American Journal of Respiratory and Critical Care Medicine, Volume 210, Issue 7, Page 919-930, October 1, 2024.

Abstract Background The relationship between the dynamic changes in insulin resistance (IR) and the prognosis of septic patients remains unclear. This study aims to investigate the correlation between the clinical subphenotype of IR represented by the triglyceride-glucose (TyG) index trajectory and the mortality rate among patients with sepsis. Methods In this retrospective cohort study, we utilized data from septic patients within the Medical Information Mart for Intensive Care (MIMIC)-IV database version 2.0 to construct trajectories of the TyG index over 72 h. Subsequently, we computed the similarity among various TyG index trajectories with the dynamic time warping (DTW) algorithm and utilized the hierarchical clustering (HC) algorithm to demarcate distinct cluster and identified subphenotypes according to the trajectory trend. Subsequently, we assessed the mortality risk between different subphenotypes using analyses such as survival analysis and validated the robustness of the results through propensity score matching (PSM) and various models. Results A total of 2350 patients were included in the study. Two trajectory trends: TyG index decreasing (n = 926) and TyG index increasing (n = 1424) were identified, which indicated corresponding to the clinical subphenotype of increased and alleviative IR respectively. The 28-day and in-hospital mortality for the increased IR group was 28.51% and 25.49% respectively. In comparison, patients in the alleviative IR group with a 28-day mortality of 23.54% and an in-hospital mortality of 21.60%. These subphenotypes exhibited distinct prognosis, time dependent Cox model showed the increased IR group with a higher 28-day mortality [hazard ratio (HR): 1.07, 95% confidence interval (CI): 1.02–1.12, P = 0.01] and in-hospital mortality [HR: 1.05, 95% CI: 1.00–1.11, P = 0.045] compared to the alleviative IR group. Sensitivity analyses with various models further validated the robustness of our findings. Conclusion Dynamic increase in the TyG index trajectory is associated with elevated mortality risk among patients with sepsis, which suggests that dynamic increased IR exacerbates the risk of poor outcomes in patients. …

Abstract Mathematical models play a crucial role in assisting public health authorities in timely disease control decision-making. For vector-borne diseases, integrating host and vector dynamics into models can be highly complex, particularly due to limited data availability, making system validation challenging. In this study, two compartmental models akin to the SIR type were developed to characterize vector-borne infectious disease dynamics. Motivated by dengue fever epidemiology, the models varied in their treatment of vector dynamics, one with implicit vector dynamics and the other explicitly modeling mosquito-host contact. Both considered temporary immunity after primary infection and disease enhancement in secondary infection, analogous to the temporary cross-immunity and the Antibody-dependent enhancement biological processes observed in dengue epidemiology. Qualitative analysis using bifurcation theory and numerical experiments revealed that the immunity period and disease enhancement outweighed the impact of explicit vector dynamics. Both models demonstrated similar bifurcation structures, indicating that explicit vector dynamics are only justified when assessing the effects of vector control methods. Otherwise, the extra equations are irrelevant, as both systems display similar dynamics scenarios. The study underscores the importance of using simple models for mathematical analysis, initiating crucial discussions among the modeling community in vector-borne diseases. …

Abstract Background The severity of infectious disease outcomes is dependent on the virulence factors of the pathogen and the host immune response. CARD8 is a major regulator of the innate immune proinflammatory response and has been suggested to modulate the host response to common inflammatory diseases. In the present study, the C10X genetic polymorphism in the CARD8 gene was investigated in relation to bacterial meningitis. Methods A total of 400 clinically suspected meningitis patients hospitalized at the University of Gondar Hospital were enrolled in the study. Cerebrospinal fluid (CSF) and blood samples were collected for laboratory investigations. The collected CSF was cultured, and all the results obtained from the culture were confirmed using direct RT‒PCR. Genotyping of whole-blood samples was performed using a TaqMan assay. The results were compared with apparently healthy controls and with PCR-negative meningitis suspected patients. Results Of the included patients, 57% were men and the most common clinical signs and symptoms were fever (81%), headache (80%), neck stiffness (76%), nausea (68%), and vomiting (67%). Microbiology culture identified 7 patients with bacterial meningitis caused by Neisseria meningitidis (n = 4) and Streptococcus pneumoniae (n = 3). The RT-PCR revealed 39 positive samples for N. meningitidis (n = 10) and S. pneumoniae (n = 29). A total of 332 whole-blood samples were genotyped with the following results: 151 (45.5%) C10X heterozygotes, 59 (17.7%) C10X homozygotes and 122 (36.7%) wild genotypes. The polymorphic gene carriers among laboratory confirmed, clinically diagnosed meningitis and healthy controls were 23(46%), 246(40%), and 1526(39%), respectively with OR = 1.27 (0.7–2.3) and OR = 1.34 (0.76–2.4). The presence of the C10X polymorphism in the CARD8 gene was more prevalent in suspected meningitis patients than in healthy controls (OR 1.2; 1.00-1.5). Homozygote C10X polymorphic gene carriers were more susceptible to infectious disease. The presence of viable or active bacterial infection was found to be associated with the presence of heterozygous C10X carriers. Conclusions A greater proportion of C10X in the CARD8 gene in confirmed bacterial meningitis patients and clinically diagnosed meningitis patients than in healthy controls. Homozygote C10X polymorphic gene carriers were more susceptible to infectious disease than heterozygote gene carriers and healthy controls. …

Abstract Background Drug-resistant tuberculosis (DR-TB) remains a threat to public health. Shorter regimens have been proposed as potentially valuable treatments for multidrug or rifampicin resistant tuberculosis (MDR/RR-TB). We undertook a systematic review and network meta-analysis to evaluate the efficacy and safety of shorter MDR/RR-TB regimens. Methods We searched PubMed/MEDLINE, Cochrane Center for Clinical Trials (CENTRAL), Scopus, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, US Food and Drug Administration, and Chinese Clinical Trial Registry for primary articles published from 2013 to July 2023. Favorable (cured and treatment completed) and unfavorable (treatment failure, death, loss to follow-up, and culture conversion) outcomes were assessed as the main efficacy outcomes, while adverse events were assessed as the safety outcomes. The network meta-analysis was performed using R Studio version 4.3.1 and the Netmeta package. The study protocol adhered to the PRISMA-NMA guidelines and was registered in PROSPERO (CRD42023434050). Result We included 11 eligible studies (4 randomized control trials and 7 cohorts) that enrolled 3,548 patients with MDR/RR-TB. Treatment with a 6-month combination of BdqLzdLfxZTrd/Eto/H had two times more favorable outcomes [RR 2.2 (95% CI 1.22, 4.13), P = 0.0094], followed by a 9–11 month combination of km/CmMfx/LfxPtoCfzZEHh [RR1.67 (95% CI 1.45, 1.92), P 

Abstract Background The prevalence of Helicobacter pylori (H. pylori) infection and its potential relationship to various diseases is currently a focus of attention. The aim of this study is to investigate the association between current and past H. pylori infections and elevated levels of microalbuminuria in type 2 diabetic patients. Methods Two hundred patients with type 2 diabetes mellitus were tested for the presence of H. pylori infection. They were divided into three groups: 52 had a current H. pylori infection, 38 had a past H. pylori infection, and 110 had no H. pylori infection. All study participants underwent assessments of plasma glucose levels, glycated hemoglobin (HbA1c), albuminuria levels, inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), as well as other relevant investigations. Results The prevalence of H. pylori infection (current and past) was detected in 90 out of 200 diabetic patients (45%). There was no statistically significant difference between the three groups in terms of age, diabetes duration, family history of DM, family history of hypertension, residence, or dyspeptic symptoms, indicating that current or past infection with H. pylori has no association with these variables. The current H. pylori infection group showed the highest levels of inflammatory markers, ESR and CRP, which were significantly different from those in the non-infected group (p = 0.013 and p 

Summary Background Treatment failure (TF) in leprosy following multidrug therapy (MDT) presents a significant challenge. The current World Health Organization (WHO) fixed-duration MDT regimen, based on lesion count, might not be adequate. Leprosy lacks clear-cut objective cure criteria, and the predictive value of post-MDT histopathological findings remains uncertain. This study aims to identify predictive factors for TF among leprosy patients who have completed the WHO-recommended MDT. Methods An analysis was conducted on 80 individuals from a national leprosy reference center, comprising 40 TF cases (with a mean relapse at 13.0 months) and 40 controls (with a mean of 113.1 months without disease signs). Various epidemiological and clinical-laboratory parameters were assessed post-MDT. Results In skin samples, the presence of foamy granuloma (OR = 7.36; 95%CI2.20-24.60; p = 0.0012) and histological bacillary index (hBI) ≥ 1+ (OR = 1.55; 95%CI1. 22-1.99; p = 0.0004) were significantly associated with TF, with odds ratios of 7.36 and 1.55, respectively. Individuals who experienced TF had a mean hBI of 3.02+ (SD ± 2.02), while the control group exhibited a mean hBI of 1.8+ (SD ± 1.88). An hBI ≥ 3 + showed a sensitivity of 73% and a specificity of 78% for TF detection (AUC: 0.75; p = 0.0001). Other histopathological features like epithelioid granulomas, and skin changes did not show significant associations (p > 0.05). Additionally, higher anti-phenolic glycolipid-I (anti-PGL-I) ELISA index (EI) levels were linked to a 1.4-fold increased likelihood for TF (OR = 1.4; 95%CI1.13-1.74; p = 0.0019). A mean EI of 4.48 (SD ± 2.80) was observed, with an EI ≥ 3.95 showing a sensitivity of 79% and a specificity of 59% for TF detection (AUC: 0.74; p = 0.0001). Moreover, the presence of Mycobacterium leprae (M. leprae) DNA in real-time polymerase chain reaction (qPCR) was associated with a 3.43-fold higher likelihood of TF. Multivariate regression analysis indicated that concurrent presentation of neural/perineural lymphocytic infiltrate, foamy granuloma, hBI ≥ 1+, and EI ≥ 1 markedly increased the likelihood of TF by up to 95.41%. Conclusion Persistence of nerve-selective lymphocytic infiltrate, foamy granulomas, and bacilli in skin biopsies, and elevated EI post-MDT, may serve as predictive factors for identifying individuals at higher probability of TF. …

Abstract Background The contribution of interspecies interactions between coinfecting pathogens to chronic refractory infection by affecting pathogenicity is well established. However, little is known about the impact of intraspecific interactions on infection relapse, despite the cross-talk of different strains within one species is more common in clinical infection. We reported a case of chronic refractory pulmonary infection relapse, caused by two methicillin-sensitive S. aureus (MSSA) strains (SA01 and SA02) and revealed a novel strategy for relapse via intraspecific cooperation. Methods The hemolytic ability, growth curve, biofilm formation, virulence genes and response of G. mellonella larvae to S. aureus infection were analysed to confirm this hypothesis. Results SA02 hemolytic activity was inhibited by SA01, along with the expression of hemolysin genes and the virulence factor Hla. Additionally, SA01 significantly enhanced the biofilm formation of SA02. AIP-RNAIII may be a possible pathway for this interaction. Compared with mono-infection, a worse outcome (decreased larval survival and increased microbial burden) of the two MSSA strains coinfected with G. mellonella confirmed that intraspecific interactions indeed enhanced bacterial survival in vivo. Conclusion The intraspecific interaction of S. aureus could lead to chronic refractory infection via pathogenicity changes. …

Abstract Background Long term respiratory complications of Corona Virus Disease-2019 (COVID-19) are of great concern. Many studies have reported altered respiratory patterns in COVID-19 recovered individuals and most of them were from severe to critically ill patients. The association of viral load at the time of infection with symptoms of long COVID-19 specifically on pulmonary functions after months of recovery is still not known. This study was aimed to assess the impact of SARS-CoV-2 viral load during mild-moderate COVID-19 disease on pulmonary functions in middle-aged population after 6–8 months of acute infection. Methods This study included 300 (102 healthy controls and 198 COVID-19 recovered) individuals between age 30–60 of either gender. Mild-moderate COVID-19 recovered individuals were recruited between a period of 6–8 months post-acute infection. Spirometry was performed with MIR-Spirolab-III. The association of spirometry pattern was compared with SARS-CoV-2 viral loads during acute infection. Results We observed up to 70% of the participants presented with either shortness of breath (11.5%), body aches (23.5%), recurrent cough (4.4%), recurrent respiratory infections (9.5%) and/or fatigue (33.3%) at follow up. In our study, 35.5% of COVID-19 recovered individuals had abnormal respiratory patterns (33.5% had restrictive and 2% had obstructive patterns). Viral load ≤ 20 CT value was associated with restrictive respiratory patterns (p = 0.004). No association was found between viral load and disease severity (p = 0.23). Conclusion In this study, we found one third of mild-moderate COVID-19 recovered individuals have restrictive respiratory patterns after 6–8 months of recovery. These findings had a strong association with SARS-CoV-2 viral loads during acute infection which has been reported for the first time in our study. Studying the relationship between viral load and pulmonary functions can contribute to identifying potential risk factors for long COVID and developing preventive measures to mitigate the long-term impact on lung health. Clinical trial number Not applicable. …

Abstract Background Heart rate is crucial for patients with septic shock, but there are few studies on the scope of heart rate. Therefore, we studied the relationship between different heart rates and mortality of critically ill patients with septic shock, and explored the optimal heart rate range, in order to provide new insights for clinical treatment of septic shock. Methods This retrospective study utilized time-series heart rate data from the Medical Information Mart for Intensive Care (MIMIC) IV database. Patients with septic shock were identified as the Sepsis 3.0 criteria and received vasopressor therapy in the first 24 h since ICU admission. We calculated the time-weighted average heart rate (TWA-HR) based on the time-series data. The restricted cubic spline (RCS) analysis was employed to investigate the nonlinear relationship between heart rate and 28-day mortality, aiming to explore the optimal heart rate control target for septic patients and using this target as the exposure factor. The primary outcome was 28-day mortality, and the secondary outcome were ICU and in-hospital mortality. For the original cohort, we applied the log-rank test to infer the relationship between heart rate and mortality. To control for bias introduced by confounders, we utilized propensity score matching (PSM) to reduce imbalances between normal TWA-HR and high TWA-HR groups, and we established a series of models [the multivariable Cox model, matching weight (MW)-adjusted Cox model, multivariable logistic regression, MW-adjusted logistic regression, and doubly robust model] as sensitivity analyses and subgroup analyses to demonstrate the robustness of our findings. Results A total of 13492 patients were included in our study. The RCS analysis based on Cox and logistic regression showed increased risk of mortality (P 

IMPORTANCE: Timely intervention for clinically deteriorating ward patients requires that care teams accurately diagnose and treat their underlying medical conditions. However, the most common diagnoses leading to deterioration and the relevant therapies provided are poorly characterized. OBJECTIVES: We aimed to determine the diagnoses responsible for clinical deterioration, the relevant diagnostic tests ordered, and the treatments administered among high-risk ward patients using manual chart review. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter retrospective observational study in inpatient medical-surgical wards at four health systems from 2006 to 2020. Randomly selected patients (1000 from each health system) with clinical deterioration, defined by reaching the 95th percentile of a validated early warning score, electronic Cardiac Arrest Risk Triage, were included. MAIN OUTCOMES AND MEASURES: Clinical deterioration was confirmed by a trained reviewer or marked as a false alarm if no deterioration occurred for each patient. For true deterioration events, the condition causing deterioration, relevant diagnostic tests ordered, and treatments provided were collected. RESULTS: Of the 4000 included patients, 2484 (62%) had clinical deterioration confirmed by chart review. Sepsis was the most common cause of deterioration (41%; n = 1021), followed by arrhythmia (19%; n = 473), while liver failure had the highest in-hospital mortality (41%). The most common diagnostic tests ordered were complete blood counts (47% of events), followed by chest radiographs (42%) and cultures (40%), while the most common medication orders were antimicrobials (46%), followed by fluid boluses (34%) and antiarrhythmics (19%). CONCLUSIONS AND RELEVANCE: We found that sepsis was the most common cause of deterioration, while liver failure had the highest mortality. Complete blood counts and chest radiographs were the most common diagnostic tests ordered, and antimicrobials and fluid boluses were the most common medication interventions. These results provide important insights for clinical decision-making at the bedside, training of rapid response teams, and the development of institutional treatment pathways for clinical deterioration.

Proceedings of the National Academy of Sciences, Volume 121, Issue 40, October 2024.

Proceedings of the National Academy of Sciences, Volume 121, Issue 40, October 2024.

Proceedings of the National Academy of Sciences, Volume 121, Issue 40, October 2024.

Proceedings of the National Academy of Sciences, Volume 121, Issue 40, October 2024.

Proceedings of the National Academy of Sciences, Volume 121, Issue 40, October 2024.

Proceedings of the National Academy of Sciences, Volume 121, Issue 41, October 2024.

Proceedings of the National Academy of Sciences, Volume 121, Issue 41, October 2024.

Concerns regarding “a cluster of pneumonia cases of unknown origin” in Wuhan, China, were globally disseminated in December, 2019. By Jan 25, 2020, Public Health England (now the UK Health Security Agency) had warned the UK Government that person-to-person transmission of the new pathogen (the ‘Wuhan coronavirus’, later named SARS-CoV-2) had been identified outside of China and that the first case had been confirmed in Europe. In the few months that followed, SARS-CoV-2 and the resulting disease, COVID-19, spread across the globe, causing an estimated 22 million excess deaths by the end of the pandemic; a global mortality level not experienced with a respiratory pathogen since the H1N1 influenza pandemic in 1918–20.

Growing up in Amsterdam, The Netherlands, Louis Bont\'s father who worked at the Netherlands Cancer Institute (NKI), often said “doctors will never make good scientists”. This way, his father provided him with a challenge to become a clinician scientist, Bont realised only decades later. Today he is Department Head of Pediatrics at the Wilhelmina Children\'s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands, where his main area of research is respiratory syncytial virus (RSV). He has also been appointed an adjunct professor at Yale University (New Haven, CT, USA).

The data from PROMIS-I suggest a clinically important benefit of colistimethate sodium delivered via the I-neb adaptive aerosol delivery system in patients with bronchiectasis and P aeruginosa infection. These results were not replicated in PROMIS-II, which was affected by the COVID-19 pandemic and prematurely terminated.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI), hospital admission, and mortality in children worldwide. Early-life RSV LRTI has also been associated with subsequent long-term respiratory sequelae, including recurrent LRTI, recurrent wheezing, asthma, and lung function impairment, and these effects can persist into adulthood as chronic respiratory disease. New preventive measures (maternal vaccine or long-acting monoclonal antibodies) have been licensed to reduce the burden of acute RSV LRTI in infants and children at high risk through passive immunisation.

Respiratory syncytial virus (RSV), an RNA virus spread by droplet infection that affects all ages, is increasingly recognised as an important pathogen in adults, especially among older people living with comorbidities. Distinguishing RSV from other acute viral infections on clinical grounds alone, with sufficient precision to be clinically useful, is not possible. The reference standard diagnosis is by PCR: point-of-care tests perform less well with lower viral loads. Testing samples from a single respiratory tract site could result in underdetection.

Invasive fungal infections in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients on antimicrobial prophylaxis is a major cause of infectious mortality, although its underlying pathophysiological mechanisms remain unclear. In a new report, Zhai and colleagues provide evidence that heteroresistance drives breakthrough Candida parapsilosis bloodstream infections in allo-HSCT recipients receiving micafungin prophylaxis.

Decomposer microbial communities are gatekeepers in the redistribution of carbon and nutrients from dead animals (carrion) to terrestrial ecosystems. The flush of decomposition products from a carcass creates a hot spot of microbial activity in the soil below, and the animal’s microbiome is released into the environment, mixing with soil communities. Changes in soil physicochemistry, especially reduced oxygen, temporarily constrain microbial nutrient cycling, and influence the timing of these processes and the fate of carrion resources. Carcass-related factors, such as mass, tissue composition, or even microbiome composition may also influence the functional assembly and succession of decomposer communities. Understanding these local scale microbially mediated processes is important for predicting consequences of carrion decomposition beyond the hot spot and hot moment.

The genetics of Plasmodium as an intracellular, mostly haploid, sexually reproducing, eukaryotic organism with a complex life cycle, presents unprecedented challenges in studying drug resistance. This article summarizes current knowledge on the genetic basis of artemisinin resistance (AR) – a main component of current drug therapies for falciparum malaria. Although centered on nonsynonymous single-nucleotide polymorphisms (nsSNPs), we describe multifaceted resistance mechanisms as part of a complex, cumulative genetic trait that involves regulation of expression by a wide array of polymorphisms in noncoding regions. These genetic variations alter transcriptome profiles linked to Plasmodium\'s development and population dynamics, ultimately influencing the emergence and spread of the resistance.

Volume 13, Issue 1, December 2024 .

Volume 13, Issue 1, December 2024 .

Volume 13, Issue 1, December 2024 .

Volume 13, Issue 1, December 2024 .

by The PLOS ONE Editors …

by Roxana Hossain, Glenda Willems, Niels Wynant, Simon Borgolte, Kristof Govaerts, Mark Varrelmann Beet yellows virus (BYV), one of the causal agents of virus yellows (VY) disease in sugar beet (Beta vulgaris subsp. vulgaris), induces economically important damage to the sugar production in Europe. In the absence of effective natural resistance traits, a deeper understanding of molecular reactions in plants to virus infection is required. In this study, the transcriptional modifications in a BYV susceptible sugar beet genotype following aphid-mediated inoculation on mature leaves were studied at three early infection stages [6, 24 and 72 hours post inoculation (hpi)] using RNA sequencing libraries. On average, 93% of the transcripts could be mapped to the B. vulgaris reference genome RefBeet-1.2.2. In total, 588 differentially expressed genes (DEGs) were identified across the three infection stages. Of these, 370 were up- regulated and 218 down-regulated when individually compared to mock-aphid inoculated leaf samples at the same time point, thereby eliminating the effect of aphid feeding itself. Using MapMan ontology for categorisation of sugar beet transcripts, early differential gene expression identified importance of the BIN categories “enzyme classification”, “RNA biosynthesis”, “cell wall organisation” and “phytohormone action”. A particularly high transcriptional change was found for diverse transcription factors, cell wall regulating proteins, signalling peptides and transporter proteins. 28 DEGs being important in “nutrient uptake”, “lipid metabolism”, “phytohormone action”, “protein homeostasis” and “solute transport”, were represented at more than one infection stage. The RT-qPCR validation of thirteen selected transcripts confirmed that BYV is down-regulating chloroplast-related genes 72 hpi, putatively already paving the way for the induction of yellowing symptoms characteristic for the disease. Our study provides deeper insight into the early interaction between BYV and the economically important crop plant sugar beet and opens up the possibility of using the knowledge of identified proviral plant factors as well as plant defense-related factors for resistance breeding.

by Jooyeon Park, Kyoung Hwa Lee, Young Goo Song, Hyungmin Park, Kwang Suk Lee Since the COVID-19 pandemic, there has been persistent emphasis on the importance of indoor air disinfection and ventilation in isolation units in the hospital environment. Nevertheless, no optimal and concrete disinfection protocol has been proposed to inactivate the viruses as quickly as possible. In this study, we experimentally evaluated various ventilation and disinfection protocols based on the combination of negative-pressure ventilation, ultraviolet (UV) light illumination, and Hypochlorous acid (HOCl) spray against three active virus species in a 3.5 cubic meters isolation unit. This small-size unit has gained attention during the pandemic due to the high demand for compact mobile laboratory systems capable of rapid disease diagnosis. In accordance with the WHO laboratory biosafety guidance, which states that all enclosed units where diagnostic work is conducted must ensure proper ventilation and disinfection activities, we aim to propose virus removal protocols for units compact enough to be installed within a van or deployed outdoor. The results confirmed the superiority (in terms of virus removal rate and time required) of the virus removal methods in the order of UV light, ventilation, and HOCl spray. Ultimately, we propose two optimal protocols: (i) UV light alone for three minutes, and (ii) UV light with ventilation for three minutes, followed by one-minute ventilation only. The time span of three minutes in the latter protocol is based on the clinical practice such that the medical staffs have a sufficient time to process the samples taken in transition to next patient to care.

by Marie Y. Detrait, Stéphanie Warnon, Raphaël Lagasse, Laurent Dumont, Stéphanie De Prophétis, Amandine Hansenne, Juliette Raedemaeker, Valérie Robin, Géraldine Verstraete, Aline Gillain, Nicolas Depasse, Pierre Jacmin, Delphine Pranger Introduction Primary refractory disease affects 30–40% of patients diagnosed with DLBCL and is a significant challenge in disease management due to its poor prognosis. Predicting refractory status could greatly inform treatment strategies, enabling early intervention. Various options are now available based on patient and disease characteristics. Supervised machine-learning techniques, which can predict outcomes in a medical context, appear highly suitable for this purpose. Design Retrospective monocentric cohort study. Patient population Adult patients with a first diagnosis of DLBCL admitted to the hematology unit from 2017 to 2022. Aim We evaluated in our Center five supervised machine-learning (ML) models as a tool for the prediction of primary refractory DLBCL. Main results One hundred and thirty patients with Diffuse Large B-cell lymphoma (DLBCL) were included in this study between January 2017 and December 2022. The variables used for analysis included demographic characteristics, clinical condition, disease characteristics, first-line therapy and PET-CT scan realization after 2 cycles of treatment. We compared five supervised ML models: support vector machine (SVM), Random Forest Classifier (RFC), Logistic Regression (LR), Naïve Bayes (NB) Categorical classifier and eXtreme Gradient Boost (XGboost), to predict primary refractory disease. The performance of these models was evaluated using the area under the receiver operating characteristic curve (ROC-AUC), accuracy, false positive rate, sensitivity, and F1-score to identify the best model. After a median follow-up of 19.5 months, the overall survival rate was 60% in the cohort. The Overall Survival at 3 years was 58.5% (95%CI, 51–68.5) and the 3-years Progression Free Survival was 63% (95%CI, 54–71) using Kaplan-Meier method. Of the 124 patients who received a first line treatment, primary refractory disease occurred in 42 patients (33.8%) and 2 patients (1.6%) experienced relapse within 6 months. The univariate analysis on refractory disease status shows age (p = 0.009), Ann Arbor stage (p = 0.013), CMV infection (p = 0.012), comorbidity (p = 0.019), IPI score (p…

by Viet Q. Dao, Crystal N. Johnson, William J. Platt Processes modifying newly deposited litter substrates should affect fine fuels in fire-managed tidal marsh ecosystems. Differences in chemical composition and dynamics of litter should arise from fire histories that generate pyrodiverse plant communities, tropical cyclones that deposit wrack as litter, tidal inundation that introduces and alters sediments and microbes, and interactions among these different processes. The resulting diversity and dynamics of available litter compounds should affect microbial (fungal and bacterial) communities and their roles in litter substrate dynamics and ecosystem responses over time. We experimentally examined effects of differences in litter types produced by different fire regimes and litter loads (simulating wrack deposition) on microbial community composition and changes over time. We established replicated plots at similar elevations within frequent tidal-inundation zones of a coastal brackish Louisiana marsh. Plots were located within blocks with different prescribed fire regimes. We deployed different measured loads of new sterilized litter collected from zones in which plots were established, then re-measured litter masses at subsequent collection times. We used DNA sequencing to characterize microbial communities, indicator families, and inferred ecosystem functions in litter subsamples. Differences in fire regimes had large, similar effects on fungal and bacterial indicator families and community compositions and were associated with alternate trajectories of community development over time. Both microbial and plant community compositional patterns were associated with fire regimes, but in dissimilar ways. Differences in litter loads introduced differences in sediment accumulation associated with tidal inundation that may have affected microbial communities. Our study further suggests that fire regimes and tropical cyclones, in the context of frequent tidal inundation, may interactively generate substrate heterogeneities and alter microbial community composition, potentially modifying fine fuels and hence subsequent fires. Understanding microbial community compositional and functional responses to fire regimes and tropical cyclones should be useful in management of coastal marsh ecosystems.

by Mohammed S. Almuhayawi, Mohammed H. Alruhaili, Mohamed K. Y. Soliman, Muyassar K. Tarabulsi, Ruba A. Ashy, Amna A. Saddiq, Samy Selim, Yasir Alruwaili, Salem S. Salem It is thought to be risk-free, environmentally benign, and safe for biological processes to produce zinc oxide nanoparticles from renewable resources. This study examined Cassia javanica’s ability to create ZnONPs. The generated ZnONPs were analyzed using a variety of techniques, such as TEM, FTIR spectroscopy, UV-Vis spectroscopy, and XRD analysis. The antibacterial potential of ZnONPs has been investigated using both Agar well diffusion and microtitreplate (MTP) methods. One method used to evaluate ZnONPs’ capacity to scavenge free radicals at different concentrations was the DPPH method. The permanent zinc oxide (ZnO) shape and the naturally occurring crystal structure of ZnONPs were validated by the XRD data. ZnONPs showed antibacterial activity with MICs of 31.7 μg/mL toward Bacillus subtilis, 62.5 μg/mL for Salmonella typhimurium, Escherichia coli while Clostridium sporogenes and Bacillus pumilus was 125μg/mL. Furthermore, ZnONPs demonstrated a range of antibiofilm activities toward Staphylococcus aureus (MRSA). ZnONPs showed an intriguing antioxidant capacity, achieving IC50 of 109.3 μg/ml μg/mL. Additionally, ZnONPs demonstrated low toxic effect on Vero cell with IC50 154.01 μg/mL as well as possible anticancer action when applied to the carcinoma cell lines HepG2 with IC50 of 47.48 μg/mL. Furthermore, ZnONPs at 62.5 μg/mL had a promising antiviral impact against HSV1 and COX B4, with antiviral activities of 75.4% and 65.8%, respectively.

by Yichong Zhao, Kenta Oono, Hiroki Takizawa, Masaaki Kotera The design of RNA plays a crucial role in developing RNA vaccines, nucleic acid therapeutics, and innovative biotechnological tools. However, existing techniques frequently lack versatility across various tasks and are dependent on pre-defined secondary structure or other prior knowledge. To address these limitations, we introduce GenerRNA, a Transformer-based model inspired by the success of large language models (LLMs) in protein and molecule generation. GenerRNA is pre-trained on large-scale RNA sequences and capable of generating novel RNA sequences with stable secondary structures, while ensuring distinctiveness from existing sequences, thereby expanding our exploration of the RNA space. Moreover, GenerRNA can be fine-tuned on smaller, specialized datasets for specific subtasks, enabling the generation of RNAs with desired functionalities or properties without requiring any prior knowledge input. As a demonstration, we fine-tuned GenerRNA and successfully generated novel RNA sequences exhibiting high affinity for target proteins. Our work is the first application of a generative language model to RNA generation, presenting an innovative approach to RNA design.

by Noelle M. Nieskens, Yukiko Miyamoto, Brianna M. Hurysz, Anthony J. O’Donoghue, Lars Eckmann Trichomonas vaginalis is the causative agent of the common sexually transmitted disease, trichomoniasis, which affects more than a hundred million people worldwide. Metronidazole and tinidazole, agents belonging to the 5-nitroheterocyclic class of antimicrobials, are most often used to treat infection, but increased resistance has been reported and adverse effects of these drugs can be significant. Consequently, an urgent need exists for the development of novel drug entities against trichomoniasis. Critical for antimicrobial drug development is the demonstration of in vivo efficacy. Murine models of vaginal T. vaginalis infection are unreliable for unknown reasons. Meanwhile, murine infections with the related bovine pathogen, Tritrichomonas foetus, tend to be more robust, although susceptibility to different antimicrobials might differ from T. vaginalis. Here, we explored the utility of T. foetus infection as a surrogate model for drug development against T. vaginalis. Four different T. foetus strains caused robust vaginal infection in young mice, while none of four diverse T. vaginalis strains did. Comparison of drug susceptibility profiles revealed that T. foetus and T. vaginalis were similarly susceptible to a range of 5-nitroheterocyclic and gold(I) compounds. By comparison, proteasome inhibitors were 10- to 15-fold less active against T. foetus than T. vaginalis, although one of the proteasome inhibitors, bortezomib, had low micromolar activity or better against multiple strains of both trichomonads. Different strains of T. foetus were used to demonstrate the utility of the murine vaginal infection models for in vivo efficacy testing, including for bortezomib and a gold(I) compound. The differences in susceptibility to proteasome inhibitors may be partially explained by differences in the proteasome subunit sequences between the two trichomonads, although the functional relevance of the proteasome was similar in both organisms. These findings indicate that T. foetus can serve as a reliable surrogate model for T. vaginalis in vitro and in murine infections in vivo, but caution must be exercised for specific drug classes with targets, such as the proteasome, that may display genetic divergence between the trichomonads.

by Rajkumar Kulandaivel, Manikandan Ramachandran, Sathishkumar Veerappampalayam Easwaramoorthy, Jaehyuk Cho Recent evolution in connected devices modelled a massive stipulation for network traffic resources and classification. Software-defined networking (SDN) enables ML techniques with the Internet of Things (IoT) to automate network traffic. This helps to reduce accuracy and improves latency. Problems by conventional techniques to categorize network traffic acquired from IoT and assign resources can be resolved through SDN solutions. This manuscript proposes a proposed network traffic classification technique on IoT with SDN called Gauss Markov and Flow-balanced Vector Radial Learning (GM-FVRL). With the network traffic features acquired from the IoT devices, SDN-enabled Gauss Markov Correlation-based IoT Network Traffic Feature Extraction is applied to extort relevant network aspects. Next, the flow-balanced radial-based ML model for network traffic categorization uses the relevant extracted network traffic features. With the aid of flow, the balanced radial basis function reduces the influence of noise due to distinct network flow. This helps to improve accuracy and minimize latency. Due to this, better precision and recall is ensured. Performance of our method has been evaluated utilizing a scheme using an SDN traffic dataset. The results show that our method classifies the network traffic with high classification accuracy and minimum latency, ensuring better precision and recall.

Publication date: Available online 30 September 2024 Source: Immunity Author(s): Ye Liu, Yifang Chen, Uyanga Batzorig, Jingting Li, Celia Fernández-Méndez, Samiksha Mahapatra, Fengwu Li, Shebin Sam, Tatsuya Dokoshi, Seung-Phil Hong, Teruaki Nakatsuji, Richard L. Gallo, George L. Sen …

Publication date: Available online 30 September 2024 Source: Immunity Author(s): Alexander Lercher, Jin-Gyu Cheong, Michael J. Bale, Chenyang Jiang, Hans-Heinrich Hoffmann, Alison W. Ashbrook, Tyler Lewy, Yue S. Yin, Corrine Quirk, Emma J. DeGrace, Luis Chiriboga, Brad R. Rosenberg, Steven Z. Josefowicz, Charles M. Rice …

Infection and Immunity, Ahead of Print.