 18years. Results The desire to avoid TB disease, previous TB treatment, encouragement from family members, and ministry of health policies emerged as key facilitators for the children and adolescents to initiate TPT. Barriers to TPT initiation included; TB and HIV-related stigma, busy carer and adolescent work schedules, reduced social support from parents and family, history of drug side effects, high pill burden and fatigue, and perception of not being ill. TPT completion was enabled by combined TPT and ART refill visits, delivery of ART and TPT within the community, and continuous education and counseling from health workers. Reported barriers to TPT completion included TB and HIV-related stigma, long waiting time. Non-disclosure of HIV status by caretakers to CALHIV and fear of side effects was cited by health workers as a barrier to starting TPT. Facilitators of TPT initiation and completion reported by healthcare workers included patient and caretaker health education, counselling about benefits of TPT and risk of TB disease, having same appointment for TPT and ART refill to reduce patient waiting time, adolescent-friendly services, and appointment reminder phone calls. Conclusion The facilitators and barriers of TPT initiation and completion among CALHIV span from individual, to health system and structural factors. Health education about benefits of TPT and risk of TB, social support, adolescent-friendly services, and joint appointments for TPT and ART refill are major facilitators of TPT initiation and completion among CALHIV in Uganda.

Abstract Introduction HIV/AIDS is one of the most dangerous diseases globally, impacting public health, economics, society, political issues, and communities. As of 2023, the World Health Organization estimates that 40.4 million people are living with HIV/AIDS. This study aimed to identify the determinants of survival time for HIV/AIDS patients in the pastoralist region of Borena at Yabelo General Hospital. Method The study design was a retrospective cohort study, with a sample size of 293 individuals living with HIV/AIDS, based on recorded data. This research utilized survival model analysis, employing Kaplan-Meier plots, the log-rank test, and Cox proportional hazard model analysis. Result Out of the total sample size, 179 (61.1%) were female and 114 (38.1%) were male. Among these males, 36 (31.6%) were deceased. The analysis using the Cox proportional hazard model revealed that the following variables were significantly associated with the survival time of HIV/AIDS patients: gender, educational status, area of residence, tuberculosis (TB), and opportunistic infections. Conclusions We concluded that individuals living with HIV/AIDS in urban areas have a lower risk of death compared to those in rural areas, indicating that rural residents have a reduced survival probability. Therefore, the Borena zone administration should focus on adult patients to enhance life expectancy.

Abstract Chronic viral infections caused by the human immunodeficiency virus (HIV), hepatitis C (HCV), and hepatitis B (HBV) are common among patients with end-stage renal disease (ESKD). These infections were once considered contraindications to kidney transplantation due to potential risks associated with long-term immunosuppression. Improved management and antiviral therapies have changed the prognosis and survival of this group of patients, along with an increased experience in transplanting people with these viral infections. We report the first successful kidney transplant in an ESKD patient on hemodialysis with a history of concomitant HIV, HCV and HBV infection in Mexico.

Abstract Background Patient management in rheumatoid arthritis (RA) has evolved to a “treat-to-target” (T2T) approach, which entails intensive treatment and regular follow-up with the goal of achieving low levels of disease activity or clinical remission. Even though a T2T approach is endorsed by professional organizations and yields superior outcomes, its implementation remains incomplete. EVEREST (EleVatE care in RhEumatoid arthritiS with Treat-to-target) is a quality-improvement initiative designed to improve the widespread implementation of a personalized T2T strategy and enable patients with RA to reach their full potential for remission. We describe the Brazilian results from the Global T2T Survey, first part of the EVEREST program. Methods Between June and September 2022, we conducted an online survey targeting rheumatologists in Brazil. Our objective was to evaluate the barriers and knowledge gaps hindering the effective implementation of T2T strategies. To achieve this, we employed a set of multiple-choice questions specifically crafted to elicit responses categorized in a structured order. Results 166 rheumatologists participated in the survey, 51% of them with more than 21 years of experience in rheumatology. Regarding the perceived challenges in the management of RA in clinical practice, the highest percentage of agreement/strong agreement among the participants was related to the contradictory results of disease activity measures (60%). In terms of the main barriers to assess the disease activity in clinical practice, the lack of adherence to treatment and contradictory assessments between patient-reported outcomes and composite measures were indicated by 75% and 59% of the participants, respectively, as a moderate/serious barrier. The most frequently knowledge and skill gaps related to the management of RA pointed out by the participants were on the difficulty to assess patients’ health literacy (54% stated to have no more than intermediate knowledge on standardized methods to assess it and 43% no more than intermediate skills on determining the level of health literacy of the patients). In general, the use of tools to support the management of RA patients in clinical practice was indicated to be unusual by the participants. Self-reflection questionnaires, patient education materials and treatment consideration checklists were pointed out as the least frequently used tools (85%, 64% and 62% of the participants stated to use them never, rarely, or only sometimes, respectively). Conclusions Our findings indicate a greater need for design, selection, and uptake of practical strategies to further improve communication between healthcare providers and patients with RA, as well as for promoting well-informed, collaborative decision-making in their care.

Abstract Backgrounds Septic arthritis is a dangerous disease that occurs when microorganisms enter synovial fluid. It needs fast and accurate management; otherwise, it can harm the patient’s life. Currently, the tests measure WBC and PMN in SF, so we hypothesized to use a proxy that is easier and faster to measure. Leukocyte esterase is an enzyme secreted by neutrophils that can be found in the synovial fluid of SA patients. In this study, we tried to investigate the sensitivity and specificity of leukocyte esterase in diagnosing septic arthritis. Methods We obtained synovial fluid samples from forty-six patients suspected of having septic arthritis and fifty-eight healthy individuals and measured the WBCs, ESR, CRP, PMN, glucose, and protein of SF in 2021. We also used the leukocyte esterase dipstick test to investigate the level of LE in synovial fluid for one minute. Results Based on clinical and paraclinical criteria, sixteen out of the forty-six patients were diagnosed with SA. When (++) was considered positive, the sensitivity and specificity of the LE dipstick test for the diagnosis of SA were 93.7% (95% CI: 81.8–100%) and 60% (95% CI: 42.4–77.5%, P = 0.000), respectively. When both (+) and (++) were considered positive, they were 100% and 43.3% (95% CI: 25.6–61.0% P = 0.000), respectively. All the patients in the control group had negative cultures and LE test readings (specificity = 100%). Conclusion The LE dipstick test can be a valuable diagnostic tool in the initial diagnosis of SA since it is affordable, fast, and reliable.

Abstract Objective To evaluate the influence of environmental factors and prematurity relating to juvenile dermatomyositis (JDM), its course and refractoriness to treatment. Methods A case-control study with 35 patients followed up at a tertiary hospital and 124 healthy controls, all residents of São Paulo. Patients were classified according to monocyclic, polycyclic or chronic disease courses and refractoriness to treatment. The daily concentrations of pollutants (inhalable particulate matter-PM10, sulfur dioxide-SO2, nitrogen dioxide-NO2, ozone-O3 and carbon monoxide-CO) were provided by the Environmental Company of São Paulo. Data from the population were obtained through a questionnaire. Results Fifteen patients had monocyclic courses, and 19 polycyclic/chronic courses. Eighteen patients were refractory to treatment. Maternal occupational exposure to inhalable agents (OR = 17.88; IC 95% 2.15–148.16, p = 0.01) and exposure to O3 in the fifth year of life (third tertile > 86.28µg/m3; OR = 6.53, IC95% 1.60–26.77, p = 0.01) were risk factors for JDM in the multivariate logistic regression model. The presence of a factory/quarry at a distance farther than 200 meters from daycare/school (OR = 0.22; IC 95% 0.06–0.77; p = 0.02) was a protective factor in the same analysis. Prematurity, exposure to air pollutants/cigarette smoke/sources of inhalable pollutants in the mother’s places of residence and work during the gestational period were not associated with JDM. Prematurity, maternal exposure to occupational pollutants during pregnancy as well as patient’s exposure to ground-level pollutants up to the fifth year of life were not associated with disease course and treatment refractoriness. Conclusion Risk factors for JDM were maternal occupational exposure and exposure to O3 in the fifth year of life.

Craig LaForce,1 Frank C Albers,2 Mark Cooper,3 Anna Danilewicz,4 Lynn Dunsire,3 Robert Rees,4 Christy Cappelletti5 1North Carolina Clinical Research, Chapel Hill, NC, USA; 2Avillion, Northbrook, IL, USA; 3BioPharmaceuticals Research and Development, AstraZeneca, Cambridge, UK; 4Avillion, London, UK; 5BioPharmaceuticals Research and Development, AstraZeneca, Durham, NC, USACorrespondence: Mark Cooper, BioPharmaceuticals Reseach and Development, AstraZeneca, Cambridge, UK, Email mark.cooper1@astrazeneca.comPurpose: Decentralized clinical trials, where trial-related activities occur at locations other than traditional clinical sites(eg participant homes, local healthcare facilities), have the potential to improve trial access for people for whom time and/or distance constraints may impede participation. Albuterol–budesonide 180/160 μg pressurized metered-dose inhaler (pMDI) is FDA approved for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients with asthma 18 years or older. BATURA (NCT05505734) is a fully decentralized study, investigating as-needed albuterol–budesonide in participants with mild asthma.Methods: BATURA is a fully decentralized, phase 3b, randomized, double-blind, event-driven exacerbation study conducted in the United States. Participants aged ≥ 12 years using as-needed short-acting β2-agonist (SABA), alone or with low-dose inhaled corticosteroid or leukotriene receptor antagonist maintenance, are randomized 1:1 to as-needed albuterol–budesonide 180/160 μg or albuterol 180 μg pMDI for up to 52 weeks (minimum 12 weeks). Participants continue their current maintenance therapy, if applicable. Participants must have used SABA for ≥ 2 days in the 2 weeks pre-enrollment and have an Asthma Impairment Risk Questionnaire score ≥ 2 at screening and randomization. All trial-related visits, including screening and consent, are conducted virtually, with study medication shipped directly to each participant’s residence. The primary objective is to evaluate the efficacy of as-needed albuterol–budesonide versus albuterol on severe asthma exacerbation risk, measured by time-to-first severe asthma exacerbation (primary endpoint). Secondary endpoints include annualized rate of severe asthma exacerbation and total systemic corticosteroid exposure. Study medication use is captured via a Hailie sensor attached to the study medication pMDI. The intended sample size is 2500 participants.Conclusion: BATURA evaluates as-needed albuterol–budesonide in participants with mild asthma. The decentralized study model enables the trial to move out of research sites into participant homes, reducing participant burden and improving access.Keywords: decentralized clinical trials, trial design, albuterol–budesonide, SABA–ICS

Shivani Srivastava,1,* Anuradha Tyagi,2,* Vishakha Anand Pawar,3,* Nawaid Hussain Khan,4,* Kavita Arora,5,6 Chaitenya Verma,7,8 Vinay Kumar9 1Department of Pathology, School of Medicine, Yale University, New Haven, CT, USA; 2Department of cBRN, Institute of Nuclear Medicine and Allied Science, Delhi, India; 3The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Faculty of Medicine, Ala-Too International University, Bishkek, Kyrgyz Republic; 5Advanced Instrumentation Research Facility, Jawaharlal Nehru University, New Delhi, India; 6School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi, India; 7Department of Pathology, Wexner Medical Center, Ohio State University, Columbus, OH, USA; 8Department of Biotechnology, SSET, Sharda University, Greater Noida, 201306, India; 9Pennsylvania State University Hershey Medical Center, 500 University Dr, Heshey, PA, USA*These authors contributed equally to this workCorrespondence: Chaitenya Verma; Vinay Kumar, Email chaitenya999@gmail.com; vinayktyagi07@gmail.comAbstract: The CAR-T cell therapy has marked the dawn of new era in the cancer therapeutics and cell engineering techniques. The review emphasizes on the challenges that obstruct the therapeutic efficiency caused by cell toxicities, immunosuppressive tumor environment, and decreased T cell infiltration. In the interest of achieving the overall survival (OS) and event-free survival (EFS) of patients, the conceptual background of potential target selection and various CAR-T cell design techniques are described which can minimize the off-target effects, reduce toxicity, and thus increase the resilience of CAR-T cell treatment in the haematological malignancies as well as in solid tumors. Furthermore, it delves into cutting-edge technologies like gene editing and synthetic biology, providing new opportunities to enhance the functionality of CAR-T cells and overcome mechanisms of immune evasion. This review provides a comprehensive understanding of the complex and diverse aspects of CAR-T cell-based gene treatments, including both scientific and clinical aspects. By effectively addressing the obstacles and utilizing the capabilities of cutting-edge technology, CAR-T cell therapy shows potential in fundamentally changing immunotherapy and reshaping the approach to cancer treatment.Keywords: CAR-T cells, immune checkpoint inhibitors, gene therapies, gene editing, predictive biomarkers

Anderson Bendera,1 Deogratias Mugisha Baryomuntebe,2 Nwanna Uchechukwu Kevin,3 Miisa Nanyingi,4 Patience Bemanya Kinengyere,5 Salaam Mujeeb,6 Esther Jachi Sulle7 1Department of Radiology and Medical Imaging, Monduli District Hospital, Arusha, Tanzania; 2Faculty of Nursing, Fins Medical University, Kampala, Uganda; 3Department of Community Health, University of Rwanda, Kigali, Rwanda; 4Department of Health Sciences, Uganda Martyrs University, Kampala, Uganda; 5AiKA Health Consults, Kampala, Uganda; 6Department of Pathology, Islamic University in Uganda, Kampala, Uganda; 7Credit Department, WEDAC Microfinance Institution Ltd, Arusha, TanzaniaCorrespondence: Anderson Bendera, Department of Radiology and Medical Imaging, Monduli District Hospital, P. O. Box 12, Arusha, Tanzania, Email andybendera@gmail.comBackground: About half of people infected with Human Immunodeficiency Virus (HIV) often present late for care, resulting in higher healthcare costs, undesired treatment outcomes, and ongoing HIV transmission. This study aimed to assess the prevalence and determinants of late HIV diagnosis and advanced HIV disease (AHD) in Tanzania.Methods: Data were obtained from the 2016– 17 Tanzania HIV impact survey. We included 677 newly diagnosed people living with HIV. Late HIV diagnosis and AHD were defined as having a CD4 cell count below 350 cells/μL or 200 cells/μL at diagnosis, respectively. Bivariate and multivariable logistic regression models were fitted to identify the determinants of late HIV diagnosis or AHD.Results: The mean age of the participants was 37.8 years (SD, 12.4). About two-thirds were women (62.6%). The prevalence of late HIV diagnosis was 42.4%, whereas the prevalence of AHD was 17.7%. Factors associated with late HIV diagnosis included age 31– 40 years (adjusted odds ratio [aOR] = 1.72, 95% confidence interval [CI]: 1.14– 2.60), age ≥ 41 years (aOR = 1.79, 95% CI: 1.16– 2.76), male sex (aOR = 1.88, 95% CI: 1.29– 2.73), and active syphilis infection (aOR=2.63, 95% CI: 1.20– 5.76). Factors associated with AHD were age 31– 40 years (aOR = 2.12, 95% CI: 1.18– 3.81), age ≥ 41 years (aOR = 2.42, 95% CI: 1.32– 4.41), male sex (aOR = 1.77, 95% CI: 1.09– 2.87), formal education (aOR = 0.49, 95% CI: 0.30– 0.81) and active syphilis infection (aOR = 2.49, 95% CI: 1.07– 5.77).Conclusion: Late HIV diagnosis and AHD are prevalent among newly diagnosed people living with HIV in Tanzania. Specific subgroups are more likely to present late for HIV care, including middle-aged and older adults, men, illiterate individuals, and those with active syphilis and HIV co-infection. Therefore, we recommend expanding HIV testing services and implementing targeted interventions to improve early access and enrollment in HIV care.Keywords: advanced HIV disease, HIV/AIDS, HIV care, late presentation, Tanzania

Clinical trials, the empirical discipline of medical experimentation conducted on human subjects, have engendered a paradigm shift in medical research. The need for new clinical studies is paramount in the Middle East and North Africa (MENA) region, with its rising cancer incidence and demand for efficient oncology treatments. This paper comprehensively reviews the challenges, opportunities, and future directions of phase I oncology clinical trials in the MENA region. Early-phase trials are vital in determining drug dosage and assessing toxicity, bridging the gap between preclinical research and clinical practice. Considering the unique landscape of MENA, this review explores regulatory aspects, specific hurdles faced, potential advantages, and areas for improvement in conducting these trials. Various future directions can be pursued to maximize the potential of phase I oncology trials in MENA. While regulatory bodies like the Ministry of Health adhere to the International Conference on Harmonization–Good Clinical Practice guidelines, a unified system meeting high standards would yield better results. Strengthening research infrastructure, establishing research centers, incorporating clinical trial education into the curriculum, and improving access to medical facilities are crucial. Enhancing consumer understanding of research would facilitate increased participation and promote sustainability in trial recruitment. Navigating various funding sources would open the door for more funding opportunities. Collaborations between academia, industry, and regulatory bodies, both international and local, should be fostered to promote knowledge sharing, resource pooling, and harmonization of standards. Such collaborations would contribute to the sustainability of clinical trial activities by leveraging collective expertise, sharing research infrastructure, and distributing the burden of regulatory compliance. By adopting these strategies, the MENA region can advance its capacity to conduct early phases of oncology trials and contribute significantly to the global medical research landscape.

A 62-year-old man presented with a slowly growing, painless lesion on his face. This eventually led to a progressive left-eye vision lesion, and the patient was subsequently diagnosed with advanced basal cell carcinoma (BCC). Of note, BCC involving cranial nerves is extremely rare, making this case unique and important to highlight. Standard treatment options for BCC involve surgery, radiation, or platinum-based chemotherapy. However, targeted therapies such as sonidegib and vismodegib – sonic hedgehog pathway inhibitors – have emerged that have been approved for treating BCC, as have anti-PD1 immunotherapies, such as cemiplimab, with their success likely based on the high tumor mutational burden seen in some of these tumors. Epidermal growth factor receptor (EGFR) inhibitors also serve a role in treating this condition as well. Molecular studies on metastatic/advanced BCC and other rare malignancies may inform treatment therapeutic decisions.

The COVID-19 pandemic has led to a rethinking of clinical trial design to maintain clinical research activity, with regulatory changes allowing for the wider implementation and development of decentralized design models. Evidence of the feasibility and benefits associated with a remote design comes mainly from observational studies or phase 2 and 3 clinical trials, in which implementation is easier with a better-established safety profile. Early drug development is a slow and expensive process in which accrual and safety are key aspects of success. Applying a decentralized model to phase 1 clinical trials could improve patient accrual by removing geographic barriers, improving patient population diversity, strengthening evidence for rare tumors, and reducing patients’ financial and logistical burdens. However, safety monitoring, data quality, shipment, and administration of the investigational product are challenges to its implementation. Based on published data for decentralized clinical trials, we propose an exploratory framework of solutions to enable the conceptualization of a decentralized model for phase 1 clinical trials.

Introduction: Disparities in incidence and outcome of rectal cancer are multifactorial in etiology but may be due, in part, to differences in gut microbiome composition. We used serial robust statistical approaches to assess baseline gut microbiome composition in a diverse cohort of patients with rectal cancer receiving definitive treatment. Methods: Microbiome composition was compared by age at diagnosis (< 50 vs ≥ 50 years), race and ethnicity (White Hispanic vs non-Hispanic), and response to therapy. Alpha diversity was assessed using the Shannon, Chao1, and Simpson diversity measures. Beta diversity was explored using both Bray-Curtis dissimilarity and Aitchison distance with principal coordinate analysis. To minimize false-positive findings, we used two distinct methods for differential abundance testing: LinDA and MaAsLin2 (all statistics two-sided, Benjamini-Hochberg corrected false discovery rate < 0.05). Results: Among 64 patients (47% White Hispanic) with median age 51 years, beta diversity metrics showed significant clustering by race and ethnicity (p < 0.001 by both metrics) and by onset (Aitchison p = 0.022, Bray-Curtis p = 0.035). White Hispanic patients had enrichment of bacterial family Prevotellaceae(LinDA fold change 5.32, MaAsLin2 fold change 5.11, combined adjusted p = 0.0007). No significant differences in microbiome composition were associated with neoadjuvant therapy response. Conclusion: We identified distinct gut microbiome signatures associated with race and ethnicity and age of onset in a diverse cohort of patients undergoing definitive treatment for rectal cancer.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematologic malignancy with limited treatment options. Currently, standard treatment strategies include clinical trials; chemotherapy regimens such as hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD); and tagraxofusp-erzs (TAG, previously SL-401) which is the first-in-class targeted therapy against CD123. TAG received Food and Drug Administration approval for frontline BPDCN treatment in December 2018 and has increasingly become an alternative to chemotherapy, offering potentially more effective and less toxic options. However, despite promising results, there are still patients who may be resistant to TAG monotherapy and/or who respond but eventually relapse. Herein, we discuss an important patient case of BPDCN treated with TAG and review BPDCN treatment strategies.

Introduction: In targeted therapies and immunotherapies, the occurrence of low-grade (e.g., grade 1–2) toxicities (LGT) is common, while dose-limiting toxicities (DLT) are relatively rare. As a result, conventional phase I trial designs, solely based on DLTs and disregarding milder toxicities, are problematic when evaluating these novel therapies. Methods: To address this issue, we propose a novel phase I design called a multiple-constraint keyboard (MC-Keyboard) that integrates multiple toxicity constraints, accounting for both DLT and LGT, for precise dose escalation and de-escalation, and identification of the maximum tolerated dose (MTD). As a model-assisted design, an important feature of MC-Keyboard is that its dose-escalation or de-escalation rule can be pretabulated and incorporated into the trial protocol before the initiation of the trial, greatly simplifying its implementation. Results: The simulation study showed that the MC-Keyboard had high accuracy in identifying the MTD and is safer than some existing designs. Conclusion: The MC-Keyboard provides a novel, simple, and safe approach to assessing safety and identifying the MTD for targeted therapies and immunotherapies.

Abstract The global spread of H5 clade 2.3.4.4 highly pathogenic avian influenza (HPAI) viruses threatens poultry and public health. The continuous circulation of these viruses has led to their considerable genetic and antigenic evolution, resulting in the formation of eight subclades (2.3.4.4a–h). Here, we examined the antigenic sites that determine the antigenic differences between two H5 vaccine strains, H5-Re8 (clade 2.3.4.4g) and H5-Re11 (clade 2.3.4.4h). Epitope mapping data revealed that all eight identified antigenic sites were located within two classical antigenic regions, with five sites in region A (positions 115, 120, 124, 126, and 140) and three in region B (positions 151, 156, and 185). Through antigenic cartography analysis of mutants with varying numbers of substitutions, we confirmed that a combination of mutations in these eight sites reverses the antigenicity of H5-Re11 to that of H5-Re8, and vice versa. More importantly, our analyses identified H5-Re11_Q115L/R120S/A156T (H5-Re11 + 3) as a promising candidate for a broad-spectrum vaccine, positioned centrally in the antigenic map, and offering potential universal protection against all variants within the clade 2.3.4.4. H5-Re11 + 3 serum has better cross-reactivity than sera generated with other 2.3.4.4 vaccines, and H5-Re11 + 3 vaccine provided 100% protection of chickens against antigenically drifted H5 viruses from various 2.3.4.4 antigenic groups. Our findings suggest that antigenic regions A and B are immunodominant in H5 viruses, and that antigenic cartography-guided vaccine design is a promising strategy for selecting a broad-spectrum vaccine.

Abstract Alzheimer’s disease (AD) is an intricate disorder involving amyloid deposits, neurofibrillary tangles, and chronic neuroinflammation. Though current Aβ-directed immunotherapies effectively eliminate amyloid plaques, their limited clinical benefits and notable safety concerns arise from overlooking two other neglected neurodegenerative features. Compelling evidence highlights synergistic cooperation between Aβ and tau, underscoring the imperative need to develop combinational therapies to target the diverse pathologies of AD. In this study, we present a dual AD vaccine combining Aβ and pTau vaccines, eliciting robust and enduring antibody responses against pathological Aβ and pTau in 3xTg transgenic mice. It significantly eradicated Aβ plaques and pTau tangles, suppressed neuroinflammatory factors, and markedly enhancing cognitive abilities in 3xTg mice. Mechanistically, peripheral antibodies penetrated the brain, recognizing and inhibiting Aβ and pTau aggregation, thereby reducing their cytotoxicity. In summary, this innovative multi-targeting immunotherapy remarkably ameliorates diverse AD pathologies, demonstrating maximum benefits in slowing the clinical progression of AD.

Summary ESKAPE pathogens are responsible for complicated nosocomial infections worldwide and are often resistant to commonly used antibiotics in clinical settings. Among ESKAPE, vancomycin-resistant Enterococcus faecium (VREfm) and methicillin-resistant Staphylococcus aureus (MRSA) are two important Gram-positive pathogens for which non-antibiotic alternatives are urgently needed. We previously showed that the lipoprotein AdcA of E. faecium elicits opsonic and protective antibodies against E. faecium and E. faecalis. Prompted by our observation, reported here, that AdcA also elicits opsonic antibodies against MRSA and other clinically relevant Gram-positive pathogens, we identified the dominant epitope responsible for AdcA cross-reactive activity and designed a hyper-thermostable and multi-presenting antigen, Sc(EH)3. We demonstrate that antibodies raised against Sc(EH)3 mediate opsonic killing of a wide-spectrum of Gram-positive pathogens, including VREfm and MRSA, and confer protection both in passive and active immunisation models. Our data indicate that Sc(EH)3 is a promising antigen for the development of vaccines against different Gram-positive pathogens.

Abstract Marek’s disease virus (MDV) integrates its genome into the telomeres of host chromosomes and causes fatal lymphomas in chickens. This integration is facilitated by telomeric repeat sequences (TMRs) at the ends of the viral genome, and is crucial for MDV-induced lymphomagenesis. The SB-1 vaccine virus is commonly used in commercial bivalent vaccines against MDV and also contains TMRs at its ends. Here, we demonstrate that SB-1 efficiently integrates its genome into the chromosomes of latently infected T cells. Deletion of the TMRs from the SB-1 genome did not affect virus replication, but severely impaired virus integration and genome maintenance in latently infected T cells and in chickens. Strikingly, the reduced integration and maintenance of latent SB-1 significantly impaired vaccine protection. Taken together, our data revealed that the TMRs facilitate SB-1 integration and that integration and/or maintenance of the latent viral genome is critical for vaccine protection.

Abstract Background Leukemia inhibitory factor (LIF) is a multifunctional member of the IL-6 cytokine family that activates downstream signaling pathways by binding to the heterodimer consisting of LIFR and gp130 on the cell surface. Previous research has shown that LIF is highly expressed in various tumor tissues (e.g. pancreatic cancer, breast cancer, prostate cancer, and colorectal cancer) and promotes cancer cell proliferation, migration, invasion, and differentiation. Moreover, the overexpression of LIF correlates with poor clinicopathological characteristics. Therefore, we hypothesized that LIF could be a promising target for the treatment of cancer. In this work, we developed the antagonist antibody 1G11 against LIF and investigated its anti-tumor mechanism and its therapeutic efficacy in mouse models. Results A series of single-chain variable fragments (scFvs) targeting LIF were screened from a naive human scFv phage library. These scFvs were reconstructed in complete IgG form and produced by the mammalian transient expression system. Among the antibodies, 1G11 exhibited the excellent binding activity to human, cynomolgus monkey and mouse LIF. Functional analysis demonstrated 1G11 could block LIF binding to LIFR and inhibit the intracellular STAT3 phosphorylation signal. Interestingly, 1G11 did not block LIF binding to gp130, another LIF receptor that is involved in forming the receptor complex together with LIFR. In vivo, intraperitoneal administration of 1G11 inhibited tumor growth in CT26 and MC38 models of colorectal cancer. IHC analysis demonstrated that p-STAT3 and Ki67 were decreased in tumor tissue, while c-caspase 3 was increased. Furthermore, 1G11 treatment improves CD3+, CD4 + and CD8 + T cell infiltration in tumor tissue. Conclusions We developed antagonist antibodies targeting LIF/LIFR signaling pathway from a naive human scFv phage library. Antagonist anti-LIF antibody exerts antitumor effects by specifically reducing p-STAT3. Further studies revealed that anti-LIF antibody 1G11 increased immune cell infiltration in tumor tissues.

Abstract Background Retinol binding protein 4 (RBP4) is a mediator of inflammation and related to skin lesion formation, which suggests its engagement in psoriasis pathology and progression. This study intended to explore the change in RBP4 after systemic treatments, and its ability to predict treatment response in psoriasis patients. Methods This prospective study enrolled 85 psoriasis patients and 20 healthy subjects. Plasma RBP4 was detected by enzyme-linked immunosorbent assay at baseline and 12th week (W12) after systemic treatments in psoriasis patients, as well as after enrollment in healthy subjects. Psoriasis Area and Severity Index (PASI) 75 and PASI 90 were evaluated at W12 in psoriasis patients. Results RBP4 at baseline was higher in psoriasis patients than in healthy subjects [median (interquartile range): 13.39 (9.71–22.92) versus 9.59 (6.57–13.72) µg/mL] (P = 0.003). In psoriasis patients, 50 (58.8%) patients achieved PASI 75 at W12, and 25 (29.4%) patients achieved PASI 90 at W12. RBP4 was decreased at W12 compared to its level at baseline (P 0.7. Conclusion Plasma RBP4 is decreased after systemic treatments, and its low baseline level and greater decline after treatments predict good treatment response in psoriasis patients.

Abstract Background Mouse brains can contain specific polyglucosan aggregates known as Periodic Acid-Schiff (PAS)-granules. Generated in astrocytes, these granules increase with age and exhibit neo-epitopes of carbohydrate nature that are recognized by natural IgM antibodies (IgMs). The existence of neoepitopes on PAS granules suggests the presence of neoepitopes in other brain structures, and this is investigated here. To this end, brain sections from SAMP8 and ICR-CD1 mice were examined at different ages. Results We have identified two novel structures that, apart from PAS granules, are recognized by natural IgMs. On one side, IgM reactive (IgM+) granular structures which are placed in the longitudinal fissure, the quadrigeminal cistern, and a region that extends from the quadrigeminal cistern to the interpeduncular cistern. This last region, located between the telencephalon and both the mesencephalon and diencephalon, is designated henceforth as the fissura magna, as it is indeed a fissure and the largest in the brain. As all these regions are extraparenchymal (EP), the IgM+ granules found in these zones have been named EP granules. These EP granules are mainly associated with fibroblasts and are not stained with PAS. On the other side, some IgM+ astrocytes have been found in the glia limitans, near the above-mentioned fissures. Remarkably, EP granules are more prevalent at younger ages, while the number of IgM+ astrocytes increases with age, similarly to the already described evolution of PAS granules. Conclusions The present work reports the presence of two brain-related structures that, apart from PAS granules, contain neo-epitopes of carbohydrate nature, namely EP granules and IgM+ astrocytes. We suggest that EP granules, associated to fibroblasts, may be part of a physiological function in brain clearance or brain-CSF immune surveillance, while both PAS granules and IgM+ astrocytes may be related to the increasing accumulation of harmful materials that occurs with age and linked to brain protective mechanisms. Moreover, the specific localisation of these EP granules and IgM+ astrocytes suggest the importance of the fissura magna in these brain-related cleaning and immune functions. The overall results reinforce the possible link between the fissura magna and the functioning of the glymphatic system.

Abstract Introduction Vertical transmission of HIV remains a major challenge in Guinea, especially, in low-resource rural areas. This paper presents the results of a pilot project designed to enhance the prevention of vertical transmission through a comprehensive improvement plan implemented across 66 large-cohort sites. Methods Data from 66 large-cohort of mother to child transmission prevention (PMTCT) sites from 2019 to 2022 were analysed to compare PMTCT metrics before (2019–2020) and after (2021–2022) the improvement initiative. Key indicators were reviewed, and trends were statistically analysed using Mann‒Whitney tests, with a p value less than 0.05 indicating statistical significance. Results The implementation of this strategy significantly increased the antiretroviral therapy rate among HIV-positive pregnant women from 66 to 94%, and full antiretroviral prophylaxis coverage was achieved in infants. However, early infant diagnosis via polymerase chain reaction testing falls short of the national target, highlighting deficiencies in laboratory and specimen transport capacities. The study also revealed regional disparities in the use of PMTCT services. Conclusion The improvement plan effectively enhanced antiretroviral therapy and prophylaxis use, demonstrating the benefits of structured interventions and capacity development. Despite improvements, challenges such as insufficient polymerase chain reaction (PCR) testing and uneven access to services remain. Future initiatives should aim to equip PMTCT sites with essential resources and promote community-driven health-seeking behaviours in underserved areas.

Abstract Introduction Refugee HIV positive mothers experience significant obstacles in accessing, utilizing and adhering to antiretroviral therapy (ART). Identifying ART non-adherence can help in the development of interventions aimed at improving adherence and subsequently effectiveness of ART among the refugee mothers. We describe the use and the factors associated with non-adherence to ART among Refugee HIV positive pregnant mothers aged 18–49 years in Kyangwali Refugee Camp, Uganda. Methods We conducted a cross-sectional study among HIV positive pregnant mothers aged 18–49 years in Kyangwali refugee camp between May and June 2023. Using a structured questionnaire, we collected data on use, and factors associated with non-adherence to ART. We used modified Poisson regression analysis to determine factors associated with non-adherence to ART. Results Of the 380 participants enrolled, 192 (50.5%) were married, mean age 32.1 years. Overall, 98.7; 95% Confidence Interval (CI) [97.5–99.8%] were using ART and 27.4; 95% CI [22.9–31.9%] were non-adherent. Non-adherence was associated with: Initiating Prevention of Mother to Child Transmission (PMTCT) care in the third trimester of pregnancy (adjusted Prevalence ration(aPR): 2.06; 95% CI: 1.27–3.35), no need to get permission to seek PMTCT services aPR 1.61; 95% CI [1.07–2.42] and poor attitude of PMTCT providers aPR 1.90; 95% CI [1.20–3.01]. Conclusion and recommendations Non-adherence to ART was generally high; therefore limiting the effectiveness of the PMTCT program in this setting. Refugee context specific education interventional programs aimed at early initiation into HIV care, strong social and psychological support from families, communities and health care providers are vital to improve adherence in this setting.

Abstract Background The World Health Organization has recommended a new method for HIV self-testing (HIVST) using oral fluid, intending to increase HIV testing rates, and linking individuals to medical care. Healthcare workers are chief health advocates in the community who need adequate knowledge and intention to use the newly recommended HIVST approach. However, studies on awareness and the intention to use oral fluid for HIV self-testing among Ethiopian healthcare workers are limited. Therefore, this study aimed to assess healthcare workers' knowledge of and intentions to use oral fluid for HIV self-testing in Hadiya Zone public hospitals in southern Ethiopia in 2022. Methods We conducted a facility-based cross-sectional study among a sample of 352 healthcare workers from 1 to 30 June 2022. The data were entered into Epidata version 4.2 and exported to SPSS version 23 for analysis. We used a logistic regression model with a 95% confidence interval for the interpretation of adjusted odds ratios (AORs) with P

Abstract Systemic autoinflammatory diseases (SAIDs) arise from dysregulated innate immune system activity, which leads to systemic inflammation. These disorders, encompassing a diverse array of genetic defects classified as inborn errors of immunity, are significant diagnostic challenges due to their genetic heterogeneity and varied clinical presentations. Although recent advances in genetic sequencing have facilitated pathogenic gene discovery, approximately 40% of SAIDs patients lack molecular diagnoses. SAIDs have distinct clinical phenotypes, and targeted therapeutic approaches are needed. This review aims to underscore the complexity and clinical significance of SAIDs, focusing on prototypical disorders grouped according to their pathophysiology as follows: (i) inflammasomopathies, characterized by excessive activation of inflammasomes, which induces notable IL-1β release; (ii) relopathies, which are monogenic disorders characterized by dysregulation within the NF-κB signaling pathway; (iii) IL-18/IL-36 signaling pathway defect-induced SAIDs, autoinflammatory conditions defined by a dysregulated balance of IL-18/IL-36 cytokine signaling, leading to uncontrolled inflammation and tissue damage, mainly in the skin; (iv) type I interferonopathies, a diverse group of disorders characterized by uncontrolled production of type I interferons (IFNs), notably interferon α, β, and ε; (v) anti-inflammatory signaling pathway impairment-induced SAIDs, a spectrum of conditions characterized by IL-10 and TGFβ anti-inflammatory pathway disruption; and (vi) miscellaneous and polygenic SAIDs. The latter group includes VEXAS syndrome, chronic recurrent multifocal osteomyelitis/chronic nonbacterial osteomyelitis, Schnitzler syndrome, and Still’s disease, among others, illustrating the heterogeneity of SAIDs and the difficulty in creating a comprehensive classification. Therapeutic strategies involving targeted agents, such as JAK inhibitors, IL-1 blockers, and TNF inhibitors, are tailored to the specific disease phenotypes.

Abstract Background The Primary Sjögren’s Syndrome Quality of Life questionnaire (PSS-QoL) is the first specific instrument to assess health-related quality of life (HRQoL) in Sjögren’s disease (SjD). The aim is to translate and cross-culturally adapt the PSS-QoL into Brazilian Portuguese and to evaluate its psychometric properties. Methods The original English version was translated into Brazilian Portuguese by two native Brazilians who were proficient in the English language. The retranslation was conducted by two native Americans proficient in Brazilian Portuguese. A committee undertook an analysis of the translated and retranslated versions, resulting in the generation of the first Brazilian version, which was submitted to the cross-cultural adaptation phase. In this phase, 50 participants with SjD responded to the instrument in Stages I and II, resulting in the generation of the second and final Brazilian version. To assess the psychometric properties, demographic and clinical data were collected from 75 patients. The HRQoL questionnaires (final Brazilian version of the PSS-QoL, Short Form-36 Health Survey (SF-36) and EuroQoL-5 dimension (EQ-5D)) were completed. Construct validity was analyzed using the Pearson or Spearman correlation coefficient. Reliability was analyzed using Cronbach’s alpha and the intraclass correlation coefficient (ICC). Results Eight questions and one response item were revised due to an incomprehension rate of greater than 15% among the participants in the cross-cultural adaptation phase. The final Brazilian version of the PSS-QoL was validated, revealing a high correlation between the total score and functional capacity (r= −0.713, p

Abstract Bruton’s tyrosine kinase (BTK), a nonreceptor tyrosine kinase, plays a remarkable role in the transmission and amplification of extracellular signals to intracellular signaling pathways. Various types of cells use the BTK pathway to communicate, including hematopoietic cells particularly B cells and T cells. The BTK pathway plays a role in controlling the proliferation, survival, and functions of B cells as well as other myeloid cells. First, second, and third-generation BTK inhibitors are currently being evaluated for the treatment of immune-mediated diseases in addition to B cell malignancies. In this article, the available evidence on the action mechanisms of BTK inhibitors is reviewed. Then, the most recent data obtained from preclinical studies and ongoing clinical trials for the treatment of autoimmune diseases, such as pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, systemic lupus erythematosus, Sjögren’s disease, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, myasthenia gravis, and inflammatory diseases such as psoriasis, chronic spontaneous urticaria, atopic dermatitis, and asthma are discussed. In addition, adverse effects and complications associated with BTK inhibitors as well as factors predisposing patients to BTK inhibitors complications are discussed.

Disorders associated with the immune system burden multiple organs, although the shared biology exists across the diseases. Preceding family-based studies reveal that immune diseases are heritable to varying degrees, providing the basis for immunogenomics. The recent cost reduction in genetic analysis intensively promotes biobank-scale studies and the development of frameworks for statistical genetics. The accumulating multi-layer omics data, including genome-wide association studies (GWAS) and RNA-sequencing at single-cell resolution, enable us to dissect the genetic backgrounds of immune-related disorders. Although autoimmune and allergic diseases are generally categorized into different disease categories, epidemiological studies reveal the high incidence of autoimmune and allergic disease complications, suggesting the shared genetics and biology between the disease categories. Biobank resources and consortia cover multiple immune-related disorders to accumulate phenome-wide associations of genetic variants and enhance researchers to analyze the shared and heterogeneous genetic backgrounds. The emerging post-GWAS and integrative multi-omics analyses provide genetic and biological insights into the multicategorical disease associations.

Luca Potestio,1,&ast; Cataldo Patruno,2,&ast; Stefano Dastoli,2 Claudio Brescia,1 Maddalena Napolitano1 1Section of Dermatology Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy; 2Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy&ast;These authors contributed equally to this workCorrespondence: Luca Potestio, Section of Dermatology Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Pansini 5, Napoli, 80131, Italy, Tel +39 081 7462457 ; Fax +39 081 7462442, Email potestioluca@gmail.comIntroduction: Even if mild forms of atopic dermatitis (AD) are usually well controlled with topical prescription drugs and emollients, the management of severe forms of the disease may be challenging, especially in special populations (SPs). These patients include groups of disadvantaged people (elderly, patients with disabilities and serious medical conditions) who are usually excluded from clinical trials. As a consequence, most of the data about the efficacy and safety of a drug in these patients derives from post-marketing experiences. In this context, the aim of our study was to retrospectively investigate the effectiveness and safety of tralokinumab in the management of AD in SPs.Methods: A 24-weeks retrospective, dual-center study was performed enrolling patients with a diagnosis of moderate-to-severe AD undergoing treatment with tralokinumab at labelled dosage. Disease severity was assessed using Eczema Area Severity Index (EASI), Pruritus–Numerical Rating Scale (P-NRS), and Dermatology Life Quality Index (DLQI) score at baseline and after 4 weeks (W4), W16, and W24. Adverse events (AEs) were monitored at the same timepoints. Statistical significance of clinical improvement (EASI, P-NRS, DLQI) at week 4, week 16, and week 24 as compared with baseline was evaluated by using Student’s t-test, considering significant a p-value < 0.05.Results: Our study enrolling 27 SPs patients showed a significant improvement in EASI and P-NRS since week 4, continuing to improve up to week 24. Similarly, DLQI significantly decreases at each timepoint as compared with baseline. Finally, no AEs were reported during the study period. Of interest, our cohort included oncologic patients, a patient with a history of severe infection, as well as subjects affected by severe neurological, psychiatric, pulmonary, and/or cardiovascular disease.Discussion: Our experience showed that tralokinumab is effective and safe in elderly patients and subjects affected by severe comorbidities.Keywords: atopic dermatitis, special populations, treatment, tralokinumab, biologics

Wei Wang,1,&ast; Ruixia Li,2,&ast; Hui Li,3 Murong Wang,3 Juncheng Wang,4 Xiaohui Wang,5 Qunfang Zhou6 1Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, People’s Republic of China; 2Department of Thyroid Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Minimally Invasive Interventional Radiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 4Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 5Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, Changsha, Hunan, People’s Republic of China; 6Department of Interventional Radiology, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaohui Wang, Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, Changsha, Hunan Province, 410005, People’s Republic of China, Tel +86-0731-83928052, Email xiaohuiwang21@163.com Qunfang Zhou, Department of Interventional Radiology, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China, Tel +86-010-66939123, Email zhouqun988509@163.comPurpose: The prognosis of infiltrative hepatocellular carcinoma (HCC) is dismal. Hepatic arterial infusion chemotherapy (HAIC) plus Lenvatinib (Len) and immune checkpoint inhibitor (ICI) have shown promising results for HCC. However, this three combination therapy on infiltrative HCC is unknown. In this study, we compared HAIC plus lenvatinib (Len) and programmed cell death protein-1 (PD-1) inhibitor with HAIC plus Len for infiltrative HCC.Patients and Methods: This multi-center cohort study included patients with infiltrative HCC who received HAIC combined with Len (HAIC+Len group, n = 173) or HAIC combined with Len and PD-1 inhibitor (HAIC+Len+ICI group, n = 128) as the first-line treatment from January 2019 to December 2021. To balance any intergroup differences, one-to-one propensity score matching (PSM) was applied. Overall survival (OS) and progression-free survival (PFS) were compared between the two groups.Results: After PSM, the median OS was 14.1 ± 1.0 and 16.1 ± 1.4 months in the HAIC+Len and HAIC+Len+ICI groups, respectively. The median PFS was 4.6 ± 0.4 months in the HAIC+Len group and 7.5 ± 0.8 months in the HAIC+Len+ICI group. The HAIC+Len+ICI group showed significantly better OS (hazard ratio [HR], 0.66; 95% CI, 0.49– 0.90; P = 0.008) and PFS (HR, 0.53; 95% confident index [CI], 0.40– 0.70; P < 0.001) compared with the HAIC+Len group. Subgroup analysis revealed that for OS in HCC without metastasis, the addition of PD-1 inhibitor was not significant (HR, 0.68; 95% CI, 0.43– 1.07; P = 0.091). No difference was observed in OS between low (2– 3 cycles) and high (4– 6 cycles) level of HAIC cycles (HR, 0.99; 95% CI, 0.67– 1.44; P = 0.938).Conclusion: The HAIC+Len+ICI group had a longer PFS and OS compared with the HAIC+Len group, demonstrating an acceptable safety profile. This triple combination strategy may be an alternative treatment for infiltrative HCC management.Plain language summary: The evidence of HAIC plus Len and PD-1 inhibitors for infiltrative HCC is limited. There was no study to evaluate the efficacy of HAIC combined with Len and PD-1 inhibitors for infiltrative HCC. In this study, we found that HAIC plus Len and PD-1 inhibitor (HAIC+Len+ICI) was associated with longer progression-free survival and overall survival than HAIC plus Len combination (HAIC+Len) for patient with infiltrative HCC. In addition, OS in patients with metastasis was improved with HAIC+Len+ICI treatment. OS in patients without metastasis, addition of PD-1 inhibitor after HAIC and Len was not beneficial. What’s more, three cycles of HAIC are adequate, especially for patients with high tumor burden, especially with main branch portal vein tumor thrombus (PVTT). Our research provides new evidence that HAIC+Len+ICI treatment significantly improved the OS and PFS of infiltrative HCC patients compared with those who received HAIC+Len treatment. It provides a strong reference for clinical treatment.Keywords: Infiltrative hepatocellular carcinoma, hepatic arterial infusion chemotherapy, Len, PD-1 inhibitor, Prognosis

Our aim is to determine the number of leukocytes, T lymphocytes and B lymphocytes and the expression of activation markers CD200 and CD23 on B lymphocytes in atopic dermatitis (AD) patients (treated and not treated with dupilumab) during the pollen season. We examined 29 patients not treated with dupilumab, 24 patients treated with dupilumab and 40 healthy subjects as a control group. The count of T and B lymphocytes and their subsets were assessed by flow cytometry. The non-parametric Kruskal–Wallis one-factor analysis of variance with post hoc by Dunn’s test with Bonferroni’s modification was used for statistical processing. Although there was a significant improvement in skin findings in patients treated with dupilumab, the changes in immunological profile show a persistent altered immune response characterized by dysregulation and overactivation of B lymphocytes. Dupilumab therapy leads to normalization of relative T regulatory lymphocytes and total memory B lymphocytes and to decreased count of absolute CD8+ T lymphocytes.Why carry out this study?Studies investigating the immunological profile of atopic dermatitis (AD) patients during the pollen season are rare. There are no studies investigating the count of B lymphocytes (CD5+, CD22+ and CD73+ B lymphocytes) and the expression of activation markers CD23 and CD200 on B lymphocytes and on their subsets during pollen season in AD patients treated and non-treated with dupilumab therapy.What was learned from the study?In atopic dermatitis (AD) patients with and without dupilumab therapy, we confirmed the significantly higher count of absolute neutrophils, absolute monocytes, absolute eosinophils, absolute basophils, non-switched B lymphocytes, transitional B lymphocytes, CD23 memory, naive, non-switched, switched and total CD23 B lymphocytes, the relative count of CD200 memory and CD200 switched B lymphocytes.In dupilumab treated patients, we confirmed the significantly higher count of relative eosinophils, relative CD16+ eosinophils, relative CD200 non-switched B lymphocytes and lower count of absolute CD8+ T lymphocytes. Further studies should focus on investigating the effect of dupilumab on CD8+ T lymphocytes and their subpopulations.In patients without dupilumab therapy, we confirmed the significantly higher count of relative neutrophils, relative T regulatory lymphocytes and total memory B lymphocytes.The changes in the count of CD5+, CD22+ and CD73+ B lymphocytes were not observed during pollen season in both groups of AD patients.

Abstract Although HPV vaccines are highly efficacious, a notable proportion of quadrivalent vaccinees are HPV18 seronegative post-vaccination. We have investigated this findings’ validity by comparing vaccine-induced antibody responses using two different immunoassays. 6558 16–17-year-old females participated in the FUTURE II (NCT00092534) and PATRICIA (NCT00122681) trials in 2002–2004. Both the quadrivalent and bivalent vaccine recipients (QVR and BVR) received three doses. Twelve-year follow-up for 648 vaccinees was conducted by the Finnish Maternity Cohort. The presence of neutralising and binding HPV antibodies was analysed via HPV pseudovirion-based neutralisation and pseudovirion-binding assays. Four percent and 14.3% of the QVRs were seronegative for neutralising and binding antibodies to HPV16 and HPV18, respectively. No BVRs were HPV16/18 seronegative post-vaccination. The antibody titres were strongly correlated between the assays, Pearson’s correlation coefficient, r [HPV16] = 0.92 and 0.85, and r [HPV18] = 0.91 and 0.86 among the QVRs and BVRs respectively. Fourteen percent of QVRs lacked detectable HPV18 antibodies in long-term follow-up.

Abstract Vaccines against COVID-19 and influenza can reduce the adverse outcomes caused by infections during pregnancy, but vaccine uptake among pregnant women has been suboptimal. We examined the COVID-19 and influenza vaccine uptake and disparities in pregnant women during the COVID-19 pandemic to inform vaccination interventions. We used data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre database in England and the Secure Anonymised Information Linkage Databank in Wales. The uptake of at least one dose of vaccine was 40.2% for COVID-19 and 41.8% for influenza among eligible pregnant women. We observed disparities in COVID-19 and influenza vaccine uptake, with socioeconomically deprived and ethnic minority groups showing lower vaccination rates. The suboptimal uptake of COVID-19 and influenza vaccines, especially in those from socioeconomically deprived backgrounds and Black, mixed or other ethnic groups, underscores the necessity for interventions to reduce vaccine hesitancy and enhance acceptance in pregnant women.

Abstract Immunizing mice with Crimean-Congo hemorrhagic fever virus (CCHFV) nucleoprotein (NP), glycoprotein precursor (GPC), or with the GP38 domain of GPC, can be protective when the proteins are delivered with viral vectors or as a DNA or RNA vaccine. Subunit vaccines are a safe and cost-effective alternative to some vaccine platforms, but Gc and Gn glycoprotein subunit vaccines for CCHFV fail to protect despite eliciting high levels of neutralizing antibodies. Here, we investigated humoral and cellular immune responses and the protective efficacy of recombinant NP, GP38, and GP38 forms (GP85 and GP160) associated with the highly glycosylated mucin-like (MLD) domain, as well as the NP + GP38 combination. Vaccination with GP160, GP85, or GP38 did not confer protection, and vaccination with the MLD-associated GP38 forms blunted the humoral immune responses to GP38, worsened clinical chemistry, and increased viral RNA in the blood compared to the GP38 vaccination. In contrast, NP vaccination conferred 100% protection from lethal outcome and was associated with mild clinical disease, while the NP + GP38 combination conferred even more robust protection by reducing morbidity compared to mice receiving NP alone. Thus, recombinant CCHFV NP alone is a promising vaccine candidate conferring 100% survival against heterologous challenge. Moreover, incorporation of GP38 should be considered as it further enhances subunit vaccine efficacy by reducing morbidity in surviving animals.

Abstract Herpes zoster (HZ), also known as shingles, is caused by the reactivation of latent varicella-zoster virus (VZV). Decreased VZV-specific T-cell immune responses significantly contribute to the development of HZ. Shingrix is a recombinant zoster vaccine that is currently used to prevent HZ. However, Shingrix has high reactogenicity and pain at the injection site due to QS21, one of the adjuvant components. In this study, we developed a new herpes zoster vaccine formulation called CVI-VZV-001, containing gE protein and a novel liposome-based adjuvant Lipo-pam™, which consists of two TLR agonists. We evaluated the immunogenicity of CVI-VZV-001 in mouse and rabbit models. CVI-VZV-001 elicited robust gE-specific T-cell immune responses and gE-specific antibody production. Specifically, CVI-VZV-001 induced polyfunctional CD4+ T cell populations that secrete multiple cytokines. Furthermore, CVI-VZV-001 sustained the gE-specific immune responses for up to six months after immunization. To ensure CVI-VZV-001’s safety for further development, we conducted a good laboratory practice (GLP) toxicity test, which confirmed that CVI-VZV-001 is safe for use. At present, CVI-VZV-001 is undergoing phase I clinical trials. This study suggests that CVI-VZV-001 can be a potent candidate for the HZ vaccine with high immunogenicity and safety.