Final Clearance Research Articles

Identification of the Skip Phenomenon Among Patients with Staphylococcus lugdunensis Infective Endocarditis: A Retrospective Review

Abstract The “skip phenomenon” (SP) is a pattern where blood cultures are intermittently positive before final clearance. We report that one-third of patients with Staphylococcus lugdunensis infective endocarditis experienced the SP. Patients with the SP experienced both a longer duration of bacteremia and hospital stay, with a higher 1-year mortality rate.

Influence of endoscopic sphincterotomy on hepatolithiasis with Oddi sphincter-preserved cholangioplasty with hepatico-subcutaneous stoma: A three-decade, real word cohort study.

Hepatolithiasis frequently presents with recurring cholangitis and complications. Oddi sphincter-preserved cholangioplasty with hepatico-subcutaneous stoma (OSPCHS), introduced in 1993, has shown favorable long-term results. Endoscopic sphincterotomy (EST) is commonly used, but its impact on OSPCHS outcomes remains unclear. From January 1993 to June 2021, 254 patients with hepatolithiasis underwent OSPCHS. A total of 31 patients had prior EST (group with EST, n = 31), while 223 did not (group without EST, n = 223). Perioperative and long-term outcomes were compared, and risk factors for stone and cholangitis recurrence were analyzed using a Cox regression model. The immediate and final stone clearance rates were 67.3% and 81.9%, respectively. Patients with prior EST had higher rates of stone recurrence (57.7% vs. 35.7%, p = .031), shorter stone-free duration (median: 51.5 vs. 112.0 months, p = .001), higher cholangitis recurrence (45.2% vs. 25.6%, p = .023), and shorter cholangitis-free duration (median: 71.0 vs. 134.0 months, p = .006). Multivariable analysis identified bilateral intrahepatic stones (HR: 1.815, p = .010) and prior EST (HR: 3.157, p = .000) as independent risk factors for stone recurrence, whereas combined hepatectomy was a protective factor (HR: 0.448, p = .001). For cholangitis recurrence, male gender (HR: 2.308, p = .001) and EST (HR: 2.241, p = .009) were independent risk factors, while complete stone clearance reduced recurrence risk (HR: 0.423, p = .002). Prior EST adversely affects the long-term outcomes of OSPCHS. Therefore, in the management of hepatolithiasis, emphasis should be placed on preserving the Oddi sphincter.

Correlation analysis and recurrence evaluation system for patients with recurrent hepatolithiasis: a multicentre retrospective study.

Methods for accurately predicting the prognosis of patients with recurrent hepatolithiasis (RH) after biliary surgery are lacking. This study aimed to develop a model that dynamically predicts the risk of hepatolithiasis recurrence using a machine-learning (ML) approach based on multiple clinical high-order correlation data. Data from patients with RH who underwent surgery at five centres between January 2015 and December 2020 were collected and divided into training and testing sets. Nine predictive models, which we named the Correlation Analysis and Recurrence Evaluation System (CARES), were developed and compared using machine learning (ML) methods to predict the patients' dynamic recurrence risk within 5 post-operative years. We adopted a k-fold cross validation with k = 10 and tested model performance on a separate testing set. The area under the receiver operating characteristic curve was used to evaluate the performance of the models, and the significance and direction of each predictive variable were interpreted and justified based on Shapley Additive Explanations. Models based on ML methods outperformed those based on traditional regression analysis in predicting the recurrent risk of patients with RH, with Extreme Gradient Boosting (XGBoost) and Light Gradient Boosting Machine (LightGBM) showing the best performance, both yielding an AUC (Area Under the receiver operating characteristic Curve) of∼0.9 or higher at predictions. These models were proved to have even better performance on testing sets than in a 10-fold cross validation, indicating that the model was not overfitted. The SHAP method revealed that immediate stone clearance, final stone clearance, number of previous surgeries, and preoperative CA19-9 index were the most important predictors of recurrence after reoperation in RH patients. An online version of the CARES model was implemented. The CARES model was firstly developed based on ML methods and further encapsulated into an online version for predicting the recurrence of patients with RH after hepatectomy, which can guide clinical decision-making and personalised postoperative surveillance.

Research and Application of Euler Cutting Path Based Optimisation Algorithm with Greedy-RRT Algorithm

With the development of social economy, mould processing enterprises have an increasingly strong demand for reducing costs and improving economic efficiency. The optimisation of steel plate cutting path is one of the key links to improve production efficiency. In this paper, the optimal cutting path problem of steel plate under different cutting tasks is investigated, and the optimal cutting path under complex geometries is found through various optimisation algorithms. For cutting task N3, the cutting path is divided into outer contour cutting, inner hole cutting and inner hole part cutting. According to the problem, all rectangular parts inside the ellipse need to be cut before the ellipse. Through the Eulerian cutting path optimisation algorithm, we solve the air-travel problem between the inner holes and the outer contour as well as the air-travel problem between the inner holes of the ellipse and the parts inside the ellipse. The total length of the finally determined optimal air-travel path is 97 units. By combining the greedy algorithm and the RRT algorithm, we determine the number and location of the bridges and design the optimal cutting path starting from the lower right corner of the steel plate. The final clearance of the bridges is 4 units, the total length of the combined optimal path clearance is 35.56 units, and the number of bridges is 8, which are located between adjacent rectangles.

Damage evolution analysis of C/SiC screwed/bonded hybrid joints based on in-situ micro-CT technique

Due to own good high temperature mechanical properties, the C/SiC screwed/bonded hybrid joints are considered as an important development direction of vehicle connection structures. However, the difficulty of directly monitoring the interior of the hybrid joints during the bearing presents a potential challenge to the structural damage assessment. In this study, the damage process of the hybrid joints subjected to tensile loading was monitored and characterized based on the in-situ micro-CT technique. The intrinsic relationship between the mechanical responses of the hybrid joints and the local damage evolution was elucidated by observing the variation of the deposited SiC void volume at the overlap interface. The dual inhomogeneity of SiC bonding layer was quantitatively characterized utilizing the average failure rate and determination coefficient. The coupling influence mechanism of prefabricated bottom hole size and online connection process on the final assembly clearance was revealed.

ECG Characteristics of Young High School Athletes in Northwest Florida

ABSTRACT Background: Sudden cardiac death in young athletes is a rare and tragic occurrence. A preparticipation physical examination (PPE) is widely used to identify athletes who might be at risk of sudden cardiac death. High school athletes in Escambia, Okaloosa, Santa Rosa, and Walton counties in Florida undergo annual sports physicals through a local sports medicine outreach program. A resting electrocardiogram (ECG) was implemented during the 2022 PPE. The aim of this study was to document the efficacy of implementing ECGs and to highlight the cardiac abnormalities identified in young athletes as part of a 1-d PPE. Methods: In total, 1,357 high school athletes (males = 879 and females = 478; age, 15.1 ± 1.3 years) completed a resting 12-lead ECG. These were interpreted by cardiologists using the International Criteria, with abnormal results being further investigated before final sports clearance. Descriptive statistics regarding ECG findings were analyzed. Results: Twenty-three ECGs (1.7%) were classified as “abnormal” and were referred for further testing. Of these, 14 athletes were cleared to participate in sports, and 6 declined further evaluation. Three athletes, all males, were not cleared for sports participation. Of these, 2 athletes presented with Wolf-Parkinson-White syndrome (0.15%), and 1 athlete (0.10%) presented with dilated cardiomyopathy. Conclusion: Adding ECG screening as part of a single-day PPE can be used as a tool in identifying cardiac abnormalities among young athletes. To our knowledge, this is the highest number of athletes screened during a PPE in 1 d nationwide.

Enhanced recovery after surgery in percutaneous transhepatic cholangioscopic lithotripsy for patients with hepatolithiasis and choledocholithiasis

BackgroundPercutaneous transhepatic cholangioscopic lithotripsy (PTCSL) provides an effective alternative procedure for the management of complex hepatolithiasis and choledocholithiasis. Enhanced recovery after surgery (ERAS) program is an evidence-based approach that was developed to reduce surgical stress and accelerate postoperative recovery. However, little is known regarding PTCSL in the context of ERAS. The aim of this study was to evaluate the efficacy and safety of PTCSL within ERAS programs. Patient and methodsThe clinical data of patients who underwent PTCSL within ERAS programs consulted at our hospital between November 2017 and November 2022 was retrospectively reviewed. Individualized perioperative ERAS items were evaluated for all patients. The demographics, intraoperative variables, and postoperative outcomes were analyzed. ResultsA total of 43 patients who underwent PTCSL were included in the study. There were 13 men and 30 women aged between 39 and 89 years with an average age of 60 years (60.49 ± 12.37). The stone clearance rate was 77 % after the first operation, and the final clearance rate was 95 %. The incidence of complications in this study is 18.6 % (8/43), including 6 patients with Clavien-Dindo I-II, and 2 patients with Clavien-Dindo III. Pleural effusion, abdominal effusion, infection, bile leakage, and biliary bleeding are the most common complications, however, all patients recovered after aggressive treatment. ConclusionPTCSL is a relatively safe, feasible, and efficient method for treating complex hepatolithiasis and choledocholithiasis within ERAS programs. Individualized ERAS entries and precise disease management are required to minimize the occurrence of complications and to provide effective treatment.

Ultrasound-guided percutaneous transhepatic one-step biliary fistulation combined with rigid choledochoscopy for recurrent hepatolithiasis

PurposePercutaneous transhepatic one-step biliary fistulation (PTOBF) is used to treat choledocholithiasis and biliary stricture. This study aimed to evaluate the safety and efficacy of ultrasound-guided PTOBF combined with rigid choledochoscopy in the treatment of recurrent hepatolithiasis.Materials and methodsThe clinical data of 37 consecutive patients who underwent PTOBF combined with rigid choledochoscopy for RHL from March 2020 to March 2022 at our hospital were retrospectively analyzed.ResultsA total of 68 percutaneous transhepatic punctures were performed in 37 patients, with a puncture success rate of 85.29% (58/68) and a dilatation success rate of 100.00% (58/58). The mean blood loss of operation was 9.84 ± 18.10 mL, the mean operation time was 82.05 ± 31.92 min, and the mean length of postoperative hospital stay was 5.59 ± 3.26 days. The initial stone clearance rate was 40.54% (15/37) and the final stone clearance rate was 100% (37/37). The incidence of postoperative complications was 10.81% (4/37), including 2 cases of pleural effusion, 1 case of hemorrhage, and 1 case of cholangitis, which recovered after treatment. During a mean follow-up period of 23 months (range 12 to 36 months), only 1 patient experienced stone recurrence.ConclusionUltrasound-guided PTOBF combined with rigid choledochoscopy in the treatment of RHL based on skilful manipulation seems to be a safe, effective and minimally invasive method with clinical application value. Further comparative studies with large sample sizes are needed in the future to confirm the reliability of its therapeutic results.

Population pharmacokinetics and individualized dosing of vancomycin for critically ill patients receiving continuous renal replacement therapy: the role of residual diuresis.

Background: Vancomycin dosing is difficult in critically ill patients receiving continuous renal replacement therapy (CRRT). Previous population pharmacokinetic (PopPK) models seldom consider the effect of residual diuresis, a significant factor of elimination, and thus have poor external utility. This study aimed to build a PopPK model of vancomycin that incorporates daily urine volume to better describe the elimination of vancomycin in these patients. Methods: We performed a multicenter retrospective study that included critically ill patients who received intermittent intravenous vancomycin and CRRT. The PopPK model was developed using the NONMEM program. Goodness-of-fit plots and bootstrap analysis were employed to evaluate the final model. Monte Carlo simulation was performed to explore the optimal dosage regimen with a target area under the curve of ≥400mg/Lh and 400-600mg/L h. Results: Overall, 113 observations available from 71 patients were included in the PopPK model. The pharmacokinetics could be well illustrated by a one-compartment model with first-order elimination, with the 24-h urine volume as a significant covariate of clearance. The final typical clearance was 1.05L/h, and the mean volume of distribution was 69.0L. For patients with anuria or oliguria, a maintenance dosage regimen of 750mg q12h is recommended. Conclusion: Vancomycin pharmacokinetics in critically ill patients receiving CRRT were well described by the developed PopPK model, which incorporates 24-h urine volume as a covariate. This study will help to better understand vancomycin elimination and benefit precision dosing in these patients.

Localization of Central Breast Lymphatics and Predefined Separation of Lobes along the Horizontal Septum

Background: The predictable localization of the neurovascular supply along the ligamentous suspension, composed of the horizontal septum, vertical ligaments, and superficial fascia, has increased safety in breast reduction. Lymphatic drainage of the breast has always been described as running close to vascular supply. However, the correlation between the lymphatic course and ligamentous suspension has not yet been considered. This study aimed to visualize the relationship, direction of lymphatic flow, and predefined separation of lobes along the horizontal septum. Methods: To investigate central drainage, methylene blue was injected subareolarly in five breasts of female cadavers before blunt preparation of the horizontal septum in anatomical studies. To visualize central and peripheral drainage, lymphographin was injected into one of the three different sites in 14 breasts; the dynamic flow of drainage was observed during subsequent septum-based breast reductions in clinical settings. Results: In all anatomical studies, a predefined section of the glandular layers allowed access to central clearance along the stained horizontal septum. Clinical investigations similarly showed clearance along the corresponding part of the ligamentous suspension, most reliably along the horizontal septum. The affected quadrant of the breast, its relation to the nipple-areola complex, and the anterior-posterior axis toward the thoracic wall mainly determine the direction of lymphatic flow. Interconnections along the ligaments may explain the unpredictability of final clearance directions. Conclusions: This study shows the horizontal septum as a guiding structure for central mammary drainage. This may encourage a septum-based approach for refinement of procedures such as oncoplastic, irradiation, and lymphedema treatments.

Adenosine, bridging chronic inflammation and tumor growth.

Adenosine (Ado) is a well-known immunosuppressive agent that may be released or generated extracellularly by cells, via degrading ATP by the sequential actions of the ectonucleotides CD39 and CD73. During inflammation Ado is produced by leukocytes and tissue cells by different means to initiate the healing phase. Ado downregulates the activation and the effector functions of different leukocyte (sub-) populations and stimulates proliferation of fibroblasts for re-establishment of intact tissues. Therefore, the anti-inflammatory actions of Ado are already intrinsically triggered during each episode of inflammation. These tissue-regenerating and inflammation-tempering purposes of Ado can become counterproductive. In chronic inflammation, it is possible that Ado-driven anti-inflammatory actions sustain the inflammation and prevent the final clearance of the tissues from possible pathogens. These chronic infections are characterized by increased tissue damage, remodeling and accumulating DNA damage, and are thus prone for tumor formation. Developing tumors may further enhance immunosuppressive actions by producing Ado by themselves, or by "hijacking" CD39+/CD73+ cells that had already developed during chronic inflammation. This review describes different and mostly convergent mechanisms of how Ado-induced immune suppression, initially induced in inflammation, can lead to tumor formation and outgrowth.

Anticipated Versus Unanticipated Incomplete Mohs Micrographic Surgery for Keratinocyte Carcinomas: Impact on Treatment Delays and Final Margin Status.

Mohs micrographic surgery may be discontinued with positive margins as an anticipated strategy for multidisciplinary care or as an unanticipated occurrence. Management of primary tumors has not been compared after anticipated versus unanticipated incomplete Mohs micrographic surgery (iMMS). To compare rates and timing of adjuvant surgery after iMMS and final margin status when iMMS is anticipated versus unanticipated. Secondary outcomes were preoperative and intraoperative clinicopathologic factors associated with iMMS. Cases of iMMS of keratinocyte carcinomas at a tertiary academic center between 2005 and 2022 were classified as anticipated (preoperative assembly of multidisciplinary teams) or unanticipated (ad hoc management of positive margins). Rate, timing, and final margin status of adjuvant surgery was compared between anticipated and unanticipated iMMS cohorts using χ2/Fisher exact test for categorical variables and t-test for continuous variables. Of 127 iMMS cases, 51.2% (65/127) were anticipated. Anticipated iMMS cases were more likely to undergo additional resection (98.5% vs 72.6%, p < .001), with fewer delays (3.9 vs 13.2 days, p < .001) and higher rates of final margin clearance (84.6% vs 59.7%, p < .001). When iMMS is anticipated as part of multidisciplinary care, patients are more likely to undergo additional resection, with fewer delays to next surgery and higher final margin clearance rates.

Utility of intraoperative pathology consultations of whipple resection specimens and their impact on final margin status

The resection margin status is a significant surgical prognostic factor for the long-term outcomes of patients undergoing pancreaticoduodenectomy (Whipple procedure). As a result, surgeons frequently rely on intraoperative consults (IOCs) involving frozen sections to evaluate margin clearance during these resections. Nevertheless, the impact of this practice on final margin status and long-term outcomes remains a topic of debate. This study aimed to assess the impact of IOCs on the clearance rate of resection margins following Whipple procedure and distal pancreatectomy. A retrospective database review of all patients who underwent Whipple procedure or distal pancreatectomy at our institution between 2018 and 2020 was performed to evaluate the utility of IOCs by gastrointestinal surgeons and its correlation with final postoperative surgical margin status. A significant variation in the frequency of IOC requests for margins among surgeons was noted. However, the use of frozen section analysis for intraoperative margin assessment was not significantly associated with the clearance rate of final post-operative margins. More frequent use of IOC did not result in higher final margin clearance rate, an important prognostic factor following Whipple procedure.

Application of image overlapping in percutaneous nephrolithotomy.

To investigate the application of ultrasound and CT image overlap in percutaneous nephrolithotomy (PCNL). A total of 140 patients with complicated kidney stones requiring PCNL were prospectively enrolled, from January 2020 to December 2022. These patients were randomly divided into 2 groups, with 70 patients each in the research group and the control group. All participants underwent dual-source, non-contrast CT scan of both kidneys and pelvis before surgery. Preoperative three-dimensional CT reconstruction and simulated puncture were performed in patients from the research group. The best puncture path was determined through ultrasound and CT image overlap. Puncture guided by regular CT and ultrasound was conducted in patients from the control group. Differences in the surgical outcomes between the two groups were compared. Compared to the control group, the research group had higher stone clearance rate in stage I PCNL, success rate of one-time puncture, less percutaneous channels, less reduction of hemoglobin and shorter procedure time. Complications in stage I PCNL were comparable in the two groups, and there was no significant change in the final stone clearance rates between the two groups. An optimal puncture channel can be chosen using ultrasound and CT image overlap. PCNL can be achieved with precise puncturing, thus achieving coincidence between imaging and anatomy and reducing the amount of blood loss during stage I of PCNL. It also shortens the procedure time and improves stone clearance rate of PCNL.

Total escape of SARS-CoV-2 from dual monoclonal antibody therapy in an immunocompromised patient

Monoclonal antibodies (mAbs) directed against the spike of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are effective therapeutic options to combat infections in high-risk patients. Here, we report the adaptation of SARS-CoV-2 to the mAb cocktail REGN-COV in a kidney transplant patient with hypogammaglobulinemia. Following mAb treatment, the patient did not clear the infection. During viral persistence, SARS-CoV-2 acquired three novel spike mutations. Neutralization and mouse protection analyses demonstrate a complete viral escape from REGN-COV at the expense of ACE-2 binding. Final clearance of the virus occurred upon reduction of the immunosuppressive regimen and total IgG substitution. Serology suggests that the development of highly neutralizing IgM rather than IgG substitution aids clearance. Our findings emphasise that selection pressure by mAbs on SARS-CoV-2 can lead to development of escape variants in immunocompromised patients. Thus, modification of immunosuppressive therapy, if possible, might be preferable to control and clearance of the viral infection.

Hypoxic postconditioning restores mitophagy against transient global cerebral ischemia via Parkin-induced posttranslational modification of TBK1

Hypoxic postconditioning (HPC) has been reported to enhance Parkin-catalyzed mitochondrial ubiquitination to restore mitophagy in hippocampal CA1 against transient global cerebral ischemia (tGCI). However, the molecular mechanism leading ubiquitinated mitochondria to final clearance during HPC-mediated mitophagy after tGCI is unclear. This study aims to investigate whether HPC restores mitophagy after tGCI through Parkin-induced K63-linked poly-ubiquitination (K63-Ub) to activate tumor necrosis factor associated factor family member associated nuclear factor κB activator -binding kinase 1 (TBK1) in CA1 of male rats. We found that HPC maintained TBK1 expression, promoted p62 and TBK1 phosphorylation in mitochondria, and enhanced their recruitments to mitochondria in CA1 after tGCI. However, these effects were partially abolished by TBK1 inhibitor BX795. K63-Ub of mitochondrial TBK1 was disturbed at 26 h of reperfusion after tGCI, which was reversed by HPC. The maintenance of K63-Ub of mitochondrial TBK1 induced by HPC was counteracted under Parkin knockdown with AAV-mediated Prkn small-interfering RNA, accompanied by the suppression on TBK1 activation and the reduction of mitochondrial p62 phosphorylation. This innovative study indicated that HPC maintained K63-Ub of TBK1 in a Parkin-dependent manner to promote TBK1 phosphorylation, and then phosphorylated TBK1 activated p62 to restore mitophagy, thereby alleviating neuronal damage in CA1 after tGCI.

Continuous Measurement of Reactive Oxygen Species Formation in Bacteria-infected Bone Marrow-derived Macrophages Using a Fluorescence Plate Reader.

Macrophages are at the center of innate immunity and are the main target cells of the intracellular pathogen Salmonella enterica serovar Typhi. The production of reactive oxygen and nitrogen species (ROS/RNS) is the host's early response to invading microbes, as oxidative stress is highly toxic for bacteria. Adequate ROS/RNS production in infected macrophages is critical for the clearance of intracellular pathogens; this is achieved by several enzymes, including inducible NADPH phagocyte oxidase (NOX) and nitric oxide synthase (iNOS), respectively. The pro-inflammatory cytokine interferon gamma (IFNγ), primarily produced by activated natural killer cells and T-helper cells type 1, is a potent inducer of iNOS. Therefore, it is crucial for infection control through oxidative microbicidal activity. To characterize the early oxidative stress response via ROS formation, which is critical for the reduction of Salmonella proliferation within macrophages, we established an in vitro model of murine macrophages infected with Salmonella enterica serovar Typhimurium (S.tm). This serovar induces a systemic infection in mice that is frequently used as a model for typhoid fever, which, in human subjects, is caused by Salmonella Typhi. We generated bone marrow-derived macrophages (BMDM) from C57BL/6N wildtype mice using macrophage colony-stimulating factor (M-CSF) stimulation for six days. Thereafter, we infected BMDM withS. tm for one hour. Shortly before infection, cells were stained with CellROXTM Deep Red reagent. In its reduced form, CellROXTM is non-fluorescent. As a result of oxidation by ROS, this reagent exhibits strong fluorescence and persists within the cells. Subsequently, changes as a result of the oxidative stress response can be measured with a TECAN Spark microplate reader over time. We designed this protocol to measure oxidative stress in macrophages through the course of an infection with an intracellular bacterium. The protocol has several advantages over established techniques. First, it allows to continuously monitor and quantify ROS production in living cells from the very start of the infection to the final clearance of the intracellular pathogen. Second, this protocol enables efficient ROS detection without stressing the cells by detaching or staining procedures. Graphical abstract.

Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients.

Cefiderocol is a siderophore cephalosporin antibiotic active against Gram-negative bacteria, including extended-spectrum beta-lactamase and carbapenemase-producing strains. The pharmacokinetics of cefiderocol has been studied in healthy subjects and particularly in phase II and III studies. This retrospective study investigated intravenous cefiderocol population pharmacokinetics in adult patients treated by cefiderocol. We studied 55 consecutive patients hospitalized in an intensive care unit. Cefiderocol plasma samples were obtained on different occasions during treatment. Plasma concentration was assayed using mass spectrometry. Data analysis was performed using a non-linear mixed-effect approach via Monolix 2020R1. A total of 205 plasma samples were obtained from 55 patients. Eighty percent of patients received cefiderocol for ventilator-associated pneumonia due to carbapenem-resistant Pseudomonas aeruginosa infection. Cefiderocol concentration time-courses were best fit to a two-compartment open model with first-order elimination. Elimination clearance was positively related to renal function (estimated by the CKD formula). Adding albumin plasma binding in the model significantly improved the model assuming a ~40% unbound drug fraction given a ~40 g/L albuminemia. The final model included CKD plus cefiderocol plasma binding effects. Fat-free mass was better than total body weight to influence, via the allometric rule, clearance and volume terms, but this effect was negligible. The final clearance based on free circulating drug (CLU) for a typical patient, CKD = 90, was 7.38 L/h [relative standard error, RSE, 22%] with a between-subject variability of 0.47 [RSE 10%] (exponential distribution). This study showed that albumin binding and CKD effects were significant predictors of unbound and total plasma cefiderocol concentrations. Our results indicate that individual adjustment of cefiderocol can be used to reach high minimum inhibitory concentrations based on an estimation of unbound drug concentration and optimize therapeutic efficacy.

COVID-19 Adaptive Humoral Immunity Models: Weakly Neutralizing Versus Antibody-Disease Enhancement Scenarios.

The interplay between the virus, infected cells and immune responses to SARS-CoV-2 is still under debate. By extending the basic model of viral dynamics, we propose here a formal approach to describe neutralisation versus weak (or non-)neutralisation scenarios and compare them with the possible effects of antibody-dependent enhancement (ADE). The theoretical model is consistent with the data available in the literature; we show that both weakly neutralising antibodies and ADE can result in final viral clearance or disease progression, but that the immunodynamics are different in each case. As a significant proportion of the world’s population is already naturally immune or vaccinated, we also discuss the implications for secondary infections after vaccination or in the presence of immune system dysfunctions.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10441-022-09447-1.

Dietary pH Enhancement Improves Metabolic Outcomes in Diet-Induced Obese Male and Female Mice: Effects of Beef vs. Casein Proteins.

(1) Consumption of diets that are caloric dense but not nutrient dense have been implicated in metabolic diseases, in part through low-grade metabolic acidosis. Mitigation strategies through dietary intervention to alleviate acidosis have not been previously reported. Our objective is to determine the effects of pH enhancement (with ammonia) in high fat diet-induced obese mice that were fed beef or casein as protein sources compared to low fat diet-fed mice. (2) Methods: B6 male and female mice were randomized (n = 10) into eight diets that differ in protein source, pH enhancement of the protein, and fat content, and fed for 13 weeks: low fat (11% fat) casein (LFC), LF casein pH-enhanced (LFCN), LF lean beef (LFB), LFBN, high fat (46%) casein (HFC), HFCN, HF beef (HFB), and HFBN. Body weights and composition, and glucose tolerance tests were conducted along with terminal serum analyses. Three-way ANOVA was performed. (3) Results: A significant effect of dietary fat (LF vs. HF) was observed across all variables in both sexes (final body weight, fat mass, glucose clearance, and serum leptin). Importantly, pH enhancement significantly reduced adiposity (males only) and final body weights (females only) and significantly improved glucose clearance in both sexes. Lastly, clear sex differences were observed across all variables. (4) Conclusions: Our findings demonstrate metabolic benefits of increasing dietary pH using ammonia, while high fat intake per se (not protein source) is the major contributor to metabolic dysfunctions. Additional research is warranted to determine mechanisms underlying the beneficial effects of pH enhancement, and interactions with dietary fat content and proteins.