Cost-effectiveness of proton beam therapy vs. conventional radiotherapy for patients with brain tumors in Sweden: results from a non-randomized prospective multicenter study.

BACKGROUND: This study assessed the cost-effectiveness of proton beam therapy (PBT) compared to conventional radiotherapy (CRT) for treating patients with brain tumors in Sweden. METHODS: Data from a longitudinal non-randomized study performed between 2015 and 2020 was used, and included adult patients with brain tumors, followed during treatment and through a one-year follow-up. Clinical and demographic data were sourced from the longitudinal study and linked to Swedish national registers to get information on healthcare resource use. A cost-utility framework was used to evaluate the cost-effectiveness of PBT vs. CRT. Patients in PBT group (n = 310) were matched with patients in CRT group (n = 40) on relevant observables using propensity score matching with replacement. Costs were estimated from a healthcare perspective and included costs related to inpatient and specialized outpatient care, and prescribed medications. The health outcome was quality-adjusted life-years (QALYs), derived from the EORTC-QLQ-C30. Generalized linear models (GLM) and two-part models were used to estimate differences in costs and QALYs. RESULTS: PBT yielded higher total costs, 14,639 US$, than CRT, 13,308 US$, with a difference of 1,372 US$ (95% CI, -4,914-7,659) over a 58 weeks' time horizon. Further, PBT resulted in non-significantly lower QALYs, 0.746 compared to CRT, 0.774, with a difference of -0.049 (95% CI, -0.195-0.097). The probability of PBT being cost-effective was < 30% at any willingness to pay. CONCLUSIONS: These results suggest that PBT cannot be considered a cost-effective treatment for brain tumours, compared to CRT. TRIAL REGISTRATION: Not applicable.

Experiences of central child health services teams regarding a special governmental investment in child health services.

BACKGROUND: Historically marked by a high infant mortality rate, Sweden's healthcare reforms have successively led to a robust, decentralized universal child health system covering over 97% of the population 0-5 years. However, inequities in health have become an increasing problem and the public health law explicitly states that health inequities should be reduced, resulting in various government initiatives. This study examines the experiences of Central Child Health Services (CCHS) teams during the implementation of the Child Health Services Accessibility Agreement between the State and the regions starting in 2017. The agreement aimed to enhance child health service accessibility, especially in socio-economically disadvantaged areas, but broadly stated guidelines and the short-term nature of funding have raised questions about its effectiveness. The aim of this study was to understand the experiences of CCHC teams in implementing the Child Health Services Accessibility Agreement, focusing on investment decisions, implementation efforts, as well as facilitators and barriers to using the funds effectively. METHODS: CCHC teams were purposefully sampled and invited via email for interviews, with follow-ups for non-respondents. Conducted from January to October 2023, the interviews were held digitally and recorded with individuals familiar with the agreement's implementation within these teams. Both authors analyzed the transcripts thematically, applying Braun and Clarke's framework. Participants represented a cross-section of Sweden's varied healthcare regions. RESULTS: Three main themes emerged from the thematic analysis: "Easy come, easy go," highlighting funding uncertainties; "What are we supposed to do?" expressing dilemmas over project prioritization and partner collaboration; and "Building castles on sand," focusing on the challenges of staff retention and foundational program stability. Respective subthemes addressed issues like fund allocation timing, strategic decision-making, and the practical difficulties of implementing extended home visiting programs, particularly in collaboration with social services. CONCLUSIONS: This study uncovered the challenges faced in implementing the Child Health Services Accessibility Agreement across different regions in Sweden. These obstacles underline the need for precise guidelines regarding the use of funds, stable financing for long-term project sustainability, and strong foundational support to ensure effective interprofessional collaboration and infrastructure development for equitable service delivery in child health services.

Imidazole Carbamates as a Promising Alternative for Treating Trichomoniasis: In Vitro Effects on the Growth and Gene Expression of Trichomonas vaginalis.

Metronidazole (MTZ) is the most common drug used against Trichomonas vaginalis (T. vaginalis) infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in T. vaginalis to MTZ. Therefore, research into new therapeutic options against T. vaginalis infections has become increasingly urgent. This study investigated the trichomonacidal activity of a series of five imidazole carbamate compounds (AGR-1, AGR-2, AGR-3, AGR-4, and AGR-5) through in vitro susceptibility assays to determine the IC50 value of each compound. All five compounds demonstrated potent trichomonacidal activity, with IC50 values in the nanomolar range and AGR-2 being the most potent (IC50 400 nM). To gain insight into molecular events related to AGR-induced cell death in T. vaginalis, we analyzed the expression profiles of some metabolic genes in the trophozoites exposed to AGR compounds and MTZ. It was found that both AGR and MTZ compounds reduced the expression of the glycolytic genes (CK, PFK, TPI, and ENOL) and genes involved in metabolism (G6PD, TKT, TALDO, NADHOX, ACT, and TUB), suggesting that disturbing these key metabolic genes alters the survival of the T. vaginalis parasite and that they probably share a similar mechanism of action. Additionally, the compounds showed low cytotoxicity in the Caco-2 and HT29 cell lines, and the results of the ADMET analysis indicated that these compounds have pharmacokinetic properties similar to those of MTZ. The findings offer significant insights that can serve as a basis for future in vivo studies of the compounds as a potential new treatment against T. vaginalis.

The small RNA-mediated gene silencing machinery is required in Arabidopsis for stimulation of growth, systemic disease resistance, and suppression of the nitrile-specifier gene NSP4 by Trichoderma atroviride.

Trichoderma atroviride is a root-colonizing fungus that confers multiple benefits to plants. In plants, small RNA (sRNA)-mediated gene silencing (sRNA-MGS) plays pivotal roles in growth, development, and pathogen attack. Here, we explored the role of core components of Arabidopsis thaliana sRNA-MGS pathways during its interaction with Trichoderma. Upon interaction with Trichoderma, sRNA-MGS-related genes paralleled the expression of Arabidopsis defense-related genes, linked to salicylic acid (SA) and jasmonic acid (JA) pathways. SA- and JA-related genes were primed by Trichoderma in leaves after the application of the well-known pathogen-associated molecular patterns flg22 and chitin, respectively. Defense-related genes were primed in roots as well, but to different extents and behaviors. Phenotypical characterization of mutants in AGO genes and components of the RNA-dependent DNA methylation (RdDM) pathway revealed that different sets of sRNA-MGS-related genes are essential for (i) the induction of systemic acquired resistance against Botrytis cinerea, (ii) the activation of the expression of plant defense-related genes, and (iii) root colonization by Trichoderma. Additionally, plant growth induced by Trichoderma depends on functional RdDM. Profiling of DNA methylation and histone N-tail modification patterns at the Arabidopsis Nitrile-Specifier Protein-4 (NSP4) locus, which is responsive to Trichoderma, showed altered epigenetic modifications in RdDM mutants. Furthermore, NSP4 is required for the induction of systemic acquired resistance against Botrytis and avoidance of enhanced root colonization by Trichoderma. Together, our results indicate that RdDM is essential in Arabidopsis to establish a beneficial relationship with Trichoderma. We propose that DNA methylation and histone modifications are required for plant priming by the beneficial fungus against B. cinerea.

Mandatory, voluntary, repetitive, or one-off post-migration follow-up for tuberculosis prevention and control: A systematic review.

BACKGROUND: Post-migration follow-up of migrants identified to be at-risk of developing tuberculosis during the initial screening is effective, but programmes vary across countries. We aimed to review main strategies applied to design follow-up programmes and analyse the effect of key programme characteristics on reported coverage (i.e., proportion of migrants screened among those eligible for screening) or yields (i.e., proportion of active tuberculosis among those identified as eligible for follow-up screening). METHODS AND FINDINGS: We performed a systematic review and meta-analysis of studies reporting yields of follow-up screening programmes. Studies were included if they reported the rate of tuberculosis disease detected in international migrants through active case finding strategies and applied a post-migration follow-up (defined as one or more additional rounds of screening after finalising the initial round). For this, we retrieved all studies identified by Chan and colleagues for their systematic review (in their search until January 12, 2017) and included those reporting from active follow-up programmes. We then updated the search (from January 12, 2017 to September 30, 2022) using Medline and Embase via Ovid. Data were extracted on reported coverage, yields, and key programme characteristics, including eligible population, mode of screening, time intervals for screening, programme providers, and legal frameworks. Differences in follow-up programmes were tabulated and synthesised narratively. Meta-analyses in random effect models and exploratory analysis of subgroups showed high heterogeneity (I2 statistic > 95.0%). We hence refrained from pooling, and estimated yields and coverage with corresponding 95% confidence intervals (CIs), stratified by country, legal character (mandatory versus voluntary screening), and follow-up scheme (one-off versus repetitive screening) using forest plots for comparison and synthesis. Of 1,170 articles, 24 reports on screening programmes from 7 countries were included, with considerable variation in eligible populations, time intervals of screening, and diagnostic protocols. Coverage varied, but was higher than 60% in 15 studies, and tended to be lower in voluntary compared to compulsory programmes, and higher in studies from the United States of America, Israel, and Australia. Yield varied within and between countries and ranged between 53.05 (31.94 to 82.84) in a Dutch study and 5,927.05 (4,248.29 to 8,013.71) in a study from the United States. Of 15 estimates with narrow 95% CIs for yields, 12 were below 1,500 cases per 100,000 eligible migrants. Estimates of yields in one-off follow-up programmes tended to be higher and were surrounded by less uncertainty, compared to those in repetitive follow-up programmes. Yields in voluntary and mandatory programmes were comparable in magnitude and uncertainty. The study is limited by the heterogeneity in the design of the identified screening programmes as effectiveness, coverage and yields also depend on factors often underreported or not known, such as baseline incidence in the respective population, reactivation rate, educative and administrative processes, and consequences of not complying with obligatory measures. CONCLUSION: Programme characteristics of post-migration follow-up screening for prevention and control of tuberculosis as well as coverage and yield vary considerably. Voluntary programmes appear to have similar yields compared with mandatory programmes and repetitive screening apparently did not lead to higher yields compared with one-off screening. Screening strategies should consider marginal costs for each additional round of screening.

Repurposing of rabeprazole as an anti-Trypanosoma cruzi drug that targets cellular triosephosphate isomerase.

Trypanosoma cruzi is the causative agent of American trypanosomiasis, which mainly affects populations in Latin America. Benznidazole is used to control the disease, with severe effects in patients receiving this chemotherapy. Previous studies have demonstrated the inhibition of triosephosphate isomerase from T. cruzi, but cellular enzyme inhibition has yet to be established. This study demonstrates that rabeprazole inhibits both cell viability and triosephosphate isomerase activity in T. cruzi epimastigotes. Our results show that rabeprazole has an IC50 of 0.4 µM, which is 14.5 times more effective than benznidazole. Additionally, we observed increased levels of methyl-glyoxal and advanced glycation end products after the inhibition of cellular triosephosphate isomerase by rabeprazole. Finally, we demonstrate that the inactivation mechanisms of rabeprazole on triosephosphate isomerase of T. cruzi can be achieved through the derivatization of three of its four cysteine residues. These results indicate that rabeprazole is a promising candidate against American trypanosomiasis.

Hypermobile Patients With Femoroacetabular Impingement Syndrome Can Be Effectively Treated Utilizing Hip Arthroscopy With Periportal Capsulotomy Closure: A Matched Cohort Analysis Compared to Patients Without Joint Hypermobility.

PURPOSE: To assess the 2-year outcomes of arthroscopic treatment with periportal capsulotomy closure for femoroacetabular impingement syndrome (FAIS) in patients with generalized ligamentous laxity (GLL). METHODS: A retrospective analysis was performed from a prospectively collected database of FAIS patients undergoing hip arthroscopy. FAIS patients with GLL were identified as having Beighton score ≥4. FAIS patients with GLL were treated with arthroscopic labral repair, osteochondroplasty, via periportal capsulotomy with subsequent capsular closure. These patients were matched by age, sex, and body mass index (BMI) with a cohort of FAIS patients without GLL who underwent the same procedure via periportal capsulotomy without capsular closure. Preoperatively, and 2 years postoperatively, patients completed patient-reported outcomes (PRO) scores, including the Hip Disability and Osteoarthritis Outcome Score (HOOS), 12-item Short-Form survey (SF-12) and the visual analog scale (VAS). RESULTS: Forty patients (5 male, 35 female) with FAIS and GLL were included (age: 29.7 ± 9.0; BMI: 23.3 ± 4.1). FAIS patients with GLL demonstrated similar significant PRO score improvements compared to a matched cohort of FAIS patients without GLL at 2 years after surgery (VAS Pain: (-)2.5 ± 3.0, (-)2.7 ± 2.7; SF-12 PCS: 17.7 ± 14.2, 16.7 ± 15.0; HOOS-Symptoms: 26.3 ± 24.0, 20.6 ± 18.1; HOOS-Pain: 29.8 ± 20.4, 24.4 ± 9.0; HOOS-ADL: 24.9 ± 18.4, 22.0 ± 19.9; HOOS-Sports: 43.6 ± 26.1, 33.1 ± 29.8; and HOOS-QOL: 44.2 ± 27.6, 41.7 ± 27.1, respectively). Both cohorts achieved minimal clinically important differences (MCID) for each HOOS subscore at equivalent high rates (70-88%). CONCLUSIONS: Patients with GLL in the setting of FAIS can be effectively treated with arthroscopy via periportal capsulotomy and capsular closure. These patients demonstrate significant improvements in PRO scores at 2 years, similar to normal laxity FAIS patients undergoing arthroscopic treatment via periportal capsulotomy without capsular closure. LEVEL OF EVIDENCE: Level III, retrospective comparative therapeutic trial.

Effect of obesity on short- and long-term complications of shoulder arthroplasty.

BACKGROUND: The proportion of patients undergoing total shoulder arthroplasty (TSA) with obesity continues to grow every year in the United States. Although comorbid obesity is common among TSA patients, the relationship of obesity on medical and surgical complications remains debated. The goal of this study was to evaluate a national database for postoperative medical and surgical complications in patients undergoing TSA with comorbid obesity. METHODS: Patients undergoing anatomic and reverse TSA were studied in the PearlDiver database. Current Procedural Terminology (CPT) and International Classification of Diseases (ICD) codes were used to compare patients with and without preoperative obesity who underwent TSA, and they were stratified based on body mass index (BMI) into nonobese, obese, morbidly obese, and superobese. A matched comparison was performed at a 1:1 ratio based on age, sex, diabetes, smoking, tobacco use, and Charlson Comorbidity Index. RESULTS: From 2010 to 2020, a total of 113,634 patients undergoing anatomic or reverse TSA were identified in a national database. During this time, the percentage of TSA patients with obesity increased every year. Matched cohort analysis demonstrated higher odds of readmission, deep vein thrombosis and pulmonary embolism, superficial infection, and prosthetic joint infection at 90 days postoperatively in the obesity group. There were no increased odds of mechanical complications or revision surgery at 2 years in the obesity group when matched to nonobese patients with similar comorbidities. CONCLUSION: The number of patients undergoing TSA with obesity is rising. Medical complications and infection after TSA are greater in obese patients even when matching for medical comorbidities, age, and sex, and rates of complication increase as BMI increases. Obesity is not an independent risk factor for mechanical surgical complications and revision surgery, and the relatively higher rates are likely due to an increased burden of other comorbidities. Surgeons should counsel obese patients appropriately regarding their perioperative risk of medical complication, but they should not expect higher rates of mechanical complication or revision surgery at 2-year follow-up when compared to a matched control group with similar comorbidities.

Human Triosephosphate Isomerase Is a Potential Target in Cancer Due to Commonly Occurring Post-Translational Modifications.

Cancer involves a series of diseases where cellular growth is not controlled. Cancer is a leading cause of death worldwide, and the burden of cancer incidence and mortality is rapidly growing, mainly in developing countries. Many drugs are currently used, from chemotherapeutic agents to immunotherapy, among others, along with organ transplantation. Treatments can cause severe side effects, including remission and progression of the disease with serious consequences. Increased glycolytic activity is characteristic of cancer cells. Triosephosphate isomerase is essential for net ATP production in the glycolytic pathway. Notably, some post-translational events have been described that occur in human triosephosphate isomerase in which functional and structural alterations are provoked. This is considered a window of opportunity, given the differences that may exist between cancer cells and their counterpart in normal cells concerning the glycolytic enzymes. Here, we provide elements that bring out the potential of triosephosphate isomerase, under post-translational modifications, to be considered an efficacious target for treating cancer.

A shared neural ensemble links distinct contextual memories encoded close in time.

Recent studies suggest that a shared neural ensemble may link distinct memories encoded close in time. According to the memory allocation hypothesis, learning triggers a temporary increase in neuronal excitability that biases the representation of a subsequent memory to the neuronal ensemble encoding the first memory, such that recall of one memory increases the likelihood of recalling the other memory. Here we show in mice that the overlap between the hippocampal CA1 ensembles activated by two distinct contexts acquired within a day is higher than when they are separated by a week. Several findings indicate that this overlap of neuronal ensembles links two contextual memories. First, fear paired with one context is transferred to a neutral context when the two contexts are acquired within a day but not across a week. Second, the first memory strengthens the second memory within a day but not across a week. Older mice, known to have lower CA1 excitability, do not show the overlap between ensembles, the transfer of fear between contexts, or the strengthening of the second memory. Finally, in aged mice, increasing cellular excitability and activating a common ensemble of CA1 neurons during two distinct context exposures rescued the deficit in linking memories. Taken together, these findings demonstrate that contextual memories encoded close in time are linked by directing storage into overlapping ensembles. Alteration of these processes by ageing could affect the temporal structure of memories, thus impairing efficient recall of related information.

Improved yield, stability, and cleavage reaction of a novel tobacco etch virus protease mutant.

The protease catalytic subunit of the nuclear inclusion protein A from tobacco etch virus (TEVp) is widely used to remove tags and fusion proteins from recombinant proteins. Some intrinsic drawbacks to its recombinant production have been studied for many years, such as low solubility, auto-proteolysis, and instability. Some point mutations have been incorporated in the amino acid protease sequence to improve its production. Here, a comprehensive review of each mutation reported so far has been made to incorporate them into a mutant called TEVp7M with a total of seven changes. This mutant with a His7tag at N-terminus was produced with remarkable purification yields (55 mg/L of culture) from the soluble fraction in a single step affinity purification. The stability of His7-TEVp7M was analyzed and compared with the single mutant TEVp S219V, making evident that His7-TEVp7M shows very constant thermal stability against pH variation, whereas TEVp S219V is highly sensitive to this change. The cleavage reaction was optimized by determining the amount of protease that could cleave a 100-fold excess substrate in the shortest possible time at 30 °C. Under these conditions, His7-TEVp7M was able to cleave His-tag in the buffers commonly used for affinity purification. Finally, a structural analysis of the mutations showed that four of them increased the polarity of the residues involved and, consequently, showed increased solubility of TEVp and fewer hydrophobic regions exposed to the solvent. Taken together, the seven changes studied in this work improved stability, solubility, and activity of TEVp producing enough protease to digest large amounts of tags or fusion proteins. KEY POINTS: • Production of excellent yields of a TEVp (TEVp7M) by incorporation of seven changes. • His-tag removal in an excess substrate in the common buffers used for purification. • Incorporated mutations improve polarity, stability, and activity of TEVp7M.

The Giardial Arginine Deiminase Participates in Giardia-Host Immunomodulation in a Structure-Dependent Fashion via Toll-like Receptors.

Beyond the problem in public health that protist-generated diseases represent, understanding the variety of mechanisms used by these parasites to interact with the human immune system is of biological and medical relevance. Giardia lamblia is an early divergent eukaryotic microorganism showing remarkable pathogenic strategies for evading the immune system of vertebrates. Among various multifunctional proteins in Giardia, arginine deiminase is considered an enzyme that plays multiple regulatory roles during the life cycle of this parasite. One of its most important roles is the crosstalk between the parasite and host. Such a molecular "chat" is mediated in human cells by membrane receptors called Toll-like receptors (TLRs). Here, we studied the importance of the 3D structure of giardial arginine deiminase (GlADI) to immunomodulate the human immune response through TLRs. We demonstrated the direct effect of GlADI on human TLR signaling. We predicted its mode of interaction with TLRs two and four by using the AlphaFold-predicted structure of GlADI and molecular docking. Furthermore, we showed that the immunomodulatory capacity of this virulent factor of Giardia depends on the maintenance of its 3D structure. Finally, we also showed the influence of this enzyme to exert specific responses on infant-like dendritic cells.

Giardia lamblia G6PD::6PGL Fused Protein Inhibitors Decrease Trophozoite Viability: A New Alternative against Giardiasis.

Treatments to combat giardiasis have been reported to have several drawbacks, partly due to the drug resistance and toxicity of current antiparasitic agents. These constraints have prompted many researchers to investigate new drugs that act against protozoan parasites. Enzyme inhibition is an important means of regulating pathogen metabolism and has recently been identified as a significant alternative target in the search for new treatments. Glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase (G6PD::6PGL) is a bifunctional enzyme involved in the pentose phosphate pathway (PPP) in Giardia lamblia (G. lamblia). The G. lamblia enzyme is unusual since, unlike the human enzyme, it is a fused enzyme. Here, we show, through inhibition assays, that an in-house chemical library of 120 compounds and four target compounds, named CNZ-7, CNZ-8, CMC-1, and FLP-2, are potent inhibitors of the G. lamblia G6PD::6PGL fused enzyme. With a constant (k2) of 2.3, 3.2, and 2.8 M−1 s−1, respectively, they provoke alterations in the secondary and tertiary protein structure and global stability. As a novel approach, target compounds show antigiardial activity, with IC50 values of 8.7, 15.2, 15.3, and 24.1 µM in trophozoites from G. lamblia. Moreover, these compounds show selectivity against G. lamblia, since, through counter-screening in Caco-2 and HT29 human cells, they were found to have low toxicity. This finding positions these compounds as a potential and attractive starting point for new antigiardial drugs.

Kinetic and Molecular Docking Studies to Determine the Effect of Inhibitors on the Activity and Structure of Fused G6PD::6PGL Protein from Trichomonas vaginalis.

Trichomoniasis is a sexually transmitted disease with a high incidence worldwide, affecting 270 million people. Despite the existence of a catalog of available drugs to combat this infection, their extensive use promotes the appearance of resistant Trichomonas vaginalis (T. vaginalis), and some side effects in treated people, which are reasons why it is necessary to find new alternatives to combat this infection. In this study, we investigated the impact of an in-house library comprising 55 compounds on the activity of the fused T. vaginalis G6PD::6PGL (TvG6PD::6PGL) protein, a protein mediating the first reaction step of the pentose phosphate pathway (PPP), a crucial pathway involved in the parasite's energy production. We found four compounds: JMM-3, CNZ-3, CNZ-17, and MCC-7, which inhibited the TvG6PD::6PGL protein by more than 50%. Furthermore, we determined the IC50, the inactivation constants, and the type of inhibition. Our results showed that these inhibitors induced catalytic function loss of the TvG6PD::6PGL enzyme by altering its secondary and tertiary structures. Finally, molecular docking was performed for the best inhibitors, JMM-3 and MCC-7. All our findings demonstrate the potential role of these selected hit compounds as TvG6PD::6PGL enzyme selective inhibitors.

Pyridyl Methylsulfinyl Benzimidazole Derivatives as Promising Agents against Giardia lamblia and Trichomonas vaginalis.

Protozoan parasites, such as Giardia lamblia and Trichomonas vaginalis, cause the most prevalent infections in humans in developing countries and provoke significant morbidity and mortality in endemic countries. Despite its side-effects, metronidazole is still the drug of choice as a giardiacidal and trichomonacidal tissue-active agent. However, the emergence of metronidazole resistance and its evolved strategies of parasites to evade innate host defenses have hindered the identification and development of new therapeutic strategies against these parasites. Here, we tested five synthesized benzimidazole derivatives as possible drugs for treating giardiasis and trichomoniasis, probing the bifunctional enzyme glucose 6-phosphate dehydrogenase::6-phosphogluconolactone from G. lamblia (GlG6PD::6PGL) and T. vaginalis (TvG6PD::6PGL) as a drug target. The investigated benzimidazole derivatives were H-B2M1, H-B2M2, H2N-BZM6, O2N-BZM7, and O2N-BZM9. The recombinant enzymes were used in inhibition assays, and in silico computational predictions and spectroscopic studies were applied to follow the structural alteration of the enzymes and identify the possible mechanism of inhibition. We identified two potent benzimidazole compounds (O2N-BZM7 and O2N-BZM9), which are capable of inhibiting both protozoan G6PD::6PGL enzymes and in vitro assays with these parasites, showing that these compounds also affect their viability. These results demonstrate that other therapeutic targets of the compounds are the enzymes GlG6PD::6PGL and TvG6PD::6PGL, which contribute to their antiparasitic effect and their possible use in antigiardial and trichomonacidal therapies.

Treatment of Labral Calcification in the Setting of Femoroacetabular Impingement Syndrome With Arthroscopic Calcification Excision, Labral Repair, and Osteoplasty Improves Outcomes.

PURPOSE: To describe the diagnosis and 2-year outcomes of arthroscopic treatment for labral calcification in the setting of femoroacetabular impingement syndrome (FAIS). METHODS: A retrospective analysis was performed from a prospectively collected database of patients with FAIS undergoing hip arthroscopy. Patients with FAIS with labral calcification were differentiated radiographically from patients with other paralabral radiopaque densities such as os acetabuli, acetabular rim fractures, and labral ossification. Patients with FAIS with labral calcification were treated with arthroscopic calcification excision, labral repair, and osteoplasty and matched by age, sex, and body mass index with a cohort of patients with FAIS without labral calcifications who underwent labral repair and osteoplasty. Pre- and 2 years postoperatively, patients completed patient-reported outcome (PRO) scores including the modified Harris Hip Score, Hip disability and Osteoarthritis Outcome Score (HOOS), 12-item Short-Form survey, and visual analog scale. RESULTS: In total, 40 hips (21 male, 19 female) with FAIS and labral calcification were included (age 36.8 ± 8.1, body mass index, 25.9 ± 4.5). Patients with FAIS with labral calcification demonstrated similar significant PRO score improvements compared with a matched cohort of patients with FAIS without labral calcification at 2 years after surgery (visual analog scale: (-)2.3 ± 0.4, (-)2.7 ± 0.5, modified Harris Hip Score: 16.1 ± 2.6, 17.1 ± 3.2; HOOS symptoms: 21.9 ± 3.7, 18.6 ± 3.6; HOOS pain: 22.1 ± 3.0, 25.0 ± 3.5; HOOS activities of daily living: 20.2 ± 2.8, 23.8 ± 3.3; HOOS sport: 35.6 ± 5.0, 35.6 ± 4.1; HOOS quality of life: 36.9 ± 4.5, 37.5 ± 4.4; 12-item Short-Form survey physical component summary: 15.5 ± 2.3, 20.1 ± 2.1, respectively). Both cohorts achieved minimal clinically important differences at equivalent rates (60%-82.5%) for all PRO scores. CONCLUSIONS: Patients with labral calcification in the setting of FAIS can be effectively treated with arthroscopic calcification excision, labral repair, and osteoplasty. These patients demonstrate significant improvements in patient-reported outcomes and achievement of minimal clinically important differences at 2 years similar to patients undergoing arthroscopic treatment for FAIS without labral calcification. LEVEL OF EVIDENCE: Level III, matched cohort study.

Hip Arthroscopy Volume and Reoperations in a Large Cross-Sectional Population: High Rate of Subsequent Revision Hip Arthroscopy in Young Patients and Total Hip Arthroplasty in Older Patients.

PURPOSE: To report contemporary trends in hip arthroscopy case volume in the United States using a large cross-sectional cohort with accurate laterality tracking for assessment of revision surgery and rates of conversion to total hip arthroplasty (THA). METHODS: Using Current Procedural Terminology codes, we queried the Mariner PearlDiver dataset for patients who underwent hip arthroscopy from 2010 to 2017. Patient demographics were recorded and subsequent hip arthroscopy procedures and THA conversion within 2 years after surgery were tracked using International Classification of Diseases, Tenth Revision codes to accurately identify laterality. Emergency department and hospital admission within 30 days after surgery were queried. RESULTS: Of the 53,103 patients undergoing hip arthroscopy procedures, hip arthroscopy case volume increased 2-fold from 2010 to 2014 but remained relatively unchanged from 2014 to 2017. The most common age group undergoing surgery was 40 to 49 years, and female patients represented 70% of cases. Two-year subsequent surgery rate was 19%, with 15.1% undergoing a revision arthroscopy and 3.9% converting to THA. The most common revision arthroscopy procedures were femoroplasty (9.5%), labral repair (8.5%), and acetabuloplasty (4.3%). Younger patients were more likely to undergo revision arthroscopy (18% age 10-19 years; 15% age 20-29 years). Older patients had a significant risk for conversion to THA within 2 years (36% age 60-69 years; 28% age 50-59 years). Female patients also demonstrated a slightly greater rate of conversion to THA (4.1% female, 3.5% male, P <.0001). Patients 20 to 29 years had the greatest risk of emergency department admission (5.4%) and hospital admission (0.8%) within 30 days of surgery. CONCLUSIONS: The rise in hip arthroscopy procedures may be starting to plateau in the United States. Cross-sectional data also indicate that there is a greater than previously reported rate of revision hip arthroscopy in patients younger than 30 years of age and conversion to THA in patients older than 50 years of age. LEVEL OF EVIDENCE: III, cross-sectional study.

Secretome Analysis of Arabidopsis-Trichoderma atroviride Interaction Unveils New Roles for the Plant Glutamate:Glyoxylate Aminotransferase GGAT1 in Plant Growth Induced by the Fungus and Resistance against Botrytis cinerea.

The establishment of plant-fungus mutualistic interaction requires bidirectional molecular crosstalk. Therefore, the analysis of the interacting organisms secretomes would help to understand how such relationships are established. Here, a gel-free shotgun proteomics approach was used to identify the secreted proteins of the plant Arabidopsis thaliana and the mutualistic fungus Trichoderma atroviride during their interaction. A total of 126 proteins of Arabidopsis and 1027 of T. atroviride were identified. Among them, 118 and 780 were differentially modulated, respectively. Bioinformatic analysis unveiled that both organisms' secretomes were enriched with enzymes. In T. atroviride, glycosidases, aspartic endopeptidases, and dehydrogenases increased in response to Arabidopsis. Additionally, amidases, protein-serine/threonine kinases, and hydro-lyases showed decreased levels. Furthermore, peroxidases, cysteine endopeptidases, and enzymes related to the catabolism of secondary metabolites increased in the plant secretome. In contrast, pathogenesis-related proteins and protease inhibitors decreased in response to the fungus. Notably, the glutamate:glyoxylate aminotransferase GGAT1 was secreted by Arabidopsis during its interaction with T. atroviride. Our study showed that GGAT1 is partially required for plant growth stimulation and on the induction of the plant systemic resistance by T. atroviride. Additionally, GGAT1 seems to participate in the negative regulation of the plant systemic resistance against B. cinerea through a mechanism involving H2O2 production.

Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase.

Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we tested giardial arginine deiminase (GlADI) as a target against giardiasis. GlADI belongs to an essential pathway in Giardia for the synthesis of ATP, which is absent in humans. In silico docking with six thiol-reactive compounds was performed; four of which are approved drugs for humans. Recombinant GlADI was used in enzyme inhibition assays, and computational in silico predictions and spectroscopic studies were applied to follow the enzyme's structural disturbance and identify possible effective drugs. Inhibition by modification of cysteines was corroborated using Ellman's method. The efficacy of these drugs on parasite viability was assayed on Giardia trophozoites, along with the inhibition of the endogenous GlADI. The most potent drug against GlADI was assayed on Giardia encystment. The tested drugs inhibited the recombinant GlADI by modifying its cysteines and, potentially, by altering its 3D structure. Only rabeprazole and omeprazole decreased trophozoite survival by inhibiting endogenous GlADI, while rabeprazole also decreased the Giardia encystment rate. These findings demonstrate the potential of GlADI as a target against giardiasis.

Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors.

Helicobacter pylori (H. pylori) is a pathogen that can remain in the stomach of an infected person for their entire life. As a result, this leads to the development of severe gastric diseases such as gastric cancer. In addition, current therapies have several problems including antibiotics resistance. Therefore, new practical options to eliminate this bacterium, and its induced affections, are required to avoid morbidity and mortality worldwide. One strategy in the search for new drugs is to detect compounds that inhibit a limiting step in a central metabolic pathway of the pathogen of interest. In this work, we tested 55 compounds to gain insights into their possible use as new inhibitory drugs of H. pylori glucose-6-phosphate dehydrogenase (HpG6PD) activity. The compounds YGC-1; MGD-1, MGD-2; TDA-1; and JMM-3 with their respective scaffold 1,3-thiazolidine-2,4-dione; 1H-benzimidazole; 1,3-benzoxazole, morpholine, and biphenylcarbonitrile showed the best inhibitory activity (IC50 = 310, 465, 340, 204 and 304 µM, respectively). We then modeled the HpG6PD protein by homology modeling to conduct an in silico study of the chemical compounds and discovers its possible interactions with the HpG6PD enzyme. We found that compounds can be internalized at the NADP+ catalytic binding site. Hence, they probably exert a competitive inhibitory effect with NADP+ and a non-competitive or uncompetitive effect with G6P, that of the compounds binding far from the enzyme's active site. Based on these findings, the tested compounds inhibiting HpG6PD represent promising novel drug candidates against H. pylori.