Antibiotic resistant bacterial infections are increasingly an issue in allogenic hematopoietic stem cell transplant patients. How antibiotic treatment impacts antibiotic resistance in the human gut microbiome remains poorly understood in vivo. Here, a total of 577 fecal samples from 233 heavily antibiotic-treated transplant patients were examined using high-resolution prescription data and shotgun metagenomics. The 13 most frequently used antibiotics were significantly associated with 154 (40% of tested associations) microbiome features. Use of broad-spectrum beta-lactam antibiotics was most markedly associated with microbial disruption and increase in resistome features. The enterococcal vanA gene was positively associated with eight of the 13 antibiotics, and in particular piperacillin/tazobactam and vancomycin. Here, we highlight the need for a high-resolution approach in understanding the development of antibiotic resistance in the gut microbiome. Our findings can be used to inform antibiotic stewardship and combat the increasing threat of antibiotic resistance.

The number of newly diagnosed human immunodeficiency virus (HIV) cases among Chinese youth 15-24 years of age shows an upward trend between 2010 and 2019.

Pericardial effusion is a relatively common cardiac pathology associated with various infectious and non-infectious etiologies. In developed countries, viral pericarditis and idiopathic reasons are the two most common causes of this condition. Mycobacterium tuberculosis is prevalent in developing countries and is the most common cause of pericardial effusion in these regions. Parasitic and bacterial etiologies are encountered less frequently. In this report, we describe the case of a large pericardial effusion in a patient with HIV and latent tuberculosis (TB). Pericardiocentesis and analysis of pericardial fluid did not reveal any specific etiology, indicating viral or idiopathic pericarditis as an etiology. We also present an analysis of global data related to pericardial effusion in HIV/AIDS patients, and the impact that the increasing availability of antiretroviral therapy (ART) worldwide over the last three decades had had on it. The CD4 count has been described as an essential factor for the prognosis of this condition. Patients with lower CD4 count levels would be at higher risk of severe pericardial effusion.

The extracorporeal membrane oxygenation (ECMO) procedure aids in the provision of prolonged cardiopulmonary support, whereas the Impella device (Abiomed, Danvers, MA) is a ventricular assist device that maintains circulation by pumping blood into the aorta from the left ventricle. Blood is circulated in parallel with the heart by Impella. It draws blood straight into the aorta from the left ventricle, hence preserving the physiological flow. ECMO bypasses the left atrium and the left ventricle, and the end consequence is a non-physiological flow. In this article, we conducted a detailed analysis of various publications in the literature and examined various modalities pertaining to the use of ECMO and Impella for cardiogenic shocks, such as efficacy, clinical outcomes, cost-effectiveness, device-related complications, and limitations. The Impella completely unloads the left ventricle, thereby significantly reducing the effort of the heart. Comparatively, ECMO only stabilizes a patient with cardiogenic shock for a short stretch of time and does not lessen the efforts of the left ventricle ("unload" it). In the acute setting, both devices reduced left ventricular end-diastolic pressure and provided adequate hemodynamic support. By comparing patients on Impella to those receiving ECMO, it was found that patients on Impella were associated with better clinical results, quicker recovery, limited complications, and reduced healthcare costs; however, there is a lack of conclusive studies performed demonstrating the reduction in long-term mortality rates. Considering the effectiveness of given modalities and taking into account the various studies described in the literature, Impella has reported better clinical outcomes although more clinical trials are needed for establishing the effectiveness of these interventional approaches in revascularization in cardiogenic shock.

The frequent outbreaks of the AIDS (Acquired Immune Deficiency Syndrome) pandemic and the limited availability of anti-Human Immunodeficiency Virus (HIV) drugs highlight the urgent need to develop new antiviral drugs. A detailed understanding of the interactions between TAR-Binding Proteins (TBP) and RNA will facilitate the discovery of new anti-AIDS drugs. In order to characterize and explore the key interactions between RNA and TBP, we focused on the wild type (WT) and three mutant TBPs (TBP6.9, TBP6.7, and TBP6.3) with RNA, multiple molecular dynamics simulation and energy computation were performed. The results showed that 12 key residues played a major role in the interaction between TBP and RNA. The mutated residues of TBP changed the interaction between their surrounding residues and RNA, thus affecting the binding of TBP to RNA. In addition, structural and energy analyses showed that in contrast with WT TBP-RNA complex, the mutated residues had little effect on the backbone structure of TBP, but changes in the van der Waals interactions and electrostatic interaction associated with the side chains are responsible for the altered the binding between three mutant TBPs and RNA complexes. The discovery of TBP-RNA recognition mechanism in our work provides some useful insights and new opportunities for the development of anti-aids drugs.

Combination antiretroviral therapy (cART) has dramatically reduced morbidity and mortality of HIV-1-infected patients. Integrase strand transfer inhibitors (INSTIs) play an important role as a key drug in cART. The second-generation INSTIs are very potent, but due to the emergence of highly resistant viruses and the demand for more conveniently usable drugs, the development of "third-generation" INSTIs and mechanistically different inhibitors is actively being pursued.

With a long epidemic history and a large number of dengue cases, Guangzhou is a key city for controlling dengue in China. The demographic information regarding dengue cases, and the genomic characteristics of the envelope gene of dengue viruses, as well as the associations between these factors were investigated from 2010 to 2019, to improve the understanding of the epidemiology of dengue in Guangzhou. Demographic data on 44,385 dengue cases reported to the Notifiable Infectious Disease Report System were analyzed using IBM SPSS Statistics v. 20. Dengue virus isolates from patient sera were sequenced, and phylogenetic trees were constructed using PhyML 3.1. There was no statistical difference in the risk of dengue infection between males and females. Unlike other areas in which dengue is endemic, the infection risk in Guangzhou increased with age. Surveillance identified four serotypes responsible for dengue infections in Guangzhou. Serotype 1 remained prevalent for most of the study period, whereas serotypes 3 and 4 were prevalent in 2012 and 2010, respectively. Different serotypes underwent genotype and sublineage shifts. The epidemiological characteristics and phylogeny of dengue in Guangzhou suggested that although it has circulated in Guangzhou for decades, it has not been endemic in Guangzhou. Meanwhile, shifts in genotypes, rather than in serotypes, might have caused dengue epidemics in Guangzhou.

The COVID-19 pandemic posed unprecedented challenges to HIV services globally. We evaluated the impact of the COVID-19 pandemic on the uptake of HIV testing in the Targeted Intervention (TI) program in Maharashtra-a high HIV burden state in India. Annual HIV testing was sustained during the pandemic year (2020-2021), at levels similar to the pre-pandemic year (2019-2020), among Female Sex Workers (FSW), Men having Sex with Men (MSM), Transgender (TG), and Truckers; but not among Migrants and Intravenous Drug Users (IDU). There was an acute decline during the lockdown across all typologies. Sharp recovery was seen among FSW, MSM, and TG during the early months of the un-lockdown. The community-based screening (CBS) approach primarily contributed to this recovery. Among migrants and truckers, recovery was delayed. There was an overall reduction of 58% in annual HIV-positive registrations. The community-based networks, participatory structures, and processes of HIV programs played an essential role in reaching the community during the pandemic.

The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2 or megalin) is representative of the phylogenetically conserved subfamily of giant LDL receptor-related proteins, which function in endocytosis and are implicated in diseases of the kidney and brain. Here, we report high-resolution cryoelectron microscopy structures of LRP2 isolated from mouse kidney, at extracellular and endosomal pH. The structures reveal LRP2 to be a molecular machine that adopts a conformation for ligand binding at the cell surface and for ligand shedding in the endosome. LRP2 forms a homodimer, the conformational transformation of which is governed by pH-sensitive sites at both homodimer and intra-protomer interfaces. A subset of LRP2 deleterious missense variants in humans appears to impair homodimer assembly. These observations lay the foundation for further understanding the function and mechanism of LDL receptors and implicate homodimerization as a conserved feature of the LRP receptor subfamily.

Conspiracy theories (evidence-free, improbable narratives about powerful agents conspiring to harm people) circulated widely during the acquired immune deficiency syndrome (AIDS) and COVID-19 epidemics. They travelled over time and space, adapted to local conditions and anxieties, and were promoted for commercial and political purposes. Russian conspiracy theories claiming the viruses were United States bioweapons appeared in both epidemics. So did 'cultropreneurs' who, as a marketing strategy for their 'alternative' therapies, promoted conspiracy theories about scientific medicine. Pro-science activists sought to counter medical misinformation and debunk faux cures, but their task was harder in the 'post-truth' social-media driven context of COVID-19. Conspiracy theories about vaccines are an ongoing challenge for public health.

Although the causes of multiple sclerosis are largely unknown, genetic and environmental components play an important role. Geographic distribution, varying with latitude, reflects both genetic and environmental influences. We conducted a retrospective exploratory observational study to characterize the disability progression of 2396 Jewish patients with relapsing-remitting multiple sclerosis, followed at the Sheba Multiple Sclerosis Center, Tel-Aviv, Israel; 188 patients who originated in Iraq and 2207 patients who originated in northern Europe. Peripheral blood microarray gene expression analysis was performed in a subgroup of patients to identify molecular pathways associated with faster disability progression. During a follow-up period of 18.8 and 19.8 years, respectively, 51.6% of patients with an Iraqi origin progressed to moderate disability defined as expanded disability status scale (EDSS) score of 3.0 to 5.5, compared to 44.2% of patients with a northern European origin (odds ratio 1.347, 95% CI 1.0-1.815, p = 0.049). An Iraqi origin was associated with increased risk of progression to moderate disability adjusted for sex, disease duration, age at onset, and treatment with immunomodulatory drugs (hazard ratio 1.323; 95% CI, 1.049-1.668, p = 0.02), but not to severe disability defined as EDSS score > = 6.0 (i.e., walking aids are required for a distance of 100 meters, (hazard ratio 1.311; 95% CI, 0.918-1.874, p = 0.136). Gene expression analysis disclosed 98 differentially expressed genes (79 over-expressed and 19 under-expressed) between relapsing-remitting multiple sclerosis patients of Iraqi origin (N = 17) and northern European (N = 34) origin. Interestingly, this gene expression was enriched with genes related to neuronal pathways associated with morphology of axons, branching of neurites, proliferation of neocortical neurons, and formation of myelin sheath, suggesting an augmented process of neurodegeneration in relapsing-remitting multiple sclerosis patients with an Iraqi origin. The study results suggest that relapsing-remitting multiple sclerosis patients with an Iraqi origin progress faster to disability possibly due to an enhanced process of neurodegeneration.

Rhesus cytomegalovirus (RhCMV)-based vaccine vectors induce immune responses that protect ~60% of rhesus macaques (RMs) from SIVmac239 challenge. This efficacy depends on induction of effector memory (EM)-biased CD8+ T cells recognizing SIV peptides presented by major histocompatibility complex (MHC)-E instead of MHC-Ia. The phenotype, durability, and efficacy of RhCMV/SIV-elicited cellular immune responses were maintained when vector spread was severely reduced by deleting the anti-host intrinsic immunity factor pp71. Here, we examined the impact of an even more stringent attenuation strategy on vector-induced immune protection against SIV. Fusion of the FK506-binding protein (FKBP) degradation domain to Rh108, the orthologue of the essential human CMV (HCMV) late gene transcription factor UL79, generated RhCMV/SIV vectors that conditionally replicate only when the FK506-analog Shield-1 is present. Despite lacking in vivo dissemination and reduced innate and B cell responses to vaccination, Rh108-deficient 68-1 RhCMV/SIV vectors elicited high frequency, durable, EM-biased, SIV-specific T cell responses in RhCMV-seropositive RM at doses of ≥106 PFU. Strikingly, elicited CD8+ T cells exclusively targeted MHC-Ia-restricted epitopes and failed to protect against SIVmac239 challenge. Thus, Rh108-dependent late gene expression is required for both induction of MHC-E-restricted T cells and protection against SIV.

Mycobacterium tuberculosis is the most common opportunistic infection among patients with human immunodeficiency virus (HIV) infection, and it is also the leading cause of death, causing approximately one-third of acquired immune deficiency syndrome deaths worldwide. China is on the World Health Organization's global list of 30 high-tuberculosis (TB) burden countries. The objective of this study was to evaluate the mortality rate, survival probabilities, and factors associated with death among patients with TB/HIV co-infection undergoing TB treatment in Sichuan, China. A retrospective cohort study was conducted using the Chinese National TB Surveillance System data of TB/HIV co-infected patients enrolled in TB treatment from January 2020 to December 2020. We calculated the mortality rate and survival probabilities using the Kaplan-Meier estimator, and a Cox proportional hazard model was conducted to identify independent risk factors for TB/HIV co-infection mortality. Hazard ratios and their respective 95% confidence intervals were also reported in this study. Of 828 TB/HIV co-infected patients, 44 (5.31%) died during TB treatment, and the crude mortality rate was 7.76 per 1000 person-months. More than half of the deaths (n = 23) occurred in the first 3 months of TB treatment. Overall survival probabilities were 97.20%, 95.16%, and 91.75% at 3rd, 6th, and 12th month respectively. The independent risk factors for mortality among TB/HIV co-infected patients were having extra-pulmonary TB and pulmonary TB co-infection, history of antiretroviral therapy interruption, and baseline cluster of differentiation 4 T-lymphocyte counts <200 cells/μL at the time of HIV diagnosis. Antiretroviral therapy is important for the survival of TB/HIV co-infected patients, and it is recommended to help prolong life by restoring immune function and preventing extra-pulmonary TB.

Current COVID-19 vaccines have been associated with a decline in infection rates, prevention of severe disease and a decrease in mortality rates. However, SARS-CoV-2 variants are continuously evolving, and development of new accessible COVID-19 vaccines is essential to mitigate the pandemic. Here, we present data on preclinical studies in mice of a receptor-binding domain (RBD)-based recombinant protein vaccine (PHH-1V) consisting of an RBD fusion heterodimer comprising the B.1.351 and B.1.1.7 SARS-CoV-2 variants formulated in SQBA adjuvant, an oil-in-water emulsion. A prime-boost immunisation with PHH-1V in BALB/c and K18-hACE2 mice induced a CD4+ and CD8+ T cell response and RBD-binding antibodies with neutralising activity against several variants, and also showed a good tolerability profile. Significantly, RBD fusion heterodimer vaccination conferred 100% efficacy, preventing mortality in SARS-CoV-2 infected K18-hACE2 mice, but also reducing Beta, Delta and Omicron infection in lower respiratory airways. These findings demonstrate the feasibility of this recombinant vaccine strategy.

Dynein is the primary minus-end-directed microtubule motor [1]. To achieve activation, dynein binds to the dynactin complex and an adaptor to form the "activated dynein complex" [2, 3]. The protein Lis1 aids activation by binding to dynein and promoting its association with dynactin and adaptor [4, 5]. Ndel1 and its orthologue Nde1 are dynein and Lis1 binding proteins that help control where dynein localizes within the cell [6]. Cell-based assays suggest that Ndel1/Nde1 also work with Lis1 to promote dynein activation, although the underlying mechanism is unclear [6]. Using purified proteins and quantitative binding assays, we found that Ndel1's C-terminal region contributes to binding to dynein and negatively regulates binding to Lis1. Using single-molecule imaging and protein biochemistry, we observed that Ndel1 inhibits dynein activation in two distinct ways. First, Ndel1 disfavors the formation of the activated dynein complex. We found that phosphomimetic mutations in Ndel1's C-terminal domain increase its ability to inhibit dynein-dynactin-adaptor complex formation. Second, we observed that Ndel1 interacts with dynein and Lis1 simultaneously and sequesters Lis1 away from its dynein binding site. In doing this, Ndel1 prevents Lis1-mediated dynein activation. Our work suggests that in vitro , Ndel1 is a negative regulator of dynein activation, which contrasts with cellular studies where Ndel1 promotes dynein activity. To reconcile our findings with previous work, we posit that Ndel1 functions to scaffold dynein and Lis1 together while keeping dynein in an inhibited state. We speculate that Ndel1 release can be triggered in cellular settings to allow for timed dynein activation.