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1.Challenges, strategies and new technologies in the field of biotransformation were presented and discussed at the 5th European Biotransformation Workshop, which was held on March 14, 2024 on the Novartis Campus in Basel, Switzerland.2. In this meeting report we summarise the presentations and discussions from this workshop.3. The topics covered are listed below:Advances in understanding drug induced liver injury (DILI) risks of carboxylic acids and targeted covalent inhibitorsBiotransformation of oligonucleotide-based therapeutics including automated software tools for metabolite identificationRecent advances in metabolite synthesisQualification and validation of a new compact Low Energy Accelerator Mass Spectrometry (LEA) system for metabolite profiling Advances in understanding drug induced liver injury (DILI) risks of carboxylic acids and targeted covalent inhibitorsBiotransformation of oligonucleotide-based therapeutics including automated software tools for metabolite identificationRecent advances in metabolite synthesisQualification and validation of a new compact Low Energy Accelerator Mass Spectrometry (LEA) system for metabolite profiling [ABSTRACT FROM AUTHOR]

Introduction: Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disease. It results from mutations in the SMN1 (survival of motor neuron) gene, which leads to the degeneration of the motor neurons of the spinal cord. The SMN2 gene, an almost identical copy of the SMN1 gene, plays a crucial role in the prognosis and treatment guidance for patients with SMA. There is a well-established relationship between the number of copies of the SMN2 gene and the type of SMA. The SMN2 gene produces approximately 10% of the functional SMN protein, and more copies of the SMN2 gene are associated with milder forms of the disease. This is because additional SMN2 genes produce more functional protein, partially compensating for the SMN1 deficiency and thus modulating the severity of the disease. Objective: To determine the CNVs of the SMN2 gene in patients with SMA for classification of the type and eligibility for modifier therapies. Materials and Methods: The study involved the molecular-genetic analysis of a group of 53 patients diagnosed at the Human Molecular Genetics Laboratory of IMC, R. Moldova. DNA extracted from these patients was analyzed using the MLPA technique with the P021 kit, designed to detect deletions or duplications in the SMN1 and SMN2 genes. Statistical analysis of the data was performed using the Chi-square test. Results: Following the genetic analysis, all patients in the biobank were retested using the MLPA P021 kit (sensitivity and specificity >99%). For all patients, the deletion of SMN1 exon 7 was confirmed, and the distribution of SMN2 copy numbers across the entire cohort was: 1 copy = 10 patients, 2 copies = 25 patients, 3 copies = 16 patients, 4 copies = 2 patients. Therefore, the distribution of SMA types among the 53 affected patients was as follows: SMA Type 1 (SMN2 = 1): 18.9%, the most severe form; SMA Type 2 (SMN2 = 2): 47.2%, the most common form; SMA Type 3 (SMN2 = 3): 30.2%; SMA Type 4 (SMN2 = 4): 3.7%, the rarest form. The Chi-square test results for the association between the number of SMN2 copies and the distribution of SMA types showed a χ² value of 12.62 and a p-value of 0.005. Conclusions: The analysis identified SMN1 gene mutations and quantified the number of SMN2 gene copies in the patient group included in the study, thus confirming the presence of SMA and characterizing the patients from the Republic of Moldova by CNVs of SMN2 and SMA types. A significant association between the number of SMN2 copies and the type of SMA was demonstrated by the Chi-square test: χ² = 12.62, p = 0.005. The distribution of SMA types is not uniform, with most patients (77%) potentially benefiting from disease-modifying treatments, such as Nusinersen (Spinraza), given an early and detailed diagnosis. This highlights the necessity of implementing this type of therapy in the Republic of Moldova. [ABSTRACT FROM AUTHOR]

The present study deals with the Fe–Ti oxides, rock magnetic and anisotropy of magnetic susceptibility (AMS) carried out to determine the magneto-mineralogical characteristics and the nature of the magnetic fabrics of the high-grade metamorphic rocks from Chilka Lake area, Eastern Ghats Mobile Belt (EGMB), India. Petrography depicted the presence of both primary and secondary magnetite and titano-magnetite as the chief magnetic minerals. Different generations of magnetite were found in these rocks corresponding to different conditions of temperature that prevailed during their oxidation, having tectonic implications depicting the crustal upliftment. Thermomagnetic analysis, isothermal remanent magnetization (IRM), hysteresis loops and backfield IRM demagnetisation show the presence of ferrimagnetic minerals of different origin. The magnetic domain is determined by Day plot, using the remanence and coercivity values from hysteresis curves, dominated by stable single domain (SSD), which reveals the potentiality to record the ancient magnetic field. AMS studies unravelled the nature of the magnetic fabrics in the region. The magnetic susceptibility ellipsoids are dominantly oblate as revealed from the Pj–Tj shape plots. The magnetic lineation is highly variable which states the multiple phased tectono-metamorphic conditions. The similarity between the magnetic and mesoscopic fabrics in the granulite is significant, whereas the anorthosites result from felsic magmatism, which occurred after the deformational phases and thus did not record any mesoscopic tectonic significance. [ABSTRACT FROM AUTHOR]

In recent decades, interest in the measurement of 10Be has increased due to its relevance in various fields of science. Trace amounts of 10Be produced from meteoric sources require sensitive accelerator mass spectrometry (AMS) measurements and robust sample preparation. The extraction, separation, and preparation of the appropriate oxide form for AMS require extensive and careful laboratory processing and certified reference materials to validate the chemical performance of the protocols used and the calibration of the AMS system in the measurement. In this work, the meteoric 10Be concentrations in two certified reference materials are characterized to establish their suitability as internal control standards for laboratory chemical preparation and AMS measurements of this radioisotope in our laboratory and the whole AMS community. [ABSTRACT FROM AUTHOR]

The LEGEND collaboration has been developing a 76Ge-based double-beta decay experimental program where precise radiopurity measurements of ultraclean materials are crucial. Ultralow concentrations of thorium and uranium, the main contributors to the detector background via their decay products, can be determined by inductively coupled plasma mass spectrometry (ICPMS) and accelerator mass spectrometry (AMS). Here we shall present recent developments in thorium and uranium mass spectrometry methods, together with basics of separation chemistry applied to process different samples. The new possibilities to measure 232Th and 238U by ICPMS and AMS at the Comenius University in Bratislava are discussed as well. [ABSTRACT FROM AUTHOR]

Terrestrial and extraterrestrial radioisotope research has been strongly dependent on the development of analytical methods which would enable to trace radioisotopes at low concentrations in subgram samples (e.g., in tree rings, ice cores, meteorites, etc.). Accelerator mass spectrometry (AMS) has become the most sensitive technique for ultralow-level analysis of long-lived radioisotopes, such as 14C, 10Be and 26Al. We review developments and applications carried out in the CENTA laboratory, and describe a recently installed fully equipped AMS line, designed for analysis of long-lived radioisotopes from tritium to curium. [ABSTRACT FROM AUTHOR]

In compact accelerator mass spectrometry (AMS) systems，the detection of low-energy ions is often interfered by interfering ions with the same magnetic rigidity and electric rigidity as the target nuclide. To address this issue，a gas detector with range detection capability was developed for low-energy small-scale AMS. By exploiting the different ranges of the target nuclide and interfering ions，all interfering ions are absorbed in an absorber chamber while the target nuclide can pass through and enter an amplification chamber with proportional amplification functionality，thus facilitating the measurement of the target nuclide. To validate the performance of the gas detector，a series of calibration experiments were conducted using 5.8 MeV alpha particles. Experimental and simulation results demonstrate that the absorber chamber effectively absorbs interfering ions of different energies，and the energy resolution of amplification chamber is around 30% for the one-way signal. At the same time，when the reduced field strength in the amplification chamber is at 5 V·mm−1·hPa−1，the signal can be amplified by about 7 times. The energy resolution of the combined signals from the absorber and the amplification chamber is improved to around 20%，laying the foundation for the measurement of nuclides such as 26Al in low-energy small-scale AMS.

The origin of micrometeorites (MMs) from asteroids and comets is well-established, but the relative contribution from these two classes remains poorly resolved. Likewise, determining the precise origin of individual MMs is an open challenge. Here, cosmic-ray exposure ages are used to resolve the spatial origins of 12 MMs collected from urban areas and Antarctica. Their 26Al and 10Be concentration, produced during cosmic-ray irradiation in space, were measured by accelerator mass spectrometry. These data are compared to results from a model simulating the transport and irradiation of the MM precursors in space. This model, for the first time, considers a variety of orbits, precursor particle sizes, compositions and densities and incorporates non-isotropic solar and galactic cosmic-ray flux profiles, depth-dependent production rates, as well as spherical evaporation during atmospheric entry. While the origin for six MMs remains ambiguous, two MMs show a preferential tendency towards an origin in the Inner Solar System (Near Earth Objects to the Asteroid Belt) and four towards an origin in the Outer Solar System (Jupiter Family Comets to the Kuiper Belt). These findings challenge the notion that dust originating from the Outer Solar System is unlikely to survive long-term transport and delivery to the terrestrial planets. This article is part of the theme issue 'Dust in the Solar System and beyond'. [ABSTRACT FROM AUTHOR]

Community Pharmacists (CPs) are easily accessible and can advocate for the appropriate use of antibiotics in children. Semi-structured interviews were conducted with 47 CPs and 46 parents/caregivers. Both groups expressed challenges to intervening when antibiotics have already been prescribed and highlighted the need for more support for CPs to make informed decisions. [ABSTRACT FROM AUTHOR]

1. Challenges, strategies and new technologies in the field of biotransformation were presented and discussed at the fourth European Biotransformation Workshop which was held in collaboration with the joint ISSX/DMDG meeting on June 15, 2023 at the University of Hertfordshire in Hatfield, UK. 2. In this meeting report we summarise the presentations and discussions from this workshop. 3. The topics covered are listed below: Unusual biotransformation reactions Biotransformation Workflows in Discovery utilising various softwares for structure elucidation Biotransformation software for the identification of peptide metabolites Accelerator Mass Spectrometry (AMS) for endogenous and xenobiotic metabolite profiling Metabolite profiling using quantitative Nuclear magnetic resonance (NMR) and liquid chromatography coupled to inductively coupled plasma-mass spectrometry (LC-ICP-MS) [ABSTRACT FROM AUTHOR]

The possible co-variation of human occupation and vegetation from the Middle Neolithic to the beginning of the Iron Age (7.5–2.8 ka BP) in Central Sicily in the context of the central Mediterranean between Middle and Late Holocene are analysed in this paper to provide new insights on Sicilian prehistoric demography. The demographic and economic trends during these millennia were reconstructed using archaeological, Accelerator Mass Spectrometry 14C dates, palynological, archaeobotanical, and zooarchaeological data from the northern, central, and southern sectors of Central Sicily through a diachronic comparison with variation in Arboreal Pollen, Anthropogenic Pollen Indicators, Olea-Juglans-Castanea pollen, microcharcoals, and Sporormiella from four pollen cores from sites in different ecosystems. A very significant spread of farming activities was found at the end of the Neolithic, together with an apparent demographic gap during the Middle Copper Age, and the emergence of agricultural landscapes at the end of the Copper Age associated with a striking increase in population. A combination of cultural and climatic changes during the late phase of the Bronze Age resulted in a subsequent overall decrease in population. [ABSTRACT FROM AUTHOR]

Accelerator mass spectrometry radiocarbon (AMS 14C) dating was used for determining the age of wedge ice. It has been found that between 11,270 and 6420 cal BP, or the Greenlandian and Northgrippian stages of the Holocene, ice wedges grew syngenetically in sandy deposits with gravel in the Chara River valley. The variations of δ18O values in the ice wedges are about 8‰, from –25.5‰ to –18.8‰. Based on the stable isotope composition of ice wedges, paleotemperature reconstructions revealed that the mean January temperature was as low as –38°C during the coldest periods of the early half of the Holocene and as high as –28°C during the warmer periods. [ABSTRACT FROM AUTHOR]

The Eastern Chukotka is considered a unique permafrost region where massive ice bodies are widespread. However, the origin and age of these ice formations are often discussed. The age of the massive ice of Chukotka was established for the first time using AMS 14C dating. It was revealed that three massive ice bodies on the coast of Mechigmen Bay were formed at the end of the Late Pleistocene: a) near the Akkani site, 21,612 to 22,147 cal BP; b) near the Lavrentiya settlement, 27,553 cal BP; and c) near the Lavrentiya settlement, 22,193 cal BP. Stable isotope values in the studied massive ice vary in a rather wide range by about 10‰ for δ18O values (from –14.8‰ to –24.5‰) and about 75‰ for the δ2H values (from –116‰ to –191‰). The studied massive ice bodies are of intrasedimental genesis and formed epigenetically during the final stage of MIS2 (22–27 cal ka BP). [ABSTRACT FROM AUTHOR]

A vibração está em toda parte em nossa vida cotidiana. Nos dias atuais, com o avanço de métodos computacionais e da ciência dos materiais, estruturas civis estão cada vez mais flexíveis e esbeltas. Uma elevada flexibilidade estrutural leva a grandes amplitudes de vibração que podem ser transmitidas às pessoas nos edifícios, causando desconforto, perda de eficiência no trabalho devido ao cansaço e até graves alterações de saúde. Nesse contexto, uma abordagem numérico-computacional é apresentada para a análise modal e transiente de estruturas do tipo shear building utilizando o programa livre Scilab. O efeito do amortecimento na estrutura é descrito pelo modelo de amortecimento de Rayleigh. Um estudo com o sistema de controle passivo AMS instalado no topo da estrutura é apresentado. O AMS é um sistema massa – mola que serve para reduzir a amplitude de vibração do sistema estrutural principal. A abordagem numérica apresentada vem a auxiliar os estudantes de física e das engenharias no que concerne à análise de vibração de sistemas estruturais. A metodologia descrita para análise dinâmica é relativamente de fácil implementação computacional e os resultados numéricos tiveram boa precisão e ficaram de acordo com os resultados disponíveis na literatura.

Objective: To detect the prevalence and associated factors of hypogonadism (HG) among men, who were admitted to urology outpatient clinics for reasons other than sexual dysfunction. Materials and Methods: This is a multicentric study designed and conducted by the Turkish Society of Urological Surgery, Andrology Study Group. Male patients between 50 and 75 years of age who were admitted to the urology outpatient clinic for complaints other than sexual dysfunction and whose total testosterone value was measured were included in the study. The correlation between testosterone value and aging male symptoms (AMS) and the international index of erectile function (IIEF) were evaluated. Patient-related factors such as age and comorbidities were also compared between patients with low testosterone values and normal testosterone values. Results: A total of 1021 patients were included in the study. The mean patient age was 69.9±8.6. The most common complaint was non-neurogenic male lower urinary tract symptoms (52.3%). HG prevalence was 38.5% according to the threshold provided in the European Association of Urology guidelines (

Objective: To detect the prevalence and associated factors of hypogonadism (HG) among men, who were admitted to urology outpatient clinics for reasons other than sexual dysfunction. Materials and Methods: This is a multicentric study designed and conducted by the Turkish Society of Urological Surgery, Andrology Study Group. Male patients between 50 and 75 years of age who were admitted to the urology outpatient clinic for complaints other than sexual dysfunction and whose total testosterone value was measured were included in the study. The correlation between testosterone value and aging male symptoms (AMS) and the international index of erectile function (IIEF) were evaluated. Patient-related factors such as age and comorbidities were also compared between patients with low testosterone values and normal testosterone values. Results: A total of 1021 patients were included in the study. The mean patient age was 69.9±8.6. The most common complaint was non-neurogenic male lower urinary tract symptoms (52.3%). HG prevalence was 38.5% according to the threshold provided in the European Association of Urology guidelines (<12 nmol/L) There was no statistically significant correlation between HG and AMS or IIEF scores. In our study, the body mass index (BMI) was found to be the most strongly correlated factor with serum testosterone levels (r=-0.183, p<0.001) Subgroup analysis revealed the prevalence of HG as 44.9% in men with BMI ≥30 kg/m². Conclusion: Our results suggest that BMI may be a risk factor for HG, and obese patients may require routine assessment of HG, including serum testosterone measurement and application of symptom questionnaires. [ABSTRACT FROM AUTHOR]

Of Cenozoic age, the Fossong-Wentcheng trachytic dome is located on the southwestern slope of Mount Bambouto. It was probably emplaced during the second period of activity (between 18.5 and 15.3 Ma) of the Mount Bambouto, within the Pan-African granitic basement rock. The dome shows aphyric and porphyritic textures with crystals such as sanidine, clinopyroxene, and oxides. These oxides may be magnetite due to the dominant ferromagnetic behavior of the rock. The dominance of planar AMS ellipsoids and low Pj values reflect the high viscosity of the magma that sets up the Fossong-Wentcheng trachytic dome. The magnetic fabric (foliation and lineation) displays roughly sub-circular trends in the central and the northern parts of the dome with the feeder zone located on its southern part where they display fabrics in the NE-SW direction with steep dips and plunges. This implies that the magma rose through a NE-SW–directed fracture in the basement granitic rock before its propagation towards the NNW-SSE direction by developing one lobe flow emplacement. [ABSTRACT FROM AUTHOR]

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Introduction and purpose: Acute mountain sickness is caused by hypoxia, of which the brain is the most sensitive. The frequency of occurrence at altitudes above 2500 m above sea level may reach up to 75% of travelers. Prevention of altitude sickness mainly concerns the travel plan and pharmacology. Our study aimed to assess the current literature on altitude sickness, and discuss the possible pathophysiology, epidemiology, and symptoms. Moreover, we underline new guidelines for the treatment, prevention, and diagnosis of altitude sickness in the context of the last guidelines and research. We conducted a PubMed literature review using keywords like "mountaineering sickness" and "altitude sickness". All article types were taken into account: clinical trial, meta-analysis, case report, case series, systematic review, randomized controlled trial, observational study, clinical study, books, and documents in the last 5 years. A brief description of the state of knowledge: In recent years, there has been a surge in the accessibility and popularity of high-altitude tourism, emphasizing the need to disseminate information about altitude sickness among travelers. This heightened accessibility has sparked a push for comprehensive research and viable solutions, aiming to address the ramifications of the increased risk associated with such endeavors. Furthermore, there's a growing call for additional research focusing on the unique medical demands posed by tourist excursions and extreme expeditions. Conclusions: It underscores the necessity for healthcare professionals equipped with specialized knowledge and expertise in both preventing and treating medical conditions arising in exceptional circumstances. [ABSTRACT FROM AUTHOR]

A rapidly emerging area of interest in high-pressure environments is that of pupillometry, where handheld quantitative infrared pupillometers (HQIPs) are able to track psycho-physiological fatigue in a fast, objective, valid, reliable, and non-invasive manner. However, the application of HQIPs in the context of athlete monitoring is yet to be determined. Therefore, the main aim of this pilot study was to examine the potential usefulness of a HQIP to monitor game-induced fatigue inside a professional female basketball setting by determining its (1) test-retest repeatability, (2) relationship with other biomarkers of game-induced fatigue, and (3) time-course from rested to fatigued states. A non-ophthalmologic practitioner performed a standardized Pupil Light Reflex (PLR) test using a medically graded HQIP among 9 professional female basketball players (2020-2021 Euro Cup) at baseline, 24-h pre-game (GD-1), 24-h post-game (GD+1) and 48-h post-game (GD+2). This was repeated over four subsequent games, equalling a total of 351 observations per eye. Two out of seven pupillometrics displayed good ICCs (0.95-0.99) (MinD and MaxD). Strong significant relationships were found between MaxD, MinD, and all registered biomarkers of game-induced fatigue (r = 0.69-0.82, p < 0.05), as well as between CV, MCV, and cognitive, lower-extremity muscle, and physiological fatigue markers (r = 0.74-0.76, p < 0.05). Three pupillometrics were able to detect a significant difference between rested and fatigued states. In particular, PC (right) (F = 5.173, η² = 0.115 p = 0.028) and MCV (right) (F = 3.976, η² = 0.090 p = 0.049) significantly decreased from baseline to GD+2, and LAT (left) (F = 4.023, η² = 0.109 p = 0.009) significantly increased from GD-1 to GD+2. HQIPs have opened a new window of opportunity for monitoring game-induced fatigue in professional female basketball players. However, future research initiatives across larger and heterogenous samples, and longer investigation periods, are required to expand upon these preliminary findings. [ABSTRACT FROM AUTHOR]

La zona de estudio, en las inmediaciones de La Seu d’Urgell (Zona Axial pirenaica), está constituida por una serie estratigráfica de rocas Cambro-Ordovícicas, en su mayoría detríticas, donde la discordancia Sarda se identifica claramente entre la Serie de Jujols y la Fm. Conglomerados de la Rabassa. Las principales estructuras son pliegues N-S de plano axial subhorizontal que muestran una foliación asociada, bien desarrollada en los niveles pelíticos (y claramente visibles en lámina delgada) y pobremente desarrollada en los niveles de arenisca. En los conglomerados suprayacentes a la discordancia Sarda (Fm. Conglomerados de la Rabassa) la foliación regional se caracteriza por tener sobreimpuestas bandas de cizalla conjugadas que rodean los clastos. Las fábricas magnéticas (principalmente paramagnéticas) son coherentes con las microestructuras observadas a pesar de que la correspondencia entre los ejes de las fábricas magnéticas y los ejes de las estructuras observadas en el campo no es sencilla. El máximo de las direcciones de lineación es bimodal (N-S y E-W), lo cual puede ser interpretado como el resultado de una interferencia de pliegues (tipo 2 de Ramsay).

ABSTRACT: Cow-calf contact (CCC) systems, although beneficial in many respects, introduce additional challenges to collect reliable data on milk production, which is important to assess individual cow efficiency and dairy farm profitability. Apart from weighing calves before and after each feeding, the amount of saleable milk lost due to calf suckling is practically impossible to measure. Here, we assess 2 indirect methods for estimating loss of saleable milk when housing cows and calves together in a robotic milking unit. In our study, treatment (CCC) cows and calves were kept together full time until the calves were 127 ± 6.6 d old (mean ± SD). Control cows were separated from their calves within 12 h of birth and then kept in the same unit as the treatment cows but with no access to either their own or treatment calves. Milk yield recording of both groups was performed from calving until pasture release at 233 ± 20 d in milk. The first estimation method relied on observed postseparation milk yield data, which were fed into a modified Wilmink regression model to determine the best-fitting lactation curve for the preseparation period. The second method was based on the cows' daily energy intake postseparation, calculated by measuring the daily feed intake and analyzing the energy content of the ration. The calculated energy intake was used to determine the average ratio between energy intake and the observed milk yield the following day for each individual cow, assuming constant rates of mobilization and deposition of body fat. The obtained ratio was then used to calculate the expected daily milk yield based on daily energy intake data during the preseparation period. In this paper, we analyzed data from 17 CCC cows kept together with their calves and 16 control cows; both groups calved from September to October 2020 and were followed up until release to pasture in May 2021. Saleable milk yield was lower in CCC cows than in control cows, both before and after separation. The 2 methods were used on data for control cows and showed milk yield loss using the lactation curve method (average of −3.4 ± 2.8 kg/d) and almost no loss using energy intake data (average of −1.4 ± 2.7 kg/d). Milk yield loss for CCC cows was estimated at average 11.3 ± 4.8 and 7.3 ± 6.6 kg milk/d, respectively. The proposed lactation curve estimation method tends to overestimate milk yield loss, whereas the method based on energy intake is more accurate. However, collecting detailed energy intake data per individual cow requires additional effort and equipment, which is not always feasible on commercial farms. Further research is needed to improve milk loss estimation and to better understand trade-offs in CCC systems.

Background: Since 2018, the Ethiopian Ministry of Health (MOH) has been working to institutionalize antimicrobial stewardship (AMS) programs across the country. The US Agency for International Development Medicines, Technologies, and Pharmaceutical Services Program supported Ethiopia’s multipronged One Health approach to combat AMR. The objective of this paper was to evaluate the effect of a quality improvement intervention to optimize the use of antimicrobials for surgical prophylaxis. Methods: Basic AMS interventions were introduced in five hospitals from January to May 2023. The AMS committees and multidisciplinary teams working at the surgical wards were trained and provided on-site support to implement surgical antibiotic prophylaxis (SAP) interventions. A before-after comparison was made for 206 medical records at baseline and 213 during the intervention phase. Qualitative data were gathered through discussions during experience-sharing workshops to supplement the quantitative results. Result: There were improvements in the presurgery dose of the prophylactic antibiotic and its timing: the doses within the recommended range increased from 11.2 % to 61.0 % (p

Radiocarbon dating by AMS accelerated ion mass spectrometry method, used from 2012 at IFIN-HH-Măgurele, offered recently the scientific frame for an interdisciplinary approach, from archaeologic and archaeometric perspectives, applied to wood samples. The first AMS results, issued in 2021 on six samples from Măguricea Branului archaeological site, have suggested a chronology around the 13th century AD, the differences being explained on terms detailed in this paper. The latter four samples, collected in the next archaeological campaign, gave very different dates. The difficulties experienced with these four samples driven us to develop new lab treatment, aiming carbonization of wood. Even so, the samples from 2022 could not be dated in a helpful manner, with parameters as terminus post quem, time-width, apparent ages. The paper could be of interest to archaeologists taking wood samples for AMS dating.

Background: Acute febrile encephalopathy (AFE) is a clinical term used to an altered mental state that either accompanies or follows a short febrile illness and is characterized by a diffuse and nonspecific brain insult manifested by a combination of coma, seizures, and decerebration. Materials and Methods: A prospective observational study was done in patients aged 13 years or above who were admitted with AFE at a Tertiary Care Center in Government General Hospital, Dept of General Medicine, Kurnool Medical College, Kurnool, Andhra Pradesh. The non-infectious causes of unconsciousness were excluded and then only a diagnosis of AFE was considered. Cerebrospinal fluid (CSF) analysis and imaging of brain was done to determine the possible etiology. Outcome was assessed at 1 month of follow up after discharge by using modified Rankin Scale (MRS). Data were analyzed and presented as mean, median, and percentages. Results: Among the 50 patients 33 (66%) are male patients.43 patients (86%) were young adults .The common presenting symptoms are fever in 41 patients (82%), headache in 29 patients (58%), altered sensorium in 19 patients(38%). Out of 50 patients studied acute febrile encephalopathy was common in males when compared to female, more common in age group 30-40 yearsAcute viral encephalitis was the most common cause accounting for 36 percentage in which Herpes Simplex Encephalitis 24 percentage Japanese encephalitis 4 percentage and other undetermined viral etiology count for 10 percentage followed by pyogenic meningitis 28 percentage followed by tuberculous meningitis 12 percentage, cerebral malaria diagnosed 2 percentage sepsis associated encephalopathy 10 percentage in which 6 percentage leptospirosis and 4 percentage scrub typhus were diagnosised. Of all the total cases 2 patient died in whichone patient with HIV associated Cryptococcus meningitis other patient with pyogenic meningitis. MRS at discharge were five in pyogenic meningitis three in viral meningitis after one month, MRS was 2 in pyogenic meningitis and the rest it was less than one Conclusions: In the present study we found that, most of the patients with meningoencephalitis were males and young adults in this study viral meningo encephalitis was the leading casue of acute febrile encephalopathy followed by pyogenic meningitis and tuberculous meningitis The outcome in cases with pyogenic meningitis can be fatal or more disabling than other aetiology. [ABSTRACT FROM AUTHOR]

Since 2018, the Ethiopian Ministry of Health (MOH) has been working to institutionalize antimicrobial stewardship (AMS) programs across the country. The US Agency for International Development Medicines, Technologies, and Pharmaceutical Services Program supported Ethiopia's multipronged One Health approach to combat AMR. The objective of this paper was to evaluate the effect of a quality improvement intervention to optimize the use of antimicrobials for surgical prophylaxis. Basic AMS interventions were introduced in five hospitals from January to May 2023. The AMS committees and multidisciplinary teams working at the surgical wards were trained and provided on-site support to implement surgical antibiotic prophylaxis (SAP) interventions. A before-after comparison was made for 206 medical records at baseline and 213 during the intervention phase. Qualitative data were gathered through discussions during experience-sharing workshops to supplement the quantitative results. There were improvements in the presurgery dose of the prophylactic antibiotic and its timing: the doses within the recommended range increased from 11.2 % to 61.0 % (p < 0.001) and the optimal timing increased from 68 % to 82.6 % (p < 0.001). The hospitals also demonstrated some nonsignificant improvement in the duration of prophylactic antibiotic use (from 35 % to 44.6 % [ p = 0.106]), with change in practice hampered by practitioners' resistance to early discontinuation for fear of infection due to perceived weaknesses in infection prevention and control practices. Nonavailability of the recommended antibiotic of choice for surgical prophylaxis was another major challenge in addressing all the elements of SAP. The intervention demonstrated a significant antibiotic-related average cost saving, 51.8 Ethiopian birr (∼1 US dollar) per patient (p = 0.028). Short-term investments with basic AMS interventions can help to improve SAP use in surgical wards. However, comprehensive success requires complementing AMS interventions with concurrent attention to proper supply chain and infection prevention and control. [ABSTRACT FROM AUTHOR]

Cow-calf contact (CCC) systems, although beneficial in many respects, introduce additional challenges to collect reliable data on milk production, which is important to assess individual cow efficiency and dairy farm profitability. Apart from weighing calves before and after each feeding, the amount of saleable milk lost due to calf suckling is practically impossible to measure. Here, we assess 2 indirect methods for estimating loss of saleable milk when housing cows and calves together in a robotic milking unit. In our study, treatment (CCC) cows and calves were kept together full time until the calves were 127 ± 6.6 d old (mean ± SD). Control cows were separated from their calves within 12 h of birth and then kept in the same unit as the treatment cows but with no access to either their own or treatment calves. Milk yield recording of both groups was performed from calving until pasture release at 233 ± 20 d in milk. The first estimation method relied on observed postseparation milk yield data, which were fed into a modified Wilmink regression model to determine the best-fitting lactation curve for the preseparation period. The second method was based on the cows' daily energy intake postseparation, calculated by measuring the daily feed intake and analyzing the energy content of the ration. The calculated energy intake was used to determine the average ratio between energy intake and the observed milk yield the following day for each individual cow, assuming constant rates of mobilization and deposition of body fat. The obtained ratio was then used to calculate the expected daily milk yield based on daily energy intake data during the preseparation period. In this paper, we analyzed data from 17 CCC cows kept together with their calves and 16 control cows; both groups calved from September to October 2020 and were followed up until release to pasture in May 2021. Saleable milk yield was lower in CCC cows than in control cows, both before and after separation. The 2 methods were used on data for control cows and showed milk yield loss using the lactation curve method (average of −3.4 ± 2.8 kg/d) and almost no loss using energy intake data (average of −1.4 ± 2.7 kg/d). Milk yield loss for CCC cows was estimated at average 11.3 ± 4.8 and 7.3 ± 6.6 kg milk/d, respectively. The proposed lactation curve estimation method tends to overestimate milk yield loss, whereas the method based on energy intake is more accurate. However, collecting detailed energy intake data per individual cow requires additional effort and equipment, which is not always feasible on commercial farms. Further research is needed to improve milk loss estimation and to better understand trade-offs in CCC systems. [Display omitted] [ABSTRACT FROM AUTHOR]

Derstine, Mia, Dominique Jean, Beth A. Beidleman, Jacqueline Pichler Hefti, David Hillebrandt, Lenka Horakova, Susi Kriemler, Kasté Mateikaité–Pipiriené, Peter Paal, Alison Rosier, Marija Andjelkovic, and Linda E. Keyes. Acute mountain sickness and high altitude cerebral edema in women: A scoping review—UIAA Medical Commission recommendations. High Alt Med Biol. 24:259–267, 2023. Background: Acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) are illnesses associated with rapid ascent to altitudes over 2,500 m in unacclimatized lowlanders. The aim of this scoping review is to summarize the current knowledge on sex differences in the epidemiology, pathophysiology, symptomatology, and treatment of AMS and HACE, especially in women. Methods and Results: The UIAA Medical Commission convened an international author team to review women's health issues at high altitude and to publish updated recommendations. Pertinent literature from PubMed and Cochrane was identified by keyword search combinations (including AMS, HACE, and high altitude), with additional publications found by hand search. The primary search focus was for articles assessing lowland women sojourning at high altitude. Results: The literature search yielded 7,165 articles, 37 of which were ultimately included. The majority of publications included did not find women at increased risk for AMS or HACE. There was extremely limited sex-specific data on risk factors or treatment. Conclusions: There is a limited amount of data on female-specific findings regarding AMS and HACE, with most publications addressing only prevalence or incidence with regard to sex. As such, general prevention and treatment strategies for AMS and HACE should be used regardless of sex. [ABSTRACT FROM AUTHOR]

In this investigation the behaviour of a linear structure of one degree of freedom is analysed, which is controlled by a tuned combined damper (ACS). This consists of two devices, a tuned mass damper (AMS) and a tuned liquid column damper (ACLS). The ACS is subjected to a stochastic seismic excitation in order to analyse the influence of the frequency content on the efficiency of the device. As a measure of efficiency, the percentage of reduction of the displacement standard deviation of the main system is considered. The optimized parameters of each device are the frequency and damping in the case of the AMS, as well as the frequency and pressure drop coefficient for the ACLS. A sensitivity analysis of the optimal parameters of the ACS is carried out, with respect to the mass ratio, period of the main structure and frequency content of the excitation. The main conclusions obtained are that the efficiency of the ACS DHW depends on the frequency content of the excitation. Furthermore, it increases as the mass ratio increases, independent of the frequency content of the excitation. On the other hand, ACS is less efficient for more flexible structures. [ABSTRACT FROM AUTHOR]

The purpose of this study is to assess the magnetic fabrics and anisotropy of magnetic susceptibility (AMS) of the Yoli anorogenic microgranite to infer its emplacement mechanism. The Yoli massif is one of the numerous Cenozoic plutons of the Cameroon Magmatic Line cutting across the Central African Pan-African Fold Belt. The pluton, emplaced as result of the reactivation of the N–S oriented Pan-African Mayo Nolti major shear zone, is made of fine-grained and porphyritic microgranite showing evidence of magmatic and submagmatic state deformations. It mostly shows ferromagnetic behavior marked by the presence of the pure magnetite crystals as susceptibility carrier. The pluton internal geometry inferred from magnetic fabrics allows to distinguish two main domains: domain I shows steep plunges and dips magnetic fabrics suggesting fan-like vertical ascent of the magma whereas magnetic fabrics in domain II indicate multidirectional moderate to low plunging lineation suggesting horizontal magma flow following steep dipping planes. These structural features suggest that the magma ascended in domain I through the reactivated N–S fault and flowed toward the south and east. Low Pj values (≤1.20) is inferred to magmatic flow, whereas the AMS oblate shapes suggest internal high stress flowing condition during emplacement, probably due to forceful emplacement through ballooning. [ABSTRACT FROM AUTHOR]

Mafic dykes are typically emplaced through primary hydraulic fracturing of undeformed crust or may make use of pre-existing crustal inhomogeneities, representing the plumbing systems of a large igneous province. The Eastern Dharwar Craton has dense exposures of several generations of Paleoproterozoic mafic dyke swarms ranging from ca. 2.37 Ga to ca. 1.79 Ga. Herein, using anisotropy of magnetic susceptibility fabric data of mafic dykes and associated host granites, the emplacement systematics of the NW- to W-trending ca. 2.21 Ga Anantapur–Kunigal dyke swarm, displaying a radiating geometry, have been studied to understand magma flow dynamics. A low-angle relationship between the silicate and opaque fabrics and good correlation with magnetic lineation, identified via petrographic studies and shape preferred orientation analyses of multiple oriented thin sections, suggest a primary flow-related magnetic anisotropy for the studied dyke samples. The classic subparallel relationship between the trend of the dyke planes and magnetic fabric of the associated host granites suggests that the radiating geometry of the ca. 2.21 Ga dyke swarm was supported by a favourable pre-existing structural grain of the country rock. We interpret the magma for the studied dyke swarm was fed laterally from a distant plume. It was emplaced as laterally propagating primary dyke fractures as well as injected into the pre-existing subparallel crustal inhomogeneities. Corroborating all these inferences, a detailed emplacement model for ca. 2.21 Ga Anantapur–Kunigal dyke swarm is also proposed. [ABSTRACT FROM AUTHOR]

Introduction The acute mountain sickness (AMS) prevalence increases with altitude; i.e.,10-25% at 2,500 m and 50-85% at ~5,000 m (Bärtsch & Swenson, 2013). Women are more likely affected by AMS than men (Richalet et al., 2012). AMS can affect exercise performance. However, the effects of the menstrual cycle (MC) on physiological responses to exercise and on tolerance to high-altitude (HA) remain underexplored. It has been reported that ovarian hormones stimulate ventilation in normoxic conditions (Saaresranta & Polo, 2002). Early findings suggest that running economy is lower in the mid-luteal (ML) compared to the early-follicular (EF) phase in normoxia (Goldsmith & Glaister, 2020). However, cycling efficiency at HA has not been explored yet. Thus, we investigated the effects of acute HA exposure on ventilatory responses at rest and during exercise in healthy females during two different phases of their MC. Methods Sixteen eumenorrheic women (age: 33 ± 7 yr; MC length: 27 ± 2 days; not taking any hormonal contraceptive) took part in this study. First, over a 6-month period, the participants’ MC were monitored using a calendar method. Then, they reached the Torino Hut (3,375 m) by cable car and spent one night at HA on two different MC phases; i.e., during the early-follicular (EF; MC day 4 ± 1) and the mid-luteal (ML; day 20 ± 2) phases. Each time, they underwent a submaximal (1.2 W/kg) test on a cycle ergometer ~17 h after arrival at HA. In addition to this, participants filled in two questionnaires, the Lake Louise AMS Score and the Groningen Sleep Quality Scale, ~16 h after arrival at HA. Results Resting ventilation was significantly higher during EF compared to ML (15.2 ± 1.9 vs. 13.2 ± 2.5 L/min, p = 0.039), while no differences were found for ventilation during exercise (53.9 ± 13.2 vs. 53.5 ± 13.4 L/min, p = 0.695), cycling efficiency (21.7 ± 0.0% vs. 19.8 ± 0.0%, p = 0.244), saturation at rest (92.4 ± 1.3 vs. 91.3 ± 3.2%, p = 0.142) and during exercise (87.2 ± 5.7 vs. 89.0 ± 4.0%, p = 0.528). Moreover, no differences in the Lake Louise AMS (2.2 ± 1.5 vs. 1.7 ± 1.5, p = 0.266) or Groningen (8.0 ± 3.3 vs. 7.5 ± 3.4, p = 0.668) scores were noted between the two MC phases. Discussion/Conclusion Despite a slightly higher resting ventilation during EF, when both oestrogens and progesterone are at their lowest levels, there were no differences in ventilatory responses to exercise and in AMS between the different phases of the MC. Consequently, there is currently very little evidence to aptly recommend a specific MC phase for mountaineering or any other HA activities (Burtscher et al., 2023). Further investigations are requested to assess whether other physiological responses to HA may be influenced by hormonal variations. References Bärtsch, P., & Swenson, E. R. (2013). Acute high-altitude illnesses. New England Journal of Medicine, 368, 2294–2302. https://doi.org/10.1056/NEJMcp1214870 Burtscher, J., Raberin, A., Brocherie, F., Malatesta, D., Manferdelli, G., Citherlet, T., Krumm, B., Bourdillon, N., Antero, J., Rasica, L., Burtscher, M. & Millet, G. P. (2023). Recommendations for women in mountain sports and hypoxia training/conditioning. Sports Medicine. Advance online publication. https://doi.org/10.1007/s40279-023-01970-6 Goldsmith, E., & Glaister, M. (2020). The effect of the menstrual cycle on running economy. The Journal of Sports Medicine and Physical Fitness, 60(4), 610–617. https://doi.org/10.23736/s0022-4707.20.10229-9 Richalet, J.-P., Larmignat, P., Poitrine, E., Letournel, M., & Canouï-Poitrine, F. (2012). Physiological risk factors for severe high-altitude illness: A prospective cohort study. American Journal of Respiratory and Critical Care Medecine, 185(2), 192–198. https://doi.org/10.1164/rccm.201108-1396OC Saaresranta, T., & Polo, O. (2002). Hormones and breathing. American College of Chest Physicians, 122(6), 2165–2182. https://doi.org/10.1378/chest.122.6.2165

Introduction and purpose: Acute mountain sickness is caused by hypoxia, of which the brain is the most sensitive. The frequency of occurrence at altitudes above 2500 m above sea level may reach up to 75% of travelers. Prevention of altitude sickness mainly concerns the travel plan and pharmacology. Our study aimed to assess the current literature on altitude sickness, and discuss the possible pathophysiology, epidemiology, and symptoms. Moreover, we underline new guidelines for the treatment, prevention, and diagnosis of altitude sickness in the context of the last guidelines and research. We conducted a PubMed literature review using keywords like "mountaineering sickness" and "altitude sickness". All article types were taken into account: clinical trial, meta-analysis, case report, case series, systematic review, randomized controlled trial, observational study, clinical study, books, and documents in the last 5 years.A brief description of the state of knowledge: In recent years, there has been a surge in the accessibility and popularity of high-altitude tourism, emphasizing the need to disseminate information about altitude sickness among travelers. This heightened accessibility has sparked a push for comprehensive research and viable solutions, aiming to address the ramifications of the increased risk associated with such endeavors. Furthermore, there's a growing call for additional research focusing on the unique medical demands posed by tourist excursions and extreme expeditions. Conclusions:It underscores the necessity for healthcare professionals equipped with specialized knowledge and expertise in both preventing and treating medical conditions arising in exceptional circumstances.

Objective. To evaluate the results of the implementation of antimicrobial stewardship (AMS) program in a multidisciplinary hospital. Materials and Methods. A retrospective intervention study was performed in the 600-bed multidisciplinary hospital of the Pirogov National Medical and Surgical Center (Moscow, Russia). The study included a number of sequential interventions, aimed at improving the prevention, diagnosis and treatment of infections, with an assessment of the following indicators dynamics: the structure of microorganisms isolated in the hospital, the level of resistance to antimicrobial drugs (AMD) among the pathogens of the ESKAPE group, the structure of prescribed AMD, as well as an assessment of clinical and economic consequences of antimicrobial resistance changes. For a comprehensive assessment of trend in antibiotic resistance and its connection with consumption of antibiotics, the drug resistance index (DRI) was used. DRI is based on the ratio of the level of resistance of the microorganism and the frequency of administration of AMD, potentially effective against this pathogen. The intervention started in 2013, so the data of 2012 (pre-intervention period) and 2022 were compared in this study. Results. The implementation of AMS program measures helped to reduce the relative frequency of ESKAPE group microorganisms in the structure of nosocomial infection pathogens in the hospital from 36.5% to 22% (p < 0.0001). The proportion of gram-negative (Gr-) isolates resistant to meropenem decreased from 32.4% to 10.9% (p < 0.0001). As a result of the introduction of AMS program, DDDh has been reduced almost three times: from 48.1 to 17.2 DDDh. The median duration of the AMT course in a specialized intensive care unit for the treatment of patients with nosocomial infections decreased from 12 to 8 days (p < 0.0001), the number of AMT days per 1 patient decreased from 7.7 to 4.2 (p < 0.0001). The proportion of ESKAPE pathogens in the structure of bloodstream infections in the hospital decreased from 53.1% to 26% (p < 0.0001), which led to decrease in mortality from 28.4% to 12.8%, (p = 0.012) and length of hospital stay from 31 to 22 days (p < 0.001) in this group of patients. Conclusions. The implementation of AMS program in a multidisciplinary hospital helps to reduce the frequency of inappropriate use of antimicrobial drugs and reduces the consumption of antibiotics, decrease the level of antimicrobial resistance, and in such way improves the results of treatment of patients with nosocomial infections.

The paper presents for the first time the materials of 4 burials from the Sintashta culture necropolis in the Orenburg Cis-Urals, where the Seima-Turbino inventory was found. The studied burials of the burial ground nearby Beryozovaya Gora were carried out according to the Seima-Turbino rite. Two of them are characterized by merging of cultural traditions. Appearance of bearers of the Seima-Turbino trasncultural phenomenon in the Orenburg Cis-Urals can be confidently associated with the migration impulse from the Western Siberia. This is evidenced by archaeological, anthropological data and the results of the analysis of light isotopes (δ¹³C and δ¹⁵N). Representatives of the Sintashta culture and bearers of the Seima-Turbino phenomenon were buried on the same burial site with the burial rite characteristics of both groups, so in this case we can talk about their peaceful coexistence. It is possible that the bearers of the Seima-Turbino phenomenon have incorporated into the Sintashta community and have kept their social status. The period of intercultural contacts, according to the radiocarbon dating of the materials from the site under discussion, falls on the XX–XVIII centuries BC. The paper also introduces for the scientific use the unpublished AMS dates of the Sintashta complexes from the Orenburg Cis-Urals.

A rapidly emerging area of interest in high-pressure environments is that of pupillometry, where handheld quantitative infrared pupillometers (HQIPs) are able to track psycho-physiological fatigue in a fast, objective, valid, reliable, and non-invasive manner. However, the application of HQIPs in the context of athlete monitoring is yet to be determined. Therefore, the main aim of this pilot study was to examine the potential usefulness of a HQIP to monitor game-induced fatigue inside a professional female basketball setting by determining its (1) test-retest repeatability, (2) relationship with other biomarkers of game-induced fatigue, and (3) time-course from rested to fatigued states. A non-ophthalmologic practitioner performed a standardized Pupil Light Reflex (PLR) test using a medically graded HQIP among 9 professional female basketball players (2020–2021 Euro Cup) at baseline, 24-h pre-game (GD-1), 24-h post-game (GD+1) and 48-h post-game (GD+2). This was repeated over four subsequent games, equalling a total of 351 observations per eye. Two out of seven pupillometrics displayed good ICCs (0.95–0.99) (MinD and MaxD). Strong significant relationships were found between MaxD, MinD, and all registered biomarkers of game-induced fatigue (r = 0.69–0.82, p < 0.05), as well as between CV, MCV, and cognitive, lower-extremity muscle, and physiological fatigue markers (r = 0.74–0.76, p < 0.05). Three pupillometrics were able to detect a significant difference between rested and fatigued states. In particular, PC (right) (F = 5.173, η 2 = 0.115 p = 0.028) and MCV (right) (F = 3.976, η 2 = 0.090 p = 0.049) significantly decreased from baseline to GD+2, and LAT (left) (F = 4.023, η 2 = 0.109 p = 0.009) significantly increased from GD-1 to GD+2. HQIPs have opened a new window of opportunity for monitoring game-induced fatigue in professional female basketball players. However, future research initiatives across larger and heterogenous samples, and longer investigation periods, are required to expand upon these preliminary findings.

Background: Antimicrobial stewardship principles guide the clinical use of antimicrobials, including vancomycin, but paediatric vancomycin prescribing practices have not been evaluated in South Africa. Objectives: To document the use, prescribing practices and monitoring of intravenous vancomycin and the spectrum of bacteria isolated on microbiological culture in children treated with intravenous vancomycin during a 12-month period at Red Cross War Memorial Children’s Hospital (RCWMCH). Method: A retrospective audit of intravenous vancomycin use in children admitted to RCWMCH during 2019 was performed. Results: All 158 vancomycin prescription episodes for 143 children were included. Overall usage of intravenous vancomycin was 63 days of therapy per 1000 patient days (interquartile range [IQR]: 38–72). The median starting dose was 15 mg/kg per dose (IQR: 14–15) and median daily dose was 45 mg/kg per day (IQR: 43–60). Vancomycin was prescribed as empiric (127/158, 80%) and directed (31/158, 20%) treatment. The median duration of treatment for the directed group (7 days) was longer than the empiric group (4 days) (p = 0.001). Vancomycin serum trough concentrations were performed in 65/98 (66%) episodes where vancomycin treatment exceeded 3 days, with only 16/65 (25%) of these samples obtained before the fourth dose. Prolonged antibiotic treatment of 14 days or more was not associated with Gram-positive bacteria on culture (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 0.17–4.2). Conclusion: Dosing errors, prolonged empiric treatment and inappropriate vancomycin monitoring were problems associated with vancomycin prescriptions. Contribution: The study identified multiple opportunities for improved vancomycin prescribing and monitoring. Further research and implementation of improved prescribing practices could contribute to the preservation of vancomycin as an effective antibiotic.

Izencitinib is a novel, orally administered pan-JAK inhibitor designed as a gut-selective therapy that was under development for the treatment of inflammatory bowel disease. The objectives of this study were to define the mass balance, routes and rates of excretion, and metabolic fate of izencitinib after oral administration of [14C]-izencitinib in humans. Six healthy adult male subjects were administered a single 100 mg (~300 μCi) oral dose of [14C]-izencitinib. Fecal excretion was the dominant route of elimination with >90% of the administered dose recovered in the feces. As expected by design, plasma concentrations of total radioactivity and izencitinib were low with the mean terminal half-life of total radioactivity (138 h) exceeding that of izencitinib (32.4 h). Izencitinib represented approximately 17% of the total circulating radioactivity, suggesting the presence of multiple circulating plasma metabolites. However, no individual metabolite exceeded 10% of total drug-related material in plasma. The major metabolites in feces, M18 and M9, were found to have unusual structures that reflected the presence of a nucleophilic carbon center in the naphthyridine ring of izencitinib. Proposed mechanisms for the formation of these metabolites involved oxidation and rearrangement (M18) and a one-carbon addition, potentially occurring through reaction with endogenous formaldehyde. Given the gut-selective properties of izencitinib, it is proposed that these novel fecal metabolites are the most relevant for evaluating the impact of metabolism on the pharmacological and toxicological properties of izencitinib, and that the circulating plasma metabolite profile is of little consequence in the assessment of the safety characteristics of izencitinib metabolites. [ABSTRACT FROM AUTHOR]