HIV Persistence, Latency, and Cure Approaches: Where Are We Now?

The latent reservoir remains a major roadblock to curing human immunodeficiency virus (HIV) infection. Currently available antiretroviral therapy (ART) can suppress active HIV replication, reduce viral loads to undetectable levels, and halt disease progression. However, antiretroviral drugs are unable to target cells that are latently infected with HIV, which can seed viral rebound if ART is stopped.

Prehospital Partial Resuscitative Endovascular Balloon Occlusion of the Aorta for Exsanguinating Subdiaphragmatic Hemorrhage.

Importance: Hemorrhage is the most common cause of preventable death after injury. Most deaths occur early, in the prehospital phase of care.

Objective: To establish whether prehospital zone 1 (supraceliac) partial resuscitative endovascular balloon occlusion of the aorta (Z1 P-REBOA) can be achieved in the resuscitation of adult trauma patients at risk of cardiac arrest and death due to exsanguination.

Cytomegalovirus-induced peroxynitrite promotes virus entry and contributes to pathogenesis in a murine model of infection.

Unlabelled: There are no licensed vaccines for human cytomegalovirus (HCMV), and current antiviral drugs that target viral proteins are toxic and prone to resistance. Targeting host pathways essential for virus replication provides an alternate strategy that may reduce opportunities for drug resistance to occur. Oxidative stress is triggered by numerous viruses including HCMV.

Defining the Effects of PKC Modulator HIV Latency-Reversing Agents on Natural Killer Cells.

Background: Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way.

Predicting blood transfusion following traumatic injury using machine learning models: A systematic review and narrative synthesis.

Background: Hemorrhage is a leading cause of preventable death in trauma. Accurately predicting a patient's blood transfusion requirement is essential but can be difficult. Machine learning (ML) is a field of artificial intelligence that is emerging within medicine for accurate prediction modeling.

Evaluating patient factors, operative management and postoperative outcomes in trauma laparotomy patients worldwide: a protocol for a global observational multicentre trauma study.

Introduction: Trauma contributes to the greatest loss of disability-adjusted life-years for adolescents and young adults worldwide. In the context of global abdominal trauma, the trauma laparotomy is the most commonly performed operation. Variation likely exists in how these patients are managed and their subsequent outcomes, yet very little global data on the topic currently exists.

ASGBI trauma committee position statement: a national audit of trauma laparotomy in the UK - an unmet need.

Patients who undergo laparotomy for major trauma are amongst the most critically unwell patients, and they have high morbidity and mortality rates. Despite 20 yr of improvements in resuscitation practices, those who present with hypotension continue to have mortality rates of up to 50%. Currently there is no mechanism for capturing national audit data on these patients, leading to their exclusion from potential quality improvement initiatives.

Selective aortic arch perfusion: a first-in-human observational cadaveric study.

Background: Selective aortic arch perfusion (SAAP) is a novel endovascular technique that combines thoracic aortic occlusion with extracorporeal perfusion of the brain and heart. SAAP may have a role in both haemorrhagic shock and in cardiac arrest due to coronary ischaemia. Despite promising animal studies, no data is available that describes SAAP in humans.

Regulatory agilities impacting review timelines for Pfizer/BioNTech's BNT162b2 mRNA COVID-19 vaccine: a retrospective study.

The appropriate use of regulatory agilities has the potential to accelerate regulatory review, utilize resources more efficiently and deliver medicines and vaccines more rapidly, all without compromising quality, safety and efficacy. This was clearly demonstrated during the COVID-19 pandemic where regulators and industry rapidly adapted to ensure continued supply of existing critical medicines and review and approve new innovative medicines. In this retrospective study, we analyze the impact of regulatory agilities on the review and approval of Pfizer/BioNTech's BNT162b2 mRNA COVID-19 Vaccine globally using regulatory approval data from 73 country/regional approvals.

Revisiting the promise, practice and progress of resuscitative endovascular balloon occlusion of the aorta.

Purpose Of Review: The use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) to temporarily control bleeding and improve central perfusion in critically injured trauma patients remains a controversial topic. In the last decade, select trauma services around the world have gained experience with REBOA. We discuss the recent observational data together with the initial results of the first randomized control trial and provide a view on the next steps for REBOA in trauma resuscitation.

Understanding pre-hospital blood transfusion decision-making for injured patients: an interview study.

Background: Blood transfusion for bleeding trauma patients is a promising pre-hospital intervention with potential to improve outcomes. However, it is not yet clear which patients may benefit from pre-hospital transfusions. The aim of this study was to enhance our understanding of how experienced pre-hospital clinicians make decisions regarding patient blood loss and the need for transfusion, and explore the factors that influence clinical decision-making.

Inhibitory IL-10-producing CD4 T cells are T-bet-dependent and facilitate cytomegalovirus persistence via coexpression of arginase-1.

Inhibitory CD4 T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity. However, the mechanisms that underpin the development of these regulatory cells, especially in the context of ongoing antigen exposure, have remained obscure. To address this knowledge gap, we undertook a comprehensive functional, phenotypic, and transcriptomic analysis of interleukin (IL)-10-producing CD4 T cells induced by chronic infection with murine cytomegalovirus (MCMV).

HIV establishes an early foothold.

The weeks following HIV acquisition are a critical time when the virus causes significant immunological damage and establishes long-term latent reservoirs. A recent study in Immunity by Gantner et al. uses single-cell analysis to explore these key early infection events, providing insights into early HIV pathogenesis and reservoir formation.

Diagnostic accuracy of clinical examination to identify life- and limb-threatening injuries in trauma patients.

Background: Timely and accurate identification of life- and limb-threatening injuries (LLTIs) is a fundamental objective of trauma care that directly informs triage and treatment decisions. However, the diagnostic accuracy of clinical examination to detect LLTIs is largely unknown, due to the risk of contamination from in-hospital diagnostics in existing studies. Our aim was to assess the diagnostic accuracy of initial clinical examination for detecting life- and limb-threatening injuries (LLTIs).

Secreted factors induced by PKC modulators do not indirectly cause HIV latency reversal.

HIV can establish a long-lived latent infection in cells harboring integrated non-expressing proviruses. Latency reversing agents (LRAs), including protein kinase C (PKC) modulators, can induce expression of latent HIV, thereby reducing the latent reservoir in animal models. However, PKC modulators such as bryostatin-1 also cause cytokine upregulation in peripheral blood mononuclear cells (PBMCs), including cytokines that might independently reverse HIV latency.

IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses.

Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that limits viral pathogenesis and exerts poorly understood immunoregulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 promotes MyD88-dependent, TLR-mediated IL-6 production following exposure to cytomegalovirus (CMV). IFITM3 also restricts IL-6 production in response to influenza and SARS-CoV-2.

Contribution of Sex Differences to HIV Immunology, Pathogenesis, and Cure Approaches.

Approximately 38 million people were living with human immunodeficiency virus (HIV) in 2020 and 53% of those infected were female. A variety of virological and immunological sex-associated differences (sexual dimorphism) in HIV infection have been recognized in males versus females. Social, behavioral, and societal influences play an important role in how the HIV pandemic has affected men and women differently.

Occult tension pneumothorax discovered following imaging for adult trauma patients in the modern major trauma system: a multicentre observational study.

Background: Tension pneumothorax following trauma is a life-threatening emergency and radiological investigation is normally discouraged prior to treatment in traditional trauma doctrines such as ATLS. Some trauma patients may be physiologically stable enough for diagnostic imaging and occult tension pneumothorax is discovered radiologically. We assessed the outcomes of these patients and compared them with those with clinical diagnosis of tension pneumothorax prior to imaging.

Intraoperative delineation of p16+ oropharyngeal carcinoma of unknown primary origin with fluorescence lifetime imaging: Preliminary report.

Background: This study evaluated whether fluorescence lifetime imaging (FLIm), coupled with standard diagnostic workups, could enhance primary lesion detection in patients with p16+ head and neck squamous cell carcinoma of the unknown primary (HNSCCUP).

Methods: FLIm was integrated into transoral robotic surgery to acquire optical data on six HNSCCUP patients' oropharyngeal tissues. An additional 55-patient FLIm dataset, comprising conventional primary tumors, trained a machine learning classifier; the output predicted the presence and location of HNSCCUP for the six patients.

Latency reversal plus natural killer cells diminish HIV reservoir in vivo.

HIV is difficult to eradicate due to the persistence of a long-lived reservoir of latently infected cells. Previous studies have shown that natural killer cells are important to inhibiting HIV infection, but it is unclear whether the administration of natural killer cells can reduce rebound viremia when anti-retroviral therapy is discontinued. Here we show the administration of allogeneic human peripheral blood natural killer cells delays viral rebound following interruption of anti-retroviral therapy in humanized mice infected with HIV-1.

Defence Medical Services' REBOA training course.

Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) enables temporary haemorrhage control and physiological stabilisation. This article describes the bespoke Defence Medical Services (DMS) training package for effectively using REBOA. The article covers how the course was designed, how the key learning objectives are taught, participant feedback and the authors' perceptions of future training challenges and opportunities.