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Innate immunity plays an important role in host defense against pathogenic infections. It involves macrophage polarization into either the pro-inflammatory M1 or the anti-inflammatory M2 phenotype, influencing immune stimulation or suppression, respectively. Epigenetic changes during immune reactions contribute to long-term innate immunity imprinting on macrophage polarization. It is becoming increasingly evident that epigenetic modulators, such as histone deacetylase (HDAC) inhibitors (HDACi), enable the enhancement of innate immunity by tailoring macrophage polarization in response to immune stressors. In this review, we summarize current literature on the impact of HDACi and other epigenetic modulators on the functioning of macrophages during diseases that have a strong immune component, such as infections. Depending on the disease context and the chosen therapeutic intervention, HDAC1, HDAC2, HDAC3, HDAC6, or HDAC8 are particularly important in influencing macrophage polarization towards either M1 or M2 phenotypes. We anticipate that therapeutic strategies based on HDAC epigenetic mechanisms will provide a unique approach to boost immunity against disease challenges, including resistant infections., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: I declare no competing interests.

The repair of infected wounds is a complex physiopathologic process. Current studies on infected wound treatment have predominantly focused on infection treatment, while the factors related to delayed healing caused by vascular damage and immune imbalance are commonly overlooked. In this study, an extracellular matrix (ECM)-like dynamic and multifunctional hyaluronic acid (HA) hydrogel with antimicrobial, immunomodulatory, and angiogenic capabilities was designed as wound dressing for the treatment of infected skin wounds. The dynamic network in the hydrogel dressing was based on reversible metal-ligand coordination formed between sulfhydryl groups and bioactive metal ions. In our design, antibacterial silver and immunomodulatory zinc ions were employed to coordinate with sulfhydrylated HA and a vasculogenic peptide. In addition to the desired bioactivities for infected wounds, the hydrogel could also exhibit self-healing and injectable abilities. Animal experiments with infected skin wound models indicated that the hydrogel dressings enabled minimally invasive injection and seamless skin wound covering and then facilitated wound healing by efficient bacterial killing, continuous inflammation inhibition, and improved blood vessel formation. In conclusion, the metal ion-coordinated hydrogels with wound-infection-desired bioactivities and ECM-like dynamic structures represent a class of tissue bionic wound dressings for the treatment of infected and chronic inflammation wounds.

Febrile neutropenia (FN) is common among hematologic malignancy patients, including recipients of hematopoietic cell transplantation (HCT) and cellular therapies such as chimeric antigen receptor (CAR)-T-cell therapy. Prompt empiric antibiotic use has been the mainstay for decades but a "one-size-fits-all" approach is no longer broadly accepted, as treatment-related infectious risk are more understood. Growing antimicrobial resistance is an increasing clinical challenge. Evolving strategies on de-escalation of broad-spectrum antibiotics in FN without identified infection are areas of particular interest., (© 2024 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Clinical pharmacists participated in the drug therapy of peritonitis caused by Methylobacterium infection in a patient with renal insufficiency. Based on the knowledge of clinical pharmacy, the patient's condition and laboratory parameters, the literature, and the pharmacokinetic/pharmacodynamic characteristics of antibiotics, amikacin in combination with ciprofloxacin was suggested for anti-infection therapy. During the treatment, clinical pharmacists timely evaluated the efficacy of antibiotics, monitored the adverse reactions, and provided individualized pharmaceutical care in the patient.

Objectives: Infections in primary care are often treated with non-steroidal anti-inflammatory drugs (NSAIDs). This study evaluates whether NSAID prescribing is associated with adverse outcomes for respiratory (RTIs) or urinary track (UTI) infections., Objectives: To determine whether there is an association between NSAID prescribing and the rate of adverse outcomes for infections for individual consulting in primary care., Design: Cohort study of electronic health records., Setting: 87 general practices in the UK Clinical Practice Research Datalink GOLD., Participants: 142 925 patients consulting with RTI or UTI., Primary and Secondary Outcome Measures: Repeat consultations, hospitalisation or death within 30 days of the initial consultation for RTI or UTI. Poisson models estimated the associations between NSAID exposure and outcome. Rate ratios were adjusted for gender, age, ethnicity, deprivation, antibiotic use, seasonal influenza vaccination status, comorbidities and general practice. Since prescribing variations by practice are not explained by case mix-hence, less impacted by confounding by indication-both individual-level and practice-level analyses are included., Results: There was an increase in hospital admission/death for acute NSAID prescriptions (RR 2.73, 95% CI 2.10 to 3.56) and repeated NSAID prescriptions (6.47, 4.46-9.39) in RTI patients, and for acute NSAID prescriptions for UTI (RR 3.03; 1.92 to 4.76). Practice-level analysis, controlling for practice population characteristics, found that for each percentage point increase in NSAID prescription, the percentages of hospital admission/death within 30 days increased by 0.32 percentage points (95% CI 0.16 to 0.47)., Conclusions: In this non-randomised study, prescription of NSAIDs at consultations for RTI or UTIs in primary care is infrequent but may be associated with increased risk of hospital admission. This supports other observational and limited trial data that NSAID prescribing might be associated with worse outcomes following acute infection and should be prescribed with caution., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Severe infection is a critical health threat to humans, and antibiotic treatment is one of the main therapeutic approaches. Nevertheless, the efficacy of various antibiotic injection regimens in severe infection patients remains uncertain. This study aimed to comprehensively evaluate the impact of various antibiotic injection strategies on patients with severe infection through a meta-analysis. Relevant research literature was collected by searching databases such as PubMed, Embase, and Cochrane Library. The retrieved literature was screened according to inclusion and exclusion criteria. Relevant data, including study design, sample size, and antibiotic regimens, were extracted from the included studies. The Cochrane Collaboration's Risk of Bias tool was employed to assess the risk of bias in each study. Statistical analysis was performed based on the results of the included studies. A total of 15 articles were included, covering various types of severe infection patients, including pulmonary and abdominal infections. The analysis provided insights into mortality rates, treatment efficacy, adverse reactions (ARs), Acute Physiology and Chronic Health Evaluation (APACHE) scores, among other outcomes. The results indicated that combination therapy was superior to monotherapy in terms of mortality rate, treatment efficacy, and APACHE scores, while the incidence of ARs was lower in the monotherapy group compared to the combination therapy group (p < 0.05). Combination therapy showed better treatment efficacy compared to monotherapy, although it was associated with a higher incidence of ARs., (© 2024 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Identification and implementation of novel drug are not only time consuming and expensive but also it poses huge challenge to reach into the market. Currently, thousands of USFDA approved drugs licence are being expired that can be repurposed for treating other diseases. Drug repurposing is an alternative solution to reduce time, cost and steps for development of drugs and their applications for treating disease. The current chapter emphases to brief the steps involved in drug discovery and drug repurposing. The chapter also includes repurposed drugs for treating bacterial, fungal and viral diseases. Unlocking the potential of already existed drug and repurposing them for other diseases that could accelerate drug discovery and aid in managing outbreaks., (Copyright © 2024. Published by Elsevier Inc.)

Objective: to develop and validate the content of a serious game on the safe management of intravenous medications in pediatrics., Method: methodological study for the development and content validation of an educational technology. The cases and challenges of the serious game were developed based on a literature review and validated by 11 nurses with training and experience in the area. Content validity and agreement indices were adopted to analyze agreement and internal consistency (minimum of 0.8)., Results: the content is based on the main antibiotics used in the clinical management of infections in hospitalized children and patient safety. Absolute agreement was obtained in 60 of the 61 items evaluated, and the minimum obtained was 0.82 in the content validation index and 0.80 in agreement. Adjustments were suggested by experts in the response statement for a specific case and implemented to improve the quality of the technology content., Conclusion: the content of the serious game Nurseped was validated by nurse experts in child health regarding clinical cases, question statements and multiple-choice answers, in addition to feedback that presents the user with an evidence-based answer after getting the challenge right or wrong.

Introduction: Distinguishing the severity of the diagnosis and an appropriate treatment plan in pediatric hand infections can be complex due to the variable amount of information available at the presentation. Inflammatory blood markers, including white blood cell count, erythrocyte sedimentation rate, and C-reactive protein are reported to aid in determining the severity of infection and response to treatment in adult hand infections. The purpose of this study was to identify the relevance of inflammatory marker levels in pediatric patients with hand and wrist infections and to determine their utility in diagnosis and treatment., Methods: This multicenter, retrospective, cohort study included patients aged 0 to 18 who received treatment for an acute hand or wrist infection between 2009 and 2020. Data collected included demographics, time to presentation, diagnosis, inflammatory markers, culture results, antibiotic treatment, and surgical treatment. Infections were categorized as deep (osteomyelitis, tenosynovitis, abscess) and superficial (paronychia, felon, cellulitis). Exclusion criteria included: patients above 18 years of age, chronic infection, open fractures, and absence of any documented inflammatory markers. Statistically, t tests were used to compare mean differences in inflammatory markers between patients who did and did not receive pretreatment antibiotics and between patients who had superficial versus deep hand infections., Results: A total of 123 patients met the inclusion criteria. Pretreatment with antibiotics before definitive management was not significantly associated with differences in laboratory markers compared with patients not pretreated with antibiotics. Deep hand infections had inflammatory markers similar to superficial infections. Patients with deep hand infections required a bedside or operative procedure 78.9% of the time compared with superficial infections (21.2%) ( P <0.001). Patients with an isolated methicillin-resistant Staphylococcus aureus infection had inflammatory marker values that were not significantly different from patients infected with all other microbes., Conclusions: Inflammatory markers were not significantly different between patients who received pretreatment with antibiotics and those who did not. While deep infections were often treated with bedside or surgical procedures, the inflammatory marker values were similar to those of superficial infections. The same held true for patients infected with culture-positive, isolated methicillin-resistant Staphylococcus aureus bacteria. Consequently, inflammatory markers may be useful to identify the presence of infection and monitor the response to treatment, they did not aid in determining the specific type of infection or selection of a treatment plan., Level of Evidence: Level III-retrospective comparative study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Case Histories: Medical records of four dogs diagnosed with protothecosis in New Zealand were reviewed. The dogs were aged between 4 and 9 years and three of the four dogs were female. Breeds were one Labrador, one Miniature Schnauzer and two crossbreeds. The reasons for initial veterinary evaluation were a cough and opaque appearance of the right eye (Case 1), diarrhoea (Cases 2 and 3), and cutaneous disease (Case 4)., Clinical Findings: The ocular signs were characterised by panuveitis, retinal detachment and secondary glaucoma. Gastrointestinal signs included chronic haemorrhagic diarrhoea due to colitis. Three cases had disseminated infection and developed both bilateral, blinding, ocular disease and chronic gastrointestinal disease. Cutaneous signs consisted of draining fistulae over the olecranon, multifocal cutaneous nodules, and ulceration and tracts of the foot pads. Disseminated protothecosis was confirmed by histopathology of biopsied ocular tissues in Cases 1 and 2 and by gastrointestinal biopsies in Case 3. Prototheca spp. were also identified in cytological specimens from Cases 1 and 4 and recovered by culture in Cases 2 and 4. Cutaneous protothecosis was diagnosed in Case 4 initially by cytology and histopathology of skin lesions, and Prototheca zopfii was confirmed by PCR of cultured organisms., Treatment and Outcome: Prior to diagnosis of protothecosis, a variety of treatments were prescribed to treat the gastrointestinal and ocular signs. After diagnosis, only Cases 2 and 4 received medication aimed at treating the protothecal infection, which was itraconazole in both cases. Following the progression of clinical signs and concerns about quality of life, all four dogs were euthanised., Diagnosis: Disseminated protothecosis in three dogs, cutaneous protothecosis in one dog., Clinical Relevance: Canine protothecosis is rarely reported, despite the ubiquity of the causal algae, and the disease usually carries an extremely grave prognosis when infection is generalised. In New Zealand, protothecosis should be considered as a differential diagnosis in dogs with panuveitis, chorioretinitis or retinal detachment, colitis, or nodular, ulcerative or fistulating cutaneous lesions.

Multidrug-resistant organisms (MDROs) are a major international health threat. In many low and middle-income countries poorly regulated antibiotic use, limited surveillance, and inadequate sanitation give rise to high rates of antibiotic resistance. A resulting reliance on last-line antibiotic options further contributes to the emergence of MDROs. The potential for these pathogens to spread across international borders is a matter of considerable concern. However, this problem is commonly framed as primarily a threat to the health security of countries where resistance is not yet endemic. In fact, it is little acknowledged that those at greatest risk from antibiotic treatment failure are individuals who move from regions of high MDRO prevalence to settings where standard empirical treatment options remain largely effective. In this perspective, we highlight the poor treatment outcomes for disseminated bacterial infections in individuals who have moved from settings in which MDROs are common to those where MDROs are currently less common. We discuss MDRO screening strategies that could avoid stigmatizing vulnerable populations by focusing on future risk of disseminated infection, rather than past risk of acquisition. In practical terms, this means screening individuals before childbirth, immunosuppressive treatments, major surgery, or other events associated with disseminated infection risk, rather than prioritizing screening for individuals from regions with high carriage rates. We argue that such measures would reduce antibiotic treatment failure and improve outcomes while protecting migrant populations from the divisive consequences of targeted screening programs., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In recent years, the accelerated development of G-quadruplexes and hydrogels has driven the development of intelligent biomaterials. Based on the excellent biocompatibility and special biological functions of G-quadruplexes, and the hydrophilicity, high-water retention, high water content, flexibility and excellent biodegradability of hydrogels, G-quadruplex hydrogels are widely used in various fields by combining the dual advantages of G-quadruplexes and hydrogels. Here, we provide a systematic and comprehensive classification of G-quadruplex hydrogels in terms of preparation strategies and applications. This paper reveals how G-quadruplex hydrogels skillfully utilize the special biological functions of G-quadruplexes and the skeleton structure of hydrogels, and expounds its applications in the fields of biomedicine, biocatalysis, biosensing and biomaterials. In addition, we deeply analyze the challenges in preparation, applications, stability and safety of G-quadruplex hydrogels, as well as potential future development directions., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: The FIGARO study aims to provide insights on real-world utilization and tolerability of facilitated subcutaneous immunoglobulin (fSCIG) for primary immunodeficiency disease (PID) or secondary immunodeficiency disease (SID)., Methods: This prospective, multicenter, observational study, evaluated medical records, charts, and diaries of patients who had received at least 1 fSCIG infusion for PID or SID. Data were analyzed by cohort (PID, SID) and age groups (pediatric [< 18 years], adult [18-64 years], older adult [≥ 65 years]). Patients were followed up to 36 months., Results: The study enrolled 156 patients: 15 pediatric, 120 adult, 21 older-adult. Twelve-month follow-up data were available for 128 patients. fSCIG was mainly prescribed for PID among patients aged < 65 years and for SID among older adults. At inclusion, 75.6% received their fSCIG infusion at home, and 78.7% self-administered. Adults were more likely to receive their initial infusion at home and self-administer (81.7% and 86.6%, respectively) than pediatric patients (53.3% each) and older adults (57.1% and 52.4%, respectively). At 12 months, the proportion of patients infusing at home and self-administering increased to 85.8% and 88.2%. Regardless of age, most patients self-administered the full fSCIG dose at home every 3-4 weeks and required a single infusion site. The tolerability profile was consistent with previous pivotal trials. Acute severe bacterial infections occurred in 0%-9.1% of patients during follow-up visits (full cohort)., Conclusions: FIGARO confirms the feasibility, tolerability, and good infection control of fSCIG in PID and SID patients across the age spectrum in both the home-setting and medical facility., Trial Registration Number: ClinicalTrials.gov NCT03054181., (© 2023. The Author(s).)

Objectives: Appropriate duration of antibiotic treatment is a key principle to reduce the emergence of bacterial resistance and antibiotic harm. The aim of this study was to document current clinical practice among Spanish paediatricians in terms of the duration of antibiotic therapy in both inpatient and outpatient settings, mapping the difference between practice and guidelines, and thus identifying opportunities to improve practice., Methods: A national exploratory work survey was distributed in 2020 as a questionnaire about seven main infectious syndromes in children: genitourinary; skin and soft tissue; osteoarticular; ear, nose and throat; pneumonia; central nervous system; and bacteraemia. The answers were contrasted with current recommendations regarding the duration of antibiotic therapy. Demographic analysis was also performed., Results: The survey was completed by 992 paediatricians in Spain, representing 9.5% of paediatricians working in the Spanish national health system. Hospital care clinicians accounted for 42.7% (6662/15590) of responses. The antibiotic duration used in practice was longer than recommended in 40.8% (6359/15590) of responses, and shorter than recommended in 16% (1705/10654) of responses. Only 25% (249/992) and 23% (229/992) of respondents indicated that they would prescribe antibiotics for the recommended treatment duration for lower urinary tract infection and community-acquired pneumonia (AI evidence). Among severe hospital-managed infections, a tendency towards longer courses of antibiotics was found for non-complicated meningococcal infections and non-complicated pneumococcal, Gram-negative and S. aureus bacteraemia., Conclusions: A noteworthy tendency towards prescribing antibiotics for longer than recommended among paediatricians was evidenced in this nationwide study, highlighting a wide range of opportunities for potential improvement., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Ulvans are water-soluble sulfated polysaccharides predominantly found in the cell wall of green algae. They hold unique characteristics that are attributed to their 3D conformation, functional groups along with the presence of saccharides and sulfate ions. Traditionally, ulvans are widely used as food supplements and probiotics owing to the high content of carbohydrates. Despite their widespread usage in food industry, an in-depth understanding is required for extrapolating their potential application as a nutraceutical and medicinal agent which could be beneficial in promoting human health and well-being. This review emphasizes novel therapeutic avenues where ulvan polysaccharides can be used beyond their nutritional applications. A collection of literature points towards multifarious applications of ulvan in various biomedical fields. Structural aspects along with extraction and purification methods have been discussed. The underlying molecular mechanisms associated with its biomedical potential in different therapeutic fields like oncology, infectious diseases, inflammation, neuroprotection and tissue engineering, etc. have been unravelled. Challenges associated with clinical translation and future perspectives have been deliberated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Objectives: There is a gap in knowledge about the effects of smoking on overall infection risk in otherwise healthy populations, possibly leading to underestimation of the dangers of smoking. The present study aimed to examine the association of smoking with the risk of infections in a large cohort of healthy blood donors., Methods: This cohort study used questionnaire and health register data from 127 831 Danish blood donors. Multivariable Cox proportional hazards analysis was applied to estimate the association of current smoking with the risk of all-cause infection defined as hospital-based treatment for infection or filled prescriptions of antimicrobials stratified for age and adjusted for relevant confounders., Results: Among 18 272 current smokers, 12 272 filled an antimicrobial prescription and 2035 received hospital-based treatment for infections. Among 101 974 non-smokers, 65 117 filled a prescription and 8501 received hospital-based treatment for infections. Smokers had a higher risk of all-cause infection than non-smokers (hazard ratio estimates were 1.27 in males and 1.33 in females for hospital-based treatment and 1.11 in males and up to 1.20 in females for filled prescriptions). Smoking was most strongly associated with an increased incidence of respiratory tract infection, abscesses, skin infection, and prescriptions for these ailments (hazard ratio up to 2.29). Furthermore, smokers' risk of filled prescriptions of broad-spectrum penicillin was increased (hazard ratio up to 1.96)., Conclusions: Current smoking was strongly associated with the risk of hospital-based treatment of infection and filled prescriptions of antimicrobials in a large cohort of healthy individuals. These findings warrant an increased focus on infectious disease risk among smokers., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: We have updated the guideline for preventing and managing perioperative infection in China, given the global issues with antimicrobial resistance and the need to optimize antimicrobial usage and improve hospital infection control levels., Methods: We conducted a comprehensive evaluation of the evidence for prevention and management of perioperative infection, based on the concepts of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The strength of recommendations was graded and voted using the Delphi method and the nominal group technique. Revisions were made to the guidelines in response to feedback from the experts., Results: There were 17 questions prepared, for which 37 recommendations were made. According to the GRADE system, we evaluated the body of evidence for each clinical question. Based on the meta-analysis results, recommendations were graded using the Delphi method to generate useful information., Conclusions: This guideline provides evidence to perioperative antimicrobial prophylaxis that increased the rational use of prophylactic antimicrobial use, with substantial improvement in the risk-benefit trade-off., (© 2023 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.)

Background: Acute infections are a common reason for children to consult primary care. Serious infections are rare but differentiating them from self-limiting illnesses remains challenging. This can lead to inappropriate antibiotic prescribing. Point-of-care C-reactive protein testing is used to guide antibiotic prescribing in adults. However, in children its use remains unclear. The purpose of this study was to assess point-of-care CRP test levels with respect to patients' characteristics, care setting, preliminary diagnosis, and management., Methods: A prospective observational study was performed in children with an acute infection presenting to ambulatory care in Belgium., Results: In this study 8280 cases were analysed, of which 6552 had a point-of-care CRP value available. A total of 276 physicians participated. The median patient age was 1.98 years (IQR 0.97 to 4.17), 37% of children presented to a general practitioner, 33% to a paediatric out-patient clinic, and 30% to the emergency department. A total of 131 different preliminary diagnoses were found, with acute upper airway infection as the most frequent. In 6% (n = 513) patients were diagnosed with a serious infection. The most common serious infection was pneumonia. Antibiotics were prescribed in 28% (n = 2030) of all episodes. The median CRP over all infectious episodes was 10 mg/L (IQR &lt; 5-29). Children below 5 years of age and those presenting to a paediatrician had a higher median CRP. Median CRP in patients with serious infections was 21 mg/L (IQR 6 to 63.5). Pneumonia had a median CRP of 48 mg/L (IQR 13-113). In the episodes with antibiotics prescription, median CRP level was 29 mg/L (IQR 10-58) compared to 7 mg/L (IQR &lt; 5-19) when they were not prescribed., Conclusion: A low POC CRP as a standalone tool did not seem to be sufficient to rule out serious infections, but its potential in assessing serious infections could increase when integrated in a clinical decision rule., Trial Registration: ClinicalTrials.gov Identifier: NCT02024282 (registered on 31/12/2013)., (© 2022. The Author(s).)

Expansion and differentiation of antigen-experienced PD-1 + TCF-1 + stem-like CD8 + T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade 1-4 . Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of 'better effector' CD8 + T cells similar to those generated in an acute infection 5 . IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed 6-10 . Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8 + T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections., (© 2022. The Author(s).)

Patients with acute graft-versus-host disease (GVHD) have an increased risk for infectious complications after allogeneic hematopoietic cell transplantation (HCT), but the risk according to response to therapy has not been well studied. We performed a retrospective analysis of the infectious complications for 1 year following allogeneic HCT at the University of Minnesota including 1143 pediatric and adult patients with and without aGVHD. The patients with aGVHD were classified into treatment response groups based on response to corticosteroids as first-line therapy: steroid-sensitive (SS; n = 114), steroid-resistant (SR; n = 103), and steroid-dependent (SD; n = 168) aGVHD. We observed that the cumulative incidence and density of infections in patients with SS aGVHD parallel the values in patients without GVHD. Infection density (ie, number of infections occurring per 100 days at risk) was greater in the patients with aGVHD compared with patients in both early and later post-transplantation periods. In GVHD patients, among the infections developed from the onset of aGVHD through 80 days of treatment, and until 1 year following transplantation, SS and SD patients had fewer bacterial and viral infections than SR patients. The overlap of nonrelapse mortality between SS and SD GVHD patients is a function of SD GVHD being responsive to steroid therapy, even if continued therapy is required. In summary, although valid goals may include reducing unneeded antibacterial antibiotic therapy and preserving microbiome diversity, these data suggest that anti-infective therapy is justified by the density of infections observed during active GVHD treatment., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Evidence on the effect of self-protection via social distancing and wearing face-masks on infections during chemotherapy is currently not available. We asked if the occurrence of acute infections during chemotherapy for advanced-stage Hodgkin lymphoma (HL) decreased when COVID-19 protection measures were in effect., Methods: We analyzed the occurrence of infections during all documented eBEACOPP cycles starting between 01 March and 30 June of 2017 to 2020 in patients treated within the GHSG HD21 study in Germany and compared the infection rates and characteristics by logistic regression models and means of descriptive statistics., Results: We analyzed 911 cycles of 313 adult patients treated with 4 to 6 cycles of eBEACOPP. We found a significant decrease in the occurrence of infections during chemotherapy for HL during COVID-19 lockdown from 131 (19.6%) of 670 cycles in 2017-2019 to 30 (12.6%) of 239 cycles during COVID-19 lockdown [OR 0.574 (95% CI 0.354-0.930), P = 0.024]. The strongest effect was evident for unspecified infections with 39 cycles (5.8%) during 2017-2019 in comparison to 5 cycles (2.1%) during COVID-19 lockdown. 20 (24.1%) of 83 patients had an infection during the COVID-19 lockdown versus 99 (43.2%) of 229 patients in the years 2017-2019 (P = 0.0023)., Conclusion: The significant decrease of infections during chemotherapy for HL during COVID-19 lockdown reveals the protective measures' potential to shield patients from transmissible pathogens. We conclude that these measures could be recommended for HL patients at risk for infections during chemotherapy., (© 2022. The Author(s).)

Biologics targeting PD-1, PD-L1, and CTLA-4 immune checkpoint proteins have been used in a variety of tumor types including small and non-small cell lung cancers, melanoma, and renal cell carcinoma. Their anti-tumor activity is achieved through amplifying components of the patient's own immune system to target immune response evading cancer cells. However, this unique mechanism of action causes a range of immune related adverse events, irAEs, that affect multiple physiological systems in the body. These irAEs, depending on severity, often cause suspension or discontinuation of therapy and, in rare cases, may lead to fatal outcomes. In this study we focused on pembrolizumab, a PD-1 inhibitor currently approved for multiple types of cancer. We analyzed over ten thousand adverse event reports from Keynote clinical trials of pembrolizumab for various cancer indications with or without co-occurring infections, and observed a statistically significant 80% increase in the risk of developing an irAE in subjects with infections., Competing Interests: The authors have declared that no competing interests exist.

Antimicrobials are essential in reducing morbidity and mortality from infectious diseases globally. However, due to the lack of effective surveillance measures and widespread overuse, there is an increasing threat to the effectiveness of antimicrobials. Although there is a global increase in antimicrobial resistance, low- and middle-income countries share a much higher burden. Antimicrobial stewardship efforts such as effective surveillance and reduction in overuse can help combat the increase in antimicrobial resistance., Competing Interests: Disclosure The authors have no financial disclosures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ionophores are a diverse class of synthetic and naturally occurring ion transporter compounds which demonstrate both direct and in-direct antimicrobial properties against a broad panel of bacterial, fungal, viral and parasitic pathogens. In addition, ionophores can regulate the host-immune response during communicable and non-communicable disease states. Although the clinical use of ionophores such as Amphotericin B, Bedaquiline and Ivermectin highlight the utility of ionophores in modern medicine, for many other ionophore compounds issues surrounding toxicity, bioavailability or lack of in vivo efficacy studies have hindered clinical development. The antimicrobial and immunomodulating properties of a range of compounds with characteristics of ionophores remain largely unexplored. As such, ionophores remain a latent therapeutic avenue to address both the global burden of antimicrobial resistance, and the unmet clinical need for new antimicrobial therapies. This review will provide an overview of the broad-spectrum antimicrobial and immunomodulatory properties of ionophores, and their potential uses in clinical medicine for combatting infection., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Microbial biofilms are represented by sessile microbial communities with modified gene expression and phenotype, adhered to a surface and embedded in a matrix of self-produced extracellular polymeric substances (EPS). Microbial biofilms can develop on both prosthetic devices and tissues, generating chronic and persistent infections that cannot be eradicated with classical organic-based antimicrobials, because of their increased tolerance to antimicrobials and the host immune system. Several complexes based mostly on 3D ions have shown promising potential for fighting biofilm-associated infections, due to their large spectrum antimicrobial and anti-biofilm activity. The literature usually reports species containing Mn(II), Ni(II), Co(II), Cu(II) or Zn(II) and a large variety of multidentate ligands with chelating properties such as antibiotics, Schiff bases, biguanides, N-based macrocyclic and fused rings derivatives. This review presents the progress in the development of such species and their anti-biofilm activity, as well as the contribution of biomaterials science to incorporate these complexes in composite platforms for reducing the negative impact of medical biofilms.

Approaches based on animal and two-dimensional (2D) cell culture models cannot ensure reliable results in modeling novel pathogens or in drug testing in the short term; therefore, there is rising interest in platforms such as organoids. To develop a toolbox that can be used successfully to overcome current issues in modeling various infections, it is essential to provide a framework of recent achievements in applying organoids. Organoids have been used to study viruses, bacteria, and protists that cause, for example, respiratory, gastrointestinal, and liver diseases. Their future as models of infection will be associated with improvements in system complexity, including abilities to model tissue structure, a dynamic microenvironment, and coinfection. Teaser. Organoids are a flexible tool for modelling viral, bacterial and protist infections. They can provide fast and reliable information on the biology of pathogens and in drug screening, and thus have become essential in combatting emerging infectious diseases., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: To assess the minimum incidence of life-threatening bronchopulmonary dysplasia (BPD), defined as need for positive pressure respiratory support or pulmonary vasodilators at 38 weeks corrected gestational age (CGA), in infants born <32 weeks gestation in the UK and Ireland; and to describe patient characteristics, management and outcomes to 1 year., Methods: Prospective national surveillance study performed via the British Paediatric Surveillance Unit from June 2017 to July 2018. Data were collected in a series of three questionnaires from notification to 1 year of age., Results: 153 notifications met the case definition, giving a minimum incidence of 13.9 (95% CI: 11.8 to 16.3) per 1000 live births <32 weeks' gestation. Median gestation was 26.1 (IQR 24.6-28) weeks, and birth weight 730 g (IQR 620-910 g). More affected infants were male (95 of 153, 62%; p<0.05). Detailed management and outcome data were provided for 94 infants. Fifteen died at median age 159 days (IQR 105-182) or 49.6 weeks CGA (IQR 43-53). Median age last receiving invasive ventilation was 50 days (IQR 22-98) and total duration of pressure support for surviving infants 103 (IQR 87-134) days. Fifty-seven (60.6%) received postnatal steroids and 22 (23.4%) pulmonary vasodilators. Death (16%) and/or major neurodevelopmental impairment (37.3%) or long-term ventilation (23.4%) were significantly associated with need for invasive ventilation near term and pulmonary hypertension., Conclusions: This definition of life-threatening BPD identified an extremely high-risk subgroup, associated with serious morbidity and mortality. Wide variability in management was demonstrated, and future prospective study, particularly in key areas of postnatal steroid use and pulmonary hypertension management, is required., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cells are richly equipped with nuclear receptors, which act as ligand-regulated transcription factors. Peroxisome proliferator activated receptors (PPARs), members of the nuclear receptor family, have been extensively studied for their roles in development, differentiation, and homeostatic processes. In the recent past, there has been substantial interest in understanding and defining the functions of PPARs and their agonists in regulating innate and adaptive immune responses as well as their pharmacologic potential in combating acute and chronic inflammatory disease. In this review, we focus on emerging evidence of the potential roles of the PPAR subtypes in macrophage biology. We also discuss the roles of dual and pan PPAR agonists as modulators of immune cell function, microbial infection, and inflammatory diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Toobian, Ghosh and Katkar.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Objective: To evaluate the prognostic accuracy of qSOFA for predicting in-hospital mortality among patients with suspected infection presenting to the ED of a public tertiary hospital in Brazil., Methods: We performed a retrospective cohort study of consecutive adult patients (age ≥ 18 years) with suspected infection who presented to an academic tertiary ED in Porto Alegre (Southern Brazil) during an 18-month period. The qSOFA was calculated by using information collected at triage and patients were followed throughout hospitalization for the primary outcome of in-hospital mortality. Sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratios with corresponding 95% CIs were calculated for the qSOFA and qSOFA65., Results: A total of 7523 ED visits of patients with suspected infection in which an intravenous antibiotic was administered within 24 h were included, which resulted in 908 in-hospital deaths (12.1%). There were 690 (9.2%) patients whose triage qSOFA was ≥2 points. When such cutoff was used, the sensitivity for in-hospital death was 24.6% (95% CI 21.8 to 27.4%) and the specificity was 92.9% (95% CI 92.3% to 93.5%). The sensitivity increased to 67.4% (95% CI 64.2% to 70.3%) when a cutoff of ≥1 was tested, but the specificity decreased to 55.3% (95% CI 54.1% to 56.5%). Using a cutoff of ≥2, the qSOFA65 had a sensitivity of 51.0% (95% CI 47.7% to 54.3%) and a specificity of 75.7% (95% CI 74.6% to 76.7%)., Conclusions: The qSOFA score yielded very low sensitivity in predicting in-hospital mortality. Emergency physicians or ED triage nurses in low-to-middle income countries should not be using qSOFA or qSOFA65 as "rule-out" screening tools in the initial evaluation of patients with suspected infection., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Neural tube defects are the second most common congenital malformation in humans. Despite significant decreases in neural tube defects and related mortality and morbidity with recent developments, infections remain an important problem. Research on the role of topical therapy for managing neural tube defects and associated infections in the neonatal period has been limited. This randomized controlled trial aimed to investigate the efficiency of topical Rifampin on infection control in paraplegic newborns with open neural tube defects., Methods: Thirty-seven patients who underwent an operation for neural tube defects were included. Topical Rifampin and cefotaxime were administered to 19 patients constituting the case group and local saline and cefotaxime were administered to a control group. Patients were examined for ventriculoperitoneal shunt infection/dysfunction, surgical site infection, urinary tract infection, and sepsis., Results: None of the patients using topical rifampin had ventriculoperitoneal shunt infection/dysfunction, surgical site infection, urinary tract infection, or sepsis. In the control group, ventriculoperitoneal shunt infection/dysfunction was found in 4 (22.2%) cases, surgical site infection in 3 (27.7%), urinary tract infection in 3 (27.7%), and sepsis in 5 (27.7%), with statistically significant differences between the groups ( p  = 0.01, p  = 0.032, p  = 0.032, and p  = 0.002, respectively). No local or systemic side effect was observed regarding rifampin use., Conclusion: Topical Rifampin is effective in minimizing complications like sepsis, surgical site infection, urinary tract infection, and ventriculoperitoneal shunt infection due to neural tube defect operations. Further research with larger numbers of cases is needed to implement this practice routinely.

The field of cellular microbiology, rooted in the co-evolution of microbes and their hosts, studies intracellular pathogens and their manipulation of host cell machinery. In this review, we highlight emerging technologies and infection models that recently promoted opportunities in cellular microbiology. We overview the explosion of microscopy techniques and how they reveal unprecedented detail at the host-pathogen interface. We discuss the incorporation of robotics and artificial intelligence to image-based screening modalities, biochemical mapping approaches, as well as dual RNA-sequencing techniques. Finally, we describe chips, organoids and animal models used to dissect biophysical and in vivo aspects of the infection process. As our knowledge of the infected cell improves, cellular microbiology holds great promise for development of anti-infective strategies with translational applications in human health., (© 2021. The Author(s).)

Introduction: Severe infections continue to impose a major burden on critically ill children and mortality rates remain stagnant. Outcomes rely on accurate and timely delivery of antimicrobials achieving target concentrations in infected tissue. Yet, developmental aspects, disease-related variables, and host factors may severely alter antimicrobial pharmacokinetics in pediatrics. The emergence of antimicrobial resistance increases the need for improved treatment approaches., Areas Covered: This narrative review explores why optimization of antimicrobial therapy in neonates, infants, children, and adolescents is crucial and summarizes the possible dosing approaches to achieve antimicrobial individualization. Finally, we outline a roadmap toward scientific evidence informing the development and implementation of precision antimicrobial dosing in critically ill children.The literature search was conducted on PubMed using the following keywords: neonate, infant, child, adolescent, pediatrics, antimicrobial, pharmacokinetic, pharmacodynamic target, Bayes dosing software, optimizing, individualizing, personalizing, precision dosing, drug monitoring, validation, attainment, and software implementation. Further articles were sought from the references of the above searched articles., Expert Opinion: Recently, technological innovations have emerged that enabled the development of individualized antimicrobial dosing approaches in adults. More work is required in pediatrics to make individualized antimicrobial dosing approaches widely operationalized in this population.

Mitochondria are the energy center of the cell. They are found in the cell cytoplasm as dynamic networks where they adapt energy production based on the cell's needs. They are also at the center of the proinflammatory response and have essential roles in the response against pathogenic infections. Mitochondria are a major site for production of Reactive Oxygen Species (ROS; or free radicals), which are essential to fight infection. However, excessive and uncontrolled production can become deleterious to the cell, leading to mitochondrial and tissue damage. Pathogens exploit the role of mitochondria during infection by affecting the oxidative phosphorylation mechanism (OXPHOS), mitochondrial network and disrupting the communication between the nucleus and the mitochondria. The role of mitochondria in these biological processes makes these organelle good targets for the development of therapeutic strategies. In this review, we presented a summary of the endosymbiotic origin of mitochondria and their involvement in the pathogen response, as well as the potential promising mitochondrial targets for the fight against infectious diseases and chronic inflammatory diseases.

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype., Competing Interests: Disclosures: P.A. Brogan reported personal fees from Sobi, Novartis, Roche, and GSK, and grants from Sobi outside the submitted work. No other disclosures were reported., (© 2021 Neehus et al.)

Emodin (6-methyl-1,3,8-trihydroxyanthraquinone) is a naturally occurring anthraquinone derivative found in roots and leaves of various plants, fungi and lichens. For a long time it has been used in traditional Chinese medicine as an active ingredient in herbs. Among other sources, it is isolated from the rhubarb Rheum palmatum or tuber fleece-flower Polygonam multiflorum . Emodin has a wide range of biological activities, including diuretic, antibacterial, antiulcer, anti-inflammatory, anticancer and antinociceptive. According to the most recent studies, emodin acts as an antimalarial and antiallergic agent, and can also reverse resistance to chemotherapy. In the present work the potential therapeutic role of emodin in treatment of inflammatory diseases, cancers and microbial infections is analysed.

Population-based studies have demonstrated that increased retinal venular calibre is a risk factor for cardiac disease, cardiac events and stroke. Venular dilatation also occurs with diabetes, obesity, dyslipidemia and autoimmune disease where it is attributed to inflammation. This study examined whether the inflammation associated with infections also affected microvascular calibre. Participants with infections and CRP levels  >  100 mg/L were recruited from the medical wards of a teaching hospital and assisted to complete a demographic and vascular risk factor questionnaire, and to undergo non-mydriatic retinal photography (Canon CR5-45NM, Japan). They were then treated with appropriate antibiotics, and underwent repeat retinal imaging when their CRP levels had fallen to less than 100 mg/L. Retinal images were examined for arteriole and venular calibre using validated semi-automated software based on Knudtson's modification of the Parr-Hubbard formula (IVAN, U Wisconsin). Differences in inflammatory markers and calibre were examined using the paired t-test for continuous variables. Determinants of calibre were calculated from multiple linear regression analysis. Forty-one participants with respiratory (27, 66%), urinary (6, 15%), skin (5, 12%), or miscellaneous (3, 7%) infections were studied. After antibiotic treatment, participants' mean CRP levels fell from 172.9 ± 68.4 mg/L to 42.2 ± 28.2 mg/L (p < 0.0001) and mean neutrophil counts fell from 9 ± 4 × 10 9 /L to 6 ± 3 × 10 9 /L (p < 0.0001). The participants' mean venular calibre (CRVE) decreased from 240.9 ± 26.9 MU to 233.4 ± 23.5 MU (p = 0.0017) but arteriolar calibre (CRAE) was unchanged (156.9 ± 15.2 MU and 156.2 ± 16.0 MU, p = 0.84). Thirteen additional participants with infections had a CRP > 100 mg/L that persisted at review (199.2 ± 59.0 and 159.4 ± 40.7 mg/L, p = 0.055). Their CRAE and CRVE were not different before and after antibiotic treatment (p = 0.96, p = 0.78). Hospital inpatients with severe infections had retinal venular calibre that decreased as their infections resolved and CRP levels fell after antibiotic treatment. The changes in venular calibre with intercurrent infections may confound retinal vascular assessments of, for example, blood pressure control and cardiac risk., (© 2021. The Author(s).)

BACKGROUND The aim of this study was to investigate the effects of doxofylline combined with ceftazidime on clinical efficacy, drug safety, and prognosis in patients with COPD complicated with infection. MATERIAL AND METHODS A total of 450 patients admitted to the Inner Mongolia BaoGang Hospital for treatment of COPD from January 2017 to December 2019 were selected to participate. All patients were randomly divided into control and observation groups, with 225 patients in each group. In addition, patients with COPD in the remission stage were matched by sex and age for a blank control group. The control group was treated with doxofylline, and the observation group was treated with ceftazidime and doxofylline. No drug intervention was given to the blank control group. Short-term efficacy, pulmonary ventilation function, patient quality of life, peripheral blood TNF-alpha and PGDF-B levels, and adverse drug reactions were observed. RESULTS The effective treatment rate in the observation group was 96.89%, which was significantly higher than that in the control group (84.00%). Measures of pulmonary ventilation function and patient quality of life in the observation group were significantly higher than those in the control group. Levels of TNF-alpha and PDGF-B in the observation group were significantly lower than those in the control group. There were no significant differences in the above indicators between the blank control group and the observation group. CONCLUSIONS Doxofylline combined with ceftazidime effectively treated patients with COPD complicated with infection. These results provide a reference for clinical treatment.

Short-chain fatty acids (SCFAs) are the main metabolites produced by the gut microbiota via the fermentation of complex carbohydrates and fibers. Evidence suggests that SCFAs play a role in the control of infections through direct action both on microorganisms and on host signaling. This review summarizes the main microbicidal effects of SCFAs and discusses studies highlighting the effect of SCFAs in the virulence and viability of microorganisms. We also describe the diverse and complex modes of action of the SCFAs on the immune system in the face of infections with a specific focus on bacterial and viral respiratory infections. A growing body of evidence suggests that SCFAs protect against lung infections. Finally, we present potential strategies that may be leveraged to exploit the biological properties of SCFAs for increasing effectiveness and optimizing patient benefits.