Temporal discrepancies in "rapid" HIV testing: explaining misdiagnoses at the point-of-care in Zimbabwe.

BACKGROUND: Rapid diagnostic tests have revolutionized the HIV response in low resource and high HIV prevalence settings. However, disconcerting levels of misdiagnosis at the point-of-care call for research into their root causes. As rapid HIV tests are technologies that cross borders and have inscribed within them assumptions about the context of implementation, we set out to explore the (mis)match between intended and actual HIV testing practices in Zimbabwe. METHODS: We examined actual HIV testing practices through participant observations in four health facilities and interviews with 28 rapid HIV testers. As time was identified as a key sphere of influence in thematic analyses of the qualitative data, a further layer of analysis juxtaposed intended (as scripted in operating procedures) and actual HIV testing practices from a temporal perspective. RESULTS: We uncover substantial discrepancies between the temporal flows assumed and inscribed into rapid HIV test kits (their intended use) and those presented by the high frequency testing and low resource and staffing realities of healthcare settings in Zimbabwe. Aside from pointing to temporal root causes of misdiagnosis, such as the premature reading of test results, our findings indicate that the rapidity of rapid diagnostic technologies is contingent on a slow, steady, and controlled environment. This not only adds a different dimension to the meaning of "rapid" HIV testing, but suggests that errors are embedded in the design of the diagnostic tests and testing strategies from the outset, by inscribing unrealistic assumptions about the context within which they used. CONCLUSION: Temporal analyses can usefully uncover difficulties in attuning rapid diagnostic test technologies to local contexts. Such insight can help explain potential misdiagnosis 'crisis points' in point-of-care testing, and the need for public health initiatives to identify and challenge the underlying temporal root causes of misdiagnosis.

Ceramide and Related Molecules in Viral Infections.

Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit.

IFNγ and TNFα mediate CCL22/MDC production in alveolar macrophages after hemorrhage and resuscitation.

Acute lung injury is a major complication of hemorrhagic shock and the required resuscitation with large volumes of crystalloid fluids and blood products. We previously identified a role of macrophage-derived chemokine (CCL22/MDC) pulmonary inflammation following hemorrhage and resuscitation. However, further details regarding the induction of CCL22/MDC and its precise role in pulmonary inflammation after trauma remain unknown. In the current study we used in vitro experiments with a murine alveolar macrophage cell line, as well as an in vivo mouse model of hemorrhage and resuscitation, to identify key regulators in CCL22/MDC production. We show that trauma induces expression of IFNγ, which leads to production of CCL22/MDC through a signaling mechanism involving p38 MAPK, NF-κB, JAK, and STAT-1. IFNγ also activates TNFα production by alveolar macrophages, potentiating CCL22/MDC production via an autocrine mechanism. Neutralization of IFNγ or TNFα with specific antibodies reduced histological signs of pulmonary injury after hemorrhage and reduced inflammatory cell infiltration into the lungs.

Therapeutic Inhaled Sphingosine for Treating Lung Infection in a Mouse Model of Critical Illness.

BACKGROUND/AIMS: Sphingosine, a sphingoid long chain base, is a natural lipid with antimicrobial properties. Recent animal studies have shown that preventive sphingosine inhalation can rescue susceptible mice, such as cystic fibrosis-, burn injured- or aged mice from bacterial pulmonary infection. While preventing lung infections in susceptible patients has obvious clinical merit, treatment strategies for an established infection are also direly needed, particularly in the times of rising antibiotic resistance. Here, we tested the potential of sphingosine in treating an established pulmonary infection. METHODS: We used a cecal ligation and puncture (CLP) model in male CF-1 mice and a Pseudomonas aeruginosa strain that was isolated from a septic patient (P. aeruginosa 762). We determined susceptibility to intranasal infection and ascertained when the pulmonary infection was established by continuous core body temperature monitoring. We quantified sphingosine levels in the tracheal epithelium by immunohistochemistry and studied the effects on sphingosine on bacterial membrane permeabilization and intracellular acidification using fluorescent probes. RESULTS: We firstdetermined that septic mice are highly susceptible to P. aeruginosa infection 2 days after indu-cing sepsis. Additionally, at this time, sphingosine levels in the tracheal epithelium are significantly reduced as compared to levels in healthy mice. Secondly, upon intranasal Pseudomonasinoculation, we ascertained that pulmonary infection was established as early as 2.5 h after inoculation as evidenced by a significant drop in core body temperature. Using these times of infection susceptibility and detection (2 days post CLP, 2.5h after inoculation) we treated with inhaled sphingosine and observed pulmonary bacterial loads reduced to levels found in infected healthy mice after inoculation and decreased infection-associated mortality. Further, our data demonstrate that sphingosine induces outer membrane permeabilization, disrupting the membrane potential and leading to intracellular acidification of the bacteria. CONCLUSION: Sphingosine shows efficacy in treating P. aeruginosa lung infections not only prophylactically, but also therapeutically.

Intraperitoneal Neutrophil IL-10 production is promoted by interferon γ in a murine model of sepsis model in the acute phase of sepsis.

The disease burden of sepsis continues to increase, with intraabdominal contamination being a significant source of infection. Sepsis is a syndrome involving both an increase in systemic inflammation as well as a regulatory component. We have previously demonstrated that neutrophils are significant IL-10 producers in the abdomen during sepsis. Here, we sought to further characterize these neutrophils and elucidate potential underlying mechanisms resulting in IL-10 generation. Using transcriptional reporter mice, we observed that IL-10 producing neutrophils were activated, non-apoptotic, and expressed C-X-C chemokine receptor type 4-expressing. Further, we observed that active Signal Transducer and Activator of Transcription 1 expression was significantly increased in IL-10 producing versus non-IL-10 producing neutrophils. During sepsis, IFN-γ blockade lead to a decrease of neutrophil IL-10 production, while peritoneal CD4 T cells were found to be the most numerous acute producers of IFN-γ. Altogether, this report demonstrates that during sepsis, mature neutrophils can potentially dampen local inflammation by IL-10 production and this can be orchestrated by CD4 T cells through an IFN-γ dependent manner.

Consumptive coagulopathy is associated with organ dysfunction during PICS.

Patients who survive the acute phase of sepsis can progress to persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Although sepsis is characterized by early hypercoagulability and delayed hypocoagulability, coagulopathy during chronic critical illness is not fully understood. The objective of this study was to determine whether sepsis-induced PICS is associated with coagulation abnormalities. Using our previously described murine PICS model, outbred mice underwent cecal ligation and puncture, and coagulability was characterized after 8 days. We found that during PICS the spleen became markedly enlarged with increased splenocytes and splenic megakaryocytes without a concomitant increase in circulating platelets. Microscopy revealed a nearly sevenfold increase in pulmonary microvascular thrombi in PICS mice, along with significantly decreased pulmonary tidal volumes and inspiratory times and with significantly increased respiratory rates. Thromboelastometry showed that PICS mice had significantly delayed clot initiation time but increased clot firmness. Finally, PICS mice displayed delayed thrombin production and decreased overall thrombin concentrations. All together, these data demonstrate a general dysregulation of coagulation resulting in microthrombus formation and compromised lung function. On the basis of these findings, we propose that consumptive coagulopathy constitutes another cardinal feature of PICS and may contribute to the ongoing tissue damage and multiple organ failure that can occur in chronic critical illness.

Amitriptyline Reduces Inflammation and Mortality in a Murine Model of Sepsis.

BACKGROUND/AIMS: During sepsis, an unchecked pro-inflammatory response can be detrimental to the host. We investigated the potential protective effect of amitriptyline (AT). METHODS: We used two murine models of sepsis: Cecal ligation and puncture and endotoxemia following LPS challenge. Aural temperatures were taken and cytokines quantified by cytometric bead assay. Lung injury was determined histologically and by protein determination in bronchoalveolar lavage fluid. Cell accumulation in the peritoneum was analyzed by flow cytometry, as well as cytokine production and p38-phosphorylation. Neutrophil chemotaxis was evaluated using an in vitro transwell assay. RESULTS: Our findings demonstrate that AT-treated septic mice have improved survival and are protected from pulmonary edema. Treatment with AT significantly decreased serum levels of KC and monocyte chemoattractant protein-1, as well as the accumulation of neutrophils and monocytes in the peritoneum of septic mice. Peritoneal IL-10 levels in septic mice were increased upon AT treatment. Direct treatment of septic mice with IL-10 recapitulated the effects of AT. Endotoxemic mice also exhibited enhanced IL-10 production upon AT-administration and peritoneal macrophages were identified as the ATinfluenced producers of IL-10. Treatment of these cells with AT in vitro resulted in increased p38-phosphorylation and IL-10 generation, whereas ceramide and p38 inhibition had the opposite effect. CONCLUSION: Altogether, AT treatment improved survival, increased IL-10 levels, and mitigated a pro-inflammatory response during sepsis. We conclude that AT is a promising therapeutic to temper inflammation during septic shock.

The Role of Chemoprophylactic Agents in Modulating Platelet Aggregability After Traumatic Brain Injury.

BACKGROUND: The pathophysiology behind the subacute but persistent hypercoagulable state after traumatic brain injury (TBI) is poorly understood but contributes to morbidity induced by venous thromboembolism. Because platelets and their microvesicles have been hypothesized to play a role in post-traumatic hypercoagulability, administration of commonly used agents may ameliorate this coagulability. We hypothesized that utilization of aspirin, ketorolac, amitriptyline, unfractionated heparin, or enoxaparin would modulate the platelet aggregation response after TBI. METHODS: Concussive TBI was induced by weight drop. Mice were then randomized to receive aspirin, ketorolac, amitriptyline, heparin, enoxaparin, or saline control at 2 and 8 h after TBI. Mice were sacrificed at 6 or 24 h after injury to determine coagulability by rotational thromboelastometry (ROTEM), platelet function testing with impedance aggregometry, and microvesicle enumeration. Platelet sphingolipid metabolites were analyzed by mass spectrometry. RESULTS: ROTEM demonstrated increased platelet contribution to maximum clot firmness at 6 h after TBI in mice that received aspirin or amitriptyline, but this did not persist at 24 h. By contrast, adenosine diphosphate- and arachidonic acid-induced platelet aggregation at 6 h was significantly lower in mice receiving ketorolac, aspirin, and amitriptyline compared with mice receiving saline at 6 h after injury and only arachidonic acid-initiated platelet aggregation was decreased by aspirin at 24 h. There were no differences in microvesicle production at either time point. Platelet sphingosine-1-phosphate levels were decreased at 6 h in the group receiving amitriptyline and increased at 24 h along with platelet ceramide levels at 24 h in the amitriptyline group. CONCLUSION: After TBI, amitriptyline decreased platelet aggregability and increased contribution to clot in a manner similar to aspirin. The amitriptyline effects on platelet function and sphingolipid metabolites may represent a possible role of the acid sphingomyelinase in the hypercoagulability observed after injury. In addition, inhibition of platelet reactivity may be an underappreciated benefit of low molecular weight heparins, such as enoxaparin.

Acid Sphingomyelinase Deficiency Ameliorates Farber Disease.

Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can't achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.

Pathological manifestations of Farber disease in a new mouse model.

Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1tmEx1 mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.

Regulation of Arthritis Severity by the Acid Sphingomyelinase.

BACKGROUND/AIMS: Rheumatoid arthritis is a chronic autoimmune disease hallmarked by inflammation in synovial joints. Treatment is hampered by the lack of a cure and current disease-modifying drugs are associated with potentially severe toxicities. METHODS: We investigated arthritis severity by measuring joint swelling and pro-inflammatory cytokine production in a murine experimental model of inflammatory arthritis (antigen-induced arthritis). We analyzed acid sphingomyelinase knock-out mice and wild-type littermates, as well as mice treated with the pharmacological acid sphingomyelinase inhibitor amitriptyline. RESULTS: Genetic ablation or pharmacological inhibition of acid sphingomyelinase reduced joint swelling and levels of pro-inflammatory cytokines in the arthritic joint. CONCLUSION: We identified acid sphingomyelinase as a novel druggable target in rheumatoid arthritis. Functional inhibitors of acid sphingomyelinase have been clinically used for decades, are well tolerated and suitable for long-term treatment. They would be immediately available for clinical development as a novel rheumatoid arthritis therapy.

Role of Acid Sphingomyelinase-Induced Signaling in Melanoma Cells for Hematogenous Tumor Metastasis.

BACKGROUND: Hematogenous metastasis of malignant tumor cells is a multistep process that requires release of tumor cells from the local tumor mass, interaction of the tumor cells with platelets in the blood, and adhesion of either the activated tumor cells or the complexes of platelets and tumor cells to the endothelial cells of the target organ. We have previously shown that the interaction of melanoma cells with platelets results in the release of acid sphingomyelinase (Asm) from activated platelets. Secreted platelet-derived Asm acts on malignant tumor cells to cluster and activate integrins; such clustering and activation are necessary for tumor cell adhesion to endothelial cells and for metastasis. METHODS: We examined the response of tumor cells to treatment with extracellular sphingomyelinase or co-incubation with wild-type and Asm-deficient platelets. We determined the phosphorylation and activation of several intracellular signaling molecules, in particular p38 kinase (p38K), phospholipase Cx03B3; (PLCx03B3;), ezrin, and extracellular signal-regulated kinases. RESULTS: Incubation of B16F10 melanoma cells with Asm activates p38 MAP kinase (p38K), phospholipase Cx03B3; (PLCx03B3;), ezrin, and extracellular signal-regulated kinases. Co-incubation of B16F10 melanoma cells with wild-type or Asm-deficient platelets showed that the phosphorylation/activation of p38K is dependent on Asm. Pharmacological blockade of p38K prevents activation of ß1 integrin and adhesion in vitro. Most importantly, inhibition of p38K activity in B16F10 melanoma cells prevents tumor cell adhesion and metastasis to the lung in vivo, a finding indicating the importance of p38K for metastasis. CONCLUSIONS: Asm, secreted from activated platelets after tumor cell-platelet contact, induces p38K phosphorylation in tumor cells. This in turn stimulates ß1 integrin activation that is necessary for adhesion and subsequent metastasis of tumor cells. Thus, inhibition of p38K might be a novel target to prevent tumor metastasis.

Fluoxetine and Sertraline Potently Neutralize the Replication of Distinct SARS-CoV-2 Variants.

The pandemic caused by SARS-CoV-2 is still a major health problem. Newly emerging variants and long-COVID-19 represent a challenge for the global health system. In particular, individuals in developing countries with insufficient health care need easily accessible, affordable and effective treatments of COVID-19. Previous studies have demonstrated the efficacy of functional inhibitors of acid sphingomyelinase against infections with various viruses, including early variants of SARS-CoV-2. This work investigated whether the acid sphingomyelinase inhibitors fluoxetine and sertraline, usually used as antidepressant molecules in clinical practice, can inhibit the replication of the former and recently emerged SARS-CoV-2 variants in vitro. Fluoxetine and sertraline potently inhibited the infection with pseudotyped virus-like particles and SARS-CoV-2 variants D614G, alpha, delta, omicron BA.1 and omicron BA.5. These results highlight fluoxetine and sertraline as priority candidates for large-scale phase 3 clinical trials at different stages of SARS-CoV-2 infections, either alone or in combination with other medications.

Responding to medical crises: AIDS treatment, responsibilisation and the logic of choice.

The framing of HIV/AIDS as a crisis has facilitated the rollout of large-scale intervention programmes that represent an enormous effort at mainstreaming biomedical rationalities and neoliberal notions of responsibilisation and self-care. Based on a 'logic of choice' (Mol 2008) and 'responsibilised citizenship' (Robins 2005a), although veiled in a language of rights and partnership, the heavy focus on individual behaviour and a pharmaceutical 'solution' to AIDS shifts the burden of responsibility for the success of the heavily funded programmes onto the shoulders of the patients and conceals alternative forms of responsibility. Analysing how HIV-positive people in Tanzania navigate life with HIV and the complex treatment regimens, this paper looks beyond biomedical rationality, which places the preservation of individual biological life at the centre of its logic, and analyses people's constant struggle to negotiate the meaning of 'responsible behaviour' in the context of their lived realities. This repositions the notion of responsibility in the realm of the social and reveals the rationality behind apparently irrational practices.

Role and effectiveness of telephone hotlines in outbreak response in Africa: A systematic review and meta-analysis.

BACKGROUND: In Africa, little is known about the role of telephone hotlines in outbreak response. We systematically reviewed the role and effectiveness of hotlines on outbreak response in Africa. METHOD: We used the Cochrane handbook and searched five databases. The protocol was registered on PROSPERO (CRD42021247141). Medline, Embase, PsycINFO, Global Health and Web of Science were searched from 30 June 2020 to August 2020 for studies on the use of telephone hotlines in outbreak response in Africa published between January 1995 and August 2020. The search was also repeated on 16 September 2022. Data on effectiveness (alerts generated, cases confirmed) were extracted from peer-reviewed studies. Meta-analysis of alerts generated, and proportion of cases confirmed was done using the random effects model. The quality of studies was assessed using the Joanna Briggs Institute (JBI) tools. The heterogeneity and publication bias were assessed using the Galbraith and funnel plots, respectively. RESULTS: Our search yielded 1251 non-duplicate citations that were assessed. 41 full texts were identified, and 21 studies were included in the narrative synthesis, while 12 were included in the meta-analysis. The hotlines were local (seven studies) or national (three studies). A combination of a local and national hotline was used in one study. The hotlines were set up for unusual respiratory events (one study), polio (one study), Ebola (10 studies), COVID-19 (two studies), malaria (one study), influenza-like illnesses (ILI) (one study) and rift valley fever in livestock (one study). Hotlines were mainly used for outbreak surveillance at the local level. A total of 332,323 alerts were generated, and 67,658 met the case definition, corresponding to an overall pooled proportion of alerts generated(sensitivity) of 38% (95%CI: 24-52%). The sensitivity was 41% (95% CI: 24-59%) for local hotlines and 26%(95%CI:5-47%) for national hotlines. Hotlines were also used for surveillance of rift valley fever in livestock (one study) vaccination promotion (one study), death reporting (five studies), rumour tracking and fighting misinformation (two studies) and community engagement (five studies). The studies were of low to moderate quality with high publication bias and heterogeneity(I2 = 99%). The heterogeneity was not explained by the sample size. CONCLUSION: These data suggest that telephone hotlines can be effective in outbreak disease surveillance in Africa. Further implementation research is needed to scale up telephone hotlines in rural areas.

The (In)visibility of Misdiagnosis in Point-of-Care HIV Testing in Zimbabwe.

There is a global trend to introduce point-of-care diagnostic tests, enabling healthcare workers at any level to test, provide results, and initiate immediate treatment if necessary. This article explores how healthcare workers conducting rapid HIV tests - in contexts of limited external quality assurance mechanisms - ascertain the accuracy of their test results. Drawing on interview data and participant observations from health facilities in Zimbabwe, we open the black box of misdiagnosis (in)visibility and reveal a range of proxies and markers that HIV testers draw on to develop certainty, or question, the reliability of their diagnostic classifications.

Rituals of care: Strategies adopted by HIV testers to avoid misdiagnosis in rapid HIV testing in Zimbabwe.

A growing number of studies highlight high levels of misdiagnosis in the scale-up of HIV rapid testing programmes, which often remain invisible to individual testers. Drawing on interviews with HIV testers and observations in four health facilities in Zimbabwe, we show that testers navigated the translation of the standardised, dis-embodied norms of laboratory-based testing into the body work of point-of-care testing through ritualisation of laboratory-practices in their daily clinical work. Yet, this was interrupted through the challenging work conditions the testers face. They ritualised careful procedures, forcing themselves to focus even if queues were long, and making quality assurance procedures part of their daily routine. They actively tried to reduce their workloads and double-checked and discussed unexpected results, especially when a test result did not match their evaluation of clients' circumstances or clinical status. This helped not only to increase confidence in the authenticity of their diagnosis, but also to share responsibility for potential errors. Existing approaches to tackle the problem of misdiagnosis through quality assurance (QA) procedures mainly focus on adjusting individual testers' performance and ensuring that basic testing resources were present, thus falling short of creating a work environment that is conducive to high quality testing.

Burn Injury Impairs Neutrophil Chemotaxis Through Increased Ceramide.

ABSTRACT: Infection is a common and often deadly complication after burn injury. A major underlying factor is burn-induced immune dysfunction, particularly with respect to neutrophils as the primary responders to infection. Temporally after murine scald injury, we demonstrate impaired bone marrow neutrophil chemotaxis toward CXCL1 ex vivo. Additionally, we observed a reduced recruitment of neutrophils to the peritoneal after elicitation 7 days after injury. We demonstrate that neutrophil ceramide levels increase after burn injury, and this is associated with decreased expression of CXCR2 and blunted chemotaxis. A major signaling event upon CXCR2 activation is Akt phosphorylation and this was reduced when ceramide was elevated. In contrast, PTEN levels were elevated and PTEN-inhibition elevated phospho-Akt levels and mitigated the burn-induced neutrophil chemotaxis defect. Altogether, this study identifies a newly described pathway of ceramide-mediated suppression of neutrophil chemotaxis after burn injury and introduces potential targets to mitigate this defect and reduce infection-related morbidity and mortality after burn.

Novel Therapeutics for the Treatment of Burn Infection.

Background: Burn injury continues to be a significant cause of morbidity and death, with infectious complications being the primary cause of death. Patients are susceptible to overwhelming infection secondary to both the physical breakdown of the skin and mucosal barrier and the immune dysfunction that accompanies the inflammatory response to a major burn. With resistance to traditional antibiosis looming as a serious threat to patient outcome, advancement in the treatment of burn infections is imperative. Methods: Between February 15 and March 15, 2020, a search of Pubmed and clinicaltrials.gov was performed using search terms such as "burn immunotherapy," "therapeutic microorganisms in burn," "burn infection clinical trials," and applicable variations. Results: Topical antimicrobial drugs continue to be standard of care for burn wound injuries, but personalized and molecular treatments that rely on immune manipulation of the host show great promise. We discuss novel therapeutics for the treatment of burn infection: Probiotics and therapeutic microorganisms, immune modulators, tailored monoclonal antibodies, and extracellular vesicles and proteins. Conclusions: The treatment strategies discussed employ manipulation of structure and function in host immune cells and pathogen virulence for improved outcomes in burn infection.

Potential Targets to Mitigate Trauma- or Sepsis-Induced Immune Suppression.

In sepsis and trauma, pathogens and injured tissue provoke a systemic inflammatory reaction which can lead to overwhelming inflammation. Concurrent with the innate hyperinflammatory response is adaptive immune suppression that can become chronic. A current key issue today is that patients who undergo intensive medical care after sepsis or trauma have a high mortality rate after being discharged. This high mortality is thought to be associated with persistent immunosuppression. Knowledge about the pathophysiology leading to this state remains fragmented. Immunosuppressive cytokines play an essential role in mediating and upholding immunosuppression in these patients. Specifically, the cytokines Interleukin-10 (IL-10), Transforming Growth Factor-ß (TGF-ß) and Thymic stromal lymphopoietin (TSLP) are reported to have potent immunosuppressive capacities. Here, we review their ability to suppress inflammation, their dynamics in sepsis and trauma and what drives the pathologic release of these cytokines. They do exert paradoxical effects under certain conditions, which makes it necessary to evaluate their functions in the context of dynamic changes post-sepsis and trauma. Several drugs modulating their functions are currently in clinical trials in the treatment of other pathologies. We provide an overview of the current literature on the effects of IL-10, TGF-ß and TSLP in sepsis and trauma and suggest therapeutic approaches for their modulation.