High Failure Research Articles

Analysis of single shaft turbojet engines structures and evaluation their safety with the use of FDM-A and FAM-C diagnostic methods

The article reviews the main stages of development of single-shaft turbojet engines. Selected construction of these engines are presented divided into three periods (before, during and after World War II) and two main jet engine schemes were discussed (with a centrifugal compressor and an axial compressor). The SO-3 jet engine installed on the TS-11 “Spark” aircraft was chosen to present the method of assessing the safety of structures. The FDM-A diagnostic methods developed in AFIT were used to experimentally verify the technical condition of the engine and FAM-C, based on the analysis of disturbances in the instantaneous rotational speed of the engine shaft. The results of tests related to the assessment of engine shaft misalignment, the assessment of the degree of wear of the engine shaft bearings and the assessment of the shaft clamping force in the bearings are presented. The summary lists the main advantages of single-shaft turbojet engines (simplicity of design for a solution with a centrifugal compressor and high thrust enabling breaking the sound barrier) and their disadvantages (complex design for a solution with an axial compressor and high failure rate of shaft bearing supports as the most loaded engine component).

The Development of the Lean Six Sigma Readiness Assessment Model for the Hotel Sector

ABSTRACT Lean Six Sigma (LSS) implementation still shows a high failure rate. Lack of readiness is one of the causes. Readiness assessment requires special exploration of each sector, including the hotel sector, where there is still no development of an LSS readiness assessment model. This study aims to develop a readiness assessment model for LSS implementation in the hotel sector. Data processing in the readiness assessment model uses the fuzzy logic method, is translated again into linguistic terms using Euclidean distance, and is ranked using the TOPSIS approach. The literature review produced 34 Readiness Factors (RF) that were validated by eight credible hotel practitioners and used as guidelines in conducting LSS readiness assessments in the hotel sector. Case studies were conducted on Hotel A and Hotel B, which showed that Hotel A was “Very Ready” and Hotel B was “Ready” to implement LSS. This research is perhaps the first of its kind in the hotel sector. This research also uses the Delphi method to collect data on the importance level, which may not have been done in collecting data on LSS readiness in any sector.

PenGym: Realistic training environment for reinforcement learning pentesting agents

Penetration testing, or pentesting, refers to assessing network system security by trying to identify and exploit any existing vulnerabilities. Reinforcement Learning (RL) has recently become an effective method for creating autonomous pentesting agents. However, RL agents are typically trained in a simulated network environment. This can be challenging when deploying them in a real network infrastructure due to the lack of realism of the simulation-trained agents.In this paper, we present PenGym, a framework for training pentesting RL agents in realistic network environments. The most significant features of PenGym are its support for real pentesting actions, full automation of the network environment creation, and good execution performance. The results of our experiments demonstrated the advantages and effectiveness of using PenGym as a realistic training environment in comparison with a simulation approach (NASim). For the largest scenario, agents trained in the original NASim environment behaved poorly when tested in a real environment, having a high failure rate. In contrast, agents trained in PenGym successfully reached the pentesting goal in all our trials. Even after fixing logical modeling issues in simulation to create the revised version NASim(rev.), experiment results with the largest scenario indicated that agents trained in PenGym slightly outperformed, and were more stable, than those trained in NASim(rev.). Thus, the average number of steps required to reach the pentesting goal was 1.4 to 8 steps better for PenGym. Consequently, PenGym provides a reliable and realistic training environment for pentesting RL agents, eliminating the need to model agent actions via simulation.

Clinical performance of zirconia-based tooth-supported fixed dental prostheses: A systematic review and meta-analysis

ObjectivesThis study aimed to investigate the clinical performance of zirconia-based fixed dental prostheses (FDPs) in comparison to metal-ceramic (MC) FDPs. MethodsA comprehensive search on MEDLINE (PubMed), Web of Science (Core Collection), Scopus up to June 2024 was conducted. Studies that compared the success, survival and complication rates between zirconia based FDPs and MC FDPs were eligible for inclusion. ResultsThirty-one articles were identified, of which 22 were included for systematic review and 7 RCTs were included for meta-analysis. 10, 9 and 3 studies were classified to mean follow-up ≤ 5 years, 5 years < mean Follow-up ≤ 10 years, mean Follow-up >10 years, respectively. In the pooled analysis, 180 bilaminar zirconia (ZC) FDPs and 206 MC FDPs were included. ZC FDPs were significantly associated with more failures (RR=3.64, p = 0.009) and more Ceramic Chipping (RR=2.92, p < 0.0001) when compared to MC FDPs. Higher risks of Framework Fracture (RR=4.57, p = 0.18), Loss of Retention (RR=4.79, p = 0.17), Secondary Caries (RR=1.25, p = 0.68), Endodontic complications (RR=1.30, p = 0.74) and Marginal Integrity (RR=1.07, p = 0.88) were also found in ZC FDPs when compared to those of MC FDPs, but with no statistical difference. ConclusionThe current evidence continues to support the preference for traditional MC FDPs over ZC FDPs. Studies indicate that ZC FDPs have higher failure rates and more complications compared to MC FDPs, with ceramic chipping being a significant concern. There is lack of long term (>10 years follow-up) evidence of the clinical performance of ZC FDPs and monolithic zirconia FDPs. Clinical significanceThe study suggests that despite the growing popularity of zirconia, evidence shows MC FDPs may still be considered preferable to ZC FDPs.

8. Herpes zoster and post herpetic neuralgia.

Patients suffering from postherpetic neuralgia (PHN) report unilateral chronic pain in one or more dermatomes after an acute herpes zoster (HZ) infection. The incidence of acute HZ ranges between three and five patients per 1000 person-years. In one out of four patients, acute HZ-related pain will transition into PHN. PHN can be very disabling for patients and reduce quality of life. Additionally, the treatment of PHN is characterized by high failure rates. The aim of this review is to give an update on the previous practical guideline published in 2011 and revised in 2015 (published in 2019) and to provide an overview of current interventional treatment options for HZ infection and PHN. The literature on the diagnosis and treatment of HZ and PHN was systematically reviewed and summarized. The most important treatment for acute HZ-related pain is antiviral therapy within 72 h of symptom onset. Additional symptomatic treatment options are analgesic drugs according to the WHO pain ladder, tricyclic antidepressants (eg, nortriptyline), and antiepileptic drugs (eg, gabapentin). If pain is not sufficiently reduced, interventional treatment such as an epidural injection with local anesthetics and corticosteroids or pulsed radiofrequency of the dorsal root ganglion (DRG) are options. Treatment for PHN is preferably transdermal capsaicin, lidocaine, or oral drugs such as antidepressants or antiepileptics. Treatment of acute HZ-related pain especially PHN is challenging. Besides the conventional treatment for PHN, interventional management is considered a new treatment option. PRF of DRG seems to be the most promising interventional management.

Convertible glenoid replacement in the anatomical total shoulder arthroplasty: medium-term results.

The older generation of high thickness metal-backed glenoid prostheses had a high failure rate. The goal of our study was to analyze the medium-term clinical and radiological results of a technically modified generation of metal backed glenoids with 35% decrease in thickness. Thirty-nine patients (43 shoulders) with a mean age of 66.5 years at surgery were examined from two to ten years (mean 71.2 months) using the Constant-Score, Subjective Shoulder Value and X-ray in a.p. and axial view. Indication for surgery included patients with glenoid types B1, B2, or B3 and/or posterior subluxation but intact rotator cuff, or patients who did not want a reverse prosthesis and had high functional demands. Inclusion criteria comprised participation in a clinical and radiological follow-up examination, along with a minimum follow-up duration of 24 months. Additionally, in all cases, the Constant Score and the Subjective Shoulder Value (PROM) had to be determined. Exclusion criteria were an incomplete dataset, implantation of a different prosthesis type, and failure to meet the minimum follow-up time. The absolute Constant Score (CS) improved significantly (p < 0.0001) from 43 ± 13 (range: 20-69) points before to 80 ± 13 (range: 46-98) points after surgery. The only preoperative negative influencing factor on the result was the glenoid protrusion according to Lévigne (p = 0.0150). No significant differences in functional outcomes were found between glenoid types A2,B1,B2 and B3. Radiolucent lines at the interface were observed in a total of four patients (13%). Radiological signs of glenoid osteolysis were seen in six patients (20%).Humeral upward migration was observed in four patients (13%) and posterior shoulder joint decentering occurred in one patient (3%). Implant-specific complications occurred in three cases (7%). Due to a massive rotator cuff tear, two cases (4.7%) had to be converted to a reversed implant, with the primary metal component remaining in place. If the implant-specific and rotator cuff-associated complications are summarized, the rate is 11.7%. All components that required conversion to an reverse implant have so far remained free of complications. Favorable clinical results can be achieved, especially in patients with an eccentric glenoid type. Severe preoperative glenoid erosion (Walch A2, B2, B3) does not appear to have any influence on postoperative functional results. The complication and revision rates are significantly better than in previous studies with conventional metal-backed glenoid components. Conversion of the anatomical glenoid component to a reverse system was always possible and good clinical results were achieved.

Primary ACL repair in a selected patient cohort: A prospective single cohort study

BackgroundAnterior cruciate ligament (ACL) tears are common knee injuries, particularly in physically active individuals. While ACL reconstruction (ACL-R) is the standard treatment, it has notable limitations. Recent interest in primary ACL repair offers a potential alternative, especially for specific tear types and patient demographics. PurposeTo evaluate the outcomes of primary ACL repair in a selected patient cohort with strict inclusion and exclusion criteria, focusing on the survival of the procedure, functional outcomes, and factors influencing success rates. MethodsThis prospective single cohort study included 61 patients who underwent primary ACL repair between June 2016 and June 2022. Patients were 50 years or younger, with recent ACL injuries and no previous knee surgeries or multiligament injuries. The primary outcomes were the survival of the repair beyond two years, measured by revision rates, and functional outcomes assessed using the Lysholm knee score, Tegner activity scale, and Lachmeter stability measurements. ResultsFifty-four patients completed a minimum follow-up of three years (average 49.6 months). The overall success rate was 82.2 %, with Sherman type 1 tears showing significantly fewer failures compared to type 2 (4.3 % vs. 31.8 %). The mean Lysholm score for successful repairs was 96, and the Tegner score dropped from a pre-injury average of 6 to 5. Adolescents had the highest failure rate (50 %), while other age groups showed better outcomes. The mean side-to-side difference in stability was 1.4 mm, favoring the control side. ConclusionPrimary ACL repair is a viable option for selected patients, particularly those with Sherman type 1 tears. While age and tear type significantly affect outcomes, the procedure shows promising results with high functional scores in successful repairs. Further research with larger cohorts and extended follow-ups is necessary to validate these findings and refine patient selection criteria. Primary ACL repair offers a less invasive alternative to ACL reconstruction, with potential for comparable outcome.

Numerical simulation of the first layer printing in electric field-assisted fused filament fabrication for robust unconventionally oriented additive manufacturing

Fused filament fabrication (FFF) stands as a prominent thermoplastic additive manufacturing technique that has a wide range of potential applications. However, the conventional FFF process encounters limitations in unconventional environments, particularly in environments devoid of gravity, such as in extraterrestrial environments or in limited manufacturing conditions where maintaining consistent nozzle standoff distance becomes a challenging task. Fluctuations in nozzle standoff distance lead to inadequate material adhesion and dimensional errors, which results in a high failure rate and prolonged completion time. Thus, the conventional FFF process requires continuous monitoring or human intervention to ensure successful operation. To overcome the shortcomings of the traditional FFF process, an electric field-assisted FFF (E-FFF) process can be utilized to reduce the need for constant supervision and enable reliable production of parts. The E-FFF process integrates a high-voltage power supply unit with a standard FFF printer, generating an electrostatic force between the nozzle and the build plate. The generated electrostatic force can effectively attract the extruded molten polymer toward the build plate, even at a larger z-height of up to 1200 μm in unconventional build platform orientations such as vertical or reverse printing orientation. In this paper, finite element analysis is used to simulate the FFF and E-FFF process. The simulation focuses on the adhesion between extruded material and build plate with extended nozzle standoff distances and predicts the minimum voltage required to achieve a good material adhesion in unconventional orientations for the E-FFF process. The simulation model demonstrated its efficacy by estimating the minimum required voltage levels necessary for successful printing within the E-FFF process across a range of nozzle standoff distances in unconventional orientations.

Research on Typical Fault Diagnosis of Gear based on GHM Multiwavelet Transform and MCKD Algorithm

Background: Gear is the key part of the transmission part of mechanical equipment, which has a high failure rate under complex working conditions or long-term operation, directly affecting the reliability of mechanical equipment. To realize online monitoring of gears and predict gear faults, whether the diagnosis of typical gear faults is accurate and timely is a key link, so it is necessary to study the diagnosis of typical gear faults. Objective: This paper aims to propose a method that can effectively diagnose typical faults of gears and is easy to program, which is beneficial to realize online monitoring of rotating machinery equipment faults. Method: A typical gear fault diagnosis method based on GHM multiwavelet transform and maximum correlation kurtosis deconvolution algorithm (MCKD) is proposed in this paper. The measured vibration signal is decomposed into components with multiple scale spaces and frequency bands through the GHM multiwavelet transform. Then, the MCKD algorithm is run to suppress the noise of GHM multiwavelet transform coefficients, and the periodic components containing fault information are retained and reconstructed. The typical faults such as gear pitting and broken teeth are tested. Results: GHM multiwavelet transform combined with MCKD algorithm can accurately locate the frequency band containing fault information from the vibration signal with multiple modulations, double sideband, and multi-frequency interference and effectively extract the fault frequency and its frequency multiplication. The root means a square error of the extracted fault frequency is 0.08. This method has a good noise suppression effect and high accuracy in extracting fault frequency. Conclusion: The method proposed in this paper is helpful in realizing automatic programming of gear fault diagnosis and is of great significance in realizing real-time monitoring and online diagnosis of rotating machinery equipment faults. More related patents will appear in the future.

Assessing the Effects of Habitat Loss and Deterioration on a Red Squirrel Translocation Site: Insights for Future Conservation Management.

Translocations, a conservation tool used to conserve and restore dwindling species, are often associated with high failure rates. Inadequate long-term monitoring of both populations and their introduction sites beyond the initial years post-translocation creates a gap in our understanding of the factors that determine translocation success or failure, resulting in less informed projects in the future. This lack of long-term monitoring is partly caused by the absence of a well-defined framework by which the success of the translocation can be measured, leading to premature and sometimes inaccurate assessments of their outcome. We investigated the long-term outcome of a red squirrel translocation in the west of Ireland, specifically assessing the habitat changes in the translocation site since the introduction in 2005, and their impact on the capacity of the forest to sustain a population of a given size. Using digitised historical map data, we showed that the translocation site experienced a 53% reduction in suitable habitat. Additionally, there was a 41%-81% reduction in the total number of red squirrels the forest could support, according to feeding survey data. Clear-felling, a forest fire and a shift in tree species composition collectively contributed to this decline in site suitability. This investigation underscores the complexity of translocation projects and emphasises the pivotal role of habitat quality in their outcomes. We advocate for detailed habitat assessments during the planning phase, avoidance of unstable habitats as translocation sites, and the implementation of long-term monitoring practices.

Implementation of Ultrasound-guided cannulation training for foundation doctors

PIVC (peripheral intravenous cannulation) is an essential skill for newly qualified foundation doctors. It has high failure rates, resulting in care delays, pain, and infection. We explored the perceived impact of ultrasound guided PIVC training on confidence when performing difficult access PIVC. We surveyed 88 foundation doctors to evaluate their perceptions on USS-PIVC. Each cohort of participants were given two sessions over a two-month period. Confidence was assessed using electronic questionnaires through 5-point Likert scales and free text responses. Confidence when performing PIVC with difficult access, regardless of USS, increased significantly following the course (p < 0.01). This was also true regarding confidence when performing USS-PIVC (p < 0.01.). Key themes identified included technical skills, confidence, and clinical utility.

Reliability-aware techno-economic assessment of floating solar power systems

Floating solar photovoltaic systems (FPV) have emerged as a promising technology to harness solar energy on water surfaces. With its numerous benefits, including increased land availability, reduced water evaporation, and improved system cooling, FPV systems hold great potential for sustainable energy generation. However, due to its unique installation and operation in water bodies, the management of aging becomes a critical factor to ensure long-term success. Consequently, reliability analysis plays a pivotal role in predicting and mitigating operational risks and estimating the economic feasibility of FPV projects. In this context, this paper presents a reliability-aware techno-economic assessment approach of FPV systems. The approach is tested with a case study in India, and the results are compared with ground-based photovoltaic (GPV) systems. Here, different failure and repair strategies are taken into account to determine the lifetime performance. Results showed that even though FPV system has higher failure rate, considering standard maintenance, the energy generated by the FPV system is 5.38% higher than similar GPV system. The cost of electricity by the PV system depends on the repair and maintenance. For normal maintenance the levelized cost of electricity (LCOE) for FPV system is calculated as 0.0551 $/kWh which is comparable to the LCOE by GPV systems, while for reduced repair actions, the LCOE of the FPV is higher than the LCOE of the GPV system.

Robotic pyelolithotomy for the treatment of large renal stones: a single-center experience over seven years.

Urolithiasis prevalence varies globally between 1-20%, influenced by regional factors. Robotic pyelolithotomy (RPL) presents an interesting alternative to PCNL, considered the gold standard for symptomatic stones smaller than 20 mm, as it carries a risk of significant complications. However, studies on RPL are limited, especially in anatomically complex cases, where RPL proves to be particularly useful. The study aims to update and review outcomes of RPL in a high-volume robotic center. A retrospective analysis of 153 patients treated with RPL for staghorn kidney stones at a single center from February 2016 to December 2023 was conducted. Data including demographics, preoperative renal function, stone characteristics, operative and postoperative outcomes, and costs were collected. Stone-free rates (SFR) and complications were assessed at follow-up intervals up to 12 months post-surgery. The study showed an initial 3-month stone-free rate (SFR) of 93.5%, which decreased to 83.5% at 12-months. This trend may reflect new stone formation rather than procedure failure. Sub-analysis revealed a significant difference in SFR between patients with pelvic and pyelocalyceal stones at each follow-up. Multivariate regression analysis identified in the pyelocalyceal group that higher BMI and larger stones were associated with higher failure rates at both 6 and 12 months. RPL is a safe and effective treatment for large renal stones, offering a high SFR and low complication rate. It is particularly beneficial in cases with complex anatomy or requiring concurrent renal procedures. However, patient selection is crucial, considering factors like stone location and size. Further research is needed to compare RPL with other treatment methods.

Very High Early Failure Rate Following Primary Repair of Acute Extensor Mechanism Disruption After Total Knee Arthroplasty

IntroductionExtensor mechanism disruption is a devastating complication following total knee arthroplasty (TKA). Despite its morbidity, there is no consensus regarding the optimal treatment strategy. We aimed to determine the survivorship, clinical outcomes, and improvement in patient-reported outcome measures (PROMs) after primary repair of acute extensor mechanism disruptions following primary or revision TKA. MethodsA retrospective review identified 41 acute extensor mechanism disruptions (33 primary TKAs and eight revision TKAs) from 2015 to 2021. The study group was 56% women, the mean BMI was 33, the mean age was 66 years, and the mean follow-up was three years. Extensor mechanism disruption occurred at the patellar tendon (n = 17), quadriceps tendon (n = 15), and patella (n = 9) at a mean of 10 months following TKA. Surgical management was primary repair (n = 30) or primary repair with augmentation (allograft or autograft) (n = 11). Kaplan-Meier analysis estimated survivorship. ResultsThe two-year survivorship free from all-cause reoperation was 72 and 23% following primary and revision TKA, respectively (P = 0.013). The two-year survivorship free from all-cause reoperation was 66% for primary repair versus 61% for primary repair with augmentation (P = 0.95). There were 17 (41%) patients who underwent reoperation, most commonly for re-rupture (n = 4) in two primary repairs and two primary repairs with augmentation (P = 0.288). Revision TKA (P = 0.049) and increased time from disruption to repair (P = 0.039) were risk factors for reoperation. The mean extensor lag did not significantly improve, nor did patients see improvement in their PROMs. ConclusionAfter primary and revision TKA, acute extensor mechanism disruption treated with primary repair with or without augmentation had very poor early survivorship free from all-cause reoperation. Patients should be counseled appropriately, and alternative surgical techniques should be considered.

Prevalence, rate, and predictors of virologic failure among adult HIV-Infected clients on second-line antiretroviral therapy (ART) in Tanzania (2018–2020): a retrospective cohort study

BackgroundAntiretroviral therapy (ART) has been proven to be highly effective in reducing the impact of human immunodeficiency virus (HIV) infection. However, as more people receive initial ART treatment, the risk of developing resistance and eventual treatment failure increases, leading to the need for second-line treatment regimens. Understanding the factors that contribute to virologic failure to second-line ART is crucial in preventing switching to the more expensive and toxic third-line regimens. This study provides information on the prevalence, rate, and predictors of virologic failure (VF) among clients on second-line ART in Tanzania.ResultsWe followed 4718 clients for 15100 person-years (PY) of observations. Of them, 1402 (29.72%) experienced virologic failure at a rate of 92.85 per 1000 PY of observations (95% CI 88.11, 97.84). Factors that were associated with VF included: having a viral load count of ≥ 1000 copies/mL during first-line ART, with a hazard ratio (HR) 4.65 (95% CI 3.57, 6.07), using lopinavir (LPV/r) as a protease inhibitor during second-line ART (HR 4.20 (95% CI 3.12, 7.10), having a CD4 count < 200 cells/mm3 during second-line ART (HR 1.89 (95% CI 1.46, 2.44), and being on ART for 13–35 months (HR 8.22 (95% CI 2.21, 30.61). Paradoxically, having a CD4 count < 200 cells/mm3 during first-line ART treatment was associated with a reduced risk of virologic failure (HR 0.77 (95% CI 0.60, 0.99).ConclusionsIn Tanzania, approximately 30% of adult clients on second-line ART experience VF at a rate of 92.71 per 1000 person-years. This high virologic failure rate underscores the urgent need for targeted interventions, such as enhancing adherence support, optimizing drug regimens, and regular viral load monitoring. These interventions will reduce the need for switching to the more costly and toxic third-line ART therapy and are also crucial for achieving the UNAIDS goal of 95% viral suppression among treated individuals by 2030.

Complex Systems and Sustainable Leadership: Enhancing Resilience and Sustainability of Community-Based Social Enterprises in Soweto, South Africa

In urban South Africa, community-based social enterprises (CBSEs) face challenges at the intersection of financial and environmental sustainability and social purpose. These enterprises address social exclusion and community development within complex institutional environments. Despite increasing governmental support, CBSEs struggle with historical inequalities, resource limitations, high poverty levels, inadequate infrastructure, and complex social dynamics. These challenges contribute to a high failure rate among SMMEs, including CBSEs, which represent approximately 71% of community-level businesses. This study examines how complex system dynamics in marginalized South African suburbs impact the sustainable leadership and resilience of CBSEs. Utilizing a qualitative approach, the study conducted 15 in-depth semi-structured interviews with CBSE leaders. The findings revealed that effective leadership in CBSEs requires extraordinary abilities to traverse complexity, adapt to changes, and engage in dynamic organizational change. The key themes identified included adaptive and flexible leadership, interdependencies and network collaboration, community engagement and co-creation, continuous learning and feedback loops, policy influence and response, and resource utilization and constraints. By applying complex systems leadership theory (CSLT) and sustainable leadership principles, the research offers insights into the mechanisms enabling CBSEs to thrive in challenging environments. These findings contribute to Social Enterprise Management and Leadership Studies, providing practical implications for policymakers and practitioners to support CBSE development and sustainability in marginalized urban communities.

Non-operative treatment for ACL rupture, rehabilitation and Cross bracing protocol, have unacceptably high failure rates relative to surgical stabilisation for return to pivoting sports.

Non-operative treatment for ACL rupture, rehabilitation and Cross bracing protocol, have unacceptably high failure rates relative to surgical stabilisation for return to pivoting sports.

A preliminary indication that HLA-A*03:01 may be associated with visceral leishmaniasis development in people living with HIV in Ethiopia.

Human immunodeficiency virus (HIV) co-infection is a major challenge for visceral leishmaniasis (VL) control, particularly in Ethiopia where the incidence of both pathogens is high. VL-HIV often leads to high rates of antileishmanial treatment failure and recurrent VL disease relapses. Considering the high prevalence of HIV and Leishmania in the Ethiopian population, preventing the progression of asymptomatic Leishmania infection to disease would be a valuable asset to VL disease control and to the clinical management of people living with HIV (PLWH). However, such a strategy requires good understanding of risk factors for VL development. In immunocompetent individuals living in Brazil, India, or Iran, the Human Leukocyte Antigen (HLA) gene region has been associated with VL development. We used NanoTYPE, an Oxford Nanopore Technologies sequencing-based HLA genotyping method, to detect associations between HLA genotype and VL development by comparing 78 PLWH with VL history and 46 PLWH that controlled a Leishmania infection, all living in a VL endemic region of North-West Ethiopia. We identified an association between HLA-A*03:01 and increased risk of VL development (OR = 3.89). These data provide candidate HLA alleles that can be further explored for inclusion in a potential Leishmania screen-and-treat strategy in VL endemic regions.

Molecular Mechanisms of Drug Resistance in Leishmania spp.

The protozoan parasite Leishmania causes leishmaniasis, a neglected tropical disease, that disproportionately affects underdeveloped countries. This disease has major health, economic, and social implications, particularly because of the limited treatment options, high cost, the severe side effects associated with available therapeutics, and the high rate of treatment failure caused by the parasites' growing resistance to current medications. In this review, we describe first the common strategies used by pathogens to develop drug resistance and then focus on the arsenal of available drugs to treat leishmaniasis, their modes of action, and the molecular mechanisms contributing to drug resistance in Leishmania spp., including the role of genomic, transcriptional, and translational control. We focus more specifically on our recent discovery of translational reprogramming as a major driver of drug resistance leading to coordinated changes in the translation of transcripts and orchestrating changes in metabolome and lipidome to support drug resistance. A thorough understanding of these mechanisms is essential to identify the key elements needed to combat resistance and improve leishmaniasis treatment methods.

The Dsc complex and its role in Golgi quality control.

Membrane proteins play crucial roles in cellular functions. However, processes such as the insertion of membrane proteins into the endoplasmic reticulum (ER), their folding into native structures, the assembly of multi-subunit membrane protein complexes, and their targeting from the ER to specific organelles are prone to errors and have a relatively high failure rate. To prevent the accumulation of defective or orphaned membrane proteins, quality control mechanisms assess folding, quantity, and localization of these proteins. This quality control is vital for preserving organelle integrity and maintaining cellular health. In this mini-review, we will focus on how selective membrane protein quality control at the Golgi apparatus, particularly through the defective for SREBP cleavage (Dsc) ubiquitin ligase complex, detects orphaned proteins and prevents their mis-localization to other organelles.