Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer.

Extracellular matrix (ECM) is a major component of the tumor environment, promoting the establishment of a pro-invasive behavior. Such environment is supported by both tumor- and stromal-derived metabolites, particularly lactate. In prostate cancer (PCa), cancer-associated fibroblasts (CAFs) are major contributors of secreted lactate, able to impact on metabolic and transcriptional regulation in cancer cells. Here, we describe a mechanism by which CAF-secreted lactate promotes in PCa cells the expression of genes coding for the collagen family. Lactate-exploiting PCa cells rely on increased α-ketoglutarate (α-KG) which activates the α-KG-dependent collagen prolyl-4-hydroxylase (P4HA1) to support collagen hydroxylation. De novo synthetized collagen plays a signaling role by activating discoidin domain receptor 1 (DDR1), supporting stem-like and invasive features of PCa cells. Inhibition of lactate-induced collagen hydroxylation and DDR1 activation reduces the metastatic colonization of PCa cells. Overall, these results provide a new understanding of the link between collagen remodeling/signaling and the nutrient environment exploited by PCa.

Listening to patients, for the patients: The COVAD Study-Vision, organizational structure, and challenges.

BACKGROUND: The pandemic presented unique challenges for individuals with autoimmune and rheumatic diseases (AIRDs) due to their underlying condition, the effects of immunosuppressive treatments, and increased vaccine hesitancy. OBJECTIVES: The COVID-19 vaccination in autoimmune diseases (COVAD) study, a series of ongoing, patient self-reported surveys were conceived with the vision of being a unique tool to gather patient perspectives on AIRDs. It involved a multinational, multicenter collaborative effort amidst a global lockdown. METHODS: Leveraging social media as a research tool, COVAD collected data using validated patient-reported outcomes (PROs). The study, comprising a core team, steering committee, and global collaborators, facilitated data collection and analysis. A pilot-tested, validated survey, featuring questions regarding COVID-19 infection, vaccination and outcomes, patient demographics, and PROs was circulated to patients with AIRDs and healthy controls (HCs). DISCUSSION: We present the challenges encountered during this international collaborative project, including coordination, data management, funding constraints, language barriers, and authorship concerns, while highlighting the measures taken to address them. CONCLUSION: Collaborative virtual models offer a dynamic new frontier in medical research and are vital to studying rare diseases. The COVAD study demonstrates the potential of online platforms for conducting large-scale, patient-focused research and underscores the importance of integrating patient perspective into clinical care. Care of patients is our central motivation, and it is essential to recognize their voices as equal stakeholders and valued partners in the study of the conditions that affect them.

Characteristics of emerging new autoimmune diseases after COVID-19 vaccination: A sub-study by the COVAD group.

BACKGROUND: Despite the overall safety and efficacy of COVID-19 vaccinations, rare cases of systemic autoimmune diseases (SAIDs) have been reported post-vaccination. This study used a global survey to analyze SAIDs in susceptible individuals' post-vaccination. METHODS: A cross-sectional study was conducted among participants with self-reported new-onset SAIDs using the COVID-19 Vaccination in Autoimmune Diseases (COVAD) 2 study dataset-a validated, patient-reported e-survey-to analyze the long-term safety of COVID-19 vaccines. Baseline characteristics of patients with new-onset SAIDs and vaccinated healthy controls (HCs) were compared after propensity score matching based on age and sex in a 1:4 ratio. RESULTS: Of 16 750 individuals, 74 (median age 52 years, 79.9% females, and 76.7% Caucasians) had new-onset SAID post-vaccination, mainly idiopathic inflammatory myopathies (IIMs) (n = 23, 31.51%), arthritis (n = 15; 20.53%), and polymyalgia rheumatica (PMR) (n = 12, 16.40%). Higher odds of new-onset SAIDs were noted among Caucasians (OR = 5.3; 95% CI = 2.9-9.7; p < .001) and Moderna vaccine recipients (OR = 2.7; 95% CI = 1.3-5.3; p = .004). New-onset SAIDs were associated with AID multimorbidity (OR = 1.4; 95% CI = 1.1-1.7; p < .001), mental health disorders (OR = 1.6; 95% CI = 1.3-1.9; p < .001), and mixed race (OR = 2.2; 95% CI = 1.2-4.2; p = .010), where those aged >60 years (OR = 0.6; 95% CI = 0.4-0.8; p = .007) and from high/medium human development index (HDI) countries (compared to very high HDI) reported fewer events than HCs. CONCLUSION: This study reports a low occurrence of new-onset SAIDs following COVID-19 vaccination, primarily IIMs, PMR, and inflammatory arthritis. Identified risk factors included pre-existing AID multimorbidity, mental health diseases, and mixed race. Revaccination was well tolerated by most patients; therefore, we recommend continuing COVID-19 vaccination in the general population. However, long-term studies are needed to understand the autoimmune phenomena arising post-vaccination.

Collating the voice of people with autoimmune diseases: Methodology for the Third Phase of the COVAD Studies.

INTRODUCTION: The growing recognition of holistic patient care highlights the various factors shaping the quality of life of individuals with autoimmune and rheumatic diseases (AIRDs). Beyond the traditional disease measures, there is an emerging acknowledgment of the less-explored aspects, including subjective well-being, social determinants of health, comorbidities, mental health, and medication adherence. Moreover, digital health services have empowered patients to engage actively in decision-making alongside clinicians. To explore these domains within the context of AIRDs, the "Collating the Voice of People with Autoimmune Diseases" COVAD survey was conceived, a successor of the previous two COVAD surveys. In this document, we present the study protocol in comprehensive detail. METHODS: The COVAD-3 survey is a cross-sectional patient self-reported e-survey incorporating multiple widely accepted scales/scores to assess various aspects of patients' lifestyles objectively. To ensure the survey's accuracy and usability across diverse regions, it will be translated into multiple languages and subjected to rigorous vetting and pilot testing. It will be distributed by collaborators via online platforms and data will be collected from patients with AIRDs, and healthy individuals over eight months. Data analysis will focus on outcome measures related to various social, demographic, economic, and psychological factors. CONCLUSION: With the increasing awareness to adopt a holistic treatment approach encompassing all avenues of life, the COVAD-3 survey aims to gain valuable insights into the impact of social, demographic, economic, and psychological determinants of health on the subjective well-being in patients with AIRDs, which will contribute to a better understanding of their overall health and well-being.

Surveillance of Sarcoptic Mange in Iberian Ibexes (Capra pyrenaica) and Domestic Goats (Capra hircus) in Southern Spain.

Sarcoptic mange is a highly contagious skin disease caused by Sarcoptes scabiei. Sera were collected from 411 Iberian ibexes, comprising 157 individuals with sarcoptic mange skin lesions and 254 clinically healthy animals, in 13 population nuclei across Andalusia (southern Spain) between 2015 and 2021. Skin samples from 88 of the 157 animals with mange-compatible lesions were also obtained. Moreover, 392 serum samples from domestic goats (Capra hircus) were collected in the same region and study period. Antibodies against S. scabiei were tested using an in-house indirect ELISA, while the presence of mites of S. scabiei was evaluated in the skin samples by potassium hydroxide digestion. Seropositivity was found in eight (3.1%) of the clinically healthy ibexes and in 104 (66.2%) of the animals with mange-compatible lesions. The presence of S. scabiei was confirmed in 57 (64.8%) out of the 88 skin samples analysed and anti-S. scabiei antibodies were found in 49 (86.0%) of these 57 mite-positive individuals. Seropositive animals were detected in population nuclei with previous records of sarcoptic mange, where S. scabiei mites were detected by potassium hydroxide digestion in individuals with sarcoptic mange-compatible external lesions. However, seropositivity was not observed in population nuclei that were historically free of this disease. None of the 392 domestic goats had antibodies against S. scabiei, suggesting an independent epidemiological cycle of sarcoptic mange in Iberian ibex populations in the study area, and a limited or null role of domestic goats in the transmission of the parasite to this wild species. Overall, our findings underscore the importance of maintaining and/or implementing integrated surveillance programs and control strategies in wildlife and livestock, to limit the risk of S. scabiei circulation in Iberian ibex populations.

Botulinum toxin injection for chronic anal fissure: a prospective controlled study with long follow-up.

BACKGROUND: Botulinum toxin is an effective therapeutic option for chronic anal fissure. However, there is no evidence about treatment standardization and long-term follow-up. We aimed to evaluate the short- and long-term efficacy and safety of botulinum toxin compared to close lateral internal sphincterotomy, with a 5-year follow-up. METHODS: This was a prospective, controlled, single-center study conducted at University Hospital of Ferrara, Ferrara, Italy. The primary outcome was fissure healing at 1 month. Secondary outcomes were Quality-of-Life (QoL) at 1 month and after 5 years, and fissure recurrence at 6 months and 5 years. RESULTS: A total of 59 patients received botulinum toxin injection (Botox), and 32 underwent lateral internal sphincterotomy. At 1 month after treatments, postoperative pain decreased faster and significantly more in the Botox group (30 vs. 60 mm; P<0.001); fissure re-epithelization was observed in 59.4% of the surgical group compared to 25.4% of Botox (P=0.0001). Anal sphincter pressures decreased more in surgical group (P=0.044), although severe anal incontinence was present only in this subset (6.2%; P=0.041). Compared to surgery, patients who received Botox had higher satisfaction rates (P<0.001). Fissure recurrence at 6 months was more common in Botox than surgical group (16.9% vs. 3.2%, respectively; P=0.053). The overall healing rate improved in all patients and persisted at 12 months and 5 years in both groups with overall high patient satisfaction despite mild anal incontinence in 21.8% in the surgery group (P<0.05). CONCLUSIONS: Botox, rather than surgery, should be considered the first-line treatment for chronic anal fissure.

Ankyloglossia in newborns: incidence and breastfeeding follow-up at 1 and 6 months.

BACKGROUND: Ankyloglossia is an anatomical variation of the lingual frenulum that negatively interferes with the functionality of the tongue. This condition can affect breastfeeding negatively. The aim of this study is to assess the prevalence of ankyloglossia among healthy babies born in Siena Hospital and the correlation between ankyloglossia and breastfeeding difficulties. METHODS: We performed an observational prospective study conducted on healthy and breastfed newborns born in Siena Hospital in the period between January and June 2022. The evaluation of lingual frenulum in the first few days of life was performed by Martinelli's Lingual Frenulum Protocol with scores for Infants (MLFPI), while the clinical assessment of breastfeeding initiation was performed by the Breastfeeding Observation and Evaluation Form according to WHO-UNICEF guidelines. We also compared the reliability in predicting breastfeeding of a tool that measured the features of the tongue frenulum: the Bristol Tongue Assessment Tool (BTT). Breastfeeding at one and six months of babies' age was assessed by telephone interview, and information among children's nutrition, weight growth and difficulties found in breastfeeding was also collected. This study was approved by the Pediatric Ethics Committee for Clinical Trials of the Tuscany Region. RESULTS: One hundred and ninety infants were included in the study; 21 (11.05%) had a MLFPI score ≥13. Data at one month of age showed a statistically higher MLFPI score (P value <0.001) in babies with breastfeeding difficulties (median score 13.0, IQR 5.5-14), than in those without (median score 5.0, IQR 2.0-7.5). Data at 6 months of age showed a similar difference in babies with and without breastfeeding difficulties (median 12.0, IQR 4.0-14.0 vs. 5.0, IQR 2.0-8.0 respectively). A MLFPI score ≥13 is positively associated with breastfeeding difficulties at 1 and 6 months. Also, the BTT was positively a risk factor for problems in breastfeeding at 1 and 6 months. CONCLUSIONS: A high MLFPI score is a risk factor of breastfeeding difficulties. In these cases, a referral to experienced personnel is advisable: they can provide the emotional and professional support to the mother-child dyad, and/or refer for surgical evaluation and frenotomy. In our cohort, the usefulness of either MLFPI score or BTT was evident in predicting breastfeeding difficulties; the rate of surgical removal of the frenulum was nonetheless low.

Characteristics and risk factors of COVID-19 breakthrough infections in Idiopathic Inflammatory Myopathies: Results from the COVAD study.

OBJECTIVES: To explore prevalence, characteristics and risk factors of COVID-19 breakthrough infections (BIs) in idiopathic inflammatory myopathies (IIM) using data from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. METHODS: A validated patient self-reporting e-survey was circulated by the COVAD study group to collect data on COVID-19 infection and vaccination in 2022. BIs were defined as COVID-19 occurring ≥14 days after 2 vaccine doses. We compared BIs characteristics and severity among IIMs, other autoimmune rheumatic and non-rheumatic diseases (AIRD, nrAID), and healthy controls (HC). Multivariable Cox regression models assessed the risk factors for BI, severe BI and hospitalisations among IIMs. RESULTS: Among 9449 included response, BIs occurred in 1447 (15.3%) respondents, median age 44 years (IQR 21), 77.4% female, and 182 BIs (12.9%) occurred among 1406 IIMs. Multivariable Cox regression among IIMs showed age as a protective factor for BIs [Hazard Ratio (HR)=0.98, 95%CI = 0.97-0.99], hydroxychloroquine and sulfasalazine use were risk factors (HR = 1.81, 95%CI = 1.24-2.64, and HR = 3.79, 95%CI = 1.69-8.42, respectively). Glucocorticoid use was a risk factor for severe BI (HR = 3.61, 95%CI = 1.09-11.8). Non-White ethnicity (HR = 2.61, 95%CI = 1.03-6.59) was a risk factor for hospitalisation. Compared with other groups, patients with IIMs required more supplemental oxygen therapy (IIM = 6.0% vs AIRD = 1.8%, nrAID = 2.2%, and HC = 0.9%), intensive care unit admission (IIM = 2.2% vs AIRD = 0.6%, nrAID, and HC = 0%), advanced treatment with antiviral or monoclonal antibodies (IIM = 34.1% vs AIRD = 25.8%, nrAID = 14.6%, and HC = 12.8%), and had more hospitalisation (IIM = 7.7% vs AIRD = 4.6%, nrAID = 1.1%, and HC = 1.5%). CONCLUSION: Patients with IIMs are susceptible to severe COVID-19 BI. Age and immunosuppressive treatments were related to the risk of BIs.

Breakthrough SARS-CoV-2 infection and disease flares in patients with rheumatoid arthritis: result from COVAD e-survey study.

COVID-19 has been suggested as a possible trigger of disease flares in patients with rheumatoid arthritis (RA). However, factors associated with disease flares remain unknown. This study aimed to identify factors associated with breakthrough infection (BIs) and disease flares in patients with RA following COVID-19. We analysed data from RA patients who participated in the COVID-19 vaccination in autoimmune diseases (COVAD) study. Demographic data, patient-reported outcomes, comorbidities, pharmacologic treatment and details regarding disease flares were extracted from the COVAD database. Factors associated with disease flare-ups were determined by multivariate logistic regression analysis. The analysis comprised 1928 patients with RA who participated in the COVAD study. Younger age, Caucasian ethnicity, comorbidities with obstructive chronic pulmonary disease and asthma were associated with COVID-19 breakthrough infection. Moreover, younger age (odds ratio (OR): 0.98, 95% CI 0.96-0.99, p < 0.001), ethnicity other than Asian, past history of tuberculosis (OR: 3.80, 95% CI 1.12-12.94, p = 0.033), treatment with methotrexate (OR: 2.55, 95% CI: 1.56-4.17, p < 0.001), poor global physical health (OR: 1.07, 95% CI 1.00-1.15, p = 0.044) and mental health (OR: 0.91, 95% CI 0.87-0.95, p < 0.001) were independent factors associated disease flares in patients with RA. Our study highlights the impact of socio-demographic factors, clinical characteristics and mental health on disease flares in patients with RA. These insights may help determine relevant strategies to proactively manage RA patients at risk of flares.

Mitochondrial genetic diversity and phylogenetic relationships of Echinococcus multilocularis in Europe.

The cestode Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a fatal zoonotic parasitic disease of the northern hemisphere. Red foxes are the main reservoir hosts and, likely, the main drivers of the geographic spread of the disease in Europe. Knowledge of genetic relationships among E. multilocularis isolates at a European scale is key to understanding the dispersal characteristics of E. multilocularis. Hence, the present study aimed to describe the genetic diversity of E. multilocularis isolates obtained from different host species in 19 European countries. Based on the analysis of complete nucleotide sequences of the cob, atp6, nad2, nad1 and cox1 mitochondrial genes (4,968 bp), 43 haplotypes were inferred. Four haplotypes represented 62.56 % of the examined isolates (142/227), and one of these four haplotypes was found in each country investigated, except Svalbard, Norway. While the haplotypes from Svalbard were markedly different from all the others, mainland Europe appeared to be dominated by two main clusters, represented by most western, central and eastern European countries, and the Baltic countries and northeastern Poland, respectively. Moreover, one Asian-like haplotype was identified in Latvia and northeastern Poland. To better elucidate the presence of Asian genetic variants of E. multilocularis in Europe, and to obtain a more comprehensive Europe-wide coverage, further studies, including samples from endemic regions not investigated in the present study, especially some eastern European countries, are needed. Further, the present work proposes historical causes that may have contributed to shaping the current genetic variability of E. multilocularis in Europe.

Flares in IIMs and the timeline following COVID-19 vaccination: a combined analysis of the COVAD-1 and -2 surveys.

OBJECTIVES: Disease flares in the post-coronavirus disease 2019 (COVID-19) vaccination period represent a prominent concern, though risk factors are poorly understood. We studied these flares among patients with idiopathic inflammatory myopathies (IIMs) and other autoimmune rheumatic diseases (AIRDs). METHODS: The COVAD-1 and -2 global surveys were circulated in early 2021 and 2022, respectively, and we captured demographics, comorbidities, AIRDs details, COVID-19 infection history and vaccination details. Flares of IIMs were defined as (a) patient self-reported, (b) immunosuppression (IS) denoted, (c) clinical sign directed and (d) with >7.9-point minimal clinically significant improvement difference worsening of Patient-Reported Outcomes Measurement Information System (PROMIS) PROMISPF10a score. Risk factors of flares were analysed using regression models. RESULTS: Of 15 165 total respondents, 1278 IIMs (age 63 years, 70.3% female, 80.8% Caucasians) and 3453 AIRDs were included. Flares of IIM were seen in 9.6%, 12.7%, 8.7% and 19.6% patients by definitions (a) to (d), respectively, with a median time to flare of 71.5 (10.7-235) days, similar to AIRDs. Patients with active IIMs pre-vaccination (OR 1.2; 95% CI 1.03, 1.6, P = 0.025) were prone to flares, while those receiving rituximab (OR 0.3; 95% CI 0.1, 0.7, P = 0.010) and AZA (OR 0.3, 95% CI 0.1, 0.8, P = 0.016) were at lower risk. Female gender and comorbidities predisposed to flares requiring changes in IS. Asthma (OR 1.62; 95% CI 1.05, 2.50, P = 0.028) and higher pain visual analogue score (OR 1.19; 95% CI 1.11, 1.27, P < 0.001) were associated with disparity between self-reported and IS-denoted flares. CONCLUSION: A diagnosis of IIMs confers an equal risk of flares in the post-COVID-19 vaccination period to AIRDs, with active disease, female gender and comorbidities conferring a higher risk. Disparity between patient- and physician-reported outcomes represents a future avenue for exploration.

A rare case of jejunal Vanek's tumor causing intussusception in an adult: a case report and comprehensive literature overview.

Inflammatory fibroid polyp, or Vanek's tumor, is an uncommon benign small bowel tumor and a rare cause of intussusception in adults. This case involves a 62-year-old man with persistent abdominal pain, diagnosed with jejunoileal intussusception. A 4 cm inflammatory fibroid polyp was discovered during surgery, leading to distal jejunal resection. Despite the rarity of adult intussusceptions, they should be considered in abdominal pain diagnoses. The optimal management approach, whether en bloc resection or initial reduction with limited resection, remains debated.

The Impact of Social Media on Vaccination: A Narrative Review.

Vaccine hesitancy poses a significant global health challenge, fueled by misinformation and anti-vaccination campaigns on social media platforms (SMPs). This study examines the influence of social media on coronavirus disease 2019 (COVID-19) and non-COVID-19 vaccination in Asia during the peri-pandemic period. Through a comprehensive analysis of available literature, we aim to elucidate the role of SMPs in shaping vaccination attitudes and behaviors. The findings highlight the detrimental impact of social media on vaccination efforts and provide insights into addressing vaccine hesitancy during this critical period. A narrative review was conducted by searching the PubMed, Scopus, and Google Scholar databases from inception to May 26, 2022. Only English-language articles involving human participants from Asian countries were included in this review. Out of the 228 articles identified through the database search, 14 articles were included in the final analysis. The prevalence of COVID-19 vaccine hesitancy or negative attitudes towards COVID-19 vaccines in Asian countries was found to be high, ranging from 20% to 55% across countries. Notably, reliance on SMPs for vaccine-related information was associated with a higher likelihood of COVID-19 vaccine hesitancy. This trend coincided with the proliferation of misinformation and conspiracy theories that portrayed COVID-19 vaccines as harmful during the pandemic. Similar patterns were observed for other types of vaccines, including polio, measles mumps and rubella, and diphtheria-tetanus-pertussis vaccines. The use of SMPs was also found to be associated with increased fear among caregivers in Asian countries, as well as a 3-4 times higher likelihood of delayed immunization. SMPs negatively impact vaccine intent in Asia due to misinformation and anti-vaccination campaigns during the pandemic. However, they can be a powerful tool for healthcare providers and policymakers to promote informed decision-making. Efforts should focus on leveraging SMPs to disseminate reliable information and combat hesitancy, fostering a well-informed and vaccinated population in Asia.

Acute Esophageal Necrosis as a Rare Complication of Metabolic Acidosis in a Diabetic Patient: A Case Report.

BACKGROUND Acute esophageal necrosis, or Gurvits syndrome, is a rare clinical process often secondary to a systemic low-flow state. It can be caused by several medical conditions, and it is thought to arise from a combination of impaired mucosal barrier and chemical and ischemic insults to the esophagus. Acute esophageal necrosis usually presents with severe complications due to delayed diagnosis and only rarely has surgical indications. We present a case of Gurvits syndrome, presumably triggered by metabolic acidosis in a diabetic patient. CASE REPORT A 61-year-old man with history of hypertension and type 2 diabetes mellitus treated with metformin, canagliflozin, glimepiride, and pioglitazone came to our attention with persistent vomiting, odynophagia, chest pain after each meal, and progressive weight loss. Arterial blood analysis showed mild metabolic acidosis, while the first esophagogastroduodenoscopy performed revealed a circumferential black appearance of the esophageal mucosa, as in concentric necrosis of the distal esophagus with possible fungal superinfection. Brushing cytology confirmed the infection by Candida spp. and the patient was treated with intravenous fluconazole. The second esophagogastroduodenoscopy, performed after 2 weeks, showed almost complete healing of the esophageal mucosa; in this case, biopsy confirmed mucosal ischemia and necrosis, without showing deep impairment of the mucosa by fungal agents. CONCLUSIONS Due to its high lethality, often caused by the underlying medical diseases, acute esophageal disease should be considered in the differential diagnosis of digestive symptoms, even without upper gastrointestinal bleeding. Prompt diagnosis and treatment of contextual collateral conditions can help clinicians to avoid the worst outcomes of the disease. Among the causative factors of metabolic acidosis leading to esophageal necrosis we recognized metformin and dapagliflozin.

The EUPEMEN (EUropean PErioperative MEdical Networking) Protocol for Bowel Obstruction: Recommendations for Perioperative Care.

Mechanical bowel obstruction is a common symptom for admission to emergency services, diagnosed annually in more than 300,000 patients in the States, from whom 51% will undergo emergency laparotomy. This condition is associated with serious morbidity and mortality, but it also causes a high financial burden due to long hospital stay. The EUPEMEN project aims to incorporate the expertise and clinical experience of national clinical specialists into development of perioperative rehabilitation protocols. Providing special recommendations for all aspects of patient perioperative care and the participation of diverse specialists, the EUPEMEN protocol for bowel obstruction, as presented in the current paper, aims to provide faster postoperative recovery and reduce length of hospital stay, postoperative morbidity and mortality rate.

COVID-19 vaccine safety during pregnancy and breastfeeding in women with autoimmune diseases: results from the COVAD study.

OBJECTIVES: We investigated COVID-19 vaccine safety in pregnant and breastfeeding women with autoimmune diseases (AID) in the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. METHODS: Delayed-onset (>7 days) vaccine-related adverse events (AE), disease flares (DF), and AID-related treatment modifications were analyzed upon diagnosis of AID versus healthy controls (HC) and the pregnancy/breastfeeding status at the time of at least one dose of vaccine. RESULTS: Among the 9201 participants to the self-administered online survey, 6787 (73.8%) were women. Forty pregnant and 52 breastfeeding patients with AID were identified, of whom the majority had received at least one dose of COVID-19 vaccine (100% and 96.2%, respectively). AE were reported significantly more frequently in pregnant than in non-pregnant patients (overall AE 45% vs 26%, p= 0.01; minor AE 40% vs 25.9%, p= 0.03; major AE 17.5% vs 4.6%, p< 0.01), but no difference was found in comparison with pregnant HC. No difference was observed between breastfeeding patients and HC with respect to AE. Post-vaccination DF were reported by 17.5% of pregnant and 20% of breastfeeding patients, and by 18.3% of age- and disease-matched non-pregnant and non-breastfeeding patients (n = 262). All pregnant/breastfeeding patients who experienced a DF were managed with glucocorticoids; 28.6% and 20% of them required initiation or change in immunosuppressants, respectively. CONCLUSION: This study provides reassuring insights into the safety of COVID-19 vaccines administered to women with AID during the gestational and post-partum periods, helping overcome hesitant attitudes, as the benefits for the mother and the fetus by passive immunization appear to outweigh potential risks.

Proteomics of immune cells from liver tumors reveals immunotherapy targets.

Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer tissue as well as monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their anti-tumor activity synergistically with PD-L1 blockade in mouse models. Our data reveal new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer.

Long-term safety of COVID vaccination in individuals with idiopathic inflammatory myopathies: results from the COVAD study.

Limited evidence on long-term COVID-19 vaccine safety in patients with idiopathic inflammatory myopathies (IIMs) continues to contribute to vaccine hesitancy. We studied delayed-onset vaccine adverse events (AEs) in patients with IIMs, other systemic autoimmune and inflammatory disorders (SAIDs), and healthy controls (HCs), using data from the second COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. A validated self-reporting e-survey was circulated by the COVAD study group (157 collaborators, 106 countries) from Feb-June 2022. We collected data on demographics, comorbidities, IIM/SAID details, COVID-19 history, and vaccination details. Delayed-onset (> 7 day) AEs were analyzed using regression models. A total of 15165 respondents undertook the survey, of whom 8759 responses from vaccinated individuals [median age 46 (35-58) years, 74.4% females, 45.4% Caucasians] were analyzed. Of these, 1390 (15.9%) had IIMs, 50.6% other SAIDs, and 33.5% HCs. Among IIMs, 16.3% and 10.2% patients reported minor and major AEs, respectively, and 0.72% (n = 10) required hospitalization. Notably patients with IIMs experienced fewer minor AEs than other SAIDs, though rashes were expectedly more than HCs [OR 4.0; 95% CI 2.2-7.0, p < 0.001]. IIM patients with active disease, overlap myositis, autoimmune comorbidities, and ChadOx1 nCOV-19 (Oxford/AstraZeneca) recipients reported AEs more often, while those with inclusion body myositis, and BNT162b2 (Pfizer) recipients reported fewer AEs. Vaccination is reassuringly safe in individuals with IIMs, with AEs, hospitalizations comparable to SAIDs, and largely limited to those with autoimmune multimorbidity and active disease. These observations may inform guidelines to identify high-risk patients warranting close monitoring in the post-vaccination period.

Timing of Chromosome DNA Integration throughout the Yeast Cell Cycle.

The dynamic mechanism of cell uptake and genomic integration of exogenous linear DNA still has to be completely clarified, especially within each phase of the cell cycle. We present a study of integration events of double-stranded linear DNA molecules harboring at their ends sequence homologies to the host's genome, all throughout the cell cycle of the model organism Saccharomyces cerevisiae, comparing the efficiency of chromosomal integration of two types of DNA cassettes tailored for site-specific integration and bridge-induced translocation. Transformability increases in S phase regardless of the sequence homologies, while the efficiency of chromosomal integration during a specific cycle phase depends upon the genomic targets. Moreover, the frequency of a specific translocation between chromosomes XV and VIII strongly increased during DNA synthesis under the control of Pol32 polymerase. Finally, in the null POL32 double mutant, different pathways drove the integration in the various phases of the cell cycle and bridge-induced translocation was possible outside the S phase even without Pol32. The discovery of this cell-cycle dependent regulation of specific pathways of DNA integration, associated with an increase of ROS levels following translocation events, is a further demonstration of a sensing ability of the yeast cell in determining a cell-cycle-related choice of DNA repair pathways under stress.