Severe Invasive Infections Linked to Novel IRAK2 Immune Variants.

In subjects with peculiar susceptibility to severe infections by common pyogenic bacteria, mutations of interleukin-1 receptor-associated kinase proteins (IRAK)1 and IRAK4 had been identified. The IRAK kinases function as downstream signal transductors following activation of pathogen recognition receptors. In 2 patients with sequential or repeated invasive infections: herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and Streptococcus pneumoniae bacteremia with candidemia respectively, novel mutations of IRAK2 were identified. These mutations compromised the capacity to ubiquinate (or functionally modify) the signal adaptor tumor necrosis factor receptor-associated factor 6 (TRAF6). The result is impairment of the cytokine TNF-alpha production. This susceptibility to a varied range of pathogens underlines a potential central role played by IRAK2 in mediating host defense in infectious diseases.

Mitochondrial chaperon TNF-receptor- associated protein 1 as a novel apoptotic regulator conferring susceptibility to Pneumocystis jirovecii pneumonia.

Molecular chaperons stabilize protein folding and play a vital role in maintaining tissue homeostasis. To this intent, mitochondrial molecular chaperons may be involved in the regulation of oxidative phosphorylation and apoptosis during stress events such as infections. However, specific human infectious diseases relatable to defects in molecular chaperons have yet to be identified. To this end, we performed whole exome sequencing and functional immune assessment in a previously healthy Asian female, who experienced severe respiratory failure due to Pneumocystis jiroveci pneumonia and non-HIV-related CD4 lymphocytopenia. This revealed that a chaperon, the mitochondrial paralog of HSP90, TRAP1, may have been involved in the patient's susceptibility to an opportunistic infection. Two rare heterozygous variants in TRAP1, E93Q, and A64T were detected. The patient's peripheral blood mononuclear cells displayed diminished TRAP1 expression, but had increased active, cleaved caspase-3, caspase-7, and elevated IL-1ß production. Transfection of A64T and E93Q variants in cell lines yielded decreased TRAP1 compared to transfected wildtype TRAP1 and re-capitulated the immunotypic phenotype of enhanced caspase-3 and caspase-7 activity. When infected with live P. jiroveci, the E93Q or A64T TRAP1 mutant expressing cells also exhibited reduced viability. Patient cells and cell lines transfected with the TRAP1 E93Q/A64T mutants had impaired respiration, glycolysis, and increased ROS production. Of note, co-expression of E93Q/A64T double mutants caused more functional aberration than either mutant singly. Taken together, our study uncovered a previously unrecognized role of TRAP1 in CD4+ lymphocytopenia, conferring susceptibility to opportunistic infections.

Adding Hyponatremia to the "Rule-of-6" Prediction Tool Improves Performance in Identifying Hospitalised Patients with COVID-19 at Risk of Adverse Clinical Outcomes.

The 'rule-of-6' prediction tool was shown to be able to identify COVID-19 patients at risk of adverse outcomes. During the pandemic, we frequently observed hyponatremia at presentation. We sought to evaluate if adding hyponatremia at presentation could improve the 'rule-of-6' prediction tool. We retrospectively analysed 1781 consecutive patients admitted to a single tertiary academic institution in Singapore with COVID-19 infection from February 2020 to October 2021. A total of 161 (9.0%) patients had hyponatremia. These patients were significantly older, with more co-morbidities and more likely to be admitted during the Delta wave (2021). They were more likely to have radiographic evidence of pneumonia (46.0% versus 13.0%, p < 0.001) and more adverse outcomes (25.5% vs. 4.1%, p < 0.001). Hyponatremia remained independently associated with adverse outcomes after adjusting for age, lack of medical co-morbidities, vaccination status, year of admission, CRP, LDH, and ferritin. The optimised cut-off for serum sodium in predicting adverse outcomes was approximately <135 mmol/L as determined by the Youden index. Although derived in early 2020, the 'rule-of-6' prediction tool continued to perform well in our later cohort (AUC: 0.72, 95%CI: 0.66-0.78). Adding hyponatremia to the 'rule-of-6' improved its performance (AUC: 0.76, 95%CI: 0.71-0.82). Patients with hyponatremia at presentation for COVID-19 had poorer outcomes even as new variants emerged.

Screening Outcomes of Mammography with AI in Dense Breasts: A Comparative Study with Supplemental Screening US.

Background Comparative performance between artificial intelligence (AI) and breast US for women with dense breasts undergoing screening mammography remains unclear. Purpose To compare the performance of mammography alone, mammography with AI, and mammography plus supplemental US for screening women with dense breasts, and to investigate the characteristics of the detected cancers. Materials and Methods A retrospective database search identified consecutive asymptomatic women (≥40 years of age) with dense breasts who underwent mammography plus supplemental whole-breast handheld US from January 2017 to December 2018 at a primary health care center. Sequential reading for mammography alone and mammography with the aid of an AI system was conducted by five breast radiologists, and their recall decisions were recorded. Results of the combined mammography and US examinations were collected from the database. A dedicated breast radiologist reviewed marks for mammography alone or with AI to confirm lesion identification. The reference standard was histologic examination and 1-year follow-up data. The cancer detection rate (CDR) per 1000 screening examinations, sensitivity, specificity, and abnormal interpretation rate (AIR) of mammography alone, mammography with AI, and mammography plus US were compared. Results Among 5707 asymptomatic women (mean age, 52.4 years ± 7.9 [SD]), 33 (0.6%) had cancer (median lesion size, 0.7 cm). Mammography with AI had a higher specificity (95.3% [95% CI: 94.7, 95.8], P = .003) and lower AIR (5.0% [95% CI: 4.5, 5.6], P = .004) than mammography alone (94.3% [95% CI: 93.6, 94.8] and 6.0% [95% CI: 5.4, 6.7], respectively). Mammography plus US had a higher CDR (5.6 vs 3.5 per 1000 examinations, P = .002) and sensitivity (97.0% vs 60.6%, P = .002) but lower specificity (77.6% vs 95.3%, P < .001) and higher AIR (22.9% vs 5.0%, P < .001) than mammography with AI. Supplemental US alone helped detect 12 cancers, mostly stage 0 and I (92%, 11 of 12). Conclusion Although AI improved the specificity of mammography interpretation, mammography plus supplemental US helped detect more node-negative early breast cancers that were undetected using mammography with AI. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Whitman and Destounis in this issue.

Performance of Risk Scores in Predicting Infective Endocarditis in Patients with Staphylococcus aureus Bacteraemia in a Prospective Asian Cohort.

Background: Several risk scores have been derived to predict the risk of infective endocarditis (IE) amongst patients with Staphylococcus aureus bacteraemia (SAB), which helps to guide clinical management. Methods: We prospectively studied 634 patients admitted with SAB. The cohort was stratified into those with or without IE, and the PREDICT Day 1, Day 5 and VIRSTA scores were tabulated. Area under the receiver operating characteristic (AUC) curves were constructed to compare the performance of each score. Results: Of the 634 patients examined, 36 (5.7%) had IE. These patients were younger (51.6 ± 20.1 vs. 59.2 ± 18.0 years, p = 0.015), tended to have community acquisition of bacteraemia (41.7% vs. 17.9%, p < 0.001), and had persistent bacteraemia beyond 72 h (19.4% vs. 6.0%, p = 0.002). The VIRSTA score had the best performance in predicting IE (AUC 0.76, 95%CI 0.66-0.86) compared with PREDICT Day 1 and Day 5. A VIRSTA score of <3 had the best negative predictive value (97.5%), compared with PREDICT Day 1 (<4) and Day 5 (<2) (94.3% and 96.6%, respectively). Conclusions: Overall, the risk scores performed well in our Asian cohort. If applied, 23.5% of the cohort with a VIRSTA ≥ 3 would require TEE, and a score of <3 had an excellent negative predictive value.

Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity.

Due to the paucity of longitudinal molecular studies of COVID-19, particularly those covering the early stages of infection (Days 1-8 symptom onset), our understanding of host response over the disease course is limited. We perform longitudinal single cell RNA-seq on 286 blood samples from 108 age- and sex-matched COVID-19 patients, including 73 with early samples. We examine discrete cell subtypes and continuous cell states longitudinally, and we identify upregulation of type I IFN-stimulated genes (ISGs) as the predominant early signature of subsequent worsening of symptoms, which we validate in an independent cohort and corroborate by plasma markers. However, ISG expression is dynamic in progressors, spiking early and then rapidly receding to the level of severity-matched non-progressors. In contrast, cross-sectional analysis shows that ISG expression is deficient and IFN suppressors such as SOCS3 are upregulated in severe and critical COVID-19. We validate the latter in four independent cohorts, and SOCS3 inhibition reduces SARS-CoV-2 replication in vitro. In summary, we identify complexity in type I IFN response to COVID-19, as well as a potential avenue for host-directed therapy.

Artificial Intelligence for Breast Cancer Detection on Mammography: Factors Related to Cancer Detection.

RATIONALE AND OBJECTIVES: Little is known about the factors affecting the Artificial Intelligence (AI) software performance on mammography for breast cancer detection. This study was to identify factors associated with abnormality scores assigned by the AI software. MATERIALS AND METHODS: A retrospective database search was conducted to identify consecutive asymptomatic women who underwent breast cancer surgery between April 2016 and December 2019. A commercially available AI software (Lunit INSIGHT, MMG, Ver. 1.1.4.0) was used for preoperative mammography to assign individual abnormality scores to the lesions and score of 10 or higher was considered as positive detection by AI software. Radiologists without knowledge of the AI results retrospectively assessed the mammographic density and classified mammographic findings into positive and negative finding. General linear model (GLM) analysis was used to identify the clinical, pathological, and mammographic findings related to the abnormality scores, obtaining coefficient ß values that represent the mean difference per unit or comparison with the reference value. Additionally, the reasons for non-detection by the AI software were investigated. RESULTS: Among the 1001 index cancers (830 invasive cancers and 171 ductal carcinoma in situs) in 1001 patients, 717 (72%) were correctly detected by AI, while the remaining 284 (28%) were not detected. Multivariable GLM analysis showed that abnormal mammography findings (ß = 77.0 for mass, ß = 73.1 for calcification only, ß = 49.4 for architectural distortion, and ß = 47.6 for asymmetry compared to negative; all Ps < 0.001), invasive tumor size (ß = 4.3 per 1 cm, P < 0.001), and human epidermal growth receptor type 2 (HER2) positivity (ß = 9.2 compared to hormone receptor positive, HER2 negative, P = 0.004) were associated with higher mean abnormality score. AI failed to detect small asymmetries in extremely dense breasts, subcentimeter-sized or isodense lesions, and faint amorphous calcifications. CONCLUSION: Cancers with positive abnormal mammographic findings on retrospective review, large invasive size, HER2 positivity had high AI abnormality scores. Understanding the patterns of AI software performance is crucial for effectively integrating AI into clinical practice.

Extracorporeal Membrane Oxygenation-Dependent Fulminant Melioidosis From Caspase 4 Mutation Reversed by Interferon Gamma Therapy.

We describe bedside-to-bench immunological and genetic elucidation of defective pyroptosis attributable to novel caspase 4 defect mediating pathogen-triggered inflammatory programmed cell death, in the setting of severe pneumonia and abscess-forming melioidosis in an overtly healthy host failing to clear Burkholderia pseudomallei infection, and how targeted adjunctive biological therapy led to a successful outcome.

COVID-19 Severity and Waning Immunity After up to 4 mRNA Vaccine Doses in 73 608 Patients With Cancer and 621 475 Matched Controls in Singapore: A Nationwide Cohort Study.

Importance: Despite patients with cancer being at risk of poor outcomes from COVID-19, there are few published studies for vaccine efficacy in this group, with suboptimal immunogenicity and waning vaccine efficacy described in small studies being a concern. Objective: To assess the incidence rate of severe COVID-19 disease outcomes associated with the number of vaccine doses received and the waning of protection over time. Design, Setting, and Participants: A prospective multicenter observational cohort study was carried out over 2 time periods (September 15, 2021, to December 20, 2021 [delta wave], and January 20, 2022, to November 11, 2022 [omicron wave]) predominated by SARS-CoV-2 delta and omicron variants, respectively. Overall, 73 608 patients with cancer (23 217 active treatment, 50 391 cancer survivors) and 621 475 controls matched by age, sex, race and ethnicity, and socioeconomic status were included. Exposure: Vaccine doses received, from zero to 4 doses, and time elapsed since last vaccine dose. Outcomes: Competing-risk regression analyses were employed to account for competing risks of death in patients with cancer. Main outcomes were incidence rate ratios (IRRs) of COVID-19 infection, hospitalization, and severe disease (defined as requirement for supplemental oxygen, intensive care, or death). The IRRs stratified by time from last vaccine dose served as indicators of waning of vaccine effectiveness over time. Results: The mean (SD) age of actively treated patients with cancer, cancer survivors, and controls were 62.7 (14.7), 62.9 (12.6), and 61.8 (14.7) years, respectively. Of 73 608 patients with cancer, 27 170 (36.9%) were men; 60 100 (81.6%) were Chinese, 7432 (10.1%) Malay, 4597 (6.2%) Indian, and 1479 (2.0%) were of other races and ethnicities. The IRRs for the 3-dose and 4-dose vs the 2-dose group (reference) for COVID-19 hospitalization and severe disease were significantly lower during both the delta and omicron waves in cancer and control populations. The IRRs for severe disease in the 3-dose group for active treatment, cancer survivors, and controls were 0.14, 0.13, and 0.07 during the delta wave and 0.29, 0.19, and 0.21 during omicron wave, respectively. The IRRs for severe disease in the 4-dose group during the omicron wave were even lower at 0.13, 0.10 and 0.10, respectively. No waning of vaccine effectiveness against hospitalization and severe disease was seen beyond 5 months after a third dose, nor up to 5 months (the end of this study's follow-up) after a fourth dose. Conclusion: This cohort study provides evidence of the clinical effectiveness of mRNA-based vaccines against COVID-19 in patients with cancer. Longevity of immunity in preventing severe COVID-19 outcomes in actively treated patients with cancer, cancer survivors, and matched controls was observed at least 5 months after the third or fourth dose.

Digital Breast Tomosynthesis Plus Ultrasound Versus Digital Mammography Plus Ultrasound for Screening Breast Cancer in Women With Dense Breasts.

OBJECTIVE: To compare the outcomes of digital breast tomosynthesis (DBT) screening combined with ultrasound (US) with those of digital mammography (DM) combined with US in women with dense breasts. MATERIALS AND METHODS: A retrospective database search identified consecutive asymptomatic women with dense breasts who underwent breast cancer screening with DBT or DM and whole-breast US simultaneously between June 2016 and July 2019. Women who underwent DBT + US (DBT cohort) and DM + US (DM cohort) were matched using 1:2 ratio according to mammographic density, age, menopausal status, hormone replacement therapy, and a family history of breast cancer. The cancer detection rate (CDR) per 1000 screening examinations, abnormal interpretation rate (AIR), sensitivity, and specificity were compared. RESULTS: A total of 863 women in the DBT cohort were matched with 1726 women in the DM cohort (median age, 53 years; interquartile range, 40-78 years) and 26 breast cancers (9 in the DBT cohort and 17 in the DM cohort) were identified. The DBT and DM cohorts showed comparable CDR (10.4 [9 of 863; 95% confidence interval {CI}: 4.8-19.7] vs. 9.8 [17 of 1726; 95% CI: 5.7-15.7] per 1000 examinations, respectively; P = 0.889). DBT cohort showed a higher AIR than the DM cohort (31.6% [273 of 863; 95% CI: 28.5%-34.9%] vs. 22.4% [387 of 1726; 95% CI: 20.5%-24.5%]; P < 0.001). The sensitivity for both cohorts was 100%. In women with negative findings on DBT or DM, supplemental US yielded similar CDRs in both DBT and DM cohorts (4.0 vs. 3.3 per 1000 examinations, respectively; P = 0.803) and higher AIR in the DBT cohort (24.8% [188 of 758; 95% CI: 21.8%-28.0%] vs. 16.9% [257 of 1516; 95% CI: 15.1%-18.9%; P < 0.001). CONCLUSION: DBT screening combined with US showed comparable CDR but lower specificity than DM screening combined with US in women with dense breasts.

Engineering of a probiotic yeast for the production and secretion of medium-chain fatty acids antagonistic to an opportunistic pathogen Candida albicans.

Candida albicans is an opportunistic pathogen, with its infection as one of the causes of morbidity or mortality. Notably, the probiotic yeast Saccharomyces cerevisiae var. boulardii has shown the potential to fight against Candida infections. In this study, we aimed to engineer a commercial boulardii strain to produce medium-chain fatty acids (MCFAs) with antagonistic effects against C. albicans. First, we identified and characterized a boulardii strain and created its auxotrophic strain Δura3. Next, we constructed and expressed a heterologous MCFA biosynthetic pathway under the control of inducible and constitutive promoters. Aside from examining MCFA production and secretion, we confirmed MCFAs' effects on C. albicans' anti-biofilm and anti-hyphal formations and the immunomodulatory effect of MCFA-containing supernatants on Caco-2 cells. We found that under constitutive promoters, the engineered boulardii strain constitutively produced and secreted a mixture of C6:0, C8:0, and C10:0. The secreted MCFAs then reduced biofilm and hyphal formations in C. albicans SC5314. We also confirmed that MCFAs upregulated the expression of virulence-related genes in SC5314. Furthermore, we found that the constitutively produced MCFAs in the supernatant induced the upregulation of immune response genes in Caco-2 cells co-cultured with SC5314, indicating MCFAs' roles in immunomodulation. Overall, the engineered boulardii strain produced and secreted MCFAs, as well as demonstrated antagonistic effects against C. albicans SC5314 and immune-modulatory effects in Caco-2. To our knowledge, this represents the first study tackling the metabolic engineering of a commercial probiotic yeast strain to constitutively produce and secrete MCFAs showing anti-Candida effects. Our study forms the basis of the potential development of a live biotherapeutics probiotic yeast against Candida infections through metabolic engineering strategies.

Clinical efficacy and long-term immunogenicity of an early triple dose regimen of SARS-CoV-2 mRNA vaccination in cancer patients.

INTRODUCTION: Three doses of SARS-CoV-2 mRNA vaccines have been recommended for cancer patients to reduce the risk of severe disease. Anti-neoplastic treatment, such as chemotherapy, may affect long-term vaccine immunogenicity. METHOD: Patients with solid or haematological cancer were recruited from 2 hospitals between July 2021 and March 2022. Humoral response was evaluated using GenScript cPASS surrogate virus neutralisation assays. Clinical outcomes were obtained from medical records and national mandatory-reporting databases. RESULTS: A total of 273 patients were recruited, with 40 having haematological malignancies and the rest solid tumours. Among the participants, 204 (74.7%) were receiving active cancer therapy, including 98 (35.9%) undergoing systemic chemotherapy and the rest targeted therapy or immunotherapy. All patients were seronegative at baseline. Seroconversion rates after receiving 1, 2 and 3 doses of SARS-CoV-2 mRNA vaccination were 35.2%, 79.4% and 92.4%, respectively. After 3 doses, patients on active treatment for haematological malignancies had lower antibodies (57.3%±46.2) when compared to patients on immunotherapy (94.1%±9.56, P<0.05) and chemotherapy (92.8%±18.1, P<0.05). SARS-CoV-2 infection was reported in 77 (28.2%) patients, of which 18 were severe. No patient receiving a third dose within 90 days of the second dose experienced severe infection. CONCLUSION: This study demonstrates the benefit of early administration of the third dose among cancer patients.

The current state of laboratory mycology in Asia/Pacific: A survey from the European Confederation of Medical Mycology (ECMM) and International Society for Human and Animal Mycology (ISHAM).

INTRODUCTION: Invasive fungal infections (IFIs) in Asia/Pacific are a particular threat to patients with malignancies, uncontrolled diabetes mellitus or undiagnosed/untreated human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS). Adequate and early access to diagnostic tools and antifungals is essential for IFI clinical management and patient survival. METHODS: Details on institution profile, self-perception on IFI, and access to microscopy, culture, serology, antigen detection, molecular testing, and therapeutic drug monitoring for IFI were collected in a survey. RESULTS: As of June 2022, 235 centres from 40 countries/territories in Asia/Pacific answered the questionnaire. More than half the centres were from six countries: India (25%), China (17%), Thailand (5%), Indonesia, Iran, and Japan (4% each). Candida spp. (93%) and Aspergillus spp. (75%) were considered the most relevant pathogens. Most institutions had access to microscopy (98%) or culture-based approaches (97%). Furthermore, 79% of centres had access to antigen detection, 66% to molecular assays, and 63% to antibody tests. Access to antifungals varied between countries/territories. At least one triazole was available in 93% of the reporting sites (voriconazole [89%] was the most common mould-active azole), whereas 80% had at least one amphotericin B formulation, and 72% had at least one echinocandin. CONCLUSION: According to the replies provided, the resources available for IFI diagnosis and management vary among Asia/Pacific countries/territories. Economical or geographical factors may play a key role in the incidence and clinical handling of this disease burden. Regional cooperation may be a good strategy to overcome shortcomings.

Advanced glycation end products modulate electrophysiological remodeling of right ventricular outflow tract cardiomyocytes: A novel target for diabetes-related ventricular arrhythmogenesis.

Diabetes mellitus is associated with cardiovascular disease and cardiac arrhythmia. Accumulation of advanced glycation end products closely correlates with cardiovascular complications through mitochondrial dysfunction or oxidative stress and evoke proliferative, inflammatory, and fibrotic reactions, which might impair cardiac electrophysiological characteristics and increase the incidence of cardiac arrhythmia. This study examined the mechanisms how advanced glycation end products may contribute to arrhythmogenesis of right ventricular outflow tract-a unique arrhythmogenic substrate. A whole-cell patch clamp, conventional electrophysiological study, fluorescence imaging, Western blot, and confocal microscope were used to study the electrical activity, and Ca2+ homeostasis or signaling in isolated right ventricular outflow tract myocytes with and without advanced glycation end products (100 µg/ml). The advanced glycation end products treated right ventricular outflow tract myocytes had a similar action potential duration as the controls, but exhibited a lower L-type Ca2+ current, higher late sodium current and transient outward current. Moreover, the advanced glycation end products treated right ventricular outflow tract myocytes had more intracellular Na+ , reverse mode Na+ -Ca2+ exchanger currents, intracellular and mitochondrial reactive oxygen species, and less intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content with upregulated calcium homeostasis proteins and advanced glycation end products related signaling pathway proteins. In conclusions, advanced glycation end products modulate right ventricular outflow tract electrophysiological characteristics with larger late sodium current, intracellular Na+ , reverse mode Na+ -Ca2+ exchanger currents, and disturbed Ca2+ homeostasis through increased oxidative stress mediated by the activation of the advanced glycation end products signaling pathway.

Whole Genome Sequencing Shows Genetic Diversity, as Well as Clonal Complex and Gene Polymorphisms Associated with Fluconazole Non-Susceptible Isolates of Candida tropicalis.

Resistance to azoles in Candida tropicalis is increasing and may be mediated by genetic characteristics. Using whole genome sequencing (WGS), we examined the genetic diversity of 82 bloodstream C. tropicalis isolates from two countries and one ATCC strain in a global context. Multilocus sequence typing (MLST) and single nucleotide polymorphism (SNP)-based phylogenies were generated. Minimum inhibitory concentrations (MIC) for antifungal agents were determined using Sensititre YeastOne YO10. Eleven (13.2%) isolates were fluconazole-resistant and 17 (20.5%) were classified as fluconazole-non susceptible (FNS). Together with four Canadian isolates, the genomes of 12 fluconazole-resistant (18 FNS) and 69 fluconazole-susceptible strains were examined for gene mutations associated with drug resistance. Fluconazole-resistant isolates contained a mean of 56 non-synonymous SNPs per isolate in contrast to 36 SNPs in fluconazole-susceptible isolates (interquartile range [IQR] 46−59 vs. 31−48 respectively; p < 0.001). Ten of 18 FNS isolates contained missense ERG11 mutations (amino acid substitutions S154F, Y132F, Y257H). Two echinocandin-non susceptible isolates had homozygous FKS1 mutations (S30P). MLST identified high genetic diversity with 61 diploid sequence types (DSTs), including 53 new DSTs. All four isolates in DST 773 were fluconazole-resistant within clonal complex 2. WGS showed high genetic variation in invasive C. tropicalis; azole resistance was distributed across different lineages but with DST 773 associated with in vitro fluconazole resistance.

Dominant Negative TRAF3 Variant With Recurrent Mycobacterium abscessus Infection and Bronchiectasis.

Host factors leading to pulmonary nontuberculous mycobacteria (PNTM) disease are poorly understood compared with disseminated NTM disease, which is linked to the interleukin 12-interferon gamma signaling pathway. We investigated the tumor necrosis factor receptor associated factor 3 (TRAF3) R338W variant in a patient with recurrent PNTM infection, demonstrating TRAF3- and TNF-α-deficient phenotypes via ex vivo immune and cloning-transfection cellular studies.

IDentif.AI-Omicron: Harnessing an AI-Derived and Disease-Agnostic Platform to Pinpoint Combinatorial Therapies for Clinically Actionable Anti-SARS-CoV-2 Intervention.

Nanomedicine-based and unmodified drug interventions to address COVID-19 have evolved over the course of the pandemic as more information is gleaned and virus variants continue to emerge. For example, some early therapies (e.g., antibodies) have experienced markedly decreased efficacy. Due to a growing concern of future drug resistant variants, current drug development strategies are seeking to find effective drug combinations. In this study, we used IDentif.AI, an artificial intelligence-derived platform, to investigate the drug-drug and drug-dose interaction space of six promising experimental or currently deployed therapies at various concentrations: EIDD-1931, YH-53, nirmatrelvir, AT-511, favipiravir, and auranofin. The drugs were tested in vitro against a live B.1.1.529 (Omicron) virus first in monotherapy and then in 50 strategic combinations designed to interrogate the interaction space of 729 possible combinations. Key findings and interactions were then further explored and validated in an additional experimental round using an expanded concentration range. Overall, we found that few of the tested drugs showed moderate efficacy as monotherapies in the actionable concentration range, but combinatorial drug testing revealed significant dose-dependent drug-drug interactions, specifically between EIDD-1931 and YH-53, as well as nirmatrelvir and YH-53. Checkerboard validation analysis confirmed these synergistic interactions and also identified an interaction between EIDD-1931 and favipiravir in an expanded range. Based on the platform nature of IDentif.AI, these findings may support further explorations of the dose-dependent drug interactions between different drug classes in further pre-clinical and clinical trials as possible combinatorial therapies consisting of unmodified and nanomedicine-enabled drugs, to combat current and future COVID-19 strains and other emerging pathogens.

Booster doses of COVID-19 vaccines for patients with haematological and solid cancer: a systematic review and individual patient data meta-analysis.

IMPORTANCE: Patients with cancer have an increased risk of severe disease and mortality from COVID-19, as the disease and antineoplastic therapy cause reduced vaccine immunogenicity. Booster doses have been proposed to enhance protection, and efficacy data are emerging from several studies. OBJECTIVE: To evaluate the proportion of COVID-19 primary vaccination non-responders with cancer who seroconvert after a booster dose. METHODS: PubMed, EMBASE, CENTRAL and medRxiv were searched from 1st January 2021 to 10th March 2022. Quality was assessed using the Joanna Briggs Institute Critical Appraisal checklist. RESULTS: After the eligibility assessment, 22 studies were included in this systematic review and 17 for meta-analysis of seroconversion in non-responders, pooling a total of 849 patients with haematological cancer and 82 patients with solid cancer. Haematological cancer non-responders exhibited lower seroconversion at 44% (95% CI 36-53%) than solid cancer at 80% (95% CI 69-87%). Individual patient data meta-analysis found the odds of having a meaningful rise in antibody titres to be significantly associated with increased duration between the second and third dose (OR 1.02, 95% CI 1.00-1.03, P ≤ 0.05), age of patient (OR 0.960, 95% CI 0.934-0.987, P ≤ 0.05) and cancer type. With patients with haematological cancer as a reference, patients with lung cancer had 16.8 times the odds of achieving a meaningful increase in antibody titres (OR 16.8, 95% CI 2.95-318, P ≤ 0.05) and gastrointestinal cancer patients had 25.4 times the odds of achieving a meaningful increase in antibody titres (OR 25.4, 95% CI 5.26-492.21, P ≤ 0.05). CONCLUSIONS: administration of a COVID-19 vaccine booster dose is effective in improving seroconversion and antibody levels. Patients with haematological cancer consistently demonstrate poorer response to booster vaccines than patients with solid cancer.