High burden of viruses and bacterial pathobionts drives heightened nasal innate immunity in children.

Studies during the COVID-19 pandemic showed that children had heightened nasal innate immune responses compared with adults. To evaluate the role of nasal viruses and bacteria in driving these responses, we performed cytokine profiling and comprehensive, symptom-agnostic testing for respiratory viruses and bacterial pathobionts in nasopharyngeal samples from children tested for SARS-CoV-2 in 2021-22 (n = 467). Respiratory viruses and/or pathobionts were highly prevalent (82% of symptomatic and 30% asymptomatic children; 90 and 49% for children <5 years). Virus detection and load correlated with the nasal interferon response biomarker CXCL10, and the previously reported discrepancy between SARS-CoV-2 viral load and nasal interferon response was explained by viral coinfections. Bacterial pathobionts correlated with a distinct proinflammatory response with elevated IL-1ß and TNF but not CXCL10. Furthermore, paired samples from healthy 1-year-olds collected 1-2 wk apart revealed frequent respiratory virus acquisition or clearance, with mucosal immunophenotype changing in parallel. These findings reveal that frequent, dynamic host-pathogen interactions drive nasal innate immune activation in children.

Gait kinematics differ by bout duration and setting.

BACKGROUND: Gait kinematics differ between settings and among young and older adults with and without knee osteoarthritis. Out-of-lab data has a variety of walking bout characteristics compared to controlled in-lab settings. The effect of walking bout duration on gait analysis results is unclear, and there is no standardized procedure for segmenting or selecting out-of-lab data for analysis. RESEARCH QUESTION: Do gait kinematics differ by bout duration or setting in young and older adults with and without knee osteoarthritis? METHODS: Ten young (28.1±3.5 yrs), ten older adults (60.8±3.3 yrs), and ten older adults with knee osteoarthritis (64.1±3.6 yrs) performed a standard in-lab gait analysis followed by a prescribed walking route outside the lab at a comfortable speed with four IMUs. Walking speed, stride length, and sagittal hip, knee, and ankle angular excursion (ROM) were calculated for each identified stride. Out-of-lab strides included straight-line, level walking divided into strides that occurred during long (>60 s) or short (≤60 s) bouts. Gait kinematics were compared between in-lab and both out-of-lab bout durations among groups. RESULTS: Significant main effects of setting or duration were found for walking speed and stride length, but there were no significant differences in hip, knee, or ankle joint ROM. Walking speed and stride length were greater in-lab followed by long and short bout out-of-lab. No significant interaction was observed between group and setting or bout duration for any spatiotemporal variables or joint ROMs. SIGNIFICANCE: Out-of-lab gait data can be beneficial in identifying gait characteristics that individuals may not encounter in the traditional lab setting. Setting has an impact on walking kinematics, so comparisons of in-lab and free-living gait may be impacted by the duration of walking bouts. A standardized approach for to analyzing out-of-lab gait data is important for comparing studies and populations.

Ambient Electroreductive Carboxylation of Unactivated Alkyl Chlorides and Polyvinyl Chloride (PVC) Upgrading.

Electrosynthesis of alkyl carboxylic acids upon activating stronger alkyl chlorides at low-energy cost is desired in producing carbon-rich feedstock. Carbon dioxide (CO2), a greenhouse gas, has been recognized as an ideal primary carbon source for those syntheses as such events also mitigate the atmospheric CO2 level, which is already alarming. On the other hand, the promising upcycling of polyvinyl chloride to polyacrylate is a high energy-demanding carbon-chloride (C-Cl) bond activation process. Molecular catalysts that can efficiently perform such transformation under ambient reaction conditions are rarely known. Herein, we reveal a Ni-pincer complex that catalyzes the electrochemical upgrading of polyvinyl chloride to polyacrylate in 95% yield. The activities of such a Ni electrocatalyst bearing a redox-active ligand were also tested to convert diverse examples of unactivated alkyl chlorides to their corresponding carboxylic acid derivatives. Furthermore, electronic structure calculations revealed that CO2 binding occurs in a resting state to yield an CO2 adduct and that the C-Cl bond activation step is the rate-determining transition state, which has an activation energy of 19.3 kcal/mol. A combination of electroanalytical methods, control experiments, and computational studies were also carried out to propose the mechanism of the electrochemical C-Cl activation process with the subsequent carboxylation step.

Assessment of the pathogen genomics landscape highlights disparities and challenges for effective AMR Surveillance and outbreak response in the East African community.

The East African Community (EAC) grapples with many challenges in tackling infectious disease threats and antimicrobial resistance (AMR), underscoring the importance of regional and robust pathogen genomics capacities. However, a significant disparity exists among EAC Partner States in harnessing bacterial pathogen sequencing and data analysis capabilities for effective AMR surveillance and outbreak response. This study assesses the current landscape and challenges associated with pathogen next-generation sequencing (NGS) within EAC, explicitly focusing on World Health Organization (WHO) AMR-priority pathogens. The assessment adopts a comprehensive approach, integrating a questionnaire-based survey amongst National Public Health Laboratories (NPHLs) with an analysis of publicly available metadata on bacterial pathogens isolated in the EAC countries. In addition to the heavy reliance on third-party organizations for bacterial NGS, the findings reveal a significant disparity among EAC member States in leveraging bacterial pathogen sequencing and data analysis. Approximately 97% (n = 4,462) of publicly available high-quality bacterial genome assemblies of samples collected in the EAC were processed and analyzed by external organizations, mainly in Europe and North America. Tanzania led in-country sequencing efforts, followed by Kenya and Uganda. The other EAC countries had no publicly available samples or had all their samples sequenced and analyzed outside the region. Insufficient local NGS sequencing facilities, limited bioinformatics expertise, lack of adequate computing resources, and inadequate data-sharing mechanisms are among the most pressing challenges that hinder the EAC's NPHLs from effectively leveraging pathogen genomics data. These insights emphasized the need to strengthen microbial pathogen sequencing and data analysis capabilities within the EAC to empower these laboratories to conduct pathogen sequencing and data analysis independently. Substantial investments in equipment, technology, and capacity-building initiatives are crucial for supporting regional preparedness against infectious disease outbreaks and mitigating the impact of AMR burden. In addition, collaborative efforts should be developed to narrow the gap, remedy regional imbalances, and harmonize NGS data standards. Supporting regional collaboration, strengthening in-country genomics capabilities, and investing in long-term training programs will ultimately improve pathogen data generation and foster a robust NGS-driven AMR surveillance and outbreak response in the EAC, thereby supporting global health initiatives.

The anticancer potential of the CLK kinases inhibitors 1C8 and GPS167 revealed by their impact on the epithelial-mesenchymal transition and the antiviral immune response.

The diheteroarylamide-based compound 1C8 and the aminothiazole carboxamide-related compound GPS167 inhibit the CLK kinases, and affect the proliferation of a broad range of cancer cell lines. A chemogenomic screen previously performed with GPS167 revealed that the depletion of components associated with mitotic spindle assembly altered sensitivity to GPS167. Here, a similar screen performed with 1C8 also established the impact of components involved in mitotic spindle assembly. Accordingly, transcriptome analyses of cells treated with 1C8 and GPS167 indicated that the expression and RNA splicing of transcripts encoding mitotic spindle assembly components were affected. The functional relevance of the microtubule connection was confirmed by showing that subtoxic concentrations of drugs affecting mitotic spindle assembly increased sensitivity to GPS167. 1C8 and GPS167 impacted the expression and splicing of transcripts in pathways relevant to tumor progression, including MYC targets and the epithelial mesenchymal transition (EMT). Finally, 1C8 and GPS167 altered the expression and alternative splicing of transcripts involved in the antiviral immune response. Consistent with this observation, depleting the double-stranded RNA sensor DHX33 suppressed GPS167-mediated cytotoxicity on HCT116 cells. Our study uncovered molecular mechanisms through which 1C8 and GPS167 affect cancer cell proliferation as well as processes critical for metastasis.

Drug-induced impairment of mitochondrial fatty acid oxidation and steatosis: assessment of causal relationship with 45 pharmaceuticals.

Drug-induced liver injury (DILI) represents a major issue for pharmaceutical companies, being a potential cause of black-box warnings on marketed pharmaceuticals, or drug withdrawal from the market. Lipid accumulation in the liver also referred to as steatosis, may be secondary to impaired mitochondrial fatty acid oxidation (mtFAO). However, an overall causal relationship between drug-induced mtFAO inhibition and the occurrence of steatosis in patients has not yet been established with a high number of pharmaceuticals. Hence, 32 steatogenic and 13 non-steatogenic drugs were tested for their ability to inhibit mtFAO in isolated mouse liver mitochondria. To this end, mitochondrial respiration was measured with palmitoyl-L-carnitine, palmitoyl-CoA + L-carnitine, or octanoyl-L-carnitine. This mtFAO tri-parametric assay was able to predict the occurrence of steatosis in patients with a sensitivity and positive predictive value above 88%. To get further information regarding the mechanism of drug-induced mtFAO impairment, mitochondrial respiration was also measured with malate/glutamate or succinate. Drugs such as diclofenac, methotrexate and troglitazone could inhibit mtFAO secondary to an impairment of the mitochondrial respiratory chain, while dexamethasone, olanzapine and zidovudine appeared to impair mtFAO directly. Mitochondrial swelling, transmembrane potential and production of reactive oxygen species were also assessed for all compounds. Only the steatogenic drugs amiodarone, ketoconazole, lovastatin and toremifene altered all these 3 mitochondrial parameters. In conclusion, our tri-parametric mtFAO assay could be useful in predicting the occurrence of steatosis in patients. The combination of this assay with other mitochondrial parameters could also help to better understand the mechanism of drug-induced mtFAO inhibition.

A semi-automated spectral approach to analyzing cyclical growth patterns using fish scales.

We introduce a new semi-automated approach to analyzing growth patterns recorded on fish scales. After manually specifying the center of the scale, the algorithm radially unwraps the scale patterns along a series of transects from the center to the edge of the scale. A sliding window Fourier transform is used to produce a spectrogram for each sampled transect of the scale image. The maximum frequency over all sampled transects of the average spectrogram yields a well-discriminated peak frequency trace that can then serve as a growth template for that fish. The spectrogram patterns of individual fish scales can be adjusted to a common period accounting for differences in date of return or size of fish at return without biasing the growth profile of the scale. We apply the method to 147 Atlantic salmon scale images sampled from 3 years and contrast the information derived with this automated approach to what is obtained using classical human operator measurements. The spectrogram analysis quantifies growth patterns using the entire scale image rather than just a single transect and provides the possibility of more robustly analyzing individual scale growth patterns. This semi-automated approach that removes essentially all the human operator interventions provides an opportunity to process large datasets of fish scale images and combined with advanced analyses such as deep learning methods could lead to a greater understanding of salmon marine migration patterns and responses to variations in ecosystem conditions.

Patient experiences with patient-led, home-based follow-up after curative treatment for colorectal cancer: a qualitative study.

OBJECTIVES: The number of patients with colorectal cancer (CRC) in need of oncological follow-up is growing. As a response, patient-led, home-based follow-up (PHFU) was developed, implemented and assessed. The aim of this study was to investigate how patients experienced PHFU. DESIGN: A qualitative study with individual semistructured interviews. Interviews were transcribed verbatim, and thematically analysed through an inductive, double-coding approach. SETTING: A university medical centre in the Netherlands. PARTICIPANTS: 12 curatively treated patients with CRC who received PHFU were included after purposive sampling. RESULTS: Overall, participants (N=12) were satisfied with PHFU. The time and cost-saving aspects for patient and hospital were evidently valued. PHFU was experienced as a shared effort, but patients felt like the primary responsibility remained in the hospital. Patients mentioned a decreased personal interaction with their healthcare provider (HCP) and felt a higher threshold to ask for help. However, all major questions were still addressed. Patients felt sufficiently competent to interpret their individual test results but experienced difficulty in interpreting repeated increases in carcinoembryonic antigen levels within the normal range. Educational status, age and a complicated disease course were seen as factors limiting the applicability of PHFU, and it was expressed that PHFU should be offered as an alternative instead of a novel standard of care. CONCLUSIONS: According to patients, PHFU has great potential. However, PHFU may not be suitable for every CRC patient, and factors such as educational status, age and disease course should be taken into consideration. Patient and HCP have a shared responsibility to help successfully organise PHFU in practice.

Mode of Antibacterial Action of Tomatidine C3-Diastereoisomers.

Tomatidine (TO) is a natural narrow-spectrum antibiotic acting on the Staphylococcus aureus small colony variant (SCV) with a minimal inhibitory concentration (MIC) of 0.06 µg/mL while it shows no activity against prototypical strains (MIC > 128 µg/mL). To expand the spectrum of activity of TO, the 3ß-hydroxyl group was substituted with an ethane-1,2-diamine, resulting in two diastereoisomers, TM-02 (C3-ß) and TM-03 (C3-α). These molecules are equally potent against prototypical S. aureus and E. coli strains (MIC 8 and 32 µg/mL, respectively), whereas TM-02 is more potent against SCV (MIC 0.5 µg/mL) and hyperpermeable E. coli strains (MIC 1 µg/mL). The differences in their modes of action were investigated. We used membrane vesicles to confirm the inhibition of the bacterial ATP synthase, the documented target of TO, and measured effects on bacterial cell membranes. Both molecules inhibited E. coli ATP synthase, with Ki values of 1.1 µM and 3.5 µM for TM-02 and TM-03, respectively, and the bactericidal effect of TM-02 was linked to ATP synthase inhibition. Furthermore, TM-02 had no major effect on the membrane fluidity and gradually reduced membrane potential. In contrast, TM-03 caused structural damages to membranes and completely disrupted the membrane potential (>90%). We were successful in broadening the spectrum of activity of TO. C3-ß-diastereoisomers may have more specific antibacterial action than C3-α.

Optimization of Ketobenzothiazole-Based Type II Transmembrane Serine Protease Inhibitors to Block H1N1 Influenza Virus Replication.

Human influenza viruses cause acute respiratory symptoms that can lead to death. Due to the emergence of antiviral drug-resistant strains, there is an urgent requirement for novel antiviral agents and innovative therapeutic strategies. Using the peptidomimetic ketobenzothiazole protease inhibitor RQAR-Kbt (IN-1, aka N-0100) as a starting point, we report how substituting P2 and P4 positions with natural and unnatural amino acids can modulate the inhibition potency toward matriptase, a prototypical type II transmembrane serine protease (TTSP) that acts as a priming protease for influenza viruses. We also introduced modifications of the peptidomimetics N-terminal groups, leading to significant improvements (from µM to nM, 60 times more potent than IN-1) in their ability to inhibit the replication of influenza H1N1 virus in the Calu-3 cell line derived from human lungs. The selectivity towards other proteases has been evaluated and explained using molecular modeling with a crystal structure recently obtained by our group. By targeting host cell TTSPs as a therapeutic approach, it may be possible to overcome the high mutational rate of influenza viruses and consequently prevent potential drug resistance.

Case Report of an exceptional spontaneous abdominal heterotopic pregnancy with superfetation: Diagnosis and treatment: Heterotopic pregnancy with superfetation (8+1 WG & 5+4 WG).

Heterotopic pregnancy is an extremely rare condition in which an intrauterine and an extrauterine pregnancy co-exist. In spontaneous conceptions, heterotopic pregnancy occurs in only 1/30 000 pregnancies. The treatment of heterotopic pregnancy must be as minimally invasive as possible to preserve the development of the intrauterine pregnancy. Superfetation, defined as the coexistence of 2 or more foetuses of different gestational ages, remains particularly exceptional and poorly explained (second ovulation? embryonic diapause?). Here, we present an extremely rare case of a spontaneous heterotopic evolutive pregnancy with superfetation, consisting of an embryo in the pouch of Douglas estimated at 8 + 1 weeks of gestation (WG) and a progressive intrauterine pregnancy estimated at 5 + 4 WG. We treated the extrauterine pregnancy with an intra-cardiac injection of potassium chloride echo-guided via the vaginal route, and the patient then underwent exploratory laparoscopy 9 days later and lavage and aspiration of the abdominal heterotopic pregnancy due to pain and biological inflammatory syndrome probably caused by pelvic mass syndrome and peritoneal irritation from the foetal necrosis. She has not yet given birth and is currently at 36 WG.

From garden to lab: C-3 chemical modifications of tomatidine unveil broad-spectrum ATP synthase inhibitors to combat bacterial resistance.

Antibiotic resistance is escalating alarmingly worldwide. Bacterial resistance mechanisms are surfacing and proliferating across the globe, jeopardizing our capacity to manage prevalent infectious illnesses. Without drastic measures, we risk entering a post-antibiotic era, where even trivial infections and injuries can cause death again. In this context, we have developed a new class of antibiotics based on tomatidine (TO), a natural product derived from tomato plants, with a novel mode of action by targeting bacterial ATP synthases. The first generation of compounds proved highly specific for small-colony variants (SCVs) of Staphylococcus aureus. However, optimization of this scaffold through extensive structure-activity relationship studies has enabled us to broaden its effectiveness to include both Gram-positive and Gram-negative bacteria. Notably, the results showed that specific C3-modification of TO could improve ATP synthase inhibition and also bypass the outer membrane barrier of Gram-negative bacteria to gain substantial growth inhibition including against multi-resistant strains.

Lipid metabolic reprogramming of hepatic CD4+ T cells during SIV infection.

While liver inflammation is associated with AIDS, little is known so far about hepatic CD4+ T cells. By using the simian immunodeficiency virus (SIV)-infected rhesus macaque (RM) model, we aimed to characterize CD4+ T cells. The phenotype of CD4+ T cells was assessed by flow cytometry from uninfected (n = 3) and infected RMs, with either SIVmac251 (n = 6) or SHIVSF162p3 (n = 6). After cell sorting of hepatic CD4+ T cells, viral DNA quantification and RNA sequencing were performed.Thus, we demonstrated that liver CD4+ T cells strongly expressed the SIV coreceptor, CCR5. We showed that viremia was negatively correlated with the percentage of hepatic effector memory CD4+ T cells. Consistent with viral sensing, inflammatory and interferon gene transcripts were increased. We also highlighted the presence of harmful CD4+ T cells expressing GZMA and members of TGFB that could contribute to fuel inflammation and fibrosis. Whereas RNA sequencing demonstrated activated CD4+ T cells displaying higher levels of mitoribosome and membrane lipid synthesis transcripts, few genes were related to glycolysis and oxidative phosphorylation, which are essential to sustain activated T cells. Furthermore, we observed lower levels of mitochondrial DNA and higher levels of genes associated with damaged organelles (reticulophagy and mitophagy). Altogether, our data revealed that activated hepatic CD4+ T cells are reprogrammed to lipid metabolism. Thus, strategies aiming to reprogram T cell metabolism with effector function could be of interest for controlling viral infection and preventing liver disorders.IMPORTANCEHuman immunodeficiency virus (HIV) infection may cause liver diseases, associated with inflammation and tissue injury, contributing to comorbidity in people living with HIV. Paradoxically, the contribution of hepatic CD4+ T cells remains largely underestimated. Herein, we used the model of simian immunodeficiency virus (SIV)-infected rhesus macaques to access liver tissue. Our work demonstrates that hepatic CD4+ T cells express CCR5, the main viral coreceptor, and are infected. Viral infection is associated with the presence of inflamed and activated hepatic CD4+ T cells expressing cytotoxic molecules. Furthermore, hepatic CD4+ T cells are reprogrammed toward lipid metabolism after SIV infection. Altogether, our findings shed new light on hepatic CD4+ T cell profile that could contribute to liver injury following viral infection.

Phenotypic characterization and epidemiology of extended-spectrum ß-lactamase-producing Enterobacteriaceae strains from urinary tract infections in Garoua, Cameroon.

Background and objectives: The emergence of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) is causing increased morbidity and mortality around the world as a result of therapeutic failures. ESBL-E are priority pathogens due to their multidrug resistance (MDR). In Northern Cameroon, ESBL-producing bacteria, particularly in urinary tract infections (UTIs), are being increasingly isolated. This study aimed to retrospectively determine the prevalence of multi-drug resistant ESBL strains isolated from UTIs in Northern Cameroon and to evaluate the effectiveness of the ATB UR Gallery of BioMérieux in diagnosing ESBL-E in clinical settings. Methods: Standard microbiology protocols and statistical tools were utilized to identify ESBL-producing bacteria and characterize their phenotypic susceptibility and resistance profiles in the study population. Results: Out of the 144 enterobacteria isolates successfully cultured, 59 (41%) were identified as MDR strains. The ATB UR EU gallery identified 33 (23%) multi-drug resistant ESBL-producing strains, while the double synergy test identified 35 strains without disc reconciliation and 38 strains after reconciliation. The most prevalent ESBL-E isolate was Escherichia coli, accounting for 77.1% of the isolates, followed by Klebsiella pneumoniae (20%) and Enterobacter aerogenes (2.9%). Additionally, the study revealed the emergence of Imipenem resistance (5.7%), a critical last-resort antibiotic. However, all ESBL strains were sensitive to Fosfomycin (FSF/FOS), demonstrating its potential as an effective therapeutic option. Moreover, 37% of the ESBL producers exhibited co-resistance to over 20 different antibiotics. Conclusion: This study provides valuable insights into the prevalence and susceptibility patterns of ESBL-E associated with UTIs in Northern Cameroon. These insights emphasizes the importance of implementing appropriate treatment guidelines and antimicrobial stewardship measures to mitigate the spread and impact of MDR ESBL-producing strains on public health.

The Therapeutic Value of Solanum Steroidal (Glyco)Alkaloids: A 10-Year Comprehensive Review.

Steroidal (glycol)alkaloids S(G)As are secondary metabolites made of a nitrogen-containing steroidal skeleton linked to a (poly)saccharide, naturally occurring in the members of the Solanaceae and Liliaceae plant families. The genus Solanum is familiar to all of us as a food source (tomato, potato, eggplant), but a few populations have also made it part of their ethnobotany for their medicinal properties. The recent development of the isolation, purification and analysis techniques have shed light on the structural diversity among the SGAs family, thus attracting scientists to investigate their various pharmacological properties. This review aims to overview the recent literature (2012-2022) on the pharmacological benefits displayed by the SGAs family. Over 17 different potential therapeutic applications (antibiotic, antiviral, anti-inflammatory, etc.) were reported over the past ten years, and this unique review analyzes each pharmacological effect independently without discrimination of either the SGA's chemical identity or their sources. A strong emphasis is placed on the discovery of their biological targets and the subsequent cellular mechanisms, discussing in vitro to in vivo biological data. The therapeutic value and the challenges of the solanum steroidal glycoalkaloid family is debated to provide new insights for future research towards clinical development.

Insulin sensitization by small molecules enhancing GLUT4 translocation.

Insulin resistance (IR) is the root cause of type II diabetes, yet no safe treatment is available to address it. Using a high throughput compatible assay that measures real-time translocation of the glucose transporter glucose transporter 4 (GLUT4), we identified small molecules that potentiate insulin action. In vivo, these insulin sensitizers improve insulin-stimulated GLUT4 translocation, glucose tolerance, and glucose uptake in a model of IR. Using proteomic and CRISPR-based approaches, we identified the targets of those compounds as Unc119 proteins and solved the structure of Unc119 bound to the insulin sensitizer. This study identifies compounds that have the potential to be developed into diabetes treatment and establishes Unc119 proteins as targets for improving insulin sensitivity.

Assessment of the inhibitory potential of anabolic steroids towards human AKR1D1 by computational methods and in vitro evaluation.

Exposure to xenobiotics can adversely affect biochemical reactions, including hepatic bile acid synthesis. Bile acids are essential for dissolving lipophilic compounds in the hydrophilic environment of the gastrointestinal tract. The critical micellar concentration of bile acids depends on the Δ4-reduction stereochemistry, with the 3-oxo-5ß-steroid-Δ4-dehydrogenase (AKR1D1) introducing the cis ring A/B conformation. Loss-of-function mutations in AKR1D1 cause hepatic cholestasis, which, if left untreated can progress into steatosis and liver cirrhosis. Furthermore, AKR1D1 is involved in clearing steroids with an A-ring Δ4-double bond. Here, we tested whether anabolic-androgenic steroids (AAS), often taken off-label at high doses, might inhibit AKR1D1, thereby potentially causing hepatotoxicity. A computational molecular model was established and used for virtual screening of the DrugBank database consisting of 2740 molecules, yielding mainly steroidal hits. Fourteen AAS were selected for in vitro evaluation, as such compounds can reach high hepatic concentrations in an abuse situation. Nandrolone, clostebol, methasterone, drostanolone, and methenolone inhibited to various extent the AKR1D1-mediated reduction of testosterone. Molecular modeling suggests that 9 out of 14 investigated AAS are competitive inhibitors. Moreover quantum mechanical calculations show that nadrolone and clostebol are substrates of AKR1D1 with different activation energy barriers for the hydrogen transfer from cofactor to the C5 position affecting their turnover. In this multidisciplinary approach, we established a molecular model of AKR1D1, identified several AAS as inhibitors, and described their binding mode. This approach may be applied to study other classes of inhibitors including non-steroidal compounds.

Early ART reduces viral seeding and innate immunity in liver and lungs of SIV-infected macaques.

Identifying immune cells and anatomical tissues that contribute to the establishment of viral reservoirs is of central importance in HIV-1 cure research. Herein, we used rhesus macaques (RMs) infected with SIVmac251 to analyze viral seeding in the liver and lungs of either untreated or early antiretroviral therapy-treated (ART-treated) RMs. Consistent with viral replication and sensing, transcriptomic analyses showed higher levels of inflammation, pyroptosis, and chemokine genes as well as of interferon-stimulating gene (ISG) transcripts, in the absence of ART. Our results highlighted the infiltration of monocyte-derived macrophages (HLA-DR+CD11b+CD14+CD16+) in inflamed liver and lung tissues associated with the expression of CD183 and CX3CR1 but also with markers of tissue-resident macrophages (CD206+ and LYVE+). Sorting of myeloid cell subsets demonstrated that CD14+CD206-, CD14+CD206+, and CD14-CD206+ cell populations were infected, in the liver and lungs, in SIVmac251-infected RMs. Of importance, early ART drastically reduced viral seeding consistent with the absence of ISG detection but also of genes related to inflammation and tissue damage. Viral DNA was only detected in CD206+HLA-DR+CD11b+ cells in ART-treated RMs. The observation of pulmonary and hepatic viral rebound after ART interruption reinforces the importance of early ART implementation to limit viral seeding and inflammatory reactions.

Primary care physicians' knowledge and confidence in providing cancer survivorship care: a systematic review.

PURPOSE: To systematically review existing literature on knowledge and confidence of primary care physicians (PCPs) in cancer survivorship care. METHODS: PubMed, Ovid MEDLINE, CINAHL, Embase, and PsycINFO were searched from inception to July 2022 for quantitative and qualitative studies. Two reviewers independently assessed studies for eligibility and quality. Outcomes were characterized by domains of quality cancer survivorship care. RESULTS: Thirty-three papers were included, representing 28 unique studies; 22 cross-sectional surveys, 8 qualitative, and 3 mixed-methods studies. Most studies were conducted in North America (n = 23) and Europe (n = 8). For surveys, sample sizes ranged between 29 and 1124 PCPs. Knowledge and confidence in management of physical (n = 19) and psychosocial effects (n = 12), and surveillance for recurrences (n = 14) were described most often. Generally, a greater proportion of PCPs reported confidence in managing psychosocial effects (24-47% of PCPs, n= 5 studies) than physical effects (10-37%, n = 8). PCPs generally thought they had the necessary knowledge to detect recurrences (62-78%, n = 5), but reported limited confidence to do so (6-40%, n = 5). There was a commonly perceived need for education on long-term and late physical effects (n = 6), and cancer surveillance guidelines (n = 9). CONCLUSIONS: PCPs' knowledge and confidence in cancer survivorship care varies across care domains. Suboptimal outcomes were identified in managing physical effects and recurrences after cancer. IMPLICATIONS FOR CANCER SURVIVORS: These results provide insights into the potential role of PCPs in cancer survivorship care, medical education, and development of targeted interventions.

Lower Extremity Inverse Kinematics Results Differ Between Inertial Measurement Unit- and Marker-Derived Gait Data.

In-lab, marker-based gait analyses may not represent real-world gait. Real-world gait analyses may be feasible using inertial measurement units (IMUs) in combination with open-source data processing pipelines (OpenSense). Before using OpenSense to study real-world gait, we must determine whether these methods estimate joint kinematics similarly to traditional marker-based motion capture (MoCap) and differentiate groups with clinically different gait mechanics. Healthy young and older adults and older adults with knee osteoarthritis completed this study. We captured MoCap and IMU data during overground walking at 2 speeds. MoCap and IMU kinematics were computed with OpenSim workflows. We tested whether sagittal kinematics differed between MoCap and IMU, whether tools detected between-group differences similarly, and whether kinematics differed between tools by speed. MoCap showed more anterior pelvic tilt (0%-100% stride) and joint flexion than IMU (hip: 0%-38% and 61%-100% stride; knee: 0%-38%, 58%-89%, and 95%-99% stride; and ankle: 6%-99% stride). There were no significant tool-by-group interactions. We found significant tool-by-speed interactions for all angles. While MoCap- and IMU-derived kinematics differed, the lack of tool-by-group interactions suggests consistent tracking across clinical cohorts. Results of the current study suggest that IMU-derived kinematics with OpenSense may enable reliable evaluation of gait in real-world settings.