Species-differences in the in vitro biotransformation of trifluoroethene (HFO-1123).

1,1,2-Trifluoroethene (HFO-1123) is anticipated for use as a refrigerant with low global warming potential. Inhalation studies on HFO-1123 in rats indicated a low potential for toxicity (NOAELs ≥ 20,000 ppm). In contrast, single inhalation exposure of Goettingen® minipigs (≥ 500 ppm) and New Zealand white rabbits (≥ 1250 ppm) resulted in severe toxicity. It has been suggested that these pronounced species-differences in toxicity may be attributable to species-differences in biotransformation of HFO-1123 via the mercapturic acid pathway. Therefore, the overall objective of this study was to evaluate species-differences in glutathione (GSH) dependent in vitro metabolism of HFO-1123 in susceptible versus less susceptible species and humans as a basis for human risk assessment. Biotransformation of HFO-1123 to S-(1,1,2-trifluoroethyl)-L-glutathione (1123-GSH) and subsequent cysteine S-conjugate ß-lyase-mediated cleavage of the corresponding cysteine conjugate (1123-CYS) was monitored in hepatic and renal subcellular fractions of mice, rats, minipigs, rabbits, and humans. While 1123-GSH formation occurred at higher rates in rat and rabbit liver S9 compared to minipig and human S9, increased ß-lyase cleavage of 1123-CYS was observed in minipig kidney cytosol as compared to cytosolic fractions of other species. Increased ß-lyase activity in minipig cytosol was accompanied by time-dependent formation of monofluoroacetic acid (MFA), a highly toxic compound that interferes with cellular energy production via inhibition of aconitase. Consistent with the significantly lower ß-lyase activity in human cytosols, the intensity of the MFA signal in human cytosols was only a fraction of the signal obtained in minipig subcellular fractions. Even though the inconsistencies between GSH and ß-lyase-dependent metabolism do not allow to draw a firm conclusion on the overall contribution of the mercapturic acid pathway to HFO-1123 biotransformation and toxicity in vivo, the ß-lyase data suggest that humans may be less susceptible to HFO-1123 toxicity compared to minipigs.

Diversity in Leadership at Musculoskeletal Oncology Fellowships in the United States.

Musculoskeletal oncology fellowship directors (MOFDs) possess the unique ability to influence treatment paradigms in musculoskeletal oncology through teaching and research. Currently, the characteristics that define this important role including demographics, training characteristics, research activity, and grant funding are poorly defined. A list of musculoskeletal oncology fellowship programs was obtained from the American Association of Hip and Knee Surgeons and Musculoskeletal Oncology Fellowship Match. Bibliometric data including the h-index were abstracted from Scopus. Demographics, training, and federal grant characteristics were collected from academic websites. Comparisons were made using t-tests and data were presented as means ± SD. The average age at the appointment was 41±9 years and most were male (80%) and Caucasian (85%). Few had an additional graduate degree (10% MS, 5% PhD). The mean h-index was 23±15 resulting from 91±56 publications. There was a positive correlation between age and h-index (r=0.398, p=0.082). Four MOFDs (20%) had at least one National Institutes of Health research grant. Sex, race, additional graduate degree, and procurement of NIH funding were not associated with higher h-index values. Full professors had higher h-index values than assistant/associate professors (p=0.014). Women and racial minorities are underrepresented among leadership positions in musculoskeletal oncology fellowship programs. This study can help provide a benchmark for departments in orthopedic surgery and aspiring orthopedic surgeons for MOFD positions.

Common High-Speed Running Thresholds Likely Do Not Correspond to High-Speed Running in Field Sports.

ABSTRACT: Freeman, BW, Talpey, SW, James, LP, Opar, DA, and Young, WB. Common high-speed running thresholds likely do not correspond to high-speed running in field sports. J Strength Cond Res 37(7): 1411-1418, 2023-The purpose of this study was to clarify what percentage of maximum speed is associated with various running gaits. Fifteen amateur field sport athletes (age = 23 ± 3.6 years) participated in a series of 55-meter running trials. The speed of each trial was determined by instructions relating to 5 previously identified gait patterns (jog, run, stride, near maximum sprint, and sprint). Each trial was filmed in slow motion (240 fps), whereas running speed was obtained using Global Positioning Systems. Contact time, stride angle, and midstance free-leg knee angle were determined from video footage. Running gaits corresponded with the following running speeds, jogging = 4.51 m·s -1 , 56%Vmax, running = 5.41 m·s -1 , 66%Vmax , striding = 6.37 m·s -1 , 78%Vmax, near maximum sprinting = 7.08 m·s -1 , 87%Vmax, and sprinting = 8.15 m·s -1 , 100%Vmax. Significant ( p < 0.05) increases in stride angle were observed as running speed increased. Significant ( p < 0.05) decreases were observed in contact time and midstance free-leg knee angle as running speed increased. These findings suggest currently used thresholds for high-speed running (HSR) and sprinting most likely correspond with jogging and striding, which likely underestimates the true HSR demands. Therefore, a higher relative speed could be used to describe HSR and sprinting more accurately in field sports.

Can low-grade chondrosarcoma in flat bones be treated with intralesional curettage and cryotherapy?

BACKGROUND AND OBJECTIVES: Chondrosarcomas in flat bones are thought to be more aggressive in their behavior, and little is known about intralesional treatment outcomes of low-grade chondrosarcoma in these locations. We tried to find the differences between patients who had low-grade chondrosarcoma in their flat bones versus those with long bone involvement with regard to (1) disease outcome, (2) functional outcome, and (3) treatment complications. METHODS: We retrospectively reviewed 44 patients with primary low-grade chondrosarcoma who were treated with intralesional curettage and cryotherapy. The patients were divided by location of tumor, group I (flat bones, seven patients) and group II (long bones, 37 patients). RESULTS: The local recurrence rate was higher in group I with 5 years disease-free survival of 80.0% in group I and 97.0% in group II (p = 0.001). All recurrent cases were noted to have initially presented with soft tissue extension (Enneking stage IB). The mean Musculoskeletal Tumor Society score at the last follow-up was 21.7 in group I and 27.9 in group II (p = 0.045). CONCLUSIONS: Intralesional curettage and cryotherapy for low-grade chondrosarcoma appear to be a safe and reasonable surgical option for patients with lesions confined to bone (Enneking stage IA). LEVEL OF EVIDENCE: Level III, retrospective cohort study. See the Guidelines for Authors for a complete description of levels of evidence.

Radiolucent Implants for Fixation of Impending and Pathologic Fractures.

Radiolucent implants offer theoretical advantages of increased ability to evaluate the fracture site for healing and recurrence and potentially less effect on radiation treatment, avoiding scatter. Their clinical utility and outcomes have yet to be proven in a well-designed randomized trial or large cohort study, although studies based on other indications have shown relative safety and they are approved by the US Food and Drug Administration for treatment of pathologic fractures. Further research is necessary to better understand when and how these implants should be implemented in practice. [Orthopedics. 2022;45(3):e115-e121.].

Fibro-Osseous Pseudotumor Arising From Nail Bed of the Great Toe: A Rare Case of Recurrence.

A fibro-osseous pseudotumor (FOPT) is a rare, rapidly enlarging, benign soft-tissue neoplasm that presents with localized pain, swelling, and redness. It typically presents in the hands and much less frequently in the feet. FOPT is characterized histologically by foci of osseous differentiation within the proliferated fibroblasts. This must be differentiated from other benign and malignant lesions. FOPT of the toes has been described in a few reports, but recurrence, following surgical excision, is extremely rare. Here we report a young, healthy female patient who presented with a rapidly growing FOPT of the left great toe. This unusual case had recurred twice following surgical excision, all within a 2-month period of time. The lesion was again completely excised, with no recurrences at follow-ups of 18 and 36 months. In conclusion, FOPT is a rare soft tissue lesion of the toes. It features fibroblastic proliferation and osseous differentiation, which needs to be differentiated from other benign and malignant tumors. The standard treatment is complete surgical excision with an excellent prognosis.

Kinetic and Structural Characterization of Sialidases (Kdnases) from Ascomycete Fungal Pathogens.

Sialidases catalyze the release of sialic acid from the terminus of glycan chains. We previously characterized the sialidase from the opportunistic fungal pathogen, Aspergillus fumigatus, and showed that it is a Kdnase. That is, this enzyme prefers 3-deoxy-d-glycero-d-galacto-non-2-ulosonates (Kdn glycosides) as the substrate compared to N-acetylneuraminides (Neu5Ac). Here, we report characterization and crystal structures of putative sialidases from two other ascomycete fungal pathogens, Aspergillus terreus (AtS) and Trichophyton rubrum (TrS). Unlike A. fumigatus Kdnase (AfS), hydrolysis with the Neu5Ac substrates was negligible for TrS and AtS; thus, TrS and AtS are selective Kdnases. The second-order rate constant for hydrolysis of aryl Kdn glycosides by AtS is similar to that by AfS but 30-fold higher by TrS. The structures of these glycoside hydrolase family 33 (GH33) enzymes in complex with a range of ligands for both AtS and TrS show subtle changes in ring conformation that mimic the Michaelis complex, transition state, and covalent intermediate formed during catalysis. In addition, they can aid identification of important residues for distinguishing between Kdn and Neu5Ac substrates. When A. fumigatus, A. terreus, and T. rubrum were grown in chemically defined media, Kdn was detected in mycelial extracts, but Neu5Ac was only observed in A. terreus or T. rubrum extracts. The C8 monosaccharide 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) was also identified in A. fumigatus and T. rubrum samples. A fluorescent Kdn probe was synthesized and revealed the localization of AfS in vesicles at the cell surface.

Sprinting and hamstring strain injury: Beliefs and practices of professional physical performance coaches in Australian football.

OBJECTIVES: The purpose of this study was to establish beliefs and practices of physical performance coaches regarding sprinting and Hamstring Strain Injury (HSI) in Australian Rules football. DESIGNS: Delphi-validated questionnaire. SETTING: Online. PARTICIPANTS: Eighteen high-performance managers of the Australian Football League. MAIN OUTCOME MEASURES: Descriptive statistics were collected to establish experience; central themes were established for the analyses of the beliefs and practices. RESULTS: Nine (50%) physical performance coaches responded to an invitation to complete the questionnaire. Participants held an undergraduate degree and had 9.2 ± 4.3 years of experience. Accelerations (n = 9), maximum speed sprints (n = 9) and running with hip flexion (n = 7) were the most common activities associated with HSI. Coaches believed sprinting, eccentric strength training and proper periodisation were effective strategies to reduce HSI risk. There's a disparity between beliefs and practices when using GPS to monitor sprinting, however, all coaches reported regular exposure to sprint training across both pre and in-season. Overstriding (n = 9) and pelvic instability (n = 6) were identified as key flaws in running mechanics. CONCLUSIONS: This information can be used to improve training strategies, whilst these findings indicate further investigations into sprint training and running mechanics for HSI risk reduction.

A Task Analysis of Client Re-engagement: Therapeutic De-escalation of High-Conflict Coparents.

Parents who are engaged in protracted conflict following a divorce are often referred to coparenting therapy. Episodes of intense conflict are common during these therapy sessions and often result in coparents disengaging from the therapist while they engage in escalating conflict with each other, potentially disrupting their progress in therapy. The purpose of this study was to identify how therapists successfully re-engage clients in the session. To understand this process, 24 disengagement events (12 successful and 12 unsuccessful) from 13 cases were analyzed using a task analytic approach. The sample included coparent dyads referred by the judicial system to a high-conflict coparenting therapy program. Task analysis was used to create a model of how re-engagement unfolds in treatment. The empirical model that resulted has five phases: (1) disengagement from the therapeutic process, (2) disruption of the conflict, (3) de-escalating the most escalated coparent, (4) de-escalating the other coparent, and (5) therapist buffered re-engagement. Successful episodes of re-engagement tended to have therapists who remained active throughout the conflict episode, used structuring interventions aimed at disrupting and then regulating the most escalated partner, blocked attempts to re-engage in conflict, and then repeated this process with the less escalated partner. Additional interventions that promote therapeutic re-engagement are described for each phase, and implications for clinicians and researchers are discussed.

Los padres que participan en un conflicto extendido después de un divorcio generalmente son derivados a terapia para la cocrianza de los hijos. Durante estas sesiones de terapia, son comunes los episodios de conflicto intenso entre los padres, quienes, como resultado, generalmente se distancian del terapeuta mientras participan en una escalada de conflictos entre sí que tiende a interrumpir su avance en la terapia. El propósito de este estudio fue identificar cómo los terapeutas reincorporan satisfactoriamente a los pacientes en la sesión. Para comprender este proceso, se analizaron 24 situaciones de distanciamiento (12 satisfactorias y 12 insatisfactorias) de 13 casos utilizando un método analítico de tareas. La muestra incluyó díadas de compañeros de crianza derivados por el sistema judicial a un programa de terapia para la cocrianza con un alto grado de conflicto. Se utilizó el análisis de tareas para crear un modelo de cómo se desarrolla la reincorporación en el tratamiento. El modelo empírico que resultó tiene cinco fases: 1) distanciamiento del proceso terapéutico, 2) interrupción del conflicto, 3) sosiego del compañero de crianza que más escaló, 4) sosiego del otro compañero de crianza, y 5) reincorporación reforzada por el terapeuta. Los episodios satisfactorios de reincorporación tendieron a tener terapeutas que permanecieron activos durante el episodio de conflicto, utilizaron intervenciones de estructuración orientadas a la interrupción y luego a la regulación al compañero de crianza que más escaló, bloquearon los intentos de reactivar el conflicto y luego repitieron este proceso con el compañero de crianza que menos escaló. Se describen otras intervenciones que promueven la reincorporación terapéutica en cada fase y las implicancias para los clínicos y los investigadores.

The effects of sprint training and the Nordic hamstring exercise on eccentric hamstring strength and sprint performance in adolescent athletes.

BACKGROUND: Hamstring strain injuries (HSI) are among the most common injuries in field-based team sports with a high-speed running component. The implementation of the Nordic hamstring exercise (NHE) is a well-documented method of improving eccentric hamstring strength to mitigate the risk of HSI occurrence. Sprint training is specific to the injury mechanism and is thought to activate the hamstrings through maximal eccentric contractions. The purpose of this study was to compare the effects of sprint training and the NHE on eccentric hamstring strength and sprint performance. METHODS: Twenty-eight participants (mean±SD age=16.21±1.34 years; height=1.75m±0.10m; body mass=68.5kg±12.1kg) completed an eccentric hamstring strength assessment and 40m sprint to assess acceleration and maximum speed. Participants were randomly allocated to either a NHE training or sprint training group. Two sessions per week for four-weeks of training was performed with baseline testing procedures repeated in the week following the intervention. Perceptions of soreness were recorded following the warm-up in each training session. RESULTS: Both the NHE (effect size=0.39, P<0.05) and sprint training (effect size=0.29, P<0.05) groups displayed significant gains in eccentric hamstring strength. The NHE group reported trivial improvements in sprint performance, whilst the sprint training group experienced a moderate improvement, specifically in maximum speed (ES=0.83 Moderate). Sprint training also produced greater perceptions of soreness than the NHE following a four-week training intervention, specifically before the start of the last session (P<0.05). CONCLUSIONS: These findings indicate that sprint training had a beneficial effect for both eccentric hamstring strength and sprint performance, whilst also producing greater soreness than the NHE following the final training session. It was concluded that a four-week block of maximum speed training may have both an injury prevention and performance enhancement benefit.

Association of sporadic and familial Barrett's esophagus with breast cancer.

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC). Based on striking aggregation of breast cancer and BE/EAC within families as well as shared risk factors and molecular mechanisms of carcinogenesis, we hypothesized that BE may be associated with breast cancer. Pedigree analysis of families identified prospectively at multiple academic centers as part of the Familial Barrett's Esophagus Consortium (FBEC) was reviewed and families with aggregation of BE/EAC and breast cancer are reported. Additionally, using a matched case-control study design, we compared newly diagnosed BE cases in Caucasian females with breast cancer (cases) to Caucasian females without breast cancer (controls) who had undergone upper endoscopy (EGD). Two familial pedigrees, meeting a stringent inclusion criterion, manifested familial aggregation of BE/EAC and breast cancer in an autosomal dominant inheritance pattern with incomplete penetrance. From January 2008 to October 2016, 2812 breast cancer patient charts were identified, of which 213 were Caucasian females who underwent EGD. Six of 213 (2.82%) patients with breast cancer had pathology-confirmed BE, compared to 1 of 241 (0.41%) controls (P-value < 0.05). Selected families with BE/EAC show segregation of breast cancer. A breast cancer diagnosis is marginally associated with BE. We postulate a common susceptibility between BE/EAC and breast cancer.

British School Chemistry Laboratories, 1830-1920.

The essay examines the British secondary school as a chemical site in the nineteenth century up until the 1920s. It sketches how chemistry became part of the secondary school curriculum in the mid-nineteenth century, discusses how school laboratories were designed, and examines to what extent school laboratories provided opportunities for original research by schoolmasters.

Stable expression of Shigella sonnei form I O-polysaccharide genes recombineered into the chromosome of live Salmonella oral vaccine vector Ty21a.

Live, attenuated Salmonella enterica serovar Typhi strain Ty21a, a licensed oral typhoid fever vaccine, has also been employed for use as a vector to deliver protective antigens of Shigella and other pathogens. Importantly, lipopolysaccharide (LPS) alone has been shown to be a potent antigen for specific protection against shigellosis. We reported previously the plasmid cloning of heterologous LPS biosynthetic genes and the expression in Ty21a of either S. sonnei or of S. dysenteriae 1 LPS's. The resulting plasmids encoding Shigella LPS's were reasonably stable for >50 generations of growth in nonselective media, but still contained an antibiotic resistance marker that is objectionable to vaccine regulatory authorities. Deletion of this antibiotic-resistance marker inexplicably resulted in significant plasmid instability. Thus, we sought a method to insert the large ∼12kb S. sonnei LPS gene region into the chromosome, that would allow for subsequent removal of a selectable marker and would result in 100% genetic stability. Toward this objective, we optimized an existing recombination method to mediate the insertion of a ∼12kb region encoding the S. sonnei LPS genes into the Ty21a genome in a region that is nonfunctional due to mutation. The resulting strain Ty21a-Ss simultaneously expresses both homologous Ty21a and heterologous S. sonnei O-antigens. This chromosomal insert was shown to be 100% genetically stable in vitro and in vivo. Moreover, Ty21a-Ss elicited strong dual anti-LPS serum immune responses and 100% protection in mice against a virulent S. sonnei challenge. This new vaccine candidate, absolutely stable for vaccine manufacture, should provide combined protection against enteric fevers due to Salmonella serovar Typhi as shown previously (and some Paratyphi infections) and against shigellosis due to S. sonnei.

Which point-of-care creatinine analyser for radiology: direct comparison of the i-Stat and StatStrip creatinine methods with different sample types.

BACKGROUND: Availability of whole blood creatinine estimation for patients scheduled to undergo radiological contrast investigations can provide information to aid patient care by reducing adverse effects and improving departmental efficiencies. METHODS: We performed imprecision studies, different patient sample type comparison in 40 participants, and a limited interference study with dopamine and dobutamine on the i-Stat and StatStrip point-of-care enzymatic analysers with the Beckman DxC800 Jaffe assay. RESULTS: Imprecision results showed that the i-Stat performed better. Patient comparison data indicated that the i-Stat provided better correlation than the StatStrip for all the different sample types with correlation coefficients (r(2)) being 0.995-0.996 and 0.918-0.995, respectively. The i-Stat results had a small positive bias of 6-9% for the three different sample types, which required different reference intervals. The StatStrip method showed greater scatter and overall small negative bias of -6% for the whole blood samples and a 10% positive bias with the plasma samples. Dopamine caused significant positive interference with the i-Stat only while dobutamine caused a small negative bias with the StatStrip method only. CONCLUSIONS: The findings indicated there are differences offered by the two systems. The StatStrip requires a very small finger prick capillary sample, calculates estimation of the glomerular filtration rate and has an adjustment option to improve correlation with the local method. The i-Stat offers better analytical imprecision and patient comparison with the laboratory method with the three sample types but showed significant interference from dopamine. A final consideration was the availability of middleware to capture patient results with the i-Stat. Based on all the study data, the i-Stat was recommended.

Lipaemic samples: effective process for lipid reduction using high speed centrifugation compared with ultracentrifugation.

INTRODUCTION: Reducing laboratory errors and improving patient safety is receiving a lot of attention. Lipaemic samples are cause of analytical errors and present challenges for laboratories, particularly for those without ultracentrifuges. Lipaemia can originate from physiological (postprandial metabolism), para-physiological causes (e.g. IV administration of lipids) as well as metabolic disturbances (e.g. hypertriglyceridaemia). MATERIALS AND METHODS: We have evaluated a procedure with 10 native lipaemic sample pools (triglyceride concentration range 11.6-42.7 mmol/L) for the ability to reduce lipid concentration using a high speed micro-centrifuge (double centrifuged at 21.885 x g for 15 min) compared with an ultracentrifuge, and provide accurate results. Results of sodium, creatinine, urate, total protein, lactate dehydrogenase (LD), magnesium and, cholesterol and triglyceride analysis on a Beckman DxC800 analyser are presented. RESULTS: Data from our tertiary level hospital showed approximately 0.7% of the samples received for lipid studies have triglyceride levels > 10 mmol/L which can potentially cause analytical interference. The mean differences from the neat aliquot to the ultracentrifuged and high speed centrifuged sample pools were: cholesterol 4.9 mmol/L and 3.1 mmol/L; and triglycerides 17.4 mmol/L and 15.0 mmol/L respectively. The data confirms high speed centrifugation is almost as effective as ultracentrifugation in lipid reduction. CONCLUSION: The procedure utilized in this study using a high speed micro-centrifuge showed it is effective in reducing lipid levels and provides a suitable alternative to ultracentrifuged samples to provide accurate results.

Early warnings of regime shifts: a whole-ecosystem experiment.

Catastrophic ecological regime shifts may be announced in advance by statistical early warning signals such as slowing return rates from perturbation and rising variance. The theoretical background for these indicators is rich, but real-world tests are rare, especially for whole ecosystems. We tested the hypothesis that these statistics would be early warning signals for an experimentally induced regime shift in an aquatic food web. We gradually added top predators to a lake over 3 years to destabilize its food web. An adjacent lake was monitored simultaneously as a reference ecosystem. Warning signals of a regime shift were evident in the manipulated lake during reorganization of the food web more than a year before the food web transition was complete, corroborating theory for leading indicators of ecological regime shifts.

Early warnings of unknown nonlinear shifts: a nonparametric approach.

Early warning signals (EWS) of regime shifts are challenging in cases where the true natural data-generating process is uncertain. Nonparametric drift-diffusion-jump models address this problem by fitting a general model that can approximate a wide range of data-generating processes. Drift measures the local rate of change. Diffusion measures relatively small shocks that occur at each time step. Jumps are large intermittent shocks. Total variance combines the contributions of diffusion and jumps. Nonparametric methods are well suited to emerging technology for automated, high-frequency sensors. Total variance is the most precisely measured indicator. Jump intensity appears to be a useful EWS. Estimates of the drift are highly uncertain unless long time series with many regime shifts are available. EWS computed from drift estimates (such as autocorrelation coefficients or return rates) have low precision and should be used with caution. Nonetheless, in the current state of knowledge, it is premature to disregard any potential EWS.

Exploring early modern chemistry: the first twenty-five years of the Society for the Study of Alchemy & Early Modern Chemistry 1935-1960.

The article uses the recently deposited archives of the Society for the History of Alchemy and Chemistry to explore the ideas, motives and disagreements of its founders and officers between 1935 and 1960. The origin of the title Ambix for the society's journal is also explained. An appendix identifies the initial membership of the society.

Leading indicators of trophic cascades.

Regime shifts are large, long-lasting changes in ecosystems. They are often hard to predict but may have leading indicators which are detectable in advance. Potential leading indicators include wider swings in dynamics of key ecosystem variables, slower return rates after perturbation and shift of variance towards lower frequencies. We evaluated these indicators using a food web model calibrated to long-term whole-lake experiments. We investigated whether impending regime shifts driven by gradual increase in exploitation of the top predator can create signals that cascade through food webs and be discerned in phytoplankton. Substantial changes in standard deviations, return rates and spectra occurred near the switch point, even two trophic levels removed from the regime shift in fishes. Signals of regime shift can be detected well in advance, if the driver of the regime shift changes much more slowly than the dynamics of key ecosystem variables which can be sampled frequently enough to measure the indicators. However, the regime shift may occur long after the driver has passed the critical point, because of very slow transient dynamics near the critical point. Thus, the ecosystem can be poised for regime shift by the time the signal is discernible. Field tests are needed to evaluate these indicators.