Addressing Antiretroviral Drug Resistance with Host-Targeting Drugs—First Steps towards Developing a Host-Targeting HIV-1 Assembly Inhibitor

The concerning increase in HIV-1 resistance argues for prioritizing the development of host-targeting antiviral drugs because such drugs can offer high genetic barriers to the selection of drug-resistant viral variants. Targeting host proteins could also yield drugs that act on viral life cycle events that have proven elusive to inhibition, such as intracellular events of HIV-1 immature capsid assembly. Here, we review small molecule inhibitors identified primarily through HIV-1 self-assembly screens and describe how all act either narrowly post-entry or broadly on early and late events of the HIV-1 life cycle. We propose that a different screening approach could identify compounds that specifically inhibit HIV-1 Gag assembly, as was observed when a potent rabies virus inhibitor was identified using a host-catalyzed rabies assembly screen. As an example of this possibility, we discuss an antiretroviral small molecule recently identified using a screen that recapitulates the host-catalyzed HIV-1 capsid assembly pathway. This chemotype potently blocks HIV-1 replication in T cells by specifically inhibiting immature HIV-1 capsid assembly but fails to select for resistant viral variants over 37 passages, suggesting a host protein target. Development of such small molecules could yield novel host-targeting antiretroviral drugs and provide insight into chronic diseases resulting from dysregulation of host machinery targeted by these drugs.     

Alcohol Use Disorders in ICD‐11: Past,Present, and Future

The Eleventh Revision of the International Classification of Diseases (ICD‐11) was formally published in May 2019. Alcohol use disorders form a key part of the section of Disorders due to Substance Use and Addictive Behaviours. This review describes and discusses the alcohol diagnoses within this section of ICD‐11, including Alcohol Dependence, Harmful Pattern of Use of Alcohol, and entities such as Alcohol Intoxication, Alcohol Withdrawal, and several alcohol‐induced mental disorders, and briefly covers Hazardous Alcohol Use, which is listed separately as a health risk factor. We summarize the historical background to the development of these diagnoses, including work within the World Health Organization since the 1970s, and the corresponding diagnoses in the current ICD‐10. The process by which ICD‐11 diagnoses have been made is described and may be summarized as a conceptual–pragmatic–confirmatory one. The available empirical data supporting the ICD‐11 diagnoses are presented, particularly in relation to the diagnostic guidelines for Alcohol Dependence. Comparison is made with the corresponding diagnoses in ICD‐10 and their nearest counterparts in the fourth and fifth editions of the Diagnostic and Statistical Manual of Mental Disorders. Field testing of the ICD‐11 diagnoses is currently in progress. A plea is made for matching of diagnoses, diagnostic guidelines/criteria, and the assessment tools intended to capture these diagnoses.     

Practice patterns of VTE chemoprophylaxis after discharge following hepatic and pancreatic resections for cancer: A survey of hepatopancreatobiliary surgeons

Journal of Thrombosis and Thrombolysis - Patients with hepatopancreatobiliary (HPB) malignancies undergoing resection are prone to venous thromboembolism (VTE), and current guidelines recommend up...     

Immunologically reactive <Emphasis Type=Italic>M. leprae</Emphasis> antigens with relevance to diagnosis and vaccine development

Background  

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that can manifest a wide variety of immunological and clinical outcomes ranging from potent humoral responses among borderline lepromatous (BL) and lepromatous (LL) patients to strong cellular responses among tuberculoid (TT) and borderline tuberculoid (BT) patients. Until recently, relatively little has been known about the immune responses to individual proteins of M. leprae recognized during leprosy.     

P ARAMEDIC U SE OF E NDOTRACHEAL T UBE I NTRODUCERS FOR THE D IFFICULT A IRWAY

Objective. To evaluate the ability of paramedics to learn and apply the skill of introducer-aided oral intubation in the setting of the simulated “difficult airway.” The authors hypothesized that, following a brief introduction to the device, intubation success rates would not differ for traditional and introducer-aided intubations of an immobilized airway mannequin. Methods. During a paramedic recertification class, experienced paramedics were given a brief didactic introduction to the “bougie-like” Flex Guide endotracheal tube introducer (ETTI). The participants were then asked to intubate adult mannequins immobilized in the head-neutral position, with and without the ETTI. “Successful placement” was defined as completion of the procedure within 30 seconds and endotracheal tube position confirmed by the investigator with direct visualization. Results. For both traditional and ETTI intubations, 34 (97%) of the 35 paramedics successfully intubated within 30 seconds. The two unsuccessful intubation attempts were recognized by the paramedic as esophageal intubations, and correct tube placement was obtained within an additional 30 seconds. Conclusion. In this study, use of the ETTI was mastered by the participants after only a brief didactic introduction to the device, with their ability to intubate an immobilized mannequin using the ETTI being equal to their ability to perform traditional intubation. These results suggest that use of the ETTI is easily learned, and may support the device's role in the prehospital management of the difficult airway.