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Abstract Ebola virus can trigger a release of pro-inflammatory cytokines with subsequent vascular leakage and impairment of clotting finally leading to multiorgan failure and shock after entering and infecting patients. Ebola virus is known to directly target endothelial cells and macrophages, even without infecting them, through direct interactions with viral proteins. These interactions affect cellular mechanics and immune processes, which are tightly linked to other key cellular functions such as metabolism. However, research regarding metabolic activity of these cells upon viral exposure remains limited, hampering our understanding of its pathophysiology and progression. Therefore, in the present study, an untargeted cellular metabolomic approach was performed to investigate the metabolic alterations of primary human endothelial cells and M1 and M2 macrophages upon exposure to Ebola virus–like particles (VLP). The results show that Ebola VLP led to metabolic changes among endothelial, M1, and M2 cells. Differential metabolite abundance and perturbed signaling pathway analysis further identified specific metabolic features, mainly in fatty acid-, steroid-, and amino acid–related metabolism pathways for all the three cell types, in a host cell specific manner. Taken together, this work characterized for the first time the metabolic alternations of endothelial cells and two primary human macrophage subtypes after Ebola VLP exposure, and identified the potential metabolites and pathways differentially affected, highlighting the important role of those host cells in disease development and progression. Key messages • Ebola VLP can lead to metabolic alternations in endothelial cells and M1 and M2 macrophages. • Differential abundance of metabolites, mainly including fatty acids and sterol lipids, was observed after Ebola VLP exposure. • Multiple fatty acid-, steroid-, and amino acid–related metabolism pathways were observed perturbed.

For neurodevelopmental disorders (NDDs), a molecular diagnosis is key for management, predicting outcome, and counseling. Often, routine DNA-based tests fail to establish a genetic diagnosis in NDDs. Transcriptome analysis (RNA sequencing [RNA-seq]) promises to improve the diagnostic yield but has not been applied to NDDs in routine diagnostics. Here, we explored the diagnostic potential of RNA-seq in 96 individuals including 67 undiagnosed subjects with NDDs. We performed RNA-seq on single individuals' cultured skin fibroblasts, with and without cycloheximide treatment, and used modified OUTRIDER Z scores to detect gene expression outliers and mis-splicing by exonic and intronic outliers. Analysis was performed by a user-friendly web application, and candidate pathogenic transcriptional events were confirmed by secondary assays. We identified intragenic deletions, monoallelic expression, and pseudoexonic insertions but also synonymous and non-synonymous variants with deleterious effects on transcription, increasing the diagnostic yield for NDDs by 13%. We found that cycloheximide treatment and exonic/intronic Z score analysis increased detection and resolution of aberrant splicing. Importantly, in one individual mis-splicing was found in a candidate gene nearly matching the individual's specific phenotype. However, pathogenic splicing occurred in another neuronal-expressed gene and provided a molecular diagnosis, stressing the need to customize RNA-seq. Lastly, our web browser application allowed custom analysis settings that facilitate diagnostic application and ranked pathogenic transcripts as top candidates. Our results demonstrate that RNA-seq is a complementary method in the genomic diagnosis of NDDs and, by providing accessible analysis with improved sensitivity, our transcriptome analysis approach facilitates wider implementation of RNA-seq in routine genome diagnostics.

In the field of electrical and electronics (E&E) technology that is evolving rapidly, the Ministry of Higher Education Malaysia emphasizes universities to ensure that the expected non-major E&E engineering graduates are fully equipped with the skills to fulfil market needs. However, it is challenging for non-major students to understand the topics taught to them through the methods as they are conventionally being delivered. Therefore, gamification and simulation such as Kahoot, Quizizz, Multisim and CircuitMod have been applied in the university to facilitate formative assessment in order to enhance interest and understanding, and also accomplish learning more effectively among non-major students. Hence, this research aims to examine the non-major students’ perception of the implementation of gamification and simulation in class for face-to-face and online settings. To achieve this, a set of questionnaires was adapted with some modifications for the purpose of data collection. It was distributed to the students from random public universities in Malaysia who are currently enrolled in E&E engineering courses at their respective universities which majority of them are from a mechanical engineering background. Research questions concentrate on the advantages and students’ perceptions of gamification and simulation in E&E engineering courses. The collected data has been analyzed using descriptive statistical analysis. Based on the perceptions of the participating non-major E&E engineering students, the majority of the respondents agreed that gamification and simulation provide a better learning experience with the highest score mean of 4.22. Moreover, gamification and simulation boost students' ability to learn, motivate them, increase their understanding, promote their well-being, and increase their achievement academically. Students hold a positive perception with 4.20 mean score, stating that it is suitable for application in the learning process as it is easy to use, fun, motivating, and more efficient. The results provided would encourage educators in Malaysian universities to better meet the needs of teaching non-major students with their lessons.

Rationale: Bacterial lung microbiota are correlated with lung inflammation and acute respiratory distress syndrome (ARDS) and altered in severe coronavirus disease (COVID-19). However, the association between lung microbiota (including fungi) and resolution of ARDS in COVID-19 remains unclear. We hypothesized that increased lung bacterial and fungal burdens are related to nonresolving ARDS and mortality in COVID-19. Objectives: To determine the relation between lung microbiota and clinical outcomes of COVID-19-related ARDS. Methods: This observational cohort study enrolled mechanically ventilated patients with COVID-19. All patients had ARDS and underwent bronchoscopy with BAL. Lung microbiota were profiled using 16S rRNA gene sequencing and quantitative PCR targeting the 16S and 18S rRNA genes. Key features of lung microbiota (bacterial and fungal burden, α-diversity, and community composition) served as predictors. Our primary outcome was successful extubation adjudicated 60 days after intubation, analyzed using a competing risk regression model with mortality as competing risk. Measurements and Main Results: BAL samples of 114 unique patients with COVID-19 were analyzed. Patients with increased lung bacterial and fungal burden were less likely to be extubated (subdistribution hazard ratio, 0.64 [95% confidence interval, 0.42-0.97]; P = 0.034 and 0.59 [95% confidence interval, 0.42-0.83]; P = 0.0027 per log10 increase in bacterial and fungal burden, respectively) and had higher mortality (bacterial burden, P = 0.012; fungal burden, P = 0.0498). Lung microbiota composition was associated with successful extubation (P = 0.0045). Proinflammatory cytokines (e.g., tumor necrosis factor-α) were associated with the microbial burdens. Conclusions: Bacterial and fungal lung microbiota are related to nonresolving ARDS in COVID-19 and represent an important contributor to heterogeneity in COVID-19-related ARDS.

Background: Surgical and nonoperative management of anterior cruciate ligament (ACL) injuries seek to mitigate the risk of knee instability and secondary meniscal injury. However, the associated risk and timing of secondary meniscal tears have not been completely elucidated. Purpose: To compare risk and timing of secondary meniscal injury between patients receiving nonoperative management, delayed ACL reconstruction (ACLR), and early ACLR using a machine learning survival analysis. Study Design: Cohort study; Level of evidence, 3. Methods: A geographic database was used to identify and review records of patients with a diagnosis of ACL rupture between 1990 and 2016 with minimum 2-year follow-up. Patients undergoing ACLR were matched 1:1 with nonoperatively treated controls. Rate and time to secondary meniscal tear were compared using random survival forest algorithms; independent models were developed and internally validated for predicting injury-free duration in both cohorts. Performance was measured using out-of-bag c-statistic, calibration, and Brier score. Model interpretability was enhanced using global variable importance and partial dependence curves. Results: The study included 1369 patients who underwent ACLR and 294 patients who had nonoperative treatment. After matching, no significant differences in rates of secondary meniscal tear were found ( P = .09); subgroup analysis revealed the shortest periods of meniscal survival in patients undergoing delayed ACLR. The random survival forest algorithm achieved excellent predictive performance for the ACLR cohort, with an out-of-bag c-statistic of 0.80 and a Brier score of 0.11. Significant variables for risk of meniscal tear for the ACLR cohort included time to return to sports or activity ≤350 days, time to surgery ≥50 days, age at injury ≤40 years, and high-impact or rotational landing sports, whereas those in the nonoperative cohort model included time to RTS ≤200 days, visual analog scale pain score >3 at consultation, hypermobility, and noncontact sports. Conclusion: Delayed ACLR demonstrated the greatest long-term risk of meniscal injury compared with nonoperative treatment or early ACLR. Risk factors for decreased meniscal survival after ACLR included increased time to surgery, shorter time to return to sports or activity, older age at injury, and involvement in high-impact or rotational landing sports. Pending careful external validation, these models may be deployed in the clinical space to provide real-time insights and enhance decision making.

PURPOSE: This study sought to develop and internally validate a machine learning model to identify risk factors and quantify overall risk of secondary meniscus injury in a longitudinal cohort after primary ACL reconstruction (ACLR). METHODS: Patients with new ACL injury between 1990 and 2016 with minimum 2-year follow-up were identified. Records were extensively reviewed to extract demographic, treatment, and diagnosis of new meniscus injury following ACLR. Four candidate machine learning algorithms were evaluated to predict secondary meniscus tears. Performance was assessed through discrimination using area under the receiver operating characteristics curve (AUROC), calibration, and decision curve analysis; interpretability was enhanced utilizing global variable importance plots and partial dependence curves. RESULTS: A total of 1,187 patients underwent ACLR; 139 (11.7%) experienced a secondary meniscus tear at a mean time of 65 months post-op. The best performing model for predicting secondary meniscus tear was the random forest (AUROC = 0.790, 95% CI: 0.785–0.795; calibration intercept = 0.006, 95% CI: 0.005–0.007, calibration slope = 0.961 95% CI: 0.956–0.965, Brier’s score = 0.10 95% CI: 0.09–0.12), and all four machine learning algorithms outperformed traditional logistic regression. The following risk factors were identified: shorter time to return to sport (RTS), lower VAS at injury, increased time from injury to surgery, older age at injury, and proximal ACL tear. CONCLUSION: Machine learning models outperformed traditional prediction models and identified multiple risk factors for secondary meniscus tears after ACLR. Following careful external validation, these models can be deployed to provide real-time quantifiable risk for counseling and timely intervention to help guide patient expectations and possibly improve clinical outcomes.

The increasing demand for food has increased dependence on chemical fertilizers that promote rapid growth and yield as well as produce toxicity and negatively affect nutritional value. Therefore, researchers are focusing on alternatives that are safe for consumption, non-toxic, cost-effective production process, and high yielding, and that require readily available substrates for mass production. The potential industrial applications of microbial enzymes have grown significantly and are still rising in the 21st century to fulfill the needs of a population that is expanding quickly and to deal with the depletion of natural resources. Due to the high demand for such enzymes, phytases have undergone extensive research to lower the amount of phytate in human food and animal feed. They constitute efficient enzymatic groups that can solubilize phytate and thus provide plants with an enriched environment. Phytases can be extracted from a variety of sources such as plants, animals, and microorganisms. Compared to plant and animal-based phytases, microbial phytases have been identified as competent, stable, and promising bioinoculants. Many reports suggest that microbial phytase can undergo mass production procedures with the use of readily available substrates. Phytases neither involve the use of any toxic chemicals during the extraction nor release any such chemicals; thus, they qualify as bioinoculants and support soil sustainability. In addition, phytase genes are now inserted into new plants/crops to enhance transgenic plants reducing the need for supplemental inorganic phosphates and phosphate accumulation in the environment. The current review covers the significance of phytase in the agriculture system, emphasizing its source, action mechanism, and vast applications.

Alternative splicing (AS) is crucial for cell-type-specific gene transcription and plays a critical role in neuronal differentiation and synaptic plasticity. De novo frameshift variants in NOVA2, encoding a neuron-specific key splicing factor, have been recently associated with a new neurodevelopmental disorder (NDD) with hypotonia, neurological features, and brain abnormalities. We investigated eight unrelated individuals by exome sequencing (ES) and identified seven novel pathogenic NOVA2 variants, including two with a novel localization at the KH1 and KH3 domains. In addition to a severe NDD phenotype, novel clinical features included psychomotor regression, attention deficit-hyperactivity disorder (ADHD), dyspraxia, and urogenital and endocrinological manifestations. To test the effect of the variants on splicing regulation, we transfected HeLa cells with wildtype and mutant NOVA2 complementary DNA (cDNA). The novel variants NM_002516.4:c.754_756delCTGinsTT p.(Leu252Phefs*144) and c.1329dup p.(Lys444Glnfs*82) all negatively affected AS events. The distal p.(Lys444Glnfs*82) variant, causing a partial removal of the KH3 domain, had a milder functional effect leading to an intermediate phenotype. Our findings expand the molecular and phenotypic spectrum of NOVA2-related NDD, supporting the pathogenic role of AS disruption by truncating variants and suggesting that this is a heterogeneous condition with variable clinical course.

In this article I address three main crises of the Anthropocene: energy and climate, biodiversity and food, and peace and security. To obtain overall sustainability, natural scientists and engineers have developed the Energy Transition Model, the Carbon Transition Model, and the Agri-food-nature Transition Model. From these models two facts stand out. The age of fossil fuels and of livestock farming will come to an end. Because a sustainable society also has sociopolitical and legal, socioeconomic and financial, sociocultural and welfare, and socioenvironmental and ecological aspects, the contribution of human scientists to overall sustainability is also crucial.

Absorptive capacity (AC) has the potential to explain performance and competitive advantage. The cumulativeness feature of AC has been broadly covered in theory but remains underdeveloped in empirical assessments. This paper aims to revisit the relationships between AC and its knowledge dimensions and to contribute to measurement theory on AC. We adopt an existing survey instrument and confirm through structural equation modelling that the relationships between AC and its knowledge dimensions are better represented by a formative model, as opposed to the more used reflective model. Based on a simplex model and the Mokken scale, we also confirm that AC is an ability, developed cumulatively through a sequence of knowledge processes. The paper contributes to construct convergence by developing and illustrating guidelines for measurement that are congruent with the seminal definitions of AC but are underrepresented in the literature. It contributes to practice by highlighting the roadmap for developing AC.

Proximal tibial osteotomy (PTO) is a well-established treatment for coronal deformity and focal cartilage defects. However, the utility of joint-preserving interventions must be weighed against potential effects on subsequent total knee arthroplasty (TKA). The purpose of this study was to determine the effect of PTO on subsequent TKA by comparing outcomes in patients with bilateral TKAs following unilateral PTO.Patients who underwent bilateral TKAs from 2000 to 2015 at a single institution and had previously undergone a unilateral valgus-producing PTO were reviewed. We evaluated 140 TKAs performed in 70 patients (24 female, 46 male) with a mean age at PTO of 50 ± 8 years. The patients underwent conversion to TKA at a mean of 14 ± 7 years following ipsilateral PTO and were followed for a mean of 25 ± 7 years (range, 6 to 40 years) following PTO. The Knee Society Score (KSS), Forgotten Joint Score-12 (FJS-12), subjective knee preference, and revision were compared between the PTO-TKA and contralateral TKA-only sides.The PTO side demonstrated similar KSS Knee subscores (41 ± 16) compared with the contralateral side (39 ± 16, p = 0.67) immediately prior to arthroplasty. Patients had significant improvements in KSS (p0.001) after TKA, with clinically similar KSS values at 2 to 15 years of follow-up when knees were compared in a pairwise fashion (p = 0.10 to 0.83). Five PTO-TKA knees (7%) and 4 control TKA-only knees (6%) underwent revision at a mean of 5 years postoperatively (p = 0.76). The number of all-cause reoperations was approximately twice as high in PTO-TKA knees (13% compared with 6% in TKA-only knees, p = 0.24). At the time of final follow-up, PTO-TKA knees demonstrated similar FJS-12 scores (72 ± 26) compared with the contralateral knees (70 ± 28, p = 0.57). Nineteen percent of patients preferred the PTO-TKA knee, 19% preferred the contralateral TKA-only knee, and 62% stated that their knees were equivalent (p0.99). The final Tegner activity score was 2.5 ± 1.4.Long-term clinical function of TKA following PTO was excellent, with patients demonstrating comparable subjective outcomes and equivalent knee preference compared with the contralateral TKA-only knees. Further, well-matched studies are needed to evaluate long-term revision and reoperation rates following PTO-TKA.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Contains fulltext : 282540.pdf (Publisher’s version ) (Open Access) INTRODUCTION/AIMS: Visual and quantitative muscle ultrasound are both valid diagnostic tools in neuromuscular diseases. To optimize muscle ultrasound evaluation and facilitate its use in neuromuscular disease, we examined the correlation between visual and quantitative muscle ultrasound analysis and their pitfalls. METHODS: Retrospective data from 994 patients with 13,562 muscle ultrasound images were analyzed. Differences in echogenicity z-score distribution per Heckmatt grade and corresponding correlation coefficients were calculated. RESULTS: Overall, there was a correlation of 0.60 between the two scoring systems, with a gradual increase in z-score with increasing Heckmatt grades and vice versa. Patients with a neuromuscular disorder had higher Heckmatt grades (p

Weissella strains are often detected in spontaneously fermented foods. Because of their abilities to produce lactic acid and functional exopolysaccharides as well as their probiotic traits, Weissella spp. improve not only the sensorial properties but also nutritional values of the fermented food products. However, some Weissella species have been associated with human and animal diseases. In the era of vast genomic sequencing, new genomic/genome data are becoming available to the public on daily pace. Detailed genomic analyses are due to provide a full understanding of individual Weissella species. In this study, the genomes of six Weissella paramesenteroides strains were de novo sequenced. The genomes of 42 W. paramesenteroides strains were compared to discover their metabolic and functional potentials in food fermentation. Comparative genomics and metabolic pathway reconstructions revealed that W. paramesenteroides is a compact group of heterofermentative bacteria with good capacity of producing secondary metabolites and vitamin Bs. Since the strains rarely harbored plasmid DNA, they did not commonly possess the genes associated with bacteriocin production. All 42 strains were shown to bear vanT gene from the glycopeptide resistance gene cluster vanG. Yet none of the strains carried virulence genes.

The current study was designed to prepare whey-carrot-based functional beverages and studying the effect on physicochemical properties during the 28 days of storage period. Different ratio of whey and carrot juice were selected for preparation of the six formulations, out of which based on the sensory acceptance only three were selected for the further storage studies (sample 1 = 45:55, sample 2 = 50:50, and sample 3 = 55:45 of carrot juice to whey ratio). During 28 days of storage, the developed beverage samples revealed a significant increase in reducing sugars, total phenolic content, and acidity. The pH, sweetness, and acceptance percentage of the beverage found to be decreased with storage period. It was also found that there is not change in the properties of the beverage storage with and without the preservative. It was revealed that beverage with less proportion of carrot juice is more acceptable quality. The results also suggest that whey can be used with fruit and vegetable to create whey-based beverage.

Reservoir top structure interpretation through seismic usually associated with uncertainty especially when sparse number of wells are available. This leads to uncertainty in gross rock volume and oil-in-place calculation. It is quite common with reservoir top interpretation picking varies significantly from optimistic to pessimistic case especially at the point distant away from wellbore.This paper integrates the geosteering distance-to-boundary (DTB) calculation from horizontal well drilling to minimize the uncertainty window of top interpretation from surface seismic to deliver more accurate remaining oil-in place.During the geosteering operation, seismic horizon interpretation of reservoir target sand with multiple scenarios in offshore field was compared with the distance to boundary calculation that map the reservoir top structure with azimuthal resistivity tool. Prior to geosteer horizontal well in the oil-rim reservoir after long production, pilot hole was drilled to update the current fluid contact. Reservoir top interpretation is revised by including horizon top structure tied to well data from the pilot hole and existing wells in the area.The revised top structure which includes the pessimistic and optimistic case generally has significant difference in remaining OIP. Upon geosteering horizontal well, DTB calculation from azimuthal resistivity tool was capable to map the top reservoir boundary in real-time with reference from the seismic top interpretation from heel to toe of the lateral with good quality mapping of entire top reservoir structure.Distance to boundary (DTB) with good quality of top reservoir structure mapping throughout the section tracked closely to optimistic case of seismic top interpretation of target sand. Geosteering with azimuthal resistivity with RSS directional tool mapped the top of the reservoir on the upside and OWC from the downside up to 4.8 m away from the tool. As the top is expected to dip down and intersected the trajectory at multiple scenarios, the mapped boundary provided insights of gentle dipping trend, suggesting the top of reservoir could extend laterally longer than pessimistic case. With the result closer to optimistic case, the calculated remaining OIP volume calculated was on the optimistic side with significant difference, larger volume, from pessimistic case of OIP calculation.Integration of seismic top interpretation with geosteering distance to boundary application in lateral well could minimize the uncertainty in reservoir top horizon interpretation. The workflow enabled to place the well in the sweet spot while managing the uncertainty of top structure. With production from horizontal well, the well production rate is expected to increase to 2900 BOPD for initial oil production compare to below 1000 BOPD prior to horizontal well drilling. This workflow could be applied for future lateral well with high uncertainty of the target to place the well in sweetspot for field life extension and production optimization.

Supplemental material, sj-pdf-1-ajs-10.1177_03635465231164400 for Medial Patellofemoral Ligament Reconstruction Using Allografts in Skeletally Immature Patients by Martin Husen, Todd A. Milbrandt, Veeraj Shah, Aaron J. Krych, Michael J. Stuart and Daniel B.F. Saris in The American Journal of Sports Medicine

Supplemental material, sj-docx-1-ajs-10.1177_03635465231168139 for Predicting the Risk of Posttraumatic Osteoarthritis After Primary Anterior Cruciate Ligament Reconstruction: A Machine Learning Time-to-Event Analysis by Yining Lu, Anna K. Reinholz, Sara E. Till, Sydney V. Kalina, Daniel B.F. Saris, Christopher L. Camp and Michael J. Stuart in The American Journal of Sports Medicine

Background: Osteochondritis dissecans (OCD) is a disorder originating in the subchondral bone, leading to focal lesions with risk of fragmentation and secondary damage of the articular cartilage. It remains controversial if surgical treatment of such lesions is equally successful in skeletally immature and mature patients. Purpose: To determine (1) the long-term clinical success rate after internal fixation of unstable OCD in skeletally immature and mature patients based on physeal status, (2) if patient-specific and procedural variables influence the risk of failure, and (3) patient-reported outcome measures over time. Study Design: Cohort study; Level of evidence, 3. Methods: A multicenter retrospective cohort study was conducted investigating skeletally immature and mature patients treated for unstable OCD lesions of the knee between 2000 and 2015. The healing rate was assessed by radiological imaging and clinical follow-up. Failure was defined as any definitive reoperation for the initially treated OCD lesion. Results: A total of 81 patients met inclusion criteria, including 25 skeletally immature patients and 56 patients with closed physes at the time of surgery. After a mean follow-up time of 11.3 ± 4 years, 58 (71.6%) patients had healed lesions, whereas the lesions failed to heal in 23 (28.4%) patients. No significant difference in risk of failure was observed based on physeal maturation status (hazard ratio, 0.78; 95% CI, 0.33-1.84; P = .56). Lateral versus medial condylar lesion location conferred an increased risk of failure ( P < .05) for both skeletally immature and mature patients. Multivariate analysis of skeletal maturity status showed that a lateral femoral condylar location was an independent risk factor for failure (hazard ratio, 0.22; 95% CI, 0.1-0.5; P < .05). The mean patient-reported outcome scores (International Knee Documentation Committee [IKDC] score and Knee injury and Osteoarthritis Outcome Score [KOOS]) increased significantly after surgery and remained high at the final follow-up ( P < .05). The final scores (mean ± SD) at a mean follow-up of 135.8 months (range, 80-249 months) were IKDC, 86.6 ± 16.7; KOOS Pain, 88.7 ± 18.1; KOOS Symptoms, 89.3 ± 12.6; KOOS Activities of Daily Living, 89.3 ± 21.6; KOOS Sport and Recreation, 79.8 ± 26.3; and KOOS Quality of Life, 76.7 ± 26.3. Conclusion: The long-term results after internal fixation of OCD fragments show high rates of healing and sustainable subjective improvement of knee function and quality of life. A healing rate of 72% was noted at a mean follow-up of 11.3 years. The stage of skeletal maturity had no significant influence on the rate of failure. Lateral femoral condylar lesion location is an independent risk factor for failure in skeletally mature and immature patients.

Background: Patellar instability has the highest incidence in adolescents aged between 14 and 18 years. The unique relationship between the medial patellofemoral ligament (MPFL) and the distal femoral physis in skeletally immature patients warrants precisely positioned MPFL graft insertion. A paucity of data are available evaluating the results of MPFL reconstruction using allograft tendon before skeletal maturity. Purposes: (1) To assess the results of MPFL reconstruction using allograft tendon in skeletally immature patients by analyzing redislocation and reoperation rates, radiological outcomes, and patient-reported outcomes and (2) to determine whether epidemiological, intraoperative, or radiographic factors influence recurrent instability and clinical outcomes. Study Design: Case series; Level of evidence, 4. Methods: Prospectively collected data were retrospectively analyzed for 69 skeletally immature patients who experienced a first-time or recurrent lateral patellar dislocation and were treated with anatomic MPFL reconstruction. Inclusion criteria were MPFL reconstruction using allograft and the availability of preoperative magnetic resonance imaging scans in the presence of open or partially open physes. Patients with Results: A total of 79 physeal-sparing MPFL reconstructions (69 patients) met the inclusion criteria. The mean age of the patient cohort was 14.7 ± 1.8 years (range, 8.5-16.9 years). Within the mean follow-up time of 37.9 ± 12.1 months (range, 24-85 months after surgery, there were 12 patients with clinical failures resulting in reoperation. Eleven patients experienced a redislocation of the patella, and 1 patient sustained a transverse noncontact patellar fracture 6 months after index surgery that required operative fixation. No injuries to the distal femoral physes were clinically observed. At the final follow-up, patients had a mean Lysholm score (1-100) of 96.5 ± 6.7, a mean Kujala score (1-100) of 96.5 ± 7.4, and a mean Tegner Activity Scale score (1-10) of 4.9 ± 1.3. Patellar height and trochlear dysplasia did not influence redislocation or clinical scores. In total, 57 of the 63 patients (90.5%) who were engaged in sports before injury returned to the same or higher level of competition. In a subgroup analysis of patients who underwent isolated MPFL reconstruction (n = 44) without concomitant procedures, 9 patients (20.5%) experienced failure and had a redislocation. A univariate analysis of hazards for failure based on patient-specific variables was carried out. A body mass index ≥30 conveyed a hazard ratio of 2.51 (95% CI, 0.63-10.1; P = .19), and the tibial tubercle-trochlear groove distance by increments of 1 mm was associated with a hazard ratio of 2.02 (95% CI, 0.51-8.11; P = .32). Conclusion: Physeal-sparing anatomic reconstruction of the MPFL using an allograft tendon in skeletally immature patients was a safe and effective treatment for patellar instability, regardless of patellar height and trochlear dysplasia. Failure rates decreased when the MPFL reconstruction was performed concomitantly with a tibial tubercle osteotomy.

Background: Long-term clinical evaluation of patient outcomes can steer treatment choices and further research for cartilage repair. Using mesenchymal stromal cells (MSCs) as signaling cells instead of stem cells is a novel approach in the field. Purpose: To report the 5-year follow-up of safety, clinical efficacy, and durability after treatment of symptomatic cartilage defects in the knee with allogenic MSCs mixed with recycled autologous chondrons in first-in-human study of 1-stage cartilage repair. Study Design: Case series; Level of evidence, 4. Methods: This study is an investigator-driven study aiming at the feasibility and safety of this innovative cartilage repair procedure. Between 2013 and 2014, a total of 35 patients (mean ± SD age, 36 ± 8 years) were treated with a 1-stage cartilage repair procedure called IMPACT (Instant MSC Product Accompanying Autologous Chondron Transplantation) for a symptomatic cartilage defect on the femoral condyle or trochlear groove. Subsequent follow-up after initial publication was performed annually using online patient-reported outcome measures with a mean follow-up of 61 months (range, 56-71 months). Patient-reported outcome measures included the KOOS (Knee injury and Osteoarthritis Outcome Score), visual analog scale for pain, and EuroQol–5 Dimensions. All clinical data and serious adverse events, including additional treatment received after IMPACT, were recorded. A failure of IMPACT was defined as a chondral defect of at least 20% of the index lesion with a need for a reintervention including a surgical procedure or an intra-articular injection. Results: Using allogenic MSCs, no signs of a foreign body response or serious adverse reactions were recorded after 5 years. The majority of patients showed statistically significant and clinically relevant improvement in the KOOS and all its subscales from baseline to 60 months: overall, 57.9 ± 16.3 to 78.9 ± 17.7 ( P < .001); Pain, 62.3 ± 18.9 to 79.9 ± 20.0 ( P = .03); Function, 61.6 ± 16.5 to 79.4 ± 17.3 ( P = .01); Activities of Daily Living, 69.0 ± 19.0 to 89.9 ± 14.9 ( P < .001); Sports and Recreation, 32.3 ± 22.6 to 57.5 ± 30.0 ( P = .02); and Quality of Life, 25.9 ± 12.9 to 55.8 ± 26.8 ( P < .001). The visual analog scale score for pain improved significantly from baseline (45.3 ± 23.6) to 60 months (15.4 ± 13.4) ( P < .001). Five cases required reintervention. Conclusion: This is the first study showing the midterm safety and efficacy of the proof of concept that allogenic MSCs augment 1-stage articular cartilage repair. The absence of serious adverse events and the clinical outcome support the longevity of this unique concept. These data support MSC-augmented chondron transplantation (IMPACT) as a safe 1-stage surgical solution that is considerably more cost-effective and a logistically advantageous alternative to conventional 2-stage cell-based therapy for articular chondral defects in the knee.

Pantai Pulau Datok merupakan salah satu pantai yang terletak pada Desa Sutera, Kecamatan Sukadana, Kabupaten Kayong Utara dengan luas 18,30 Ha atau 0,18 Km2, dan garis pantai sepanjang 1,18 Km. Sebagai salah satu objek wisata kawasan Pantai Pulau Datok sudah terdapat beberapa prasarana dan sarana. Tujuan penelitian ini ialah untuk mengetahui kebutuhan prasarana dan sarana pada Pantai Pulau Datok berdasarkan persepsi pengunjung. Pendekatan penelitian yang digunakan ialah deskriptif kualitatif dengan teknik analisis statistik deskriptif dan analisis buffer. Pada analisis prasarana dan sarana berdasarkan persepsi pengunjung indikator pertanyaan telah ditentukan yaitu prasarana berupa jaringan listrik, jalan, telekomunikasi, drainase, persampahan, air bersih. Sarana berupa sarana ibadah, olahraga, toilet umum, akomodasi, pos keamanan, tempat bermain anak, tempat pertunjukan seni, atraksi pantai, lahan parkir, kursi/saung, perdagangan, pusat informasi, dan rambu keamanan. Berdasarkan hasil analisis yang didapat, terdapat beberapa hasil analisis yang berbeda yaitu sangat setuju, setuju dan netral jika dilakukannya penambahan prasarana dan sarana tersebut.

Purpose The purpose of this review is to perform a meta-analysis of studies reporting meniscus repair outcomes. Pooled analyses of such studies will provide an accurate estimate of the outcomes that can be expected following meniscal repair at various postoperative time points. Methods A meta-analysis of meniscal repair failure (defined as persistent symptoms, lack of healing on magnetic resonance imaging or revision surgery) and other clinical outcomes was performed following meniscal repair. Patients included had traumatic, nondegenerative meniscal tears, were skeletally mature, and had specific time-points after surgery. Repairs included were performed either in isolation, or with concomitant ACL reconstruction. Because of the inherent heterogeneity of single-arm meta-analyses, pooled analyses were performed using a random-effects model. Results Rates of all-cause meniscal repair failure was pooled to be 12% at 0-1 years (95% CI: .09-.16), 15% at 2-3 years (95% CI: .11-.20), and 19% at 4-6 years (95% CI: .13-.24). Sensitivity analysis for studies performing meniscal repair entirely on patients with concomitant ACL reconstruction (ACLR) showed comparable rates of failure at similar time intervals. Development of osteoarthritis, in patients with knees previously free from articular pathologies, was 4% at 2-3 years (95% CI: .02-.07), and 10% at 4-6 years (95% CI: .03-.25). Conclusion Meniscus repair for traumatic injuries have an all-cause failure rate that increases from 12% to 19% through a time period ranging from 1-6 years following surgery. The failure rates were comparable for patients with meniscal repairs performed with concomitant ACLRs. Level of Evidence IV; Systematic Review of Level II-IV Studies.

Background: Meniscal allograft transplant (MAT) is an important treatment option for young patients with deficient menisci; however, there is a lack of consensus on the optimal method of allograft fixation. Hypothesis: The various methods of MAT fixation have measurable and significant differences in outcomes. Study Design: Meta-analysis; Level of evidence, 4. Methods: A single-arm meta-analysis of studies reporting graft failure, reoperations, and other clinical outcomes after MAT was performed. Studies were stratified by suture-only, bone plug, and bone bridge fixation methods. Proportionate rates of failure and reoperation for each fixation technique were pooled with a mixed-effects model, after which reconstruction of relative risks with confidence intervals was performed using the Katz logarithmic method. Results: A total of 2604 patients underwent MAT. Weighted mean follow-up was 4.3 years (95% CI, 3.2-5.6 years). During this follow-up period, graft failure rates were 6.2% (95% CI, 3.2%-11.6%) for bone plug fixation, 6.9% (95% CI, 4.5%-10.3%) for suture-only fixation, and 9.3% (95% CI, 6.2%-13.9%) for bone bridge fixation. Transplanted menisci secured using bone plugs displayed a lower risk of failure compared with menisci secured via bone bridges (RR = 0.97; 95% CI, 0.94-0.99; P = .02). Risks of failure were not significantly different when comparing suture fixation to bone bridge (RR = 1.02; 95% CI, 0.99-1.06; P = .12) and bone plugs (RR = 0.99; 95% CI, 0.96-1.02; P = .64). Allografts secured using bone plugs were at a lower risk of requiring reoperations compared with those secured using sutures (RR = 0.91; 95% CI, 0.87-0.95; P < .001), whereas allografts secured using bone bridges had a higher risk of reoperation when compared with those secured using either sutures (RR = 1.28; 95% CI, 1.19-1.38; P < .001) or bone plugs (RR = 1.41; 95% CI, 1.32-1.51; P < .001). Improvements in Lysholm and International Knee Documentation Committee scores were comparable among the different groups. Conclusion: This meta-analysis demonstrates that bone plug fixation of transplanted meniscal allografts carries a lower risk of failure than the bone bridge method and has a lower risk of requiring subsequent operations than both suture-only and bone bridge methods of fixation. This suggests that the technique used in the fixation of a transplanted meniscal allograft is an important factor in the clinical outcomes of patients receiving MATs.

Excessive antibiotic prescriptions as well as their misuse in agriculture are the main causes of antimicrobial resistance which poses a growing threat to public health. It necessitates the search for novel chemicals to combat drug resistance. Since ancient times, naturally occurring medicines have been employed and the enormous variety of bioactive chemicals found in nature has long served as an inspiration for researchers looking for possible therapeutics. Secondary metabolites from microorganisms, particularly those from actinomycetes, have made it incredibly easy to find new molecules. Different actinomycetes species account for more than 70% of naturally generated antibiotics currently used in medicine, and they also produce a variety of secondary metabolites, including pigments, enzymes, and anti-inflammatory compounds. They continue to be a crucial source of fresh chemical diversity and a crucial component of drug discovery. This review summarizes some uncommon sources of antifungal metabolites and highlights the importance of further research on these unusual habitats as a source of novel antimicrobial molecules.

Kuruts are traditional acid-coagulated fermented dairy products in semisolid or dried form. The present study used probiotic Lacticaseibacillus rhamnosus GG (LGG) and Cryptococcus laurentii yeast, a kurut isolate, to make mixed-fermentation kurut. In addition, kurut was fermented with L. rhamnosus GG as starter. Kurut was also fermented with kefir grains representing a traditional way to initiate the fermentation. The viability of probiotic L. rhamnosus GG strain and physicochemical properties of semisolid kurut products were monitored during storage over 22 days at 4°C. The tested probiotic strain showed viability higher than 7 log CFU/mL in both mixed-fermentation and single-strain-fermentation kurut during storage at 4°C. When prepared with probiotic bacteria, the syneresis values of mixed-fermentation kurut were lower (p > 0.05) than single-strain-fermentation kurut. The flavor and overall acceptability scores for kurut prepared using the combination of probiotic LGG and C. laurentii yeast as starter culture were higher than for the other samples at 11 days of storage (p > 0.05). Taking the above into consideration, probiotic kuruts obtained by milk fermentation inoculated with co-culture of L. rhamnosus GG and C. laurentii yeast could be potential probiotic products to be produced in the dairy industry.

Nowadays, microplastics pollution has become a global concern as it endangers the ecology and marine animals and causes health threats to human beings. This paper demonstrated a simulation of an optical planar waveguide sensor design for microplastics detection in water via Wave Optics Module-COMSOL Multiphysics®. The design optimisation of the sensor was conducted by changing the cladding thickness ranging from 0 to 5 µm. The change in analyte refractive index ranging from 1.480 to 1.500 refractive index unit (RIU) in reference to the microplastics’ refractive index has been performed to evaluate the simulated sensing performance. The simulation results showed that reducing the cladding thickness can vastly improve the sensor sensitivity. The sensor showed the highest sensitivity in the absence of cladding layer i.e.; the cladding thickness of 0 µm with 107 difference in the order of magnitude of sensitivity compared to that of 5-µm thickness. Thus, the optimised sensor design with 0 µm cladding thickness assures an excellent sensor for microplastics detection in water.

Allogeneic mesenchymal stromal cells (MSCs) are used in the 1-stage treatment of articular cartilage defects. The aim of this study is to investigate whether transport of mitochondria exists between chondrocytes and MSCs and to investigate whether the transfer of mitochondria to chondrocytes contributes to the mechanism of action of MSCs.Chondrocytes and MSCs were stained with MitoTracker, and CellTrace was used to distinguish between cell types. The uptake of fluorescent mitochondria was measured in cocultures using flow cytometry. Transport was visualized using fluorescence microscopy. Microvesicles were isolated and the presence of mitochondria was assessed. Mitochondria were isolated from MSCs and transferred to chondrocytes using MitoCeption. Pellets of chondrocytes, chondrocytes with transferred MSC mitochondria, and cocultures were cultured for 28 days. DNA content and proteoglycan content were measured. Mitochondrial DNA of cultured pellets and of repair cartilage tissue was quantified.Mitochondrial transfer occurred bidirectionally within the first 4 hours until 16 hours of coculture. Transport took place via tunneling nanotubes, direct cell-cell contact, and extracellular vesicles. After 28 days of pellet culture, DNA content and proteoglycan deposition were higher in chondrocyte pellets to which MSC mitochondria were transferred than the control groups. No donor mitochondrial DNA was traceable in the biopsies, whereas an increase in MSC mitochondrial DNA was seen in the pellets.These results suggest that mitochondrial transport plays a role in the chondroinductive effect of MSCs on chondrocytes

Articular cartilage defects are common and can result in substantial pain and disability, prompting operative intervention, which commonly includes chondral debridement. Controlled defect preparation up to but not beyond the calcified cartilage layer is key to clinical success, but this remains technically challenging. We present a technique highlighting the substantial decrease in curette stroke volume and associated shift to a lower pitch when achieving satisfactory open cartilage defect debridement. These audiologic cues correlate well with histologic accuracy of debridement. Therefore, quantifiable pitch and volume changes serve as valuable technical cues for precise defect preparation at the time of joint preservation surgery. Classifications I: knee, II: cartilage., Technique Video Video 1 Surgical video demonstrating the technical use of pitch and volume changes during chondral defect preparation in joint preservation surgery.

In this paper, I reflect on two of my intertwined research interests. The first is my professional engagement with researching drug use and abuse in Ireland, especially heroin addiction, in applied ethnographic projects, generally answering a specific set of questions on how services for ‘drug addiction’ work. My second interest is the historical construction of ‘addiction’ and the discursive intersections that produce various kinds of power, subjects, and techniques around this concept. I find the dialectical relationship between heroin and methadone in Ireland, especially the emergence of heroin ‘injecting rooms’, as a window into how drugs are social things. Drugs and the bodies who take them live in complex moral worlds, not as inert objects surrounded by abstract human creations. These worlds are an integral part of how ‘addiction’ works and how drugs treating addiction are actually used. Without a deeper understanding of such complexities we will continue to miss key issues in the lives of people we hope to help.

Background: Some surgeons are now considering fixation of traumatic chondral-only fragments in juvenile knees, but few data remain to guide treatment. Purpose: To determine if surgical fixation of chondral-only fragments in the juvenile knee results in an adequate healing response with successful imaging and clinical outcomes. Study Design: Case series; Level of evidence, 4. Methods: Data were collected on 16 skeletally immature patients treated with fixation of chondral-only fragments with a minimum 1-year follow-up. Patients were selected by the operating surgeons based on the quality and size of the chondral fragment. Demographic data, lesion characteristics, surgical procedure details, complications, and postoperative imaging were assessed. Validated outcome measures were collected pre- and postoperatively and included the following scores: International Knee Documentation Committee (IKDC), Marx Activity Scale, Knee injury and Osteoarthritis Outcome Score (KOOS), Hospital for Special Surgery Pediatric Functional Activity–Brief Scale (HSS Pedi-FABS), Patient-Reported Outcomes Measurement Information System (PROMIS)–Physical Health and PROMIS–Psychological Health, and Tegner. Results: The mean age of our patient cohort was 14.9 years. The mean size of the repaired defects measured 3.2 cm2. Injury sites included the patella (n = 1), medial femoral condyle (n = 3), trochlea (n = 4), and lateral femoral condyle (n = 8). Within the mean follow-up time of 42.3 months (range, 15-145), there was 1 clinical failure with loosening of the chondral fragment and the need for reoperation. At a mean follow-up of 3.5 years, the mean (interquartile range) patient-reported outcome scores were as follows: IKDC, 95.2 (94.3-100); Marx Activity Scale, 11.5 (11.5-16); KOOS, 95.81 (93.5-95.81); HSS Pedi-FABS, 16.94 (11.5-26); PROMIS–Physical Health, 93.75% (90%-100%); PROMIS–Psychological Health, 90% (88.75%-100%); and Tegner, 5.69 (4.75-7). All patients who were engaged in sports before injury returned to the same or higher level of competition with the exception of 1 patient. Conclusion: Primary repair of chondral-only injuries with internal fixation can be a successful treatment option in selected patients. Clinical and imaging results at final follow-up suggest that reintegration of the cartilage fragment is achievable and leads to excellent clinical function and a high return-to-sports rate.

Seasonal windows of opportunity are intervals within a year that provide improved prospects for growth, survival, or reproduction. However, few studies have sufficient temporal resolution to examine how multiple factors combine to constrain the seasonal timing and extent of developmental opportunities. Here, we document seasonal changes in milkweed (

Contemporary theoretical physics enters a deep crisis resulting from its positivistic and post-positivistic approach, which assumes that reality is mechanical and atomistic made of point-like particles or one-dimensional strings where the essence of matter, energy, space and time, gravity and other forces are undetectable mysteries. However, within this paper I will endeavour to show that the Universe (reality) is dialectical (relational) and is thus accessible by dialectical logic. The fundamental discovery of the Unity Principle derived on the base of dialectical logic is presented illustrating the exact mechanism how the physical Universe may work at its macro and micro levels. New fundamentals of theoretical physics are built

The inhibition of the nuclear receptor retinoic-acid-receptor-related orphan receptor γt (RORγt) is a promising strategy in the treatment of autoimmune diseases. RORγt features an allosteric binding site within its ligand-binding domain that provides an opportunity to overcome drawbacks associated with orthosteric modulators. Recently, trisubstituted isoxazoles were identified as a novel class of allosteric RORγt inverse agonists. This chemotype offers new opportunities for optimization into selective and efficacious allosteric drug-like molecules. Here, we explore the structure-activity relationship profile of the isoxazole series utilizing a combination of structure-based design, X-ray crystallography, and biochemical assays. The initial lead isoxazole (FM26) was optimized, resulting in compounds with a ∼10-fold increase in potency (low nM), significant cellular activity, promising pharmacokinetic properties, and a good selectivity profile over the peroxisome-proliferated-activated receptor γ and the farnesoid X receptor. We envisage that this work will serve as a platform for the accelerated development of isoxazoles and other novel chemotypes for the effective allosteric targeting of RORγt.

The aim of this study was to compare the antioxidant potential of the yogurt and kefir produced from ewe, camel, goat, and cow milk. The antioxidant activity of the samples was assessed by measuring total phenolic content (TPC), 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity, ferric reducing antioxidant power (FRAP) and 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical reducing capacity during 20-day storage at 4 ºC. Kefir and yogurt prepared from ewe and camel milk had significantly higher antioxidative potential than samples made from goat and cow milk (P