Effect of In Vivo Administration of Fibrinogen Concentrate Versus Cryoprecipitate on Ex Vivo Clot Degradation in Neonates Undergoing Cardiac Surgery.

BACKGROUND: Neonates undergoing cardiac surgery require fibrinogen replacement to restore hemostasis after cardiopulmonary bypass (CPB). Cryoprecipitate is often the first-line treatment, but recent studies demonstrate that fibrinogen concentrate (RiaSTAP; CSL Behring) may be acceptable in this population. This investigator-initiated, randomized trial compares cryoprecipitate to fibrinogen concentrate in neonates undergoing cardiac surgery (ClinicalTrials.gov NCT03932240). The primary end point was the percent change in ex vivo clot degradation from baseline at 24 hours after surgery between groups. Secondary outcomes included intraoperative blood transfusions, coagulation factor levels, and adverse events. METHODS: Neonates were randomized to receive cryoprecipitate (control group) or fibrinogen concentrate (study group) as part of a post-CPB transfusion algorithm. Blood samples were drawn at 4 time points: presurgery (T1), after treatment (T2), arrival to the intensive care unit (ICU) (T3), and 24 hours postsurgery (T4). Using the mixed-effect models, we analyzed the percent change in ex vivo clot degradation from a patient's presurgery baseline at each time point. Intraoperative blood product transfusions, coagulation factor levels, perioperative laboratory values, and adverse events were collected. RESULTS: Thirty-six neonates were enrolled (intent to treat [ITT]). Thirteen patients in the control group and seventeen patients in the study group completed the study per protocol (PP). After normalizing to the patient's own baseline (T1), no significant differences were observed in clot degradation at T2 or T3. At T4, patients in the study group had greater degradation when compared to those in the control group (826.5%, 95% confidence interval [CI], 291.1-1361.9 vs -545.9%, 95% CI, -1081.3 to -10.4; P < .001). Study group patients received significantly less median post-CPB transfusions than control group patients (ITT, 27.2 mL/kg [19.0-36.9] vs 41.6 [29.2-52.4]; P = .043; PP 26.7 mL/kg [18.8-32.2] vs 41.2 mL/kg [29.0-51.4]; P < .001). No differences were observed in bleeding or thrombotic events. CONCLUSIONS: Neonates who received fibrinogen concentrate, as compared to cryoprecipitate, have similar perioperative ex vivo clot degradation with faster degradation at 24 hours postsurgery, less post-CPB blood transfusions, and no increased bleeding or thrombotic complications. Our findings suggest that fibrinogen concentrate adequately restores hemostasis and reduces transfusions in neonates after CPB without increased bleeding or thrombosis risk.

Simultaneous Presentation of B-Acute Lymphoblastic Leukemia and Streptococcus agalactiae Meningitis in a 3-Year-old Girl.

Infection is a major cause of treatment-related morbidity and mortality in pediatric acute lymphoblastic leukemia (ALL). Most children with ALL who develop life-threatening bacterial infections do so during induction therapy. We describe a rare case of ALL presenting simultaneously with Streptococcus agalactiae group B Streptococcus bacteremia and meningitis in a 3-year-old girl. She received appropriate antimicrobial therapy and a 2-drug early induction regimen consisting of vincristine and dexamethasone, leading to slow neurologic recovery and a favorable initial response to anti-neoplastic therapy as evidenced by minimal residual disease of 1.12% on day 15 of induction.

The survival benefit of adjuvant trastuzumab with or without chemotherapy in the management of small (T1mic, T1a, T1b, T1c), node negative HER2+ breast cancer.

There is limited data regarding the added benefit of adjuvant systemic therapy in the management of small, node-negative, HER2+ breast cancer. In a multi-institutional retrospective analysis using the American Society of Clinical Oncology CancerLinQ database, we compared survival outcomes among T1a-c N0 HER2+ patients diagnosed between 2010 to 2021 who received locoregional therapy alone or in combination with adjuvant trastuzumab (+/- chemotherapy). Primary outcomes were invasive disease-free survival (iDFS) and overall survival (OS). Of the 1,184 patients, 436 received locoregional therapy alone. We found a statistically significant improvement in iDFS (HR 0.73, P = 0.003) and OS (HR 0.63, P = 0.023) on univariate analysis with adjuvant trastuzumab with or without chemotherapy which remained statistically significant on multivariate analysis. Three-arm univariate analysis found that iDFS was significantly improved with trastuzumab monotherapy (P = 0.003) and combination therapy (P = 0.027) compared to observation. Subgroup data suggests that T1b/c tumors derive the greatest benefit.

Cleavage of the syncytial protein of J paramyxovirus is required for its ability to promote cell-cell fusion.

Cell-cell fusion mediated by most paramyxovirus requires fusion protein (F) and attachment protein (H, HN, or G). The F protein is proteolytic cleaved to be fusogenically active. J paramyxovirus (JPV) has a unique feature in the family Paramyxoviridae: It encodes an integral membrane protein, syncytial protein (SP, formerly known as transmembrane protein, TM), which is essential in JPV-promoted cell-cell fusion (i.e., syncytial). In this study, we report that cleavage of SP is essential for its syncytial-promoting activity. We have identified the cleavage site of SP at amino acid residues 172 to 175, LKTG, and deletion of the "LKTG" residues abolished SP protein cleavage and its ability to promote cell-cell fusion. Replacing the cleavage site LKTG with a factor Xa protease cleavage site allows cleavage of the SP with factor Xa protease and restores its ability to promote cell-cell fusion. Furthermore, results from a hemifusion assay indicate that cleavage of SP plays an important role in the progression from the intermediate hemifusion state to a complete fusion. This work indicates that SP has many characteristics of a fusion protein. We propose that SP is likely a cell-cell fusion-promoting protein.

Modulation of diabetic wound healing using carbon monoxide gas-entrapping materials.

Diabetic wound healing is uniquely challenging to manage due to chronic inflammation and heightened microbial growth from elevated interstitial glucose. Carbon monoxide (CO), widely acknowledged as a toxic gas, is also known to provide unique therapeutic immune modulating effects. To facilitate delivery of CO, we have designed hyaluronic acid-based CO-gas-entrapping materials (CO-GEMs) for topical and prolonged gas delivery to the wound bed. We demonstrate that CO-GEMs promote the healing response in murine diabetic wound models (full-thickness wounds and pressure ulcers) compared to N2-GEMs and untreated controls.

Structural basis for inhibition of the lysosomal two-pore channel TPC2 by a small molecule antagonist.

Two pore channels are lysosomal cation channels with crucial roles in tumor angiogenesis and viral release from endosomes. Inhibition of the two-pore channel 2 (TPC2) has emerged as potential therapeutic strategy for the treatment of cancers and viral infections, including Ebola and COVID-19. Here, we demonstrate that antagonist SG-094, a synthetic analog of the Chinese alkaloid medicine tetrandrine with increased potency and reduced toxicity, induces asymmetrical structural changes leading to a single binding pocket at only one intersubunit interface within the asymmetrical dimer. Supported by functional characterization of mutants by Ca2+ imaging and patch clamp experiments, we identify key residues in S1 and S4 involved in compound binding to the voltage sensing domain II. SG-094 arrests IIS4 in a downward shifted state which prevents pore opening via the IIS4/S5 linker, hence resembling gating modifiers of canonical VGICs. These findings may guide the rational development of new therapeutics antagonizing TPC2 activity.

Screening chest wall ultrasound in the mastectomy patient.

BACKGROUND: While there are clear guidelines regarding chest wall ultrasound in the symptomatic patient, there is conflicting evidence regarding the use of ultrasound in the screening of women post-mastectomy. OBJECTIVE: To assess the utility of screening chest wall ultrasound after mastectomy and to assess features of detected malignancies. METHODS: This IRB approved, retrospective study evaluates screening US examinations of the chest wall after mastectomy. Asymptomatic women presenting for screening chest wall ultrasound from January 2016 through May 2017 were included. Cases of known active malignancy were excluded. All patients had at least one year of clinical or imaging follow-up. 43 exams (8.5 %) were performed with a history of contralateral malignancy, 465 exams (91.3 %) were performed with a history of ipsilateral malignancy, and one exam (0.2 %) was performed in a patient with bilateral prophylactic mastectomy. RESULTS: During the 17-month period, there were 509 screening US in 389 mastectomy patients. 504 (99.0 %) exams were negative/benign. Five exams (1.0 %) were considered suspicious, with recommendation for biopsy, which was performed. Out of 509 exams, 3 (0.6 %) yielded benign results, while 2 (0.39 %) revealed recurrent malignancy, with a 95 % confidence interval (exact binomial) of 0.05 % to 1.41 % for screening ultrasound. Both patients who recurred had previously recurred, and both had initial cancer of lobular histology. CONCLUSION: Of 509 chest wall screening US exams performed in mastectomy, 2 malignancies were detected, and each patient had history of invasive lobular carcinoma and at least one prior recurrence prior to this study, suggesting benefit of screening ultrasound in these populations.

A semi-structured interview is associated with bariatric surgery outcomes.

Pre-surgical psychological evaluations (PSPE) are required by many insurance companies and used to help identify risk factors that may compromise bariatric post-surgical outcomes. These evaluations, however, are not yet standardized. The present study investigated the utility of a semi-structured assessment, Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT), on post-surgical outcomes across 18 months. A total of 272 adult patients underwent a psychosocial evaluation and received bariatric surgery November 2017 to September 2020 at a Midwestern academic medical center. Average age at pre-surgical evaluation was 45.2 (SD = 10.7) years and 82.3% of patients were female (n = 224). With an a priori α of 0.05, multi-level modeling with weight as the outcome and regression with complications as the outcome were used. Higher SIPAT Patient Readiness, indicating difficulty with adhering to health behaviors and a reduced understanding of bariatric surgery, was associated with elevated patient weight at the 18-month follow-up (𝛽 = 0.129, p = 0.03). Higher SIPAT Social Support, was associated with patient weight at the 18-month follow-up, with reduced support associated with greater weight (𝛽 = 0.254, p = 0.004). Higher SIPAT Social Support also was associated with a greater risk of complications across the 18-month follow-up window (𝛽 = -0.108, p = 0.05). Patients with higher readiness to adhere to behavioral changes, and those reporting an intact social support system, generally weighed less at 18 months. The SIPAT may be considered as part of the standardized pre-surgical assessment, however, further research is required to elucidate its utility.

Effectiveness of Community Education for Breast Cancer Screening.

OBJECTIVE: Screening based on individual risk factors results in detection of earlier, more curable breast cancer. There is expectation that improved public education about the importance of personalized screening will result in earlier diagnoses and reduced breast cancer mortality. The purpose of this study is to evaluate the effectiveness of community education on patient perceptions about risk-based screening. METHODS: This study is Health Insurance Portability and Accountability Act-compliant and institutional review board exempt. A standardized curriculum was used by radiologists and experts to conduct nine 1-hour patient education sessions between October 2018 and January 2019 about breast cancer risk factors and screening options. Patient participants completed voluntary, anonymous pre-event and post event surveys to determine if the presented educational program led to attitude changes. Survey results were summarized using statistical analysis including mean, median, range, and percentage of participants responding and comparison of pre- and post event fear and anxiety. RESULTS: Of 336 education session participants, 59.5% (200/336) completed the pre-event and 44.3% (149/336) completed the post event surveys, Respondents reported decreased anxiety and fear regarding breast cancer screening following educational sessions, with 36.1% (64/178) reporting anxiety pre-event compared to 23.3% (31/133) post event, although the difference was not statistically significant (P = .96). Additionally, 64.7% (55/85) of participants stated they were more likely to schedule breast cancer screening based on individual risk factors, and 98.0% (145/148) of participants reported increased knowledge on post event surveys. CONCLUSION: This study demonstrates the importance and effectiveness of community-based educational programs in increasing knowledge of risk-based screening and potentially reducing anxiety related to screening.

Impact of formulation on solid oxygen-entrapping materials to overcome tumor hypoxia.

Tumor hypoxia, resulting from rapid tumor growth and aberrant vascular proliferation, exacerbates tumor aggressiveness and resistance to treatments like radiation and chemotherapy. To increase tumor oxygenation, we developed solid oxygen gas-entrapping materials (O2-GeMs), which were modeled after clinical brachytherapy implants, for direct tumor implantation. The objective of this study was to investigate the impact different formulations of solid O2-GeMs have on the entrapment and delivery of oxygen. Using a Parr reactor, we fabricated solid O2-GeMs using carbohydrate-based formulations used in the confectionary industry. In evaluating solid O2-GeMs manufactured from different sugars, the sucrose-containing formulation exhibited the highest oxygen concentration at 1 mg/g, as well as the fastest dissolution rate. The addition of a surface coating to the solid O2-GeMs, especially polycaprolactone, effectively prolonged the dissolution of the solid O2-GeMs. In vivo evaluation confirmed robust insertion and positioning of O2-GeMs in a malignant peripheral nerve sheath tumor, highlighting potential clinical applications.

Multivariate and regional age-related change in basal ganglia iron in neonates.

In the perinatal period, reward and cognitive systems begin trajectories, influencing later psychiatric risk. The basal ganglia is important for reward and cognitive processing but early development has not been fully characterized. To assess age-related development, we used a measure of basal ganglia physiology, specifically brain tissue iron, obtained from nT2* signal in resting-state functional magnetic resonance imaging (rsfMRI), associated with dopaminergic processing. We used data from the Developing Human Connectome Project (n = 464) to assess how moving from the prenatal to the postnatal environment affects rsfMRI nT2*, modeling gestational and postnatal age separately for basal ganglia subregions in linear models. We did not find associations with tissue iron and gestational age [range: 24.29-42.29] but found positive associations with postnatal age [range:0-17.14] in the pallidum and putamen, but not the caudate. We tested if there was an interaction between preterm birth and postnatal age, finding early preterm infants (GA < 35 wk) had higher iron levels and changed less over time. To assess multivariate change, we used support vector regression to predict age from voxel-wise-nT2* maps. We could predict postnatal but not gestational age when maps were residualized for the other age term. This provides evidence subregions differentially change with postnatal experience and preterm birth may disrupt trajectories.

Treatment effect of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of fistulizing Crohn's disease are durable at 12 months.

BACKGROUND: Mesenchymal stem cells have been administered via direct injection to treat perianal Crohn's fistulizing disease. We herein sought to determine the safety and durability of treatment response to 12 months with 3 individual phase IB/IIA clinical trials of mesenchymal stem cells for refractory perianal, rectovaginal, and ileal pouch fistulas in the setting of Crohn disease. METHODS: Three phase IB/IIA randomized placebo-controlled single-blinded clinical trials were performed for (1) perianal fistulas, (2) rectovaginal fistula, and (3) ileal pouch in situ with anovaginal and/or perianal fistulas. Bone marrow-derived mesenchymal stem cells (75 million in 7.5 mL) were injected at the time of exam under anesthesia on day 0 and month 3. Outcome measures were adverse events and combined clinical and pelvic magnetic resonance imaging healing at month 6 and month 12. RESULTS: Across all 3 trials, 64 patients were enrolled; 49 were treatment and 15 were control. At 6 months, combined clinical and radiographic healing was achieved in 83.3%, 33.3%, and 30.8% of the perianal, rectovaginal, and pouch fistula treatment cohorts, respectively. At 12 months, the treatment response was durable, with 67.7% of perianal, 37.5% of rectovaginal, and 46.2% of peripouch fistulas maintaining complete clinical and radiographic healing. Two patients in the perianal fistula control cohort achieved combined clinical and radiographic healing at 12 months, whereas 0% of rectovaginal and pouch control patients healed. CONCLUSION: Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal, rectovaginal, and peripouch fistulizing Crohn's disease. Treatment results are durable at 12 months.

Neonatal Cystitis Makes Adult Female Rat Urinary Bladders More Sensitive to Low Concentration Microbial Antigens.

Purpose: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain disorder. Patients with IC/BPS often experience "flares" of symptom exacerbation throughout their lifetime, initiated by triggers, such as urinary tract infections. This study sought to determine whether neonatal bladder inflammation (NBI) alters the sensitivity of adult rat bladders to microbial antigens. Methods: Female NBI rats received intravesical zymosan treatments on postnatal days P14-P16 while anesthetized; Neonatal Control Treatment (NCT) rats were anesthetized. In adults, bladder and spinal cord Toll-like receptor type 2 and 4 (TLR2, TLR4) contents were determined using ELISAs. Other rats were injected intravesically with lipopolysaccharide (LPS; mimics an E. coli infection; 25, 50, 100, or 200 µg/mL) or Zymosan (mimics yeast infection; 0.01, 0.1, 1, and 10 mg/mL) solutions on the following day. Visceromotor responses (VMRs; abdominal contractions) to graded urinary bladder distention (UBD, 10-60 mm Hg, 20s) were quantified as abdominal electromyograms (EMGs). Results: Bladder TLR2 and TLR4 protein levels increased in NBI rats. These rats displayed statistically significant, dose-dependent, robustly augmented VMRs following all but the lowest doses of LPS and Zymosan tested, when compared with their adult treatment control groups. The NCT groups showed minimal responses to LPS in adults and minimally increased EMG measurements following the highest dose of Zymosan. Conclusion: The microbial antigens LPS and Zymosan augmented nociceptive VMRs to UBD in rats that experienced NBI but had little effect on NCT rats at the doses tested. The greater content of bladder TLR2 and TLR4 proteins in the NBI group was consistent with increased responsiveness to their agonists, Zymosan and LPS, respectively. Given that patients with IC/BPS have a higher incidence of childhood urinary tract infections, this increased responsiveness to microbial antigens may explain the flares in symptoms following "subclinical" tract infections.

Aortic rupture during STABILISE (stent-assisted balloon-induced intimal disruption and relamination in aortic dissection repair) technique.

The STABILISE (stent-assisted balloon-induced intimal disruption and relamination in aortic dissection repair) technique has shown promising results for treating type B aortic dissections, but the potential exists for fatal adverse effects. We present a case of infrarenal aortic rupture while using a compliant balloon to balloon mold the true lumen inside previously placed bare metal stents during the STABILISE technique. Caution is advised for providers who wish to perform the STABILISE technique, and we recommend using a semi-compliant balloon sized to the smallest total aortic diameter to mitigate the risk of rupture.

Differentiation Syndrome in Acute Leukemia: APL and Beyond.

Differentiation syndrome (DS) is a frequent and potentially life-threatening clinical syndrome first recognized with the advent of targeted therapeutics for acute promyelocytic leukemia (APL). DS was subsequently observed more broadly with targeted therapeutics for acute myeloid leukemia (AML). DS is typically characterized by fever, dyspnea, hypotension, weight gain, pleural or pericardial effusions, and acute renal failure. The incidence in patients with APL ranges from 2 to 37%, with the wide variation likely attributed to different diagnostic criteria, use of prophylactic treatment, and different treatment regimens. Treatment with corticosteroids +/- cytoreductive therapy should commence as soon as DS is suspected to reduce DS-related morbidity and mortality. The targeted anti-leukemic therapy should be discontinued in patients with severe DS. Here, we discuss the pathogenesis of DS, clinical presentations, diagnostic criteria, management strategies, and implementation of prospective tracking on clinical trials.

A comparative analysis of gene and protein expression in chronic and acute models of photoreceptor degeneration in adult zebrafish.

Background: Adult zebrafish are capable of photoreceptor (PR) regeneration following acute phototoxic lesion (AL). We developed a chronic low light (CLL) exposure model that more accurately reflects chronic PR degeneration observed in many human retinal diseases. Methods: Here, we characterize the morphological and transcriptomic changes associated with acute and chronic models of PR degeneration at 8 time-points over a 28-day window using immunohistochemistry and 3'mRNA-seq. Results: We first observed a differential sensitivity of rod and cone PRs to CLL. Next, we found no evidence for Müller glia (MG) gliosis or regenerative cell-cycle re-entry in the CLL model, which is in contrast to the robust gliosis and proliferative response from resident MG in the AL model. Differential responses of microglia between the models was also observed. Transcriptomic comparisons between the models revealed gene-specific networks of PR regeneration and degeneration, including genes that are activated under conditions of chronic PR stress. Finally, we showed that CLL is at least partially reversible, allowing for rod and cone outer segment outgrowth and replacement of rod cell nuclei via an apparent upregulation of the existing rod neurogenesis mechanism. Discussion: Collectively, these data provide a direct comparison of the morphological and transcriptomic PR degeneration and regeneration models in zebrafish.

Long-Term Insect Repellent Electrospun Microfibers from Recycled Poly(ethylene terephthalate).

In recent years, there has been an increase in the incidence of insect-borne diseases. Topically applied insect repellents are used to prevent these infectious diseases, but concerns of skin permeability and rapid evaporation rates have made way for alternative preventative methods. Encapsulation of insect repellents in polymeric materials allows for nonskin contact methods of repellent delivery with extended-release profiles without the need for reapplication. Poly(ethylene terephthalate) (PET) is widely used in textiles as well as food packaging and other single-use applications. This short product lifespan makes PET a major environmental pollutant; thus, recycling of PET is of great interest and utility. We report on the fabrication and evaluation of recycled PET microfibers containing N,N-diethyl-meta-toluamide (DEET) and picaridin and the first evaluation of dual repellent loading (DEET/picaridin) via electrospinning. The electrospun microfibers displayed a repellent retention up to 97% within the polymer network upon processing. Release profiles were characterized by isothermal thermogravimetric analysis (TGA). Hansen solubility parameters correlated release profiles with the chemical affinity between PET and the repellent substrate. Insect repellency was assessed against live mosquitoes using a novel bioassay method. Repellency was observed to be as high as 100% for over 1 week and 80% for over 3 weeks. Our method allows for long-lasting repellency with the potential for large-scale textile manufacturing.

Nitrogen carrier gas for the separation of trace explosives on CI-GC/MS.

Fluctuations in ultra high purity (UHP) helium supply has the potential to negatively impact critical research efforts. Disruptions have increased significantly with suppliers prioritizing delivery to medical facilities. Due to the greater demand for helium, supply issues are likely to continue through the coming years. Many gas chromatography (GC)-based analytical methods rely on the supply of UHP helium, including those developed for the quantification of trace explosives. Vapor validation is critical in establishing sensor performance, limits of detection, and instrument performance. An alternate carrier gas must be established to maintain these critical functionalities. To circumvent the UHP helium disruptions, UHP nitrogen was explored as a replacement carrier gas in negative mode chemical ionization-gas chromatography/mass spectrometry (CI-GC/MS). Although, hydrogen is considered an acceptable alternative to helium in most GC-based separations, its' use as a replacement was omitted due to reactivity resulting in degradation of the CI-MS detector and incompatibility with the programmable temperature vaporization inlet on the GC used in this work. Herein discusses the method development of nitrogen carrier gas in the separation of an explosives mixture. Adjustments in flow rate, initial oven temperature, and ramp rate were made to achieve comparable analysis to that of helium. By lowering the flow rate and initial oven temperature peak resolution and sensitivity increased when using nitrogen carrier gas. Development of this method allows for continual laboratory output in times of helium scarcity.

Perspectives of patients undergoing neoadjuvant chemotherapy for breast cancer during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic resulted in a lapse in routine health care and cancer screenings for many individuals. This study sought to improve our understanding of the impact of the COVID-19 pandemic on women being treated for breast cancer, both in general, and specifically related to their diagnosis. METHODS: Semi-structured interviews were conducted between August 2021 and February 2022 with women who were receiving neoadjuvant chemotherapy for early-stage breast cancer at the Stefanie Spielman Comprehensive Breast Center in Columbus, Ohio. Interviews were recorded and transcribed verbatim. Transcripts were coded using deductive dominant thematic analysis and inductive coding that allowed for categorization of data as well as identification of emergent themes. RESULTS: Data collected from our 19 interviews revealed that the COVID-19 pandemic posed important challenges for breast cancer patients including fear of COVID-19 infection and feelings of isolation. Most interviewees noted they had been vaccinated against COVID-19 because of a desire to protect themselves and others from getting sick. Some women also expressed concerns about having delayed their screening mammograms due to the pandemic. Several patients described unexpected positive aspects of the pandemic such as being able to spend more time with family and having the ability to continue working because of the option to work from home during their cancer treatment. CONCLUSIONS: Our findings provide important insight about the impact of COVID-19 on breast cancer patients. We highlight the positives that have been reported because of the pandemic, as well as the need to address delayed breast cancer screening.

Combined intranasal and intramuscular parainfluenza 5-, simian adenovirus ChAdOx1- and poxvirus MVA-vectored vaccines induce synergistically HIV-1-specific T cells in the mucosa.

Introduction: The primary goal of this work is to broaden and enhance the options for induction of protective CD8+ T cells against HIV-1 and respiratory pathogens. Methods: We explored the advantages of the parainfluenza virus 5 (PIV5) vector for delivery of pathogen-derived transgenes alone and in combination with the in-human potent regimen of simian adenovirus ChAdOx1 prime-poxvirus MVA boost delivering bi-valent mosaic of HIV-1 conserved regions designated HIVconsvX. Results: We showed in BALB/c mice that the PIV5 vector expressing the HIVconsvX immunogens could be readily incorporated with the other two vaccine modalities into a single regimen and that for specific vector combinations, mucosal CD8+ T-cell induction was enhanced synergistically by a combination of the intranasal and intramuscular routes of administration. Discussion: Encouraging safety and immunogenicity data from phase 1 human trials of ChAdOx1- and MVA-vectored vaccines for HIV-1, and PIV5-vectored vaccines for SARS-CoV-2 and respiratory syncytial virus pave the way for combining these vectors for HIV-1 and other indications in humans.