Gut microbiota and immune profiling of microbiota-humanised versus wildtype mouse models of hepatointestinal schistosomiasis.

Mounting evidence of the occurrence of direct and indirect interactions between the human blood fluke, Schistosoma mansoni, and the gut microbiota of rodent models raises questions on the potential role(s) of the latter in the pathophysiology of hepatointestinal schistosomiasis. However, substantial differences in both the composition and function between the gut microbiota of laboratory rodents and that of humans hinders an in-depth understanding of the significance of such interactions for human schistosomiasis. Taking advantage of the availability of a human microbiota-associated mouse model (HMA), we have previously highlighted differences in infection-associated changes in gut microbiota composition between HMA and wildtype (WT) mice. To further explore the dynamics of schistosome-microbiota relationships in HMA mice, in this study we (i) characterize qualitative and quantitative changes in gut microbiota composition of a distinct line of HMA mice (D2 HMA) infected with S. mansoni prior to and following the onset of parasite egg production; (ii) profile local and systemic immune responses against the parasite in HMA as well as WT mice and (iii) assess levels of faecal inflammatory markers and occult blood as indirect measures of gut tissue damage. We show that patent S. mansoni infection is associated with reduced bacterial alpha diversity in the gut of D2 HMA mice, alongside expansion of hydrogen sulphide-producing bacteria. Similar systemic humoral responses against S. mansoni in WT and D2 HMA mice, as well as levels of faecal lipocalin and markers of alternatively activated macrophages, suggest that these are independent of baseline gut microbiota composition. Qualitative comparative analyses between faecal microbial profiles of S. mansoni-infected WT and distinct lines of HMA mice reveal that, while infection-induced alterations of the gut microbiota composition are highly dependent on the baseline flora, bile acid composition and metabolism may represent key elements of schistosome-microbiota interactions through the gut-liver axis.

Metaphyseal Fixation Using Cones and Sleeves for Severe Proximal Tibial Bone Loss.

BACKGROUND: Tibial bone defects are commonly encountered in revision total knee arthroplasty (rTKA) and can be managed with metaphyseal cones or sleeves. Few studies have directly compared tibial cones and sleeves in rTKA, and none have limited this comparison to the most severe tibial defects. The purpose of this study was to evaluate and compare the outcomes of metaphyseal cones and sleeves for tibial reconstruction in rTKA regarding implant fixation and clinical outcomes. METHODS: A retrospective review was conducted on patients undergoing rTKA in which metaphyseal cones or sleeves were utilized for addressing metaphyseal bone loss (34 cones and 18 sleeves). Tibial bone loss was classified according to the Anderson Orthopaedic Research Institute bone defect classification, with types 2B and 3 being included. Patient-reported outcomes and postoperative complications were collected, and a radiographic evaluation of osseointegration or loosening was performed. RESULTS: There were 52 knees included (34 cones, 18 sleeves), with a median follow-up of 41.0 months. All-cause implant survival was 100% at 2 years and 96% (95% confidence interval: 76 to 99%) at 4 years, with 98% of tibial components demonstrating osseointegration at the final follow-up. During follow-up, there were a total 11 revisions, of which 1 sleeve was revised secondary to implant loosening. Tibial sleeves had a higher risk of revision compared to tibial cones (P < .01), and sleeves fixed with a hybrid technique were more likely to need revision than cones fixed by the same method (P = .01). CONCLUSIONS: Porous metaphyseal tibial cones and tibial metaphyseal sleeves both performed well at a 41-month median follow-up with no difference in aseptic survivorship between the 2 constructs. Both demonstrate high rates of osseointegration, low rates of aseptic failure, and significant improvement in Knee Society Scores in patients with severe tibial defects in rTKA.

Highly Cross-Linked Polyethylene in Patients 50 Years of Age and Younger: A 20-year Follow-Up Analysis.

BACKGROUND: Highly cross-linked polyethylene (HXLPE) has been an excellent bearing for total hip arthroplasty (THA) due to improved wear characteristics compared to conventional materials. Patients 50 years of age or younger are at high risk for wear-related complications of their THA, and few studies have followed these patients who have HXPLE into the third decade. METHODS: In a retrospective review of 88 consecutive THAs performed in 77 patients aged 50 years and younger (mean 41; range, 20 to 50), in which HXLPE was utilized, they were evaluated for their clinical and radiographic results at an average of 20-year follow-up (range, 18 to 24). The current study reports on longer-term follow-up from our previously published series at shorter follow-up times. Patients were categorized by femoral head material: cobalt chrome (n = 14), ceramic (n = 30), and oxidized zirconium (n = 22) and by femoral head size: 26 mm (n = 12), 28 mm (n = 46), and 32 mm (n = 8). Harris Hip Scores were collected preoperatively and at the most recent follow-up. Radiographs were evaluated for linear and volumetric wear, radiolucent lines, and osteolysis. RESULTS: Mean Harris Hip Scores improved from 47.1 (standard deviation [SD] 8.8) preoperatively to 92.0 (SD 7.7) (P < .0001) at 20-year follow-up. There was one hip that was revised for recurrent instability, and no hip demonstrated radiographic evidence of loosening or osteolysis. The mean polyethylene linear wear rate was 0.017 (SD 0.012) mm/y, and the mean polyethylene volumetric wear rate was 3.15 (SD 2.8) mm3/year, with no significant differences based on articulation type or head size. CONCLUSIONS: Total hip arthroplasty with HXLPE in patients ≤ 50 years of age continues to demonstrate excellent long-term clinical and radiographic outcomes with low wear characteristics at 20-year follow-up, regardless of femoral head material or size.

Long-term polyethylene wear rates and clinical outcomes of oxidized zirconium femoral heads on highly cross-linked polyethylene in total hip arthroplasty.

Aims: Oxidized zirconium (OxZi) and highly cross-linked polyethylene (HXLPE) were developed to minimize wear and risk of osteolysis in total hip arthroplasty (THA). However, retrieval studies have shown that scratched femoral heads may lead to runaway wear, and few reports of long-term results have been published. The purpose of this investigation is to report minimum ten-year wear rates and clinical outcomes of THA with OxZi femoral heads on HXLPE, and to compare them with a retrospective control group of cobalt chrome (CoCr) or ceramic heads on HXLPE. Methods: From 2003 to 2006, 108 THAs were performed on 96 patients using an OxZi head with a HXLPE liner with minimum ten-year follow-up. Harris Hip Scores (HHS) were collected preoperatively and at the most recent follow-up (mean 13.3 years). Linear and volumetric liner wear was measured on radiographs of 85 hips with a minimum ten-year follow-up (mean 14.5 years). This was compared to a retrospective control group of 45 THAs using ceramic or CoCr heads from October 1999 to February 2005, with a minimum of ten years' follow-up. Results: Average HHS improved from 50.8 to 91.9 and 51.0 to 89.8 in the OxZi group and control group, respectively (p = 0.644), with no osteolysis in either group. Linear and volumetric wear rates in the OxZi group averaged 0.03 mm/year and 3.46 mm3/year, respectively. There was no statistically significant difference in HHS scores, nor in linear or volumetric wear rate between the groups, and no revision for any indication. Conclusion: The radiological and clinical outcomes, and survivorship of THA with OxZi femoral heads and HXLPE liners, were excellent, and comparable to CoCr or ceramic heads at minimum ten-year follow-up. Wear rates are below what would be expected for development of osteolysis. OxZi-HXLPE is a durable bearing couple with excellent long-term outcomes.

Novel Technique for the Identification of Hip Implants Using Artificial Intelligence.

BACKGROUND: The anticipated growth of total hip arthroplasty will result in an increased need for revision total hip arthroplasty. Preoperative planning, including identifying current implants, is critical for successful revision surgery. Artificial intelligence (AI) is promising for aiding clinical decision-making, including hip implant identification. However, previous studies have limitations such as small datasets, dissimilar stem designs, limited scalability, and the need for AI expertise. To address these limitations, we developed a novel technique to generate large datasets, tested radiographically similar stems, and demonstrated scalability utilizing a no-code machine learning solution. METHODS: We trained, validated, and tested an automated machine learning-implemented convolutional neural network to classify 9 radiographically similar femoral implants with a metaphyseal-fitting wedge taper design. Our novel technique uses computed tomography-derived projections of a 3-dimensional scanned implant model superimposed within a computed tomography pelvis volume. We employed computer-aided design modeling and MATLAB to process and manipulate the images. This generated 27,020 images for training (22,957) and validation (4,063) sets. We obtained 786 test images from various sources. The performance of the model was evaluated by calculating sensitivity, specificity, and accuracy. RESULTS: Our machine learning model discriminated the 9 implant models with a mean accuracy of 97.4%, sensitivity of 88.4%, and specificity of 98.5%. CONCLUSIONS: Our novel hip implant detection technique accurately identified 9 radiographically similar implants. The method generates large datasets, is scalable, and can include historic or obscure implants. The no-code machine learning model demonstrates the feasibility of obtaining meaningful results without AI expertise, encouraging further research in this area.

Development of substituted benzimidazoles as inhibitors of human aldehyde dehydrogenase 1A isoenzymes.

Aldehyde dehydrogenase 1A (ALDH1A) isoforms may be a useful target for overcoming chemotherapy resistance in high-grade serous ovarian cancer (HGSOC) and other solid tumor cancers. However, as different cancers express different ALDH1A isoforms, isoform selective inhibitors may have a limited therapeutic scope. Furthermore, resistance to an ALDH1A isoform selective inhibitor could arise via induction of expression of other ALDH1A isoforms. As such, we have focused on the development of pan-ALDH1A inhibitors, rather than on ALDH1A isoform selective compounds. Herein, we report the development of a new group of pan-ALDH1A inhibitors to assess whether broad spectrum ALDH1A inhibition is an effective adjunct to chemotherapy in HGSOC. Optimization of the CM10 scaffold, aided by ALDH1A1 crystal structures, led to improved biochemical potencies, improved cellular efficacy as demonstrated by reduction in ALDEFLUOR signal in HGSOC cells, and substantial improvements in liver microsomal stability. Based on this work we identified two compounds 17 and 25 suitable for future in vivo proof of concept experiments.

Synthetic Mirnov diagnostic for the validation of experimental observations.

A synthetic Mirnov diagnostic has been developed to investigate the capabilities and limitations of an arrangement of Mirnov coils in terms of a mode analysis. Eight test cases have been developed, with different coil arrangements and magnetic field configurations. Three of those cases are experimental configurations of the stellarator Wendelstein 7-X. It is observed that, for a high triangularity of the flux surfaces, the arrangement of the coils plays a significant role in the exact determination of the poloidal mode number. For the mode analysis, torus and magnetic coordinates have been used. In most cases, the reconstruction of the poloidal mode number of a prescribed mode was found to be more accurate in magnetic coordinates. As an application, the signal of an Alfvén eigenmode, which has been calculated with a three-dimensional magnetohydrodynamics code, is compared to experimental observations at Wendelstein 7-X. For the chosen example, the calculated and measured mode spectra agree very well and additional information on the toroidal mode number and localization of the mode has been inferred.

Wear, Osteolysis, and Aseptic Loosening Following Total Hip Arthroplasty in Young Patients with Highly Cross-Linked Polyethylene: A Review of Studies with a Follow-Up of over 15 Years.

Total hip arthroplasty (THA) has in recent years trended toward a younger, more physically demanding patient population. Mid- to long-term studies of all ages of THA patients using highly cross-linked polyethylene (HXLPE) have been favorable, but concerns about its long-term failure and wear-related complications remain for young THA patients. In this narrative review, a search of the PubMed/MEDLINE and Cochrane databases was performed, and we identified six studies with a minimum 15-year follow-up of HXLPE with various femoral head materials. Wear-related revisions were exceedingly low for patients under the age of 55, with variable reports of non-clinically significant osteolysis. Higher activity levels, a larger femoral head size, and femoral head material were not associated with greater long-term wear rates. Young THA with metal or ceramic on HXLPE is exceedingly durable with favorable outcomes at follow-ups of over 15 years.

Circumstances of Hospitalization Impact Outcomes of Pulmonary Embolism.

Clinical tools that stratify risk of acute pulmonary embolism (PE) are useful in guiding therapeutic decision making, although may neglect pragmatic and potentially impactful characteristics of hospitalization during care of venous thromboembolism (VTE). Using a retrospective cohort design, consecutive patients discharged after inpatient care for acute PE were retrospectively evaluated for features of hospitalization, including patient characteristics, treatment efficiency, and circumstances of hospitalization. A proportional hazards model incorporated nontraditional risk factors to assess their association with a primary composite endpoint of in-hospital bleeding or death after adjusting for conventional PE risk estimators, including the Pulmonary Artery Severity Index (PESI) and right ventricular/left ventricular (RV/LV) ratio. From January 2016 to December 2018, 822 patients were discharged after treatment for acute PE, including high-risk (5.0%), intermediate-risk (64.2%), and low-risk (30.8%) PE. In-hospital death was 10-fold higher among those with high-risk PE compared to intermediate risk PE (36.6% vs 3.0%, P < 0.001). Overall, 60.4% of hospitalizations were primarily attributed to presentation with VTE. High risk PE was observed more frequently as a secondary event during hospitalizations ostensibly unrelated to VTE (26.8%). After adjustment for PESI score and RV/LV ratio, hypoalbuminia, IVC filter, and non-VTE hospitalization had strong associations with the primary composite outcome. Along with known markers of risk associated with PE, hypoalbuminia, IVC filter placement, and PE complicating hospitalization for circumstances not primarily related to VTE had strong associations with bleeding and death. These findings highlight the complex circumstances of acute PE care and need to refine practical risks.

Infection prevention and control between legal requirements and German Society for Hygiene and Microbiology expert assessments: a cross-sectional study in September-November 2022.

BACKGROUND: In contrast to the beginning of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), pandemic, more and more hospital issues are now regulated by policy. AIM: To identify differences between expert recommendations and legal requirements regarding infection prevention and control (IPC) strategies. METHODS: A cross-sectional study was conducted between 29th September 2022 and 3rd November 2022 addressing 1319 members of the German Society for Hygiene and Microbiology. The response rate was 12%. This paper reports the expert recommendations on different IPC strategies. FINDINGS: The majority (66%) of experts recommended universal mask usage, with 34% recommending it seasonally, even after the SARS-CoV-2 pandemic. Medical microbiology (MM) experts were more likely to recommend continuing to wear the masks indefinitely compared with IPC experts. Concerning the mask type, medical masks were recommended more frequently by IPC experts (47.3%), while FFP2 masks were preferred by MM experts (31.8%). The majority (54.7%) of experts recommended universal screening of employees, mainly in settings with extremely vulnerable patients and if regional incidence rates were high, at a frequency of twice per week. The dominant advice (recommended by at least 50% of experts) for employees exposed to SARS-CoV-2 was daily testing and wearing a mask, regardless of the length of exposure. CONCLUSIONS: Expert recommendations deviate from the legal requirements and appear to be more differentiated and proportional. The influence of specific experience and expertise on mask recommendations should be investigated in more detail. For relevant policy decisions, a quick, focused and broad-based consultation of expertise could be of added value.

Motion compensation for non-periodic dynamic tracer distributions in multi-patch magnetic particle imaging.

Objective.While the spatial and temporal resolution of magnetic particle imaging is very high, the size of the field of view is limited due to physiological constraints. Multi-patch scans allow for covering larger areas by sequentially scanning smaller subvolumes, so-called patches. The visualization of tracer dynamics with a high temporal resolution are of particular interest in many applications, e.g. cardiovascular interventions or blood flow measurements. The reconstruction of non-periodic dynamic tracer distributions is currently realized by the reconstruction of a time-series of frames under the assumption of nearly static behavior during the scan of each frame. While this approach is feasible for limited velocities, it results in data gaps in multi-patch scans leading thus to artifacts for strong dynamics. In this article, we are aiming for the reconstruction of dynamic tracer concentrations with high velocities and the compensation of motion and multi-patch artifacts.Approach.We present a reconstruction method for dynamic tracer distributions using a dynamic forward model and representing the concentration within each voxel by a spline curve. The method is evaluated with simulated single- and multi-patch data.Main results.The dynamic model enables for the reconstruction of fast tracer dynamics from few frames and the spline approach approximates the missing data which reduces multi-patch artifacts.Significance.The presented method allows to compensate motion and multi-patch artifacts and to reconstruct fast dynamic tracer distributions with arbitrary motion patterns.

In-Hospital Mortality and Related Outcomes for Elevated Risk Acute Pulmonary Embolism Treated With Mechanical Thrombectomy Versus Routine Care.

PURPOSE: To compare in-hospital mortality and other hospitalization related outcomes of elevated risk patients (Pulmonary Embolism Severity Index [PESI] score of 4 or 5, and, European Society of Cardiology [ESC] classification of intermediate-high or high risk) with acute central pulmonary embolism (PE) treated with mechanical thrombectomy (MT) using the Inari FlowTriever device versus those treated with routine care (RC). MATERIALS AND METHODS: Retrospective data was collected of all patients with acute, central PE treated at a single institution over 2 concurrent 18-month periods. All collected patients were risk stratified using the PESI and ESC Guidelines. The comparison was made between patients with acute PE with PESI scores of 4 or 5, and, ESC classification of intermediate-high or high risk based on treatment type: MT and RC. The primary endpoint evaluated was in-hospital mortality. Secondary endpoints included intensive care unit (ICU) length of stay, total hospital length of stay, and 30-day readmission. RESULTS: Fifty-eight patients met inclusion criteria, 28 in the MT group and 30 in the RC group. Most RC patients were treated with systemic anticoagulation alone (24 of 30). In-hospital mortality was significantly lower for the MT group than for the RC group (3.6% vs 23.3%, P < .05), as was the average ICU length of stay (2.1 ± 1.2 vs 6.1 ± 8.6 days, P < .05). Total hospital length of stay and 30-day readmission rates were similar between MT and RC groups. CONCLUSION: Initial retrospective comparison suggests MT can improve in-hospital mortality and decrease ICU length of stay for patients with acute, central PE of elevated risk (PESI 4 or 5, and, ESC intermediate-high or high risk).

The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma.

Survival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors in improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. This is important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity-often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.

Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy.

There is strong evidence that inhibition of one or more Aldehyde Dehydrogenase 1A (ALDH1A) isoforms may be beneficial in chemotherapy-resistant ovarian cancer and other tumor types. While many previous efforts have focused on development of ALDH1A1 selective inhibitors, the most deadly ovarian cancer subtype, high-grade serous (HGSOC), exhibits elevated expression of ALDH1A3. Herein, we report continued development of pan-ALDH1A inhibitors to assess whether broad spectrum ALDH1A inhibition is an effective adjunct to chemotherapy in this critical tumor subtype. Optimization of the CM39 scaffold, aided by metabolite ID and several new ALDH1A1 crystal structures, led to improved biochemical potencies, improved cellular ALDH inhibition in HGSOC cell lines, and substantial improvements in microsomal stability culminating in orally bioavailable compounds. We demonstrate that two compounds 68 and 69 are able to synergize with chemotherapy in a resistant cell line and patient-derived HGSOC tumor spheroids, indicating their suitability for future in vivo proof of concept experiments.

Injury prevention knowledge, beliefs, and practices among women's football teams in South Africa.

Background: Numerous factors account for injury prevention or lack thereof in any team setting. With the increasing burden of injuries in women's football, and limited human resources accessible in sub-Saharan Africa, it is important to investigate the ways in which standardised injury prevention practices can be achieved. Objectives: The study aimed to evaluate injury prevention knowledge, beliefs, and practices in women's football teams in the University Sport South Africa (USSA) Football League in Gauteng Province, South Africa. Methods: A cross-sectional self-administered survey was conducted among women's football teams registered to participate in the USSA Football League in South Africa's Gauteng Province. Results: A total of 107 respondents participated in the study, which included both players (n=98; 92%) and their support staff (n=9; 9%). The median (interquartile range) age of the participants was 22 (20-25) years. In the population sampled, 36% of the participants perceived that they had adequate knowledge of injury prevention practices in football, while others felt they had limited knowledge of the basic injury prevention programmes (IPPs). The results also indicated that the injury prevention practices of coaches (93%) and their beliefs in this regard (70%) are sufficient for achieving the basic injury prevention goals. Most of the respondents (89%) indicated that a medical support system is important in attaining the goals of injury prevention. Conclusion: Members of women's teams in the USSA Football League have recognised limited knowledge about the basic IPPs, while they do employ some of the basic injury prevention practices in football. These practices could be influenced by the beliefs of the coaches and the players, and most of them believe that IPPs are important. It is essential as key stakeholders that coaches' and players' education and knowledge of injury prevention strategies should be considered as an integral part of the process to succeed. It should be strongly highlighted and implemented, thus augmenting the credibility, trust and compliance for IPPs in the sport.

Management of inferior vena cava thrombosis with the FlowTriever and ClotTriever systems.

OBJECTIVE: Although inferior vena cava (IVC) thrombosis is infrequently encountered, it carries a significant risk of post-thrombotic syndrome and pulmonary embolus. Recent studies show no difference in the incidence of post-thrombotic syndrome in patients with iliofemoral deep venous thrombosis (DVT) treated with pharmacothrombolysis vs anticoagulation alone; however, there is an associated increased risk of bleeding. The treatment of IVC thrombosis is less well-studied and the hemodynamic changes may be more significant with pharmacothrombolysis, although the bleeding risk remains. The ClotTriever and FlowTriever systems remove thrombus from veins without the use of thrombolytics. Our study evaluates outcomes of patients undergoing mechanical thrombectomy for the treatment of IVC thrombosis using the ClotTriever and FlowTriever devices. METHODS: A retrospective chart review was performed to identify consecutive patients who underwent mechanical thrombectomy for the treatment of IVC thrombosis using the ClotTriever and/or FlowTriever systems from November 2018 to January 2020 at four data-sharing institutions. The decision of which device(s) to use was at the discretion of the surgeon. Patient demographics, symptomatology, and imaging characteristics were captured at presentation and follow-up. RESULTS: A total of 15 patients met the inclusion criteria; 10 were male, and the average age was 59 years. The majority of patients were symptomatic at presentation (n = 14), had a prior history of DVT (n = 13), and had a preexisting IVC filter (n = 8). Eleven patients presented with acute onset (<1 week) of symptoms, whereas three patients had subacute (1-4 weeks) symptoms. Most patients had an associated iliofemoral DVT (n = 13) and were treated with both ClotTriever and FlowTriever (n = 8); others were treated with either ClotTriever or FlowTriever alone (n = 5 and n = 2, respectively). Technical success was achieved in all but two patients, one who had a nonocclusive thrombus densely adherent to a preexisting IVC filter and another who had a chronic rubbery clot in the IVC that could not be cleared. No patient required concomitant lytic therapy or a postoperative stay in the intensive care unit. Furthermore, there were no postoperative bleeding events, myocardial infarctions, pulmonary emboli, renal impairments, or deaths. The median length of stay was 3 days (range, 1-37 days). Patients underwent postoperative follow-up (n = 7) as well as extended follow-up (>6 months; n = 8). All patients who achieved technical success were asymptomatic without evidence of reocclusion of the IVC on follow-up imaging. CONCLUSIONS: In our multicenter series of 15 patients, The ClotTriever and FlowTriever showed promise in the treatment of IVC thrombosis without the use of fibrinolytic drugs, with no bleeding events and no requirement for intensive care unit stay.

Interferon-Induced Protein 44 and Interferon-Induced Protein 44-Like Restrict Replication of Respiratory Syncytial Virus.

Cellular intrinsic immunity, mediated by the expression of an array of interferon-stimulated antiviral genes, is a vital part of host defense. We have previously used a bioinformatic screen to identify two interferon-stimulated genes (ISG) with poorly characterized function, interferon-induced protein 44 (IFI44) and interferon-induced protein 44-like (IFI44L), as potentially being important in respiratory syncytial virus (RSV) infection. Using overexpression systems, CRISPR-Cas9-mediated knockout, and a knockout mouse model, we investigated the antiviral capability of these genes in the control of RSV replication. Overexpression of IFI44 or IFI44L was sufficient to restrict RSV infection at an early time postinfection. Knocking out these genes in mammalian airway epithelial cells increased levels of infection. Both genes express antiproliferative factors that have no effect on RSV attachment but reduce RSV replication in a minigenome assay. The loss of Ifi44 was associated with a more severe infection phenotype in a mouse model of infection. These studies demonstrate a function for IFI44 and IFI44L in controlling RSV infection.IMPORTANCE RSV infects all children under 2 years of age, but only a subset of children get severe disease. We hypothesize that susceptibility to severe RSV necessitating hospitalization in children without predefined risk factors is, in part, mediated at the antiviral gene level. However, there is a large array of antiviral genes, particularly in the ISG family, the mechanism of which is poorly understood. Having previously identified IFI44 and IFI44L as possible genes of interest in a bioinformatic screen, we dissected the function of these two genes in the control of RSV. Through a range of overexpression and knockout studies, we show that the genes are antiviral and antiproliferative. This study is important because IFI44 and IFI44L are upregulated after a wide range of viral infections, and IFI44L can serve as a diagnostic biomarker of viral infection.

Room Temperature Terahertz Electroabsorption Modulation by Excitons in Monolayer Transition Metal Dichalcogenides.

The interaction between off-resonant laser pulses and excitons in monolayer transition metal dichalcogenides is attracting increasing interest as a route for the valley-selective coherent control of the exciton properties. Here, we extend the classification of the known off-resonant phenomena by unveiling the impact of a strong THz field on the excitonic resonances of monolayer MoS2. We observe that the THz pump pulse causes a selective modification of the coherence lifetime of the excitons, while keeping their oscillator strength and peak energy unchanged. We rationalize these results theoretically by invoking a hitherto unobserved manifestation of the Franz-Keldysh effect on an exciton resonance. As the modulation depth of the optical absorption reaches values as large as 0.05 dB/nm at room temperature, our findings open the way to the use of semiconducting transition metal dichalcogenides as compact and efficient platforms for high-speed electroabsorption devices.

Does Coronal Plane Malalignment of the Tibial Insert in Total Ankle Arthroplasty Alter Distal Foot Bone Mechanics? A Cadaveric Gait Study.

BACKGROUND: Total ankle arthroplasty (TAA) is becoming a more prevalent treatment for end-stage ankle arthritis. However, the effects of malalignment on TAA remain poorly understood. QUESTIONS/PURPOSES: The purpose of this study was to quantify the mechanical effects of coronal plane malalignment of the tibial insert in TAA using cadaveric gait simulation. Specifically, we asked, is there a change in (1) ankle joint congruency, (2) kinematic joint position, (3) kinematic ROM, (4) peak plantar pressure, and (5) center of pressure with varus and valgus malalignment? METHODS: A modified TAA was implanted into seven cadaveric foot specimens. Wedges were used to simulate coronal plane malalignment of the tibial insert. The degree of malalignment (tibial insert angle [TIA] and talar component angle [TCA]) was quantified radiographically for neutral and 5°, 10°, and 15° varus and valgus wedges. Dynamic walking at 1/6 of physiological speed was simulated using a robotic gait simulator. A motion capture system was used to measure foot kinematics, and a pressure mat was used to measure plantar pressure. Joint congruency was quantified as the difference between TIA and TCA. Continuous joint position, joint ROM, peak plantar pressure, and center of pressure for varus and valgus malalignment compared with neutral alignment were estimated using linear mixed effects regression. Pairwise comparisons between malalignment conditions and neutral were considered significant if both the omnibus test for the overall association between outcome and malalignment and the individual pairwise comparison (adjusted for multiple comparisons within a given outcome) had p ≤ 0.05. RESULTS: Descriptively, the TIA and TCA were both less pronounced than the wedge angle and component incongruence was seen (R = 0.65; p < 0.001). Varus malalignment of the tibial insert shifted the tibiotalar joint into varus and internally rotated the joint. The tibiotalar joint's ROM slightly increased as the TIA shifted into varus (1.3 ± 0.7° [mean ± SD] [95% confidence interval -0.7 to 3.4]; p = 0.03), and the first metatarsophalangeal joint's ROM decreased as the TIA shifted into varus (-1.9 ± 0.9° [95% CI -5.6 to 1.7]; p = 0.007). In the sagittal plane, the naviculocuneiform joint's ROM slightly decreased as the TIA shifted into varus (-0.9 ± 0.4° [95% CI -2.1 to 0.3]; p = 0.017). Hallux pressure increased as the TIA became more valgus (59 ± 50 kPa [95% CI -88 to 207]; p = 0.006). The peak plantar pressure slightly decreased in the third and fourth metatarsals as the TIA shifted into valgus (-15 ± 17° [95% CI -65 to 37]; p = 0.03 and -8 ± 4° [95% CI -17 to 1]; p = 0.048, respectively). The fifth metatarsal's pressure slightly decreased as the TIA shifted into valgus (-18 ± 12 kPa [95% CI -51 to 15]) or varus (-7 ± 18 kPa [95% CI -58 to 45]; p = 0.002). All comparisons were made to the neutral condition. CONCLUSIONS: In this cadaver study, coronal plane malalignment in TAA altered foot kinematics and plantar pressure. In general, varus TAA malalignment led to varus shift and internal rotation of the tibiotalar joint, a slight increase in the tibiotalar ROM, and a slight decrease in the first metatarsophalangeal ROM, while a valgus TAA malalignment was manifested primarily through increased hallux pressure with a slight off-loading of the third and fourth metatarsals. CLINICAL RELEVANCE: This study may increase our understanding of the biomechanical processes that underlie the unfavorable clinical outcomes (such as, poor patient-reported outcomes or implant loosening) that have been associated with coronal plane malalignment of the tibial component in TAA.