Local Salmonella immunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor.

The efficacy of antitumoral responses can be increased using combinatorial vaccine strategies. We recently showed that vaccination could be optimized by local administration of diverse molecular or bacterial agents to target and augment antitumoral CD8 T cells in the genital mucosa (GM) and increase regression of cervical cancer in an animal model. Non muscle-invasive bladder cancer is another disease that is easily amenable to local therapies. In contrast to data obtained in the GM, in this study we show that intravesical (IVES) instillation of synthetic toll-like receptor (TLR) agonists only modestly induced recruitment of CD8 T cells to the bladder. However, IVES administration of Ty21a, a live bacterial vaccine against typhoid fever, was much more effective and increased the number of total and vaccine-specific CD8 T cells in the bladder approximately 10 fold. Comparison of chemokines induced in the bladder by either CpG (a TLR-9 agonist) or Ty21a highlighted the preferential increase in complement component 5a, CXCL5, CXCL2, CCL8, and CCL5 by Ty21a, suggesting their involvement in the attraction of T cells to the bladder. IVES treatment with Ty21a after vaccination also significantly increased tumor regression compared to vaccination alone, resulting in 90% survival in an orthotopic murine model of bladder cancer expressing a prototype tumor antigen. Our data demonstrate that combining vaccination with local immunostimulation may be an effective treatment strategy for different types of cancer and also highlight the great potential of the Ty21a vaccine, which is routinely used worldwide, in such combinatorial therapies

Immunogenic Human Papillomavirus Pseudovirus-Mediated Suicide-Gene Therapy for Bladder Cancer.

Bladder cancer is the second most common urological malignancy in the world. In 70% of cases it is initially diagnosed as non-muscle-invasive bladder cancer (NMIBC) and it is amenable to local treatments, with intravesical (IVES) Bacillus-Calmette-Guerin (BCG) immunotherapy being routinely used after transurethral resection of the lesion. However, this treatment is associated with significant side-effects and treatment failures, highlighting the necessity of novel strategies. One potent approach is the suicide-gene mediated therapy/prodrug combination, provided tumor-specificity can be ensured and anti-tumor immune responses induced. Using the mouse syngeneic orthotopic MB49-bladder tumor model, here we show that IVES human papillomavirus non-replicative pseudovirions (PsV) can pseudoinfect tumors with a ten-fold higher efficacy than normal bladders. In addition, PsV carrying the suicide-gene herpes-simplex virus thymidine kinase (PsV-TK) combined to Ganciclovir (GCV) led to immunogenic cell-death of tumor cells in vitro and to MB49-specific CD8 T-cells in vivo. This was associated with reduction in bladder-tumor growth and increased mice survival. Altogether, our data show that IVES PsV-TK/GCV may be a promising alternative or combinatory treatment for NMIBC

Vaccine coverage and factors associated with vaccine adherence in persons with HIV at an urban infectious disease clinic

Information on vaccination rates and factors associated with adherence in persons with HIV (PWH) is limited. We report vaccine adherence in 653 adult PWH attending an urban Infectious Disease Clinic from January 2015 to December 2021. Vaccines evaluated included influenza, pneumococcal, tetanus, hepatitis A virus (HAV) and hepatitis B virus (HBV), human papillomavirus (HPV), and zoster vaccines. Vaccine reminders were triggered at every visit, and all vaccines were accessible in the clinic. The mean age was 50 y (±SD 13), male gender was 78.6%, and black race was 74.3%. The overall adherence to all recommended vaccines was 63.6%. Vaccine adherence was \u3e90% for influenza, pneumococcal, and tetanus, \u3e80% for HAV and HBV, and ≥60% for HPV and zoster vaccines. The main predictor of adherence to all vaccines was ≥2 annual clinic visits (odds ratio [OR] 3.45; 95% confidence interval [CI] 2.36-5.05; p \u3c .001). Other predictors included an assigned primary care provider within the system (OR 2.89 [95% CI 1.71-5.00, p \u3c .001]) and CD4 \u3e200 cell/mm(3) at entry into care (OR 1.91 [95% CI 1.24-2.94, p = .0003]). Retention in care combined with vaccine reminders and accessibility of vaccines in the clinic can achieve high vaccine uptake in PWH

Intravesical Ty21a vaccine promotes dendritic cells and T cell-mediated tumor regression in the MB49 bladder cancer model

Preclinical data shows that intravesical instillation of Ty21a/Vivotif\uae, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus-Calmette-Gu\ue9rin (BCG) immunotherapy for nonmuscle-invasive bladder cancer (NMIBC). Here we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor-regression towards the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor-bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 106 to 108 colony-forming units. By immunohistochemistry and morphology, both BCG and Ty21a instillations were associated with bladder inflammation, which was decreased with the use of low, but effective, doses of Ty21a. Flow cytometry analysis showed a significant infiltration of T cells, natural killer (NK) cells, and myeloid cells, compared with controls, after a single dose of Ty21a, whereas this was only observed after multiple doses of BCG. The induced myeloid cells were predominantly neutrophils and Ly6C+CD103+ dendritic cells (DC), the latter being significantly more numerous after instillation of Ty21a than BCG. Ex vivo infection of human leukocytes with Ty21a, but not BCG, similarly significantly increased DC frequency. CD4+ and CD8+ T cells, but not NK cells nor neutrophils, were required for effective Ty21a bladder tumor responses. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms of intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients

Low- Versus High-Dose Methylprednisolone in Adult Patients With Coronavirus Disease 2019: Less Is More

Background: Corticosteroids use in severe coronavirus disease 2019 (COVID-19) improves survival; however, the optimal dose is not established. We aim to evaluate clinical outcomes in patients with severe COVID-19 receiving high-dose corticosteroids (HDC) versus low-dose corticosteroids (LDC). Methods: This was a quasi-experimental study conducted at a large, quaternary care center in Michigan. A corticosteroid dose change was implemented in the standardized institutional treatment protocol on November 17, 2020. All patients admitted with severe COVID-19 that received corticosteroids were included. Consecutive patients in the HDC group (September 1 to November 15, 2020) were compared to the LDC group (November 30, 2020 to January 20, 2021). High-dose corticosteroids was defined as 80 mg of methylprednisolone daily in 2 divided doses, and LDC was defined as 32-40 mg of methylprednisolone daily in 2 divided doses. The primary outcome was all-cause 28-day mortality. Secondary outcomes included progression to mechanical ventilation, hospital length of stay (LOS), discharge on supplemental oxygen, and corticosteroid-associated adverse events. Results: Four-hundred seventy patients were included: 218 (46%) and 252 (54%) in the HDC and LDC groups, respectively. No difference was observed in 28-day mortality (14.5% vs 13.5%, P = .712). This finding remained intact when controlling for additional variables (odds ratio, 0.947; confidence interval, 0.515-1.742; P = .861). Median hospital LOS was 6 and 5 days in the HDC and LDC groups, respectively (P \u3c .001). No differences were noted in any of the other secondary outcomes. Conclusions: Low-dose methylprednisolone had comparable outcomes including mortality to high-dose methylprednisolone for the treatment of severe COVID-19

Low- Versus High-Dose Methylprednisolone in Adult Patients With Coronavirus Disease 2019: Less Is More

Background: Corticosteroids use in severe coronavirus disease 2019 (COVID-19) improves survival; however, the optimal dose is not established. We aim to evaluate clinical outcomes in patients with severe COVID-19 receiving high-dose corticosteroids (HDC) versus low-dose corticosteroids (LDC). Methods: This was a quasi-experimental study conducted at a large, quaternary care center in Michigan. A corticosteroid dose change was implemented in the standardized institutional treatment protocol on November 17, 2020. All patients admitted with severe COVID-19 that received corticosteroids were included. Consecutive patients in the HDC group (September 1 to November 15, 2020) were compared to the LDC group (November 30, 2020 to January 20, 2021). High-dose corticosteroids was defined as 80 mg of methylprednisolone daily in 2 divided doses, and LDC was defined as 32-40 mg of methylprednisolone daily in 2 divided doses. The primary outcome was all-cause 28-day mortality. Secondary outcomes included progression to mechanical ventilation, hospital length of stay (LOS), discharge on supplemental oxygen, and corticosteroid-associated adverse events. Results: Four-hundred seventy patients were included: 218 (46%) and 252 (54%) in the HDC and LDC groups, respectively. No difference was observed in 28-day mortality (14.5% vs 13.5%, P = .712). This finding remained intact when controlling for additional variables (odds ratio, 0.947; confidence interval, 0.515-1.742; P = .861). Median hospital LOS was 6 and 5 days in the HDC and LDC groups, respectively (P \u3c .001). No differences were noted in any of the other secondary outcomes. Conclusions: Low-dose methylprednisolone had comparable outcomes including mortality to high-dose methylprednisolone for the treatment of severe COVID-19

Measurement of global polarization of {\Lambda} hyperons in few-GeV heavy-ion collisions

The global polarization of {\Lambda} hyperons along the total orbital angular momentum of a relativistic heavy-ion collision is presented based on the high statistics data samples collected in Au+Au collisions at \sqrt{s_{NN}} = 2.4 GeV and Ag+Ag at 2.55 GeV with the High-Acceptance Di-Electron Spectrometer (HADES) at GSI, Darmstadt. This is the first measurement below the strangeness production threshold in nucleon-nucleon collisions. Results are reported as a function of the collision centrality as well as a function of the hyperon transverse momentum (p_T) and rapidity (y_{CM}) for the range of centrality 0--40%. We observe a strong centrality dependence of the polarization with an increasing signal towards peripheral collisions. For mid-central (20--40%) collisions the polarization magnitudes are (%) = 6.0 \pm 1.3 (stat.) \pm 2.0 (syst.) for Au+Au and (%) = 4.6 \pm 0.4 (stat.) \pm 0.5 (syst.) for Ag+Ag, which are the largest values observed so far. This observation thus provides a continuation of the increasing trend previously observed by STAR and contrasts expectations from recent theoretical calculations predicting a maximum in the region of collision energies about 3 GeV. The observed polarization is of a similar magnitude as predicted by 3D fluid dynamics and the UrQMD plus thermal vorticity model and significantly above results from the AMPT model.Comment: 8 pages, 4 figure

Inclusive e+^+e−^- production in collisions of pions with protons and nuclei in the second resonance region of baryons

Inclusive e$^+$e$^-$ production has been studied with HADES in $\pi^-$ + p, $\pi^-$ + C and $\pi^- + \mathrm{CH}_2$ reactions, using the GSI pion beam at $\sqrt{s_{\pi p}}$ = 1.49 GeV. Invariant mass and transverse momentum distributions have been measured and reveal contributions from Dalitz decays of $\pi^0$, $\eta$ mesons and baryon resonances. The transverse momentum distributions are very sensitive to the underlying kinematics of the various processes. The baryon contribution exhibits a deviation up to a factor seven from the QED reference expected for the dielectron decay of a hypothetical point-like baryon with the production cross section constrained from the inverse $\gamma$ n$\rightarrow \pi^-$ p reaction. The enhancement is attributed to a strong four-momentum squared dependence of the time-like electromagnetic transition form factors as suggested by Vector Meson Dominance (VMD). Two versions of the VMD, that differ in the photon-baryon coupling, have been applied in simulations and compared to data. VMD1 (or two-component VMD) assumes a coupling via the $\rho$ meson and a direct coupling of the photon, while in VMD2 (or strict VMD) the coupling is only mediated via the $\rho$ meson. The VMD2 model, frequently used in transport calculations for dilepton decays, is found to overestimate the measured dielectron yields, while a good description of the data can be obtained with the VMD1 model assuming no phase difference between the two amplitudes. Similar descriptions have also been obtained using a time-like baryon transition form factor model where the pion cloud plays the major role.Comment: (HADES collaboration

Development of novel immunotherapies against bladder cancer

Le cancer de la vessie est le deuxième cancer urologique le plus fréquent dans le monde. La plupart des patients (75%) sont initialement diagnostiqués avec un cancer non musculo- invasif. Après résection trans-urétrale, ie traitement standard pour ce type de lésion chez les patients présentant un risque important de récidive/progression consiste en une série d'instillations intravésicales du Bacille de Calmette-Guerin (i.e. le vaccin BCG). Cependant cette "BCG thérapie" est associée à des effets secondaires non négligeables et s'avère inefficace dans 30% des cas, des limitations donc importantes qui soulignent la nécessité de développer des stratégies thérapeutiques alternatives. L'utilisation d'antigènes associés aux tumeurs (TAA) comme vaccin, combinée à une application locale d'immunostimulants sur le site tumoral, est une approche prometteuse en vue de maximiser les réponses immunitaires anti-tumorales localement. Nous montrons que la bactérie vivante atténuée Ty21a, issue du vaccin Vivotif® contre la fièvre typhoïde, peut être utilisée comme immunostimulant intravésical (IVES), mais ce uniquement dans le cas où la bactérie est en phase exponentielle de croissance (Vivotif exp). En effet, l'instillation IVES de Vivotif exp à la suite d'une vaccination par un TAA, un antigène mineur d'histocompatibilité mâle H-Y (Uty), permet d'augmenter de 15 fois le nombre de cellules T CD8 totales et spécifiques de l'antigène dans la vessie. Le recrutement des cellules T est TLR4-dépendent, ce qui suggère un rôle des lipopolysaccharides du Vivotif exp. Par ailleurs, en comparaison avec le contenu bactérien de la capsule de Vivotif, les bactéries en phase exponentielle de croissance permettent également une augmentation préférentielle des chemokines C5/C5a, CXCL1, CXCL2 et CXCL5 dans la vessie, mais pas du nombre de cellules T exprimant les récepteurs apparentés (C5aR et CXCR2). De plus, combiner la vaccination Uty avec le Vivotif exp en IVES permet d'améliorer la survie des souris présentant une tumeur orthotopique de la vessie exprimant l'antigène Uty (lignée tumorale murine MB49). Puisque pour certains cancers, aucun TAA - du moins exprimé à tous les stades tumoraux - n'est identifié, il est nécessaire de développer d'autres approches non vaccinales. Dans une deuxième partie de ce travail de thèse, nous avons donc investigué deux stratégies permettant d'induire une destruction des cellules tumorales, la thérapie génique par gène de suicide, d'une part, et la thérapie photodynamique dans le proche infrarouge (NIR-PDT), d'autre part. Pour appliquer ces thérapies, nous avons utilisé comme vecteur sûr et non toxique une forme non réplicative du virus du « Human Papillomavirus » (HPV) capable de "pseudo-infecter" préférentiellement les souris présentant des tumeurs vésicales (MB49). L'utilisation de pseudovirions (PsV) HPV portant comme gène suicide la thymidine kinase, une enzyme du virus de l'herpès simplex, suivi d'un traitement par la prodrogue Ganciclovir, permet de tuer 90% des cellules MB49 in-vitro ainsi que de ralentir significativement le développement des tumeurs vésicales in-vivo. Par ailleurs, l'emploi de particules pseudo- virales HPV couplées à la phtalocyanine IR700, un pigment photosensible présentant un pouvoir cytotoxique une fois activé, permet de tuer, après application d'une lumière dans le proche infrarouge, quasi 100% des cellules MB49 in-vitro et, plus important, de régresser des tumeurs in-vivo. De façon générale, ce travail de thèse présente des approches thérapeutiques innovantes et prometteuses pour le traitement des patients avec un cancer non musculo-invasif de la vessie. -- Bladder cancer is the second most common urological malignancy in the world. At initial diagnosis, non-muscle invasive bladder cancer (NMIBC) accounts for 75% of bladder cancer. The standard of care of NMIBC consists of intravesical (IVES) treatments with Bacillus- Calmette-Guerin (BCG) following transurethral resections of the lesions. However, repeated BCG treatments are associated with significant side effects and treatment failure may occur in 30% of the cases, underlying the necessity of alternative therapeutic strategies. The use of tumor-associated antigens (TAA) as vaccines followed by the local application of immunostimulants where the tumor resides is a promising approach to increase anti-tumor immune responses locally. We show that live attenuated Ty21a bacteria used from the vivotif® vaccine against typhoid fever can efficiently be used as IVES immunostimulant, only if bacteria are grown to exponential phase (Vivotif exp). In this condition, IVES immunostimulation after TAA vaccination with a minor histocompatibility male antigen HY (Uty) resulted in more than 15-fold increase of both vaccine-specific and total CD8-T cells in the bladder. T cell recruitment was mediated by TLR-4 suggesting that it was mainly mediated by lipopolysaccharides of Vivotif exp. In addition, these bacteria, as compared to the bacterial content of the vivotif capsule preferentially increased C5/C5a, CXCL1, CXCL2 and CXCL5 chemokines, but not the numbers of T cells expressing the cognate receptors (C5aR and CXCR2). Combination of IVES Vivotif exp with Uty vaccination improved survival of mice with pre-established orthotopic Uty-expressing MB49 murine bladder tumors, as compared to vaccination alone. As known TAA are not identified in all cancers, or not expressed in all stages of the tumor, we further investigated two potent approaches able of initiating tumor-cell destruction, suicide-gene therapy and near-infrared (NIR) photodynamic therapy (PDT). Towards a safe and non-toxic application of these therapies, we used Human Papillomavirus (HPV) replication-defective vectors that were able to preferentially pseudo-infect MB49-tumor bearing mice. HPV pseudovirions (PsV) carrying the Herpex-Simplex virus thymidine kinase suicide-gene followed by treatment with the prodrug Ganciclovir resulted in 90% of MB49 cell-death in-vitro and was able to significantly reduce bladder tumor growth in-vivo. Furthermore, HPV virus-like particles coupled to a NIR phtalocyanine dye, IR700 in combination with specific NIR light led to almost 100% of MB49 cell-death in-vitro and more interestingly, to bladder tumors shrinkage in-vivo. Overall, in this thesis, we offer promising therapeutic approaches for application in NMIBC patients

Musculoskeletal pain among bakery workers in Lebanon: a national survey

This study examined the association of self-reports of repetitive hand movements, perceptions of the work environment, and somatization with upper extremity musculoskeletal pain among bakery workers, an understudied population globally. Surveys were conducted in 504 randomly selected bakeries across Lebanon and administered through face-to-face interviews at the workplace. The survey included items on musculoskeletal pain, general health, workplace environment, activities, and socio-demographics. The findings showed that 23% of bakery workers reported upper extremity pain. Workers who reported poor health (OR = 2.08; 95% CI = 1.12–3.87) and those who perceived that the work environment negatively affects their health (OR = 2.04; 95% CI = 1.26–3.33) were twice as likely to experience upper extremity musculoskeletal pain. Somatization was positively associated with reporting upper extremity musculoskeletal pain (OR = 1.51; 95% CI = 1.22–1.86). Workers that reported having another job were three times more likely to report upper musculoskeletal pain (OR = 2.76; 95% CI = 1.31–5.79). The need for interventions in the work environment and work strategies is evident