The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo.

The COVID-19 pandemic has led to the deaths of millions of people and severe global economic impacts. Small molecule therapeutics have played an important role in the fight against SARS-CoV-2, the virus responsible for COVID-19, but their efficacy has been limited in scope and availability, with many people unable to access their benefits, and better options are needed. EDP-235 is specifically designed to inhibit the SARS-CoV-2 3CLpro, with potent nanomolar activity against all SARS-CoV-2 variants to date, as well as clinically relevant human and zoonotic coronaviruses. EDP-235 maintains potency against variants bearing mutations associated with nirmatrelvir resistance. Additionally, EDP-235 demonstrates a ≥ 500-fold selectivity index against multiple host proteases. In a male Syrian hamster model of COVID-19, EDP-235 suppresses SARS-CoV-2 replication and viral-induced hamster lung pathology. In a female ferret model, EDP-235 inhibits production of SARS-CoV-2 infectious virus and RNA at multiple anatomical sites. Furthermore, SARS-CoV-2 contact transmission does not occur when naïve ferrets are co-housed with infected, EDP-235-treated ferrets. Collectively, these results demonstrate that EDP-235 is a broad-spectrum coronavirus inhibitor with efficacy in animal models of primary infection and transmission.

An ex vivo sequential ligament transection model of flatfoot.

BACKGROUND: The ligaments implicated in the earliest stages of developing a progressive collapsing foot deformity are poorly understood. Commonly employed cadaveric flatfoot models are created from simultaneous transection of multiple ligaments, making it difficult to assess early changes in pressure distribution from ligaments critical for maintaining load distribution. A serial transection of ligaments may provide insight into changes in pressure distribution under the foot to identify a potential combination of ligaments that may be involved in early deformities. METHODS: Specimens were loaded using a custom designed axial and tendon loading system. Plantar pressure data for the forefoot and hindfoot were recorded before and after six sequential ligament complex transections. FINDINGS: Sectioning the plantar fascia (first) and short/long plantar ligaments (second) failed to generate appreciable differences in load distribution. Dividing the spring ligament (third) led to changes in hindfoot load distribution with a shift towards the lateral column indicative of hindfoot valgus angulation. All subsequent conditions resulted in similar patterns in hindfoot plantar load distribution. An anterior shift in the center of pressure only occurred after transection of all six ligament complexes. INTERPRETATION: Loss of the plantar fascia and short/long plantar ligaments are not critical in maintaining plantar load distribution or contact area. However, the additional loss of the spring ligament caused notable changes in hindfoot load distribution, indicating the combination of these three ligament complexes is particularly critical for preventing peritalar subluxation. Minimal changes in load distribution occurred when performing additional transections to reach a complete flatfoot deformity.

Anesthetic key points in a patient with a terminal ileum neuroendocrine tumor and a rare carcinoid left heart disease presented for non-cardiac surgery: case report.

BACKGROUND: Carcinoid tumors are rare neuroendocrine malignancies presenting in an increasing number in our center. The incidence of carcinoid tumors is approximatively between 2.5 and 5 cases per 100,000 people of whom about 50% develop carcinoid syndrome. Once the carcinoid syndrome has developed, a carcinoid cardiomyopathy can occur. Carcinoid heart disease (CaHD) remains a serious and rare complication associated with a significant increase in morbidity and mortality. Although carcinoid tumors have been known and studied for several years, there are still scarce data on the anesthetic management and the peri operative period. CASE PRESENTATION: We describe a case of a Caucasian 44-year-old woman with an unusual presentation of left CaHD with an ileal neuroendocrine tumor and liver metastases. Our preoperative somatostatin administration protocol, limit the cardiac damage. The maintenance of stable hemodynamics, the use of balanced anesthetic technique, all along with a good understanding of the pathology, played a major role in the successful management of anesthesia. This case report allows us to introduce our decision algorithm for the management of this type of pathology in our tertiary hospital, Cliniques Universitaires Saint-Luc. CONCLUSION: Despite the paucity of data, anesthetic management of patients with carcinoid tumor can be safely performed with effective hemodynamic monitoring and a good understanding of the pathophysiology. Knowledge and application of a clear institutional algorithm for octreotide administration and multidisciplinary consultation at a referral center are essential for the management of these patients.

Tumor acidosis-induced DNA damage response and tetraploidy enhance sensitivity to ATM and ATR inhibitors.

Tumor acidosis is associated with increased invasiveness and drug resistance. Here, we take an unbiased approach to identify vulnerabilities of acid-exposed cancer cells by combining pH-dependent flow cytometry cell sorting from 3D colorectal tumor spheroids and transcriptomic profiling. Besides metabolic rewiring, we identify an increase in tetraploid cell frequency and DNA damage response as consistent hallmarks of acid-exposed cancer cells, supported by the activation of ATM and ATR signaling pathways. We find that regardless of the cell replication error status, both ATM and ATR inhibitors exert preferential growth inhibitory effects on acid-exposed cancer cells. The efficacy of a combination of these drugs with 5-FU is further documented in 3D spheroids as well as in patient-derived colorectal tumor organoids. These data position tumor acidosis as a revelator of the therapeutic potential of DNA repair blockers and as an attractive clinical biomarker to predict the response to a combination with chemotherapy.

Rapid Postgrafting Reaction to Prepare Quaternized Polycarbazoles.

We report a rapid postgrafting reaction to prepare alkyl ammonium functionalized polycarbazoles from a commercially available monomer. This novel synthetic approach provides benefit to preparing the high molecular weight quaternized polycarbazoles within 1 h of Friedel-Crafts polycondensation, avoiding the synthesis and purification step to prepare a functionalized monomer. The postgrafting reaction produces hexyl alkyl ammonium functionalized polycarbazole with 100% grafting degree. However, the postgrafting reaction produced only 60% grafting with propyl alkyl ammonium due to the competitive elimination reaction because of the higher acidity of ß-hydrogen in the propyl alkyl group resulting from the proximity of the bromide and ammonium groups. The hexyl alkyl ammonium functionalized polycarbazole has a high hydroxide conductivity of 103 mS cm-1 at 80 °C and showed excellent alkaline stability with less than 3% loss of ion group after 1 M NaOH treatment at 80 °C for 500 h. This study highlights that the postgrafting reaction provides a pathway for the scale-up synthesis of quaternized aryl ether-free polyaromatics.

Time trend in surgical indications and outcomes in ulcerative colitis-A two decades in-depth retrospective analysis.

BACKGROUND: Recent data regarding the impact of biologics and new surgical techniques on the indications and outcomes of colectomy for ulcerative colitis (UC) are limited. AIMS: The present study aimed at determining the trend of colectomy in UC by comparing colectomy indications and outcomes between 2000 and 2010 and 2011-2020. METHODS: This observational retrospective study was conducted in two tertiary hospitals, including consecutive patients who underwent colectomy between 2000 and 2020. All data concerning UC history, treatment and surgeries were collected. RESULTS: Among the 286 patients included, 87 underwent colectomy in 2001-2010 and 199 in 2011-2020. Patients' characteristics were similar between groups, except for prior biologic exposure (50.6 % vs. 74.9%; p<0.001). The indications of colectomy significantly decreased for refractory UC (50.6 % vs. 37.7%; p = 0.042), but were similar for acute severe UC (36.8 % vs. 42.2%; p = 0.390) and (pre)neoplastic lesions (12.6 % vs. 20.1%; p = 0.130). A widespread use of laparoscopy (47.7 % vs. 81.4%; p<0.001) was associated with fewer early complications (12.6 % vs. 5.5%; p = 0.038). CONCLUSION: Over the last two decades, the proportion of surgery for refractory UC significantly decreased compared to other surgical indications while surgical outcomes improved despite larger exposure to biologics.

Disease-Specific Finite element Analysis of the Foot and Ankle.

Finite-element analysis is a computational modeling technique that can be used to quantify parameters that are difficult or impossible to measure externally in a geometrically complex structure such as the foot and ankle. It has been used to improve our understanding of pathomechanics and to evaluate proposed treatments for several disorders, including progressive collapsing foot deformity, ankle arthritis, syndesmotic injury, ankle fracture, plantar fasciitis, diabetic foot ulceration, hallux valgus, and lesser toe deformities. Parameters calculated from finite-element models have been widely used to make predictions about their biomechanical correlates.

Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer.

Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4−82.6), 88.1% (95%-CI, 85.7−90.4), 93.4% (95%-CI, 91.1−95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18−0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17−0.50); p < 0.0001) of the patient's gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01−0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.

A computational model of force within the ligaments and tendons in progressive collapsing foot deformity.

Progressive collapsing foot deformity results from degeneration of the ligaments and posterior tibial tendon (PTT). Our understanding of the relationship between their failures remains incomplete. We sought to improve this understanding through computational modeling of the forces in these soft tissues. The impact of PTT and ligament failures on force changes in the remaining ligaments was investigated by quantifying ligament force changes during simulated ligament and tendon cutting in a validated finite element model of the foot. The ability of the PTT to restore foot alignment was also evaluated by increasing the PTT force in a foot with attenuated ligaments and comparing the alignment angles to the intact foot. We found that failure of any one of the ligaments led to overloading the remaining ligaments, except for the plantar naviculocuneiform, first plantar tarsometatarsal, and spring ligaments, where removing one led to unloading the other two. The combined attenuation of the plantar fascia, long plantar, short plantar, and spring ligaments significantly overloaded the deltoid and talocalcaneal ligaments. Isolated PTT rupture had no effect on foot alignment but did increase the force in the deltoid and spring ligaments. Moreover, increasing the force within the PTT to 30% of body weight was effective at restoring foot alignment during quiet stance, primarily through reducing hindfoot valgus and forefoot abduction as opposed to improving arch collapse. Our findings suggest that early intervention might be used to prevent the progression of deformity. Moreover, strengthening the PTT through therapeutic exercise might improve its ability to restore foot alignment.

Evaluation of assumptions in foot and ankle biomechanical models.

BACKGROUND: A variety of biomechanical models have been used in studies of foot and ankle disorders. Assumptions about the element types, material properties, and loading and boundary conditions are inherent in every model. It was hypothesized that the choice of these modeling assumptions could have a significant impact on the findings of the model. METHODS: We investigated the assumptions made in a number of biomechanical models of the foot and ankle and evaluated their effects on the results of the studies. Specifically, we focused on: (1) element choice for simulation of ligaments and tendons, (2) material properties of ligaments, cortical and trabecular bones, and encapsulating soft tissue, (3) loading and boundary conditions of the tibia, fibula, tendons, and ground support. FINDINGS: Our principal findings are: (1) the use of isotropic solid elements to model ligaments and tendons is not appropriate because it allows them to transmit unrealistic bending and twisting moments and compressive forces; (2) ignoring the difference in elastic modulus between cortical and trabecular bones creates non-physiological stress distribution in the bones; (3) over-constraining tibial motion prevents anticipated deformity within the foot when simulating foot deformities, such as progressive collapsing foot deformity; (4) neglecting the Achilles tendon force affects almost all kinetic and kinematic parameters through the foot; (5) the axial force applied to the tibia and fibula is not equal to the ground reaction force due to the presence of tendon forces. INTERPRETATION: The predicted outcomes of a foot model are highly sensitive to the model assumptions.

The APOE locus is linked to decline in general cognitive function: 20-years follow-up in the Doetinchem Cohort Study.

Cognitive decline is part of the normal aging process. However, some people experience a more rapid decline than others due to environmental and genetic factors. Numerous single nucleotide polymorphisms (SNPs) have been linked to cognitive function, but only a few to cognitive decline. To understand whether cognitive function and cognitive decline are driven by the same mechanisms, we investigated whether 433 SNPs previously linked to cognitive function and 2 SNPs previously linked to cognitive decline are associated with both general cognitive functioning at baseline and general cognitive decline up to 20-years follow-up in the Doetinchem Cohort Study (DCS). The DCS is a longitudinal population-based study that enrolled men and women aged 20-59 years between 1987-1991, with follow-up examinations every 5 years. We used data of rounds 2-6 (1993-2017, n = 2559). General cognitive function was assessed using four cognition tests measuring memory, speed, fluency and flexibility. With these test scores, standardized residuals (adjusted for sex, age and examination round) were calculated for each cognition test at each round and subsequently combined into one general cognitive function measure using principal component analyses. None of the 435 previously identified variants were associated with baseline general cognitive function in the DCS. But rs429358-C, a coding apolipoprotein E (APOE) SNP and one of the variants previously associated with cognitive decline, was associated with general cognitive decline in our study as well (p-value = 1 × 10-5, Beta = -0.013). These findings suggest that decline of general cognitive function is influenced by other mechanisms than those that are involved in the regulation of general cognitive function.

High-intensity aerobic interval training and resistance training are feasible in rectal cancer patients undergoing chemoradiotherapy: a feasibility randomized controlled study.

Background: There has been growing evidence of the benefits of high-intensity aerobic interval training (HIIT) and resistance training (RES) for populations with cancer. However, these two modalities have not yet been performed alone in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (NACR T). Therefore, this study aimed to determine the feasibility of HIIT and RES in rectal cancer patients undergoing NACR T. Materials and methods: Rectal cancer patients set to undergo NACRT were randomly assigned to HIIT intervention, RES intervention, or the usual care. Feasibility of HIIT and RES was assessed by measuring recruitment rate, adherence (retention rate, attendance rate, and exercise sessions duration and intensity), and adverse events. Endpoints (changes in fatigue, health-related quality of life, depression, daytime sleepiness, insomnia, sleep quality, functional exercise capacity, and executive function) were assessed at baseline and at week 5. Results: Among the 20 eligible patients, 18 subjects were enrolled and completed the study, yielding a 90% recruitment rate and 100% retention rate. Attendance at exercise sessions was excellent, with 92% in HIIT and 88% in RES. No exercise-related adverse events occurred. Conclusion: This study demonstrated that HIIT and RES are feasible in rectal cancer patients undergoing NACR T. Trial registration: www.clinicaltrials.gov, NCT03252821 (date of registration: March 30, 2017).

Akkermansia muciniphila Reduces Peritonitis and Improves Intestinal Tissue Wound Healing after a Colonic Transmural Defect by a MyD88-Dependent Mechanism.

Anastomotic leakage is a major complication following colorectal surgery leading to peritonitis, complications, and mortality. Akkermansia muciniphila has shown beneficial effects on the gut barrier function. Whether A. muciniphila reduces peritonitis and mortality during colonic leakage is unknown. Whether A. muciniphila can directly modulate the expression of genes in the colonic mucosa in humans has never been studied. We investigated the effects of a pretreatment (14 days) with live A. muciniphila prior to surgical colonic perforation on peritonitis, mortality, and wound healing. We used mice with an inducible intestinal-epithelial-cell-specific deletion of MyD88 (IEC-MyD88 KO) to investigate the role of the innate immune system in this context. In a proof-of-concept pilot study, healthy humans were exposed to A. muciniphila for 2 h and colonic biopsies taken before and after colonic instillation for transcriptomic analysis. Seven days after colonic perforation, A.-muciniphila-treated mice had significantly lower mortality and severity of peritonitis. This effect was associated with significant improvements of wound histological healing scores, higher production of IL22, but no changes in the mucus layer thickness or genes involved in cell renewal, proliferation, or differentiation. All these effects were abolished in IEC-MyD88 KO mice. Finally, human subjects exposed to A. muciniphila exhibited an increased level of the bacterium at the mucus level 2 h after instillation and significant changes in the expression of different genes involved in the regulation of cell cycling, gene transcription, immunity, and inflammation in their colonic mucosa. A. muciniphila improves wound healing during transmural colonic wall defect through mechanisms possibly involving IL22 signaling and requiring MyD88 in the intestinal cells. In healthy humans, colonic administration of A. muciniphila is well tolerated and changes the expression of genes involved in the immune pathways.