Prevalence of Rotational Malalignment After Infrapatellar Versus Suprapatellar Intramedullary Nailing of Tibial Shaft Fractures.

Background: Up to 30% of patients with a tibial shaft fracture sustain iatrogenic rotational malalignment (RM) after infrapatellar (IP) nailing. Although IP nailing remains the management of choice for most patients, suprapatellar (SP) nailing has been gaining popularity. It is currently unknown whether SP nailing can provide superior outcomes with regard to tibial RM. The aim of this study was to compare the differences in the prevalence of RM following IP versus SP nailing. Methods: This retrospective study included 253 patients with a unilateral, closed tibial shaft fracture treated with either an IP or SP approach between January 2009 and April 2023 in a Level-I trauma center. All patients underwent a postoperative, protocolized, bilateral computed tomography (CT) scan for RM assessment. Results: RM was observed in 30% and 33% of patients treated with IP and SP nailing, respectively. These results indicate no significant difference (p = 0.639) in the prevalence of RM between approaches. Furthermore, there were no significant differences in the distribution (p = 0.553) and direction of RM (p = 0.771) between the 2 approaches. With the IP and SP approaches, nailing of left-sided tibial shaft fractures resulted in predominantly internal RM (85% and 73%, respectively), while nailing of right-sided tibial shaft fractures resulted in predominantly external RM (90% and 80%, respectively). The intraobserver reliability for the CT measurements was 0.95. Conclusions: The prevalence of RM was not influenced by the entry point of tibial nailing (i.e., IP versus SP). Hence, the choice of surgical approach should rely on factors other than the risk of RM. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Genomic insights into the population history and adaptive traits of Latin American Criollo cattle.

Criollo cattle, the descendants of animals brought by Iberian colonists to the Americas, have been the subject of natural and human-mediated selection in novel tropical agroecological zones for centuries. Consequently, these breeds have evolved distinct characteristics such as resistance to diseases and exceptional heat tolerance. In addition to European taurine (Bos taurus) ancestry, it has been proposed that gene flow from African taurine and Asian indicine (Bos indicus) cattle has shaped the ancestry of Criollo cattle. In this study, we analysed Criollo breeds from Colombia and Venezuela using whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) array data to examine population structure and admixture at high resolution. Analysis of genetic structure and ancestry components provided evidence for African taurine and Asian indicine admixture in Criollo cattle. In addition, using WGS data, we detected selection signatures associated with a myriad of adaptive traits, revealing genes linked to thermotolerance, reproduction, fertility, immunity and distinct coat and skin coloration traits. This study underscores the remarkable adaptability of Criollo cattle and highlights the genetic richness and potential of these breeds in the face of climate change, habitat flux and disease challenges. Further research is warranted to leverage these findings for more effective and sustainable cattle breeding programmes.

Endurance training and hydroxyurea have synergistic effects on muscle function and energetics in sickle cell disease mice.

Sickle cell disease (SCD) is an hemoglobinopathy resulting in the production of an abnormal Hb (HbS) which can polymerize in deoxygenated conditions, leading to the sickling of red blood cells (RBC). These alterations can decrease the oxygen-carrying capacity leading to impaired function and energetics of skeletal muscle. Any strategy which could reverse the corresponding defects could be of interest. In SCD, endurance training is known to improve multiples muscle properties which restores patient's exercise capacity but present reduced effects in anemic patients. Hydroxyurea (HU) can increase fetal hemoglobin production which can reduce anemia in patients. The present study was conducted to determine whether HU can improve the effects of endurance training to improve muscle function and energetics. Twenty SCD Townes mice have been trained for 8 weeks with (n = 11) or without (n = 9) HU. SCD mice muscle function and energetics were analyzed during a standardized rest-exercise-recovery protocol, using Phosphorus-31 Magnetic resonance spectroscopy (31P-MRS) and transcutaneous stimulation. The combination of training and HU specifically decreased fatigue index and PCr consumption while muscle oxidative capacity was improved. These results illustrate the potential synergistic effects of endurance training and HU on muscle function and energetics in sickle cell disease.

Endurance training improves oxygen uptake/demand mismatch, metabolic flexibility and recovery in patients with sickle cell disease.

Patients with sickle cell disease (SCD) display lower slope coefficients of the oxygen uptake (V_O2) vs. work rate (W) relationship (delineating an O2 uptake/demand mismatch) and a poor metabolic flexibility. Because endurance training (ET) increases the microvascular network and oxidative enzymes activity including one involved in lipid oxidation, ET might improve the slope coefficient of the V_O2 vs. W curve and the metabolic flexibility of SCD patients. ET may also contribute to improve patient post-exercise cardiopulmonary and metabolic recovery. Fifteen patients with SCD performed a submaximal incremental test on a cycle ergometer before (SIT1) and after (SIT2) 8 weeks of ET. Minute ventilation, ventilation rate (VR), heart rate (HR), V_O2, CO2 production, respiratory exchange ratio, carbohydrate/lipid utilization and partitioning (including %Lipidox) and blood lactate concentration ([lactate]b) were measured during and after SIT1 and SIT2. At baseline, the slope coefficient of the V_O2 vs. W curve positively correlated with total hemoglobin, mean corpuscular hemoglobin and percentage of HbF. After training, the slope coefficient of the V_O2 vs. W curve was significantly higher and the [lactate]b increase was delayed. If patients' energy metabolism apparently relied largely on carbohydrate sources during SIT1, %Lipidox tended to increase at low exercise intensities during SIT2, supporting a training-induced improvement of metabolic flexibility in patients with SCD. Post-exercise recovery of VR, V_E/V_CO2, HR and [lactate]b was faster after training. We concluded that ET in patients with SCD i) ameliorated the oxygen uptake/demand mismatch, ii) blunted the metabolic inflexibility, and iii) improved post-exercise cardiopulmonary and metabolic responses.

Association between perioperative non-steroidal anti-inflammatory drug use and cardiovascular complications after non-cardiac surgery in older adult patients.

BACKGROUND: We investigated in older adult non-cardiac surgical patients whether receipt of perioperative non-steroidal anti-inflammatory drugs (NSAIDs) is associated with increased incidence of postoperative cardiovascular complications. METHODS: We retrospectively extracted the information for patients with age ≥  65 years who had inpatient non-cardiac surgery with a duration of ≥  1 h from the American College of Surgeons-National Surgical Quality Improvement Program registry data acquired at the University of Washington Medical Center. We compared patients who received NSAIDs perioperatively to those who did not receive NSAIDs, on the two composite outcomes: (1) the incidence of postoperative cardiovascular complications within 30 days of the surgery, and (2) the incidence of combined postoperative gastrointestinal and renal complications, and length of postoperative hospital stay. We used separate multivariable logistic regression models to analyze the two composite outcomes and a Poisson regression model for the length of hospital stay. RESULTS: The receipt of perioperative NSAIDs was not associated with postoperative cardiovascular complications (estimated odds ratio (OR), 1.78; 95% confidence interval (CI), 0.97 to 3.25; P =  0.06), combined renal and gastrointestinal complications (estimated OR, 1.30; 95% CI, 0.53 to 3.20; P =  0.57), and length of postoperative hospital stay in days (incidence rate ratio, 1.06; 95% CI, 0.93 to 1.21; P =  0.39). CONCLUSIONS: In older adult non-cardiac surgical patients, receipt of perioperative NSAIDs was not associated with increased incidences of postoperative cardiovascular complications, and renal and gastrointestinal complications within 30 days after surgery, or length of postoperative hospital stay.

Population Pharmacokinetics of Cabotegravir Following Oral Administration and Long-Acting Intramuscular Injection in Real-World People with HIV.

Long-acting cabotegravir has been studied mainly in the stringent framework of clinical trials, which does not necessarily reflect the situation of people with HIV (PWH) in routine clinical settings. The present population pharmacokinetic analysis aims to build real-world reference percentile curves of cabotegravir concentrations, accounting for patient-related factors that may affect cabotegravir exposure. The second objective is to simulate whether dosing interval adjustments of cabotegravir could be considered in specific subpopulations. Overall, 238 PWH contributed to 1,038 cabotegravir levels (186 during the initial oral administration phase and 852 after intramuscular injection). Cabotegravir pharmacokinetics was best described using a one-compartment model with distinct first order-absorption for oral and intramuscular administrations, and identical volume and clearance. Our model showed almost 40% faster absorption and 30% higher clearance than previously reported, resulting in a time to steady-state of 8 months and an elimination half-life of 4.6 weeks for long-acting cabotegravir. Sex and body mass index significantly influenced absorption, and bodyweight affected clearance. Model-based simulations showed that cabotegravir trough concentrations in females were 25% lower 4 weeks after the intramuscular loading dose, but 42% higher during the late maintenance phase. Finally, simulations indicated that in females, despite significantly higher cabotegravir concentrations, longer intervals between injections may not consistently ensure levels above the 4-fold protein-adjusted 90% inhibitory target concentration.

Rotational Malalignment After Intramedullary Nailing of Tibial Shaft Fractures Is Predictable.

OBJECTIVES: Intramedullary nailing is the treatment of choice for most tibial shaft fractures (TSF). However, an iatrogenic pitfall may be rotational malalignment. The aim of this retrospective analysis was to determine predictors of rotational malalignment following intramedullary nailing of TSF. DESIGN: Retrospective study. SETTING: Single level 1 trauma center. PATIENT SELECTION CRITERIA: Patients who had a unilateral intramedullary nailing for TSF with a low-dose bilateral postoperative CT to assess rotational malalignment. OUTCOME MEASURES AND COMPARISONS: Bivariable analysis followed by multivariable analysis was then undertaken to assess for any independent predictors, such as fracture type/sight, surgeon experience, and side of fracture, predictive of rotational malalignment. RESULTS: In total, 154 patients (71% male, median age 37 years) were included in this study. Thirty-nine percent of variability in postoperative rotational malalignment could be explained using a model including (increased) tibial torsion of the noninjured side (mean [38.9 degrees ± 9.02 degrees] considered normal tibial torsion), side of tibial fracture, and spiral-type tibial fracture (R2 = 0.39, P ≤ 0.001, F = 31.40). In this model, there was a negative linear association between degrees of torsion on the noninjured side and rotational malalignment (-0.45, P < 0.001)-as baseline torsion increased from mean by 1 degree, malrotation in the opposite direction of 0.54 degrees seen. Positive linear associations between right-sided TSF and rotational malalignment (8.59 P < 0.001) as well as spiral fractures and rotational malalignment (5.03, P < 0.01) were seen. CONCLUSIONS: This study demonstrates that baseline reduced (internal) tibial torsion of the noninjured limb, spiral fractures, and right-sided TSF are predictive of postoperative external rotational malalignment. Conversely, increased baseline (external) tibial torsion of the noninjured limb and left-sided TSF are predictive of postoperative internal rotational malalignment. Surgeons may use this regression model preoperatively to predict what sort of postoperative rotational difference their patient may be prone to. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Individualized physiology-based digital twin model for sports performance prediction: a reinterpretation of the Margaria-Morton model.

Performance in many racing sports depends on the ability of the athletes to produce and maintain the highest possible work i.e., the highest power for the duration of the race. To model this energy production in an individualized way, an adaptation and a reinterpretation (including a physiological meaning of parameters) of the three-component Margaria-Morton model were performed. The model is applied to the muscles involved in a given task. The introduction of physiological meanings was possible thanks to the measurement of physiological characteristics for a given athlete. A method for creating a digital twin was therefore proposed and applied for national-level cyclists. The twins thus created were validated by comparison with field performance, experimental observations, and literature data. Simulations of record times and 3-minute all-out tests were consistent with experimental data. Considering the literature, the model provided good estimates of the time course of muscle metabolite concentrations (e.g., lactate and phosphocreatine). It also simulated the behavior of oxygen kinetics at exercise onset and during recovery. This methodology has a wide range of applications, including prediction and optimization of the performance of individually modeled athletes.

Design of a Porous Silicon Biosensor: Characterization, Modeling, and Application to the Indirect Detection of Bacteria.

The design of a porous silicon (PSi) biosensor is not often documented, but is of the upmost importance to optimize its performance. In this work, the motivation behind the design choices of a PSi-based optical biosensor for the indirect detection of bacteria via their lysis is detailed. The transducer, based on a PSi membrane, was characterized and models were built to simulate the analyte diffusion, depending on the porous nanostructures, and to optimize the optical properties. Once all performances and properties were analyzed and optimized, a theoretical response was calculated. The theoretical limit of detection was computed as 104 CFU/mL, based on the noise levels of the optical setup. The experimental response was measured using 106 CFU/mL of Bacillus cereus as model strain, lysed by bacteriophage-coded endolysins PlyB221. The obtained signal matched the expected response, demonstrating the validity of our design and models.

Risk factors for severe morbidity and definitive stoma after elective surgery for sigmoid diverticulitis: a multicenter national cohort study.

BACKGROUND: In the decision to perform elective surgery, it is of great interest to have data about the outcomes of surgery to individualize patients who could safely undergo sigmoid resection. The aim of this study was to provide information on the outcomes of elective sigmoid resection for sigmoid diverticular disease (SDD) at a national level. METHODS: All consecutive patients who had elective surgery for SDD (2010-2021) were included in this retrospective, multicenter, cohort study. Patients were identified from institutional review board-approved databases in French member centers of the French Surgical Association. The endpoints of the study were the early and the long-term postoperative outcomes and an evaluation of the risk factors for 90-day severe postoperative morbidity and a definitive stoma after an elective sigmoidectomy for SDD. RESULTS: In total, 4617 patients were included. The median [IQR] age was 61 [18.0;100] years, the mean ± SD body mass index (BMI) was 26.8 ± 4 kg/m2, and 2310 (50%) were men. The indications for surgery were complicated diverticulitis in 50% and smoldering diverticulitis in 47.4%. The procedures were performed laparoscopically for 88% and with an anastomosis for 83.8%. The severe complication rate on postoperative day 90 was 11.7%, with a risk of anastomotic leakage of 4.7%. The independent risk factors in multivariate analysis were an American Society of Anesthesiologists (ASA) score ≥ 3, an open approach, and perioperative blood transfusion. Age, perioperative blood transfusion, and Hartmann's procedure were the three independent risk factors for a permanent stoma. CONCLUSIONS: This series provides a real-life picture of elective sigmoidectomy for SDD at a national level. TRIAL REGISTRATION: Comité National Information et Liberté (CNIL) (n°920361).

Guidance for the Interpretation of Long-Acting Cabotegravir and Rilpivirine Concentrations Based on Real-World Therapeutic Drug Monitoring Data and Documented Failures.

The interpretation of long-acting cabotegravir and rilpivirine concentrations is complicated by the lack of consensus on the threshold to consider. Building on real-world therapeutic drug monitoring data and documented virologic failures, this article provides a reappraisal of the existing thresholds and guidance for the interpretation of cabotegravir and rilpivirine concentrations.

Real-world trough concentrations and effectiveness of long-acting cabotegravir and rilpivirine: a multicenter prospective observational study in Switzerland.

Background: The efficacy and tolerability of long-acting cabotegravir and rilpivirine were demonstrated in Phase III trials. However, low concentrations combined with other risk factors have been associated with an increased risk of virologic failure. This study aims to verify whether drug concentrations measured in a real-world setting are consistent with those previously reported. Methods: SHCS-879 is a nationwide observational study within the Swiss HIV Cohort Study for the monitoring of people with HIV (PWH) on long-acting cabotegravir plus rilpivirine. Samples were collected from March 2022 to March 2023. Findings: Overall, 725 samples were obtained from 186 PWH. Our data show a large inter-individual variability in cabotegravir and rilpivirine concentrations, with some individuals exhibiting repeatedly low concentrations. Rilpivirine trough concentrations were consistent with those from Phase III trials, while cabotegravir concentrations were lower. The first concentrations quartile was only slightly above the target of 664 ng/mL. Exploratory statistical analyses found 35% (p < 0·01) lower cabotegravir trough in males compared to females. Overall, 172 PWH (92%) remained suppressed and three experienced virologic failures (1·6%), of those, two had sub-optimal drug exposure. No association was found between low trough levels and detectable viral load. Interpretation: Real-world cabotegravir concentrations are substantially lower than previously reported. However, these concentrations appear sufficient to ensure sustained virological suppression in almost every PWH. These reassuring data challenge the rather conservative thresholds adopted to date, which may raise unnecessary concerns. Yet, our study reveals that some PWH have repeatedly very low drug levels, for reasons that remain to be elucidated. Funding: This work was funded by the Swiss National Science Foundation, grant number N◦ 324730_192449. This study received no support from pharmaceutical industries. This study was performed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #201369), by SHCS project #879, and by the SHCS research foundation. The SHCS data were gathered by the Five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers).

Population pharmacokinetic analysis of doravirine in real-world people with HIV.

AIMS: The pharmacokinetics of doravirine has been studied in clinical trials but not in real-world settings. Our study aims to characterize and identify factors influencing doravirine (a CYP3A4 substrate) pharmacokinetics in real-world people with HIV (PWH). METHODS: A total of 174 doravirine concentrations measured in 146 PWH followed up in the therapeutic drug monitoring (TDM) program at the University Hospital of Lausanne (Switzerland) between 2019 and 2023 were included in the analysis. Demographic data, clinical information and comedications were recorded during the routine SHCS visits (every 3-6 months). Population pharmacokinetic analysis and Monte Carlo simulations to investigate the clinical significance of the covariates retained in the final model were performed using NONMEM. RESULTS: A one-compartment model with first-order absorption and linear elimination best described doravirine pharmacokinetics. Potent CYP3A4 inhibitors and, to a lesser extent age, were the only tested covariates to significantly impact doravirine clearance (CL). Potent CYP3A4 inhibitors reduced CL by 50%, and a 30% decrease in CL was observed in an 80-year-old compared with a 55-year-old PWH. The effect of potent CYP3A4 inhibitors was prominent, explaining 59% of between-subject variability in CL. Model-based simulations predicted 2.8-fold and 1.6-fold increases in median steady-state trough and maximum doravirine concentrations, respectively, when a potent CYP3A4 inhibitor was co-administered. CONCLUSIONS: Our findings show that potent CYP3A4 inhibitors and age influence doravirine pharmacokinetics. However, given the good tolerability of doravirine, dosing adjustment of doravirine is probably not mandatory in those situations. TDM remains useful essentially in specific clinical situations, such as hepatic impairment, suspected nonadherence or pregnancy.

The history of Coast Salish "woolly dogs" revealed by ancient genomics and Indigenous Knowledge.

Ancestral Coast Salish societies in the Pacific Northwest kept long-haired "woolly dogs" that were bred and cared for over millennia. However, the dog wool-weaving tradition declined during the 19th century, and the population was lost. In this study, we analyzed genomic and isotopic data from a preserved woolly dog pelt from "Mutton," collected in 1859. Mutton is the only known example of an Indigenous North American dog with dominant precolonial ancestry postdating the onset of settler colonialism. We identified candidate genetic variants potentially linked with their distinct woolly phenotype. We integrated these data with interviews from Coast Salish Elders, Knowledge Keepers, and weavers about shared traditional knowledge and memories surrounding woolly dogs, their importance within Coast Salish societies, and how colonial policies led directly to their disappearance.

Ancient chicken remains reveal the origins of virulence in Marek's disease virus.

The pronounced growth in livestock populations since the 1950s has altered the epidemiological and evolutionary trajectory of their associated pathogens. For example, Marek's disease virus (MDV), which causes lymphoid tumors in chickens, has experienced a marked increase in virulence over the past century. Today, MDV infections kill >90% of unvaccinated birds, and controlling it costs more than US$1 billion annually. By sequencing MDV genomes derived from archeological chickens, we demonstrate that it has been circulating for at least 1000 years. We functionally tested the Meq oncogene, one of 49 viral genes positively selected in modern strains, demonstrating that ancient MDV was likely incapable of driving tumor formation. Our results demonstrate the power of ancient DNA approaches to trace the molecular basis of virulence in economically relevant pathogens.

Physical Exercise or Activity and Energy Balance or Metabolism in the Context of Health and Diseases.

Regular long-lasting physical exercise demands a tremendous amount of metabolic energy [...].

In Vitro Investigation into the Effect of Cryopreservation on the Mechanical Characteristics of Dental Hard Tissues.

Previous research has reported on hidden damage within the dentin introduced by cryopreservation, but the effect on the mechanical properties of the hard tissues at tooth level remains unclear. The main objective of this study is to investigate the effect of cryopreservation on the mechanical properties of teeth. A matched sample of 234 premolars of 117 children (9 ≤ age ≤ 16 years), bilaterally extracted for orthodontic reasons, were included. For each child, one tooth was randomly allocated to the cryopreservation group and the contralateral tooth was assigned to the control group. Static compression tests were performed to determine load to failure, stiffness, and toughness. In a subgroup of 20 teeth, a cyclic preloading or chewing simulation was performed. Additionally, the fracture mode was determined, and the microstructure of the fractured surfaces was examined using a scanning electron microscope (SEM). Linear mixed model analyses could not detect a statistical difference in the mean load to failure (p = 0.549), mean toughness (p = 0.968), or mean stiffness (p = 0.150) between cryopreserved and non-cryopreserved teeth. No significant difference in load to failure after cyclic preloading was detected between groups (p = 0.734). SEM analysis revealed comparable fracture characteristics between groups. It is concluded that cryopreservation does not affect the mean load to failure, stiffness, or toughness of teeth, indicating that hidden damage in the dentin is not critical at tooth level.

A Single-Run HPLC-MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis.

The treatment of drug-resistant Mycobacterium tuberculosis relies on complex antibiotic therapy. Inadequate antibiotic exposure can lead to treatment failure, acquired drug resistance, and an increased risk of adverse events. Therapeutic drug monitoring (TDM) can be used to optimize the antibiotic exposure. Therefore, we aimed to develop a single-run multiplex assay using high-performance liquid chromatography-mass spectrometry (HPLC-MS) for TDM of patients with multidrug-resistant, pre-extensively drug-resistant and extensively drug-resistant tuberculosis. A target profile for sufficient performance, based on the intended clinical application, was established and the assay was developed accordingly. Antibiotics were analyzed on a zwitterionic hydrophilic interaction liquid chromatography column and a triple quadrupole mass spectrometer using stable isotope-labeled internal standards. The assay was sufficiently sensitive to monitor drug concentrations over five half-lives for rifampicin, rifabutin, levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, terizidone/cycloserine, ethambutol, delamanid, pyrazinamide, meropenem, prothionamide, and para-amino salicylic acid (PAS). Accuracy and precision were sufficient to support clinical decision making (≤±15% in clinical samples and ±20-25% in spiked samples, with 80% of future measured concentrations predicted to fall within ±40% of nominal concentrations). The method was applied in the TDM of two patients with complex drug-resistant tuberculosis. All relevant antibiotics from their regimens could be quantified and high-dose therapy was initiated, followed by microbiological conversion. In conclusion, we developed a multiplex assay that enables TDM of the relevant first- and second-line anti-tuberculosis medicines in a single run and was able to show its applicability in TDM of two drug-resistant tuberculosis patients.