Third and Fourth Vaccine Doses Broaden and Prolong Immunity to SARS-CoV-2 in Adult Patients with Immune-Mediated Inflammatory Diseases.

Previous studies have reported impaired humoral responses after SARS-CoV-2 mRNA vaccination in patients with immune-mediated inflammatory diseases (IMIDs), particularly those treated with anti-TNF biologics. We previously reported that IMID patients diagnosed with inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, or rheumatoid arthritis exhibited greater waning of Ab and T cell responses than healthy control subjects after SARS-CoV-2 vaccine dose 2. Fewer data are available on the effects of third and fourth doses. This observational cohort study collected plasma and PBMCs from healthy control subjects and untreated or treated patients with IMIDs prevaccination and after one to four doses of SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273). SARS-CoV-2-specific Ab levels, neutralization, and T cell cytokine release were measured against wild-type and Omicron BA.1 and BA.5 variants of concern. Third vaccine doses substantially restored and prolonged Ab and T cell responses in patients with IMIDs and broadened responses against variants of concern. Fourth-dose effects were subtle but also prolonged Ab responses. However, patients with IMIDs treated with anti-TNF, especially patients with inflammatory bowel disease, exhibited lower Ab responses even after the fourth dose. Although T cell IFN-γ responses were maximal after one dose, IL-2 and IL-4 production increased with successive doses, and early production of these cytokines was predictive of neutralization responses at 3-4 mo postvaccination. Our study demonstrates that third and fourth doses of the SARS-CoV-2 mRNA vaccines sustain and broaden immune responses to SARS-CoV-2, supporting the recommendation for three- and four-dose vaccination regimens in patients with IMIDs.

Informing a Canadian Skin Science Trainee Program Based on the State of Trainee Programs Offered by International Academic Societies.

BACKGROUND: For dermatology to effectively address the ever-growing medical needs, longstanding communication barriers across investigators working in different research pillars and practicing clinicians must be improved. To address this problem, trainee-specific programs are now evolving to align their educational landscape across basic science, translational and clinical research programs. OBJECTIVES: To establish a Skin Investigation Network of Canada (SkIN Canada) training roadmap for the career and skill development of future clinicians, clinican scientists and basic scientists in Canada. This Working Group aims to strengthen and harmonize collaborations and capacity across the skin research community. METHODS: The Working Group conducted a search of established international academic societies which offered trainee programs with mandates similar to SkIN Canada. Societies' program items and meetings were evaluated by use of an interview survey and/or the collection of publicly available data. Program logistics, objectives and feedback were assessed for commonalities and factors reported or determined to improve trainee experience. RESULTS: Through the various factors explored, the Working Group discovered the need for increasing program accessibility, creating opportunities for soft skill development, emphasizing the importance of current challenges, collecting and responding to feedback, and improving knowledge sharing to bridge pillars of skin research. CONCLUSIONS: Although improvements have been made to trainee education in recent years, a plurality of approaches exist and many of the underlying roadblocks remain unresolved. To establish fundamental clinician-basic scientist collaboration and training efforts, this Working Group highlights important factors to include and consider in building a trainee program and emphasizes the importance of trainee education.

Local Hyperthermia at 44°C Is Effective in Clearing Cervical High-Risk Human Papillomaviruses: A Proof-of-Concept, Randomized Controlled Clinical Trial.

BACKGROUND: Persistent infection by high-risk human papillomavirus (HPV) is the leading cause of cervical intraepithelial neoplasia and cervical carcinoma. Local hyperthermia at 44ºC has been proven efficacious to clear cutaneous or anogenital warts caused by HPV infection. This study aims to assess the effect of hyperthermia at 44ºC on the clearance of high-risk HPV. METHODS: A randomized, patient-blind, sham treatment-controlled trial was conducted in 4 medical centers. We enrolled patients with positive high-risk HPVs and normal or insignificant cytological findings (negative/atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion). Participants were randomly assigned (1:1) to receive either hyperthermia at 44ºC or 37ºC, for 30 minutes in each session. Patients in both groups received treatment once a day for 3 consecutive days, plus 2 more sessions 10 ±â€…3 days later. The primary outcome was clearance rate of HPV 3 months after treatment. RESULTS: After a 3-month follow-up, hyperthermia treatment at 44ºC and 37ºC achieved HPV clearance rates of 85.19% (23/27) and 50% (13/26), respectively (P = .014). There was no significant difference of treatment response between patients with single and multiple type of HPV by 44ºC hyperthermia treatment. There were no significant adverse events recorded during the treatment period in both groups. CONCLUSIONS: Local hyperthermia at 44ºC safely and significantly aids in clearing cervical high-risk HPVs, the effect of which helps halt the progression of cervical transformation and transmission of the virus. CLINICAL TRIALS REGISTRATION: NCT03436251.

Intracellular Bacterial Pathogens Trigger the Formation of U Small Nuclear RNA Bodies (U Bodies) through Metabolic Stress Induction.

Invasive bacterial pathogens induce an amino acid starvation (AAS) response in infected host cells that controls host defense in part by promoting autophagy. However, whether AAS has additional significant effects on the host response to intracellular bacteria remains poorly characterized. Here we showed that Shigella, Salmonella, and Listeria interfere with spliceosomal U snRNA maturation in the cytosol. Bacterial infection resulted in the rerouting of U snRNAs and their cytoplasmic escort, the survival motor neuron (SMN) complex, to processing bodies, thus forming U snRNA bodies (U bodies). This process likely contributes to the decline in the cytosolic levels of U snRNAs and of the SMN complex proteins SMN and DDX20 that we observed in infected cells. U body formation was triggered by membrane damage in infected cells and was associated with the induction of metabolic stresses, such as AAS or endoplasmic reticulum stress. Mechanistically, targeting of U snRNAs to U bodies was regulated by translation initiation inhibition and the ATF4/ATF3 pathway, and U bodies rapidly disappeared upon removal of the stress, suggesting that their accumulation represented an adaptive response to metabolic stress. Importantly, this process likely contributed to shape the host response to invasive bacteria because down-regulation of DDX20 expression using short hairpin RNA (shRNA) amplified ATF3- and NF-κB-dependent signaling. Together, these results identify a critical role for metabolic stress and invasive bacterial pathogens in U body formation and suggest that this process contributes to host defense.