Real-World Experience With Maribavir for Treatment of Cytomegalovirus Infection in High-Risk Solid Organ Transplant Recipients.

We evaluated use of maribavir (MBV) for treatment of 15 episodes of refractory/resistant cytomegalovirus infection in 13 solid organ transplant recipients. Treatment failure due to treatment-emergent MBV resistance or early virological recurrence after MBV discontinuation occurred in 7 (47%) episodes. Sustained viral clearance was achieved in 6 (40%) episodes.

Bacillus subtilis-derived peptides disrupt quorum sensing and biofilm assembly in multidrug-resistant Staphylococcus aureus.

Multidrug-resistant Staphylococcus aureus is one of the most clinically important pathogens in the world, with infections leading to high rates of morbidity and mortality in both humans and animals. The ability of S. aureus to form biofilms protects cells from antibiotics and promotes the transfer of antibiotic resistance genes; therefore, new strategies aimed at inhibiting biofilm growth are urgently needed. Probiotic species, including Bacillus subtilis, are gaining interest as potential therapies against S. aureus for their ability to reduce S. aureus colonization and virulence. Here, we search for strains and microbially derived compounds with strong antibiofilm activity against multidrug-resistant S. aureus by isolating and screening Bacillus strains from a variety of agricultural environments. From a total of 1,123 environmental isolates, we identify a single strain B. subtilis 6D1, with a potent ability to inhibit biofilm growth, disassemble mature biofilm, and improve antibiotic sensitivity of S. aureus biofilms through an Agr quorum sensing interference mechanism. Biochemical and molecular networking analysis of an active organic fraction revealed multiple surfactin isoforms, and an uncharacterized peptide was driving this antibiofilm activity. Compared with commercial high-performance liquid chromatography grade surfactin obtained from B. subtilis, we show these B. subtilis 6D1 peptides are significantly better at inhibiting biofilm formation in all four S. aureus Agr backgrounds and preventing S. aureus-induced cytotoxicity when applied to HT29 human intestinal cells. Our study illustrates the potential of exploring microbial strain diversity to discover novel antibiofilm agents that may help combat multidrug-resistant S. aureus infections and enhance antibiotic efficacy in clinical and veterinary settings. IMPORTANCE: The formation of biofilms by multidrug-resistant bacterial pathogens, such as Staphylococcus aureus, increases these microorganisms' virulence and decreases the efficacy of common antibiotic regimens. Probiotics possess a variety of strain-specific strategies to reduce biofilm formation in competing organisms; however, the mechanisms and compounds responsible for these phenomena often go uncharacterized. In this study, we identified a mixture of small probiotic-derived peptides capable of Agr quorum sensing interference as one of the mechanisms driving antibiofilm activity against S. aureus. This collection of peptides also improved antibiotic killing and protected human gut epithelial cells from S. aureus-induced toxicity by stimulating an adaptive cytokine response. We conclude that purposeful strain screening and selection efforts can be used to identify unique probiotic strains that possess specially desired mechanisms of action. This information can be used to further improve our understanding of the ways in which probiotic and probiotic-derived compounds can be applied to prevent bacterial infections or improve bacterial sensitivity to antibiotics in clinical and agricultural settings.

Hydration State Throughout Porcine Lumbar Intervertebral Discs: Comparing Fresh and Frozen-Thawed Specimens.

Water content in intervertebral discs (IVDs) is essential for physiological and mechanical function. Freezing post-mortem tissue prior to biomechanical testing is a common practice to prevent tissue degradation, but this process has been theorized to alter hydration within IVDs. The hydration state throughout porcine lumbar IVDs, a common lumbar surrogate, is unknown as are the effects of freezing on porcine IVD hydration. Nineteen porcine lumbar spines were stored in one of the three conditions: frozen (- 20 °C) wrapped in saline-soaked gauze, frozen (- 20 °C) without saline, or fresh. Water content was measured in four disc regions within each of 89 discs: nucleus pulposus (NP), inner (AF-A), intermediate (AF-B), and outer (AF-C) annulus fibrosus. A three-factor, repeated measure analysis of variance was conducted for storage condition, spinal level, and repeated measure disc region. No significant differences were observed in spinal level or storage condition as a main effect. Mean hydration was significantly different in each disc region with mass percentage of water found to be 88.8 ± 1.7% in NP, 79.6 ± 3.8% in AF-A, 71.9 ± 3.7% in AF-B, and 62.3 ± 3.3% in AF-C. No significant differences were shown in NP and AF-C regions between storage conditions. Two significant differences in storage condition were observed in AF-A and AF-B regions, but there is likely no biological difference in these populations. Water content throughout porcine lumbar IVD was determined and results suggest one freeze-thaw cycle at - 20 °C does not alter the overall hydration within the porcine lumbar IVD.

Obstruction from endometriosis causing hydronephrosis and complex renal pelvis rupture: A case report.

Endometriosis presents a diagnostic conundrum due to its diverse clinical manifestations, ranging from asymptomatic to acute obstructive uropathy. This is a case of a 30-year-old woman with a history of endometriosis and rapidly progressing left flank pain culminating in rupture of the renal pelvis in her left kidney. Initial investigations revealed left-sided hydronephrosis without evidence of nephrolithiasis. Subsequent imaging showed active extravasation indicative of urinary obstruction attributable to endometriosis. Placement of a left nephrostomy tube alleviated her symptoms, and follow-up imaging revealed a distal ureteral stricture. A stent was subsequently placed, which resolved the obstruction and obviated the need for extensive surgical intervention. In this case, the patient's history of endometriosis prompted consideration of its role in urinary obstruction, despite the absence of typical symptoms, and underscores the importance of considering endometriosis as a potential cause of acute urinary obstruction, particularly in patients with a history of the disease. Physicians in the emergency department should maintain a high index of suspicion for endometriosis-related complications to facilitate timely intervention and prevent adverse outcomes. Awareness of the variable presentations of endometriosis is paramount for ensuring comprehensive patient care and optimal outcomes.

Biofidelity and Limitations of Instrumented Mouthguard Systems for Assessment of Rigid Body Head Kinematics.

Instrumented mouthguard systems (iMGs) are commonly used to study rigid body head kinematics across a variety of athletic environments. Previous work has found good fidelity for iMGs rigidly fixed to anthropomorphic test device (ATD) headforms when compared to reference systems, but few validation studies have focused on iMG performance in human cadaver heads. Here, we examine the performance of two boil-and-bite style iMGs in helmeted cadaver heads. Three unembalmed human cadaver heads were fitted with two instrumented boil-and-bite mouthguards [Prevent Biometrics and Diversified Technical Systems (DTS)] per manufacturer instructions. Reference sensors were rigidly fixed to each specimen. Specimens were fitted with a Riddell SpeedFlex American football helmet and impacted with a rigid impactor at three velocities and locations. All impact kinematics were compared at the head center of gravity. The Prevent iMG performed comparably to the reference system up to ~ 60 g in linear acceleration, but overall had poor correlation (CCC = 0.39). Prevent iMG angular velocity and BrIC generally well correlated with the reference, while underestimating HIC and overestimating HIC duration. The DTS iMG consistently overestimated the reference across all measures, with linear acceleration error ranging from 10 to 66%, and angular acceleration errors greater than 300%. Neither iMG demonstrated consistent agreement with the reference system. While iMG validation efforts have utilized ATD testing, this study highlights the need for cadaver testing and validation of devices intended for use in-vivo, particularly when considering realistic (non-idealized) sensor-skull coupling, when accounting for interactions with the mandible and when subject-specific anatomy may affect device performance.

Racial differences in baroreflex function: Implications for the cardiovascular conundrum.

Study objective: African Americans (AAs) show early signs of vascular dysfunction paired with elevated blood pressure (BP) and total peripheral resistance (TPR), which is thought to underlie their increased rates of cardiovascular health complications relative to European Americans (EAs). AAs paradoxically have higher cardiac vagal tone, indexed by heart rate variability (HRV), which is cardio-protective. This paradox has been termed the Cardiovascular Conundrum. The physiological mechanism underlying this phenomenon is not well understood. We examined race differences in baroreflex function, which might be an important mechanism underlying the Cardiovascular Conundrum. Design: Participants completed a 5-minute baseline period where resting cardiac metrics were assessed. Setting: Laboratory. Participants: 130 college-aged individuals (54 women, 57 AAs). Main outcome measures: Baroreflex function was indexed as baroreflex sensitivity (BRS; the magnitude of changes in cardiovascular activity in accordance with BP changes) and effectiveness (BEI; the ratio of BP changes that elicit changes in cardiovascular activity) in the cardiac, vascular, and myocardial limbs. Results and conclusions: Results showed AAs to have higher HRV and cardiac BRS in comparison to EAs, suggesting the baroreflex is more sensitive to correcting the heart period for changes in BP among AAs compared to EAs. However, AAs showed lower vascular BEI relative to EAs, suggesting less effective control of TPR. In sum, lower BEI in the vascular branch might be an important mechanism underlying the Cardiovascular Conundrum (i.e., higher HRV and BP) and by extension, health disparities in cardiovascular diseases between AAs and EAs.

Donor-derived infections in the United States: Opportunities to learn from the Disease Transmission Advisory Committee's experience.

The Disease Transmission Advisory Committee (DTAC) of the Organ Procurement and Transplantation Network focuses on issues related to the transmission of disease through organ transplantation. Providing a review of potential cases of transmission, translating aggregate data into actionable education and guidance for the transplant community, and providing input for policy development, DTAC aims to improve the safety of organ transplantation through a reduction in donor-derived transmission events. Through its nearly 20-year history, DTAC has provided education, guidance, and policy, addressed numerous emerging infections, and continuously focused on the community's understanding of risk assessment related to donor-derived transmission. By updating the DTAC mission to both decrease transmission and safely expand the donor pool with additional guidance to safely use organs previously not considered for transplantation due to transmission concerns, the Committee's role will remain critical.

Autism gene variants disrupt enteric neuron migration and cause gastrointestinal dysmotility.

The comorbidity of autism spectrum disorders and severe gastrointestinal symptoms is well-established, yet the molecular underpinnings remain unknown. The identification of high-confidence large-effect autism risk genes offers the opportunity to identify convergent, underlying biology by studying these genes in the context of the gastrointestinal system. Here we show that the expression of these genes is enriched in human prenatal gut neurons as well as their migratory progenitors, suggesting that the development and/or function of these neurons may be disrupted by autism-associated pathogenic variants, leading to gastrointestinal dysfunction. Here we document the prevalence of gastrointestinal issues in patients with large-effect variants in sixteen of these genes, highlighting dysmotility, consistent with potential enteric neuron dysfunction. Using the high-throughput diploid frog Xenopus tropicalis , we individually target five of these genes ( SYNGAP1, CHD8, SCN2A, CHD2 , and DYRK1A ) and observe disrupted enteric neuronal progenitor migration for each. More extensive analysis of DYRK1A reveals that perturbation causes gut dysmotility in vivo , which can be ameliorated by treatment with a selective serotonin reuptake inhibitor (escitalopram) or a serotonin receptor 6 agonist, identified by in vivo drug screening. This work suggests that atypical development of enteric neurons contributes to the gastrointestinal distress commonly seen in individuals with autism and that increasing serotonin signaling may be a productive therapeutic avenue.

Rationally Minimizing Natural Product Libraries Using Mass Spectrometry.

Natural product libraries are crucial to drug development, but large libraries drastically increase the time and cost during initial high throughput screens. Here, we developed a method that leverages liquid chromatography-tandem mass spectrometry spectral similarity to dramatically reduce library size, with minimal bioactive loss. This method offers a broadly applicable strategy for accelerated drug discovery with cost reductions, which enable implementation in resource-limited settings.

Can the Velocity of a 1RM Hang Power Clean Be Used to Estimate a 1RM Hang High Pull?

ABSTRACT: Suchomel, TJ, Techmanski, BS, Kissick, CR, and Comfort, P. Can the velocity of a 1RM hang power clean be used to estimate a 1RM hang high pull? J Strength Cond Res 38(7): 1321-1325, 2024-The purpose of this study was to estimate the 1-repetition maximum hang high pull (1RM HHP) using the peak barbell velocity of a 1RM hang power clean (HPC). Fifteen resistance-trained men (age = 25.5 ± 4.5 years, body mass = 88.3 ± 15.4 kg, height = 176.1 ± 8.5 cm, relative 1RM HPC = 1.3 ± 0.2 kg·kg-1) with previous HPC experience participated in 2 testing sessions that included performing a 1RM HPC and HHP repetitions with 20, 40, 60, and 80% of their 1RM HPC. Peak barbell velocity was measured using a linear position transducer during the 1RM HPC and HHP repetitions performed at each load. The peak barbell velocity achieved during the 1RM HPC was determined as the criterion value for a 1RM performance. Subject-specific linear regression analyses were completed using slope-intercept equations created from the peak velocity of the 1RM HPC and the peak barbell velocities produced at each load during the HHP repetitions. The peak barbell velocity during the 1RM HPC was 1.74 ± 0.30 m·s-1. The average load-velocity profile showed that the estimated 1RM HHP of the subjects was 98.0 ± 19.3% of the 1RM HPC. Although a 1RM HHP value may be estimated using the peak barbell velocity during the HPC, strength and conditioning practitioners should avoid this method because of the considerable variation within the measurement. Additional research examining different methods of load prescription for weightlifting pulling derivatives is needed.

Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export.

Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.

Safety concern of recombination between self-amplifying mRNA vaccines and viruses is mitigated in vivo.

Self-amplifying mRNA (SAM) vaccines can be rapidly deployed in the event of disease outbreaks. A legitimate safety concern is the potential for recombination between alphavirus-based SAM vaccines and circulating viruses. This theoretical risk needs to be assessed in the regulatory process for SAM vaccine approval. Herein, we undertake extensive in vitro and in vivo assessments to explore recombination between SAM vaccine and a wide selection of alphaviruses and a coronavirus. SAM vaccines were found to effectively limit alphavirus co-infection through superinfection exclusion, although some co-replication was still possible. Using sensitive cell-based assays, replication-competent alphavirus chimeras were generated in vitro as a result of rare, but reproducible, RNA recombination events. The chimeras displayed no increased fitness in cell culture. Viable alphavirus chimeras were not detected in vivo in C57BL/6J, Rag1-/- and Ifnar-/- mice, in which high levels of SAM vaccine and alphavirus co-replicated in the same tissue. Furthermore, recombination between a SAM-spike vaccine and a swine coronavirus was not observed. In conclusion we state that although the ability of SAM vaccines to recombine with alphaviruses might be viewed as an environmental safety concern, several key factors substantially mitigate against in vivo emergence of chimeric viruses from SAM vaccine recipients.

The histone methyltransferase SETD2 regulates HIV expression and latency.

Understanding the mechanisms that drive HIV expression and latency is a key goal for achieving an HIV cure. Here we investigate the role of the SETD2 histone methyltransferase, which deposits H3K36 trimethylation (H3K36me3), in HIV infection. We show that prevention of H3K36me3 by a potent and selective inhibitor of SETD2 (EPZ-719) leads to reduced post-integration viral gene expression and accelerated emergence of latently infected cells. CRISPR/Cas9-mediated knockout of SETD2 in primary CD4 T cells confirmed the role of SETD2 in HIV expression. Transcriptomic profiling of EPZ-719-exposed HIV-infected cells identified numerous pathways impacted by EPZ-719. Notably, depletion of H3K36me3 prior to infection did not prevent HIV integration but resulted in a shift of integration sites from highly transcribed genes to quiescent chromatin regions and to polycomb repressed regions. We also observed that SETD2 inhibition did not apparently affect HIV RNA levels, indicating a post-transcriptional mechanism affecting HIV expression. Viral RNA splicing was modestly reduced in the presence of EPZ-719. Intriguingly, EPZ-719 exposure enhanced responsiveness of latent HIV to the HDAC inhibitor vorinostat, suggesting that H3K36me3 can contribute to a repressive chromatin state at the HIV locus. These results identify SETD2 and H3K36me3 as novel regulators of HIV integration, expression and latency.

Human and Porcine Lumbar Endplate Injury Risk in Repeated Flexion-Compression.

Low back pain (LBP) affects 50-80% of adults at some point in their lifetime, yet the etiology of injury is not well understood. Those exposed to repeated flexion-compression are at a higher risk for LBP, such as helicopter pilots and motor vehicle operators. Animal injury models offer insight into in vivo injury mechanisms, but interspecies scaling is needed to relate animal results to human. Human (n = 16) and porcine (n = 20) lumbar functional spinal units (FSUs) were loaded in repeated flexion-compression (1 Hz) to determine endplate fracture risk over long loading exposures. Flexion oscillated from 0 to 6° and peak applied compressive stress ranged from 0.65 to 2.38 MPa for human and 0.64 to 4.68 MPa for porcine specimens. Five human and twelve porcine injuries were observed. The confidence intervals for human and porcine 50% injury risk curves in terms of stress and cycles overlapped, indicating similar failure behavior for this loading configuration. However, porcine specimens were more tolerant to the applied loading compared to human, demonstrated by a longer time-to-failure for the same applied stress. Optimization revealed that time-to-failure in human specimens was approximately 25% that of porcine specimens at a given applied stress within 0.65-2.38 MPa. This study determined human and porcine lumbar endplate fracture risks in long-duration repeated flexion-compression that can be directly used for future equipment and vehicle design, injury prediction models, and safety standards. The interspecies scale factor produced in this study can be used for previous and future porcine lumbar injury studies to scale results to relevant human injury.

Postoperative pain control and opioid use with transversus abdominis plane block and scheduled multimodal pain management in patients undergoing cesarean section.

OBJECTIVE: The impact of a transversus abdominis plane (TAP) block in patients undergoing cesarean section requires further evaluation. The aim of this study was to compare postoperative pain scores and opioid use in cesarean surgery patients undergoing either a TAP block and scheduled multimodal pain management (SMPM) or SMPM alone. METHODS: In this retrospective, dual cohort study, cesarean surgery patients underwent neuraxial anesthesia and a TAP block (SMPM/TAP) or SMPM; the TAP block incorporated ropivacaine (20-30 mL) administered bilaterally. The group analyses involved a comparison of postoperative pain scores using the visual analog scale and opioid consumption at 24 and 24-48 h. RESULTS: There were 94 (52.8%) patients in the SMPM/TAP group and 84 (47.2%) subjects in the SMPM alone group. At 24 h postoperatively, the SMPM/TAP group exhibited significantly lower pain scores (4.07 vs 4.54) than the SMPM group (P < 0.001) and reduced opioid consumption (2.29 vs 3.28 mg; P < 0.001). However, at 24-48 h, the SMPM group demonstrated lower pain scores (5.46 vs 5.98) compared to the SMPM/TAP group (P < 0.001) and reduced opioid consumption (8.75 vs 10.21 mg; P < 0.001); overall opioid consumption was higher (12.50 vs 12.02 mg) in the SMPM/TAP group (P < 0.001). CONCLUSION: The TAP block improved cesarean surgery patients' pain scores and reduced opioid consumption at 24 h postoperatively but the effect of the TAP block was ephemeral as the SMPM/TAP group exhibited inferior pain scores and greater opioid consumption compared to the SMPM group at 24-48 h postoperatively.

Microplastics dysregulate innate immunity in the SARS-CoV-2 infected lung.

Introduction: Global microplastic (MP) pollution is now well recognized, with humans and animals consuming and inhaling MPs on a daily basis, with a growing body of concern surrounding the potential impacts on human health. Methods: Using a mouse model of mild COVID-19, we describe herein the effects of azide-free 1 µm polystyrene MP beads, co-delivered into lungs with a SARS-CoV-2 omicron BA.5 inoculum. The effect of MPs on the host response to SARS-CoV-2 infection was analysed using histopathology and RNA-Seq at 2 and 6 days post-infection (dpi). Results: Although infection reduced clearance of MPs from the lung, virus titres and viral RNA levels were not significantly affected by MPs, and overt MP-associated clinical or histopathological changes were not observed. However, RNA-Seq of infected lungs revealed that MP exposure suppressed innate immune responses at 2 dpi and increased pro-inflammatory signatures at 6 dpi. The cytokine profile at 6 dpi showed a significant correlation with the 'cytokine release syndrome' signature observed in some COVID-19 patients. Discussion: The findings are consistent with the recent finding that MPs can inhibit phagocytosis of apoptotic cells via binding of Tim4. They also add to a growing body of literature suggesting that MPs can dysregulate inflammatory processes in specific disease settings.

An update and review of arthropod vector sensory systems: Potential targets for behavioural manipulation by parasites and other disease agents.

For over a century, vector ecology has been a mainstay of vector-borne disease control. Much of this research has focused on the sensory ecology of blood-feeding arthropods (black flies, mosquitoes, ticks, etc.) with terrestrial vertebrate hosts. Of particular interest are the cues and sensory systems that drive host seeking and host feeding behaviours as they are critical for a vector to locate and feed from a host. An important yet overlooked component of arthropod vector ecology are the phenotypic changes observed in infected vectors that increase disease transmission. While our fundamental understanding of sensory mechanisms in disease vectors has drastically increased due to recent advances in genome engineering, for example, the advent of CRISPR-Cas9, and high-throughput "big data" approaches (genomics, proteomics, transcriptomics, etc.), we still do not know if and how parasites manipulate vector behaviour. Here, we review the latest research on arthropod vector sensory systems and propose key mechanisms that disease agents may alter to increase transmission.

Escherichia coli non-coding regulatory regions are highly conserved.

Microbial genome sequences are rapidly accumulating, enabling large-scale studies of sequence variation. Existing studies primarily focus on coding regions to study amino acid substitution patterns in proteins. However, non-coding regulatory regions also play a distinct role in determining physiologic responses. To investigate intergenic sequence variation on a large-scale, we identified non-coding regulatory region alleles across 2350 Escherichia coli strains. This 'alleleome' consists of 117 781 unique alleles for 1169 reference regulatory regions (transcribing 1975 genes) at single base-pair resolution. We find that 64% of nucleotide positions are invariant, and variant positions vary in a median of just 0.6% of strains. Additionally, non-coding alleles are sufficient to recover E. coli phylogroups. We find that core promoter elements and transcription factor binding sites are significantly conserved, especially those located upstream of essential or highly-expressed genes. However, variability in conservation of transcription factor binding sites is significant both within and across regulons. Finally, we contrast mutations acquired during adaptive laboratory evolution with wild-type variation, finding that the former preferentially alter positions that the latter conserves. Overall, this analysis elucidates the wealth of information found in E. coli non-coding sequence variation and expands pangenomic studies to non-coding regulatory regions at single-nucleotide resolution.

Acute Kidney Injury in a Previously Healthy 56-Year-Old Male Following a Direct Visual Internal Urethrotomy of a Bulbar Stricture.

Acute kidney injury (AKI) is a frequent finding in acutely ill and hospitalized patients arising from various etiologies. Anuric AKI, a more pronounced form of AKI in which less than 100 cc of urine is produced per day, is most frequently encountered in hospitalized, septic, and post-surgical patients, often secondary to shock or bilateral urinary tract obstruction. The development of anuric AKI in previously healthy patients after outpatient urological procedures presents a unique challenge to physicians, as many outpatient procedures require the routine perioperative administration of multiple nephrotoxic medications. Further complicating this clinical scenario, some surgical procedures that intrinsically involve iatrogenic injury to the kidney, ureter, bladder, or nearby organ can rarely lead to a phenomenon known as reflex anuria, an anuric state typically associated with AKI. Here, we report an unusual case of a previously healthy 56-year-old male who developed anuric AKI two days after direct visual internal urethrotomy (DVIU) for the treatment of a bulbar stricture. Non-contrast CT revealed no signs of an obstructive process, and laboratory findings supported an intrarenal cause of AKI. Consideration was given to non-steroidal anti-inflammatory drugs (NSAID)-induced nephrotoxicity, gentamicin-associated acute tubular necrosis, and propofol infusion syndrome, in addition to their potential synergistic effects. We also explore this as the first reported case of reflex anuria occurring at the level of the bulbar urethra, as most cases have involved direct injury to the kidney or ureter. Over the course of 10 days, our patient responded well to treatment with supportive measures and dialysis, with his vomiting, electrolyte abnormalities, renal state, and anuria eventually improving.

The association between single-nucleotide polymorphisms within type 1 interferon pathway genes and human immunodeficiency virus type 1 viral load in antiretroviral-naïve participants.

BACKGROUND: Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL). METHODS: Two cohorts of antiretroviral (ART) naïve participants living with HIV (PLWH) with either early (START) or advanced infection (FIRST) were analysed separately. Type 1 IFN genes (n = 17) and receptor subunits (IFNAR1, IFNAR2) were examined for both cumulated type 1 IFN pathway analysis and individual gene analysis. SKAT-O was applied to detect associations between the genotype and HIV-1 study entry viral load (log10 transformed) as a proxy for set point VL; P-values were corrected using Bonferroni (P < 0.0025). RESULTS: The analyses among those with early infection included 2429 individuals from five continents. The median study entry HIV VL was 14,623 (IQR 3460-45100) copies/mL. Across 673 SNPs within 19 type 1 IFN genes, no significant association with study entry VL was detected. Conversely, examining individual genes in START showed a borderline significant association between IFNW1, and study entry VL (P = 0.0025). This significance remained after separate adjustments for age, CD4+ T-cell count, CD4+/CD8+ T-cell ratio and recent infection. When controlling for population structure using linear mixed effects models (LME), in addition to principal components used in the main model, this was no longer significant (p = 0.0244). In subgroup analyses stratified by geographical region, the association between IFNW1 and study entry VL was only observed among African participants, although, the association was not significant when controlling for population structure using LME. Of the 17 SNPs within the IFNW1 region, only rs79876898 (A > G) was associated with study entry VL (p = 0.0020, beta = 0.32; G associated with higher study entry VL than A) in single SNP association analyses. The findings were not reproduced in FIRST participants. CONCLUSION: Across 19 type 1 IFN genes, only IFNW1 was associated with HIV-1 study entry VL in a cohort of ART-naïve individuals in early stages of their infection, however, this was no longer significant in sensitivity analyses that controlled for population structures using LME.