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Aims: Brepocitinib is a tyrosine kinase 2/Janus kinase 1 inhibitor being investigated for the treatment of several autoimmune diseases. This study assessed the absorption, distribution, metabolism and excretion of oral brepocitinib, and the absolute oral bioavailability (F) and fraction absorbed (Fa) using a 14C microtracer approach. Methods: This was a phase 1 open‐label, nonrandomized, fixed sequence, two‐period, single‐dose study of brepocitinib in healthy male participants. Participants received a single oral 60 mg dose of 14C brepocitinib (~300 nCi) in Period A, then an unlabelled oral 60 mg dose followed by an intravenous (IV) 30 μg dose of 14C labelled brepocitinib (~300 nCi) in Period B. Mass balance, pharmacokinetic parameters and safety were assessed. Results: Six participants were enrolled. Brepocitinib was absorbed rapidly following oral administration. In Period A, total recovery of the oral dose was 96.7% ± 6.3% (88.0% ± 8.0% in urine, 8.7% ± 2.1% in faeces). In Period B, a small fraction (6.0% of the oral dose) was recovered unchanged in urine. F and Fa were 74.6% (90% confidence interval 67.3%, 82.8%) and 106.9%, respectively. Brepocitinib demonstrated an acceptable safety profile and was well tolerated following oral or oral then IV administrations. No deaths, serious adverse events or discontinuations were reported. Conclusion: Intestinal absorption of brepocitinib was essentially complete after oral administration, with F ~75%. Drug‐related material recovery was high, with the majority excreted in urine. The major route of elimination of brepocitinib was renal excretion as metabolites, whereas urinary elimination of unchanged brepocitinib was minor. NCT: NCT03770039. [ABSTRACT FROM AUTHOR]

Typically human absorption, distribution, metabolism, and excretion (ADME) studies are executed using radiolabeled (e.g., carbon‐14) material, the synthesis of which is a time‐consuming activity. In this study, we were able to assess the metabolism and excretion of unlabeled nirmatrelvir (PF‐07321332) within the first‐in‐human study via a novel application of quantitative fluorine (19F) nuclear magnetic resonance (NMR) spectroscopy in place of a standard radiolabel ADME study. Six healthy participants received a single 300‐mg oral dose of nirmatrelvir (in combination with ritonavir), and excreta were collected up to 10 days. Virtually all drug‐related material was recovered within 5 days, and mass balance was achieved with 84.9 ± 8.9% (range = 70.7–95.5%) of the administered dose recovered in urine and feces. The excretion of fluorine‐containing material in urine and feces was 47.0% and 33.7%, respectively. Unchanged nirmatrelvir represented 82.5% of the normalized drug‐related material with a carboxylic acid metabolite M5, derived from hydrolysis of the P2 amide bond, present at 12.1% of dose. Nirmatrelvir was the only drug‐related entity observed in plasma. Approximately 4.2% of the dose was excreted as metabolite M8 (measured by liquid chromatography–mass spectrometry), which was 19F NMR silent due to hydrolysis of the trifluoroacetamide moiety. Hydrolysis of nirmatrelvir to M5 and M8 was shown to occur in cultures of human gut microflora. This successful demonstration of quantitative 19F NMR spectroscopy to establish the mass‐balance, excretion, and metabolic profile of nirmatrelvir offers an advantageous means to execute human ADME studies for fluorine‐containing compounds early in drug development. [ABSTRACT FROM AUTHOR]

Zimlovisertib (PF‐06650833) is a selective, reversible inhibitor of interleukin‐1 receptor‐associated kinase 4 (IRAK4) with anti‐inflammatory effects. This phase 1, open‐label, fixed‐sequence, two‐period, single‐dose study aimed to evaluate the mass balance and excretion rate of zimlovisertib in healthy male participants using a 14C‐microtracer approach. All six participants received 300 mg 14C‐zimlovisertib with lower radioactivity per mass unit orally in Period A, then unlabeled zimlovisertib 300 mg orally and 14C‐zimlovisertib 135 μg intravenously (IV) in Period B. Study objectives included extent and rate of excretion of 14C‐zimlovisertib, pharmacokinetics, and safety and tolerability of oral and IV zimlovisertib. Total radioactivity recovered in urine and feces was 82.4% ± 6.8% (urine 23.1% ± 12.3%, feces 59.3% ± 9.7%) in Period A. Zimlovisertib was absorbed rapidly following oral administration, with the fraction absorbed estimated to be 44%. Absolute oral bioavailability of the 300‐mg dose was 17.4% (90% confidence interval 14.1%, 21.5%) using the dose‐normalized area under the concentration–time curve from time 0 to infinity. There were no deaths, serious adverse events (AEs), severe AEs, discontinuations or dose reductions due to AEs, and no clinically significant laboratory abnormalities. These results demonstrate that zimlovisertib had low absolute oral bioavailability and low absorption (<50%). [ABSTRACT FROM AUTHOR]

Salinity–induced land degradation poses a threat to environment and food production globally. Farmers' participatory research (2014–18) was carried out to assess the potential of gypsum (Gyp) and pressmud (PM) in alleviating the sodicity stress, and improvement in soil organic carbon (SOC) pools and its stability in the Trans Indo–Gangetic Plains of India. Intensive rice–wheat cultivation using alkali water increased soil pH, exchangeable sodium percentage (ESP), and bulk density (BD) causing a net depletion in SOC. Gypsum (supplies soluble Ca2+) and pressmud (mobilizes native CaCO3) mediated amelioration (Gyp + PM) significantly decreased soil sodification and compaction, and improved total organic carbon (TOC; 32%–64%) over the unamended control. Higher left–over C for SOC stabilization, crop biomass, and rhizodeposition returned through Gyp + PM significantly improved SOC pools and C sequestration culminating in ~25% yield superiority over the unamended control. Within SOC pools, highest proportion was equally retained in very labile and non–labile C pools. On average, the passive pool contained ~45% of TOC; albeit to a greater contribution through PM followed by Gyp + PM and Gyp. Rice–wheat system yield (RWSY) was positively correlated with SOC pools and indices while negatively correlated with soil pH, ESP, BD, CaCO3, and recalcitrant index. Multiple regression analysis showed stratification ratio, CaCO3, sensitivity index, and BD as key variables for yield prediction under the existing levels of soil sodicity. The key insights suggest ecosystem‐based approach using Gyp + PM in restoring the degraded lands, enhancing crop resilience and system (SOC enrichment and storage) stability, and achieving UN–Sustainable Development Goals related to food security and land degradation neutrality. [ABSTRACT FROM AUTHOR]

We assessed the improvement potential of pressmud – a sugar industry waste – on soil properties, physiological adaptation and yield‐related traits in a rice–wheat rotation in sodicity‐affected Ghaghar basin of Haryana, India. Large‐scale (0.2–0.4 ha) participatory trials comprising two treatments, with (+PM) and without (–PM) pressmud, were conducted on 125 farmers' fields covering non‐sodic (NS), slightly sodic (SS) and moderately sodic (MS) soils. Pressmud application (10 Mg ha−1) led to appreciable reductions in soil pH (1.6–3.6%) and exchangeable sodium percentage (ESP; 10.4–20.1%) with concomitant improvements in plant physiological and yield‐related traits across different soil alkali classes, albeit to a greater extent in SS and MS soils than in NS soils. Compared to prevailing farmers' practices (–PM), transformative improvements in mean leaf relative water content (RWC) (4 and 7%), membrane injury (MII) (−12 and −14%), photosynthetic rate (Pn) (21 and 25%), stomatal conductance (gS) (26 and 21%), transpiration rate (E) (38 and 22%), proline (P) (−19 and −20%) and Na+/K+ accumulation in shoot (NaK_S) (−24 and −22%) and root (NaK_R) (−23 and −27%) were observed in both rice and wheat grown under PM ameliorated soils. On an average, rice and wheat yields were increased by 15.8 and 14.6% in SS and 18.9 and 16.7% in MS soils, respectively, with pressmud application. Principal Component Analysis (PCA) showed significant correlations among highly weighted variables including physiological and yield‐related traits to influence the rice–wheat productivity with PM addition in SS and MS soils. Sustained use of this organic waste in agricultural lands seems to be an affordable solution for overcoming sodicity‐induced land degradation, and achieving developmental goals of environmental and livelihood security. [ABSTRACT FROM AUTHOR]

Introduction: Control strategies for human infections are often investigated using individual‐based models (IBMs) to quantify their impact in terms of mortality, morbidity and impact on transmission. Genetic selection can be incorporated into the IBMs to track the spread of mutations whose origin and spread are driven by the intervention and which subsequently undermine the control strategy; typical examples are mutations which encode drug resistance or diagnosis‐ or vaccine‐escape phenotypes. Methods and results: We simulated the spread of malaria drug resistance using the IBM OpenMalaria to investigate how the finite sizes of IBMs require strategies to optimally incorporate genetic selection. We make four recommendations. Firstly, calculate and report the selection coefficients, s, of the advantageous allele as the key genetic parameter. Secondly, use these values of "s" to calculate the wait time until a mutation successfully establishes itself in the pathogen population. Thirdly, identify the inherent limits of the IBM to robustly estimate small selection coefficients. Fourthly, optimize computational efficacy: when "s" is small, fewer replicates of larger IBMs may be more efficient than a larger number of replicates of smaller size. Discussion: The OpenMalaria IBM of malaria was an exemplar and the same principles apply to IBMs of other diseases. [ABSTRACT FROM AUTHOR]

Background: Cancer rehabilitation is an integral part of the continuum of care for survivors. Due to the increasing number of survivors, physiatrists commonly see cancer patients in their general practices. Essential to guiding the field is to understand the current training and practice patterns of cancer rehabilitation physicians.Objectives: To assess current trends in training and practice for cancer rehabilitation physicians, including the level of burnout among providers in this field.Design: Cross-sectional descriptive survey study.Setting: Online survey.Participants: American physicians who are affiliated with the Cancer Rehabilitation Physician Consortium (CRPC) of the American Academy of Physical Medicine and Rehabilitation (AAPM&R). The CRPC is a group of cancer rehabilitation providers (both fellowship-trained and not fellowship-trained) with the mission of furthering cancer rehabilitation medicine through education, research, and networking.Methods: All CRPC physicians were invited to complete a voluntary and anonymous 43-question online survey. The survey was conceived by a group of eight experts interested in providing additional information to the current literature regarding the training and practice in the cancer rehabilitation field.Main Outcome Measurements: Training, practice, opioid prescribing, and professional support.Results: Thirty-seven of 50 physicians participated (response rate = 74%). Respondents were from various states, the three most common being New York (16%, n = 6), Texas (16%, n = 6), and Massachusetts (11%, n = 4). About 57% (n = 21) of the respondents were employed in an academic medical center and 73% (n = 27) reported their primary departmental affiliation was Physical Medicine and Rehabilitation (PM&R). Approximately 78% (n = 29) credited mentorship early in training for their interest in the field. More than half (54%, n = 20) either strongly agreed or agreed that cancer rehabilitation fellowship training is necessary for graduating physiatrists who plan to treat oncology patients/survivors. National PM&R meetings were the primary source of continuing education for 86% (n = 31). Sixty-five percent (n = 24), strongly agreed or agreed that cancer rehabilitation physiatrists should know how to prescribe opioids, and 35% (n = 13) reported prescribing them when appropriate. About 54% (n = 20) rated their level of burnout as low or very low, and more than half (51%, n = 19) believed their burnout level was lower than physiatrists treating other rehabilitation populations.Conclusions: Cancer rehabilitation is a growing subspecialty in PM&R, and most physiatrists in general practice will treat many survivors-often for neurologic or musculoskeletal impairments related to cancer or its treatment. Cancer rehabilitation physicians perceive that they have relatively low levels of burnout, and early mentorship and fellowship training is beneficial. Professional conferences and mentorship are a primary source for continuing education.Level Of Evidence: IV. [ABSTRACT FROM AUTHOR]

A 6-year-old firstborn girl, of a non-consanguineous marriage, presented with a history of short fingers and absent nails of the right hand since birth. Radiography showed the absence of middle and distal phalanges of digits 2-4 and hypoplasia of proximal phalanx of the third digit in the right hand. Thus, anonychia and hyponychia are closely associated with underlying bone deformities and proper distal and/or middle phalanx is mandatory for nail development.4 Such patients generally have cosmetic complaints but no functional deficits. [Extracted from the article]

Bibliometrics, including conventional and alternative metrics, measure the scholarly impact an article has on a scientific field.[1] Conventional metrics take time to accumulate and include measures such as citation count, impact factor, H-index, and download count. However, the third top-ranked topic in each journal was different; Sports Medicine in I PM&R i , (#2, tied with Exercise) I , i Non-Traumatic Brain Injury in I Archives i (#3), and Medical Technology in I AJPM&R i (#3). To our knowledge, this is the first attempt to characterize rehabilitation journal articles ranked highest by alternative metrics. [Extracted from the article]

A re-circulating fluidised bed (RCFB) reactor is proposed here for gaseous fuel combustion using chemical-looping combustion (CLC). A single RCFB reactor was operated in alternate oxidation and reduction cycles for simulating the interconnected reactors arrangement for CLC. For this, a Perspex made transparent, concentric, semicircular cold model of RCFB reactor was used with three grades of Indian Standard sand. Operational parameters like bed inventory, pressure drop, particle size, suspension density, solid circulation rate, bed voidage and fluidisation gas velocity were studied to how they affect the performance of the RCFB reactor. The solid circulation rate has been found to increase with the increase in the bed inventory. Proper solid circulation rate is very much required for proper heat and mass transfer in an interconnected fluidised bed reactors system. The bed voidage is observed to be high during the aeration cycle and low during the reduction cycle. A high bed voidage during the oxidation cycle is appropriate for the fast oxidation reaction of the metal oxides. However, a low bed voidage is required for proper heat transfer for an endothermic reduction reaction in the fuel reactor. Suspension density in the downcomer of the RCFB reactor has been found to be increasing with bed inventory for both the oxidation and reduction cycles, which is good for the bed-to-wall heat transfer. A good observed solid circulation rate, operating voidage and suspension density add to the capability of RCFB to run CLC. [ABSTRACT FROM AUTHOR]

Aims: Brepocitinib is a tyrosine kinase 2/Janus kinase 1 inhibitor being investigated for the treatment of several autoimmune diseases. This study assessed the absorption, distribution, metabolism and excretion of oral brepocitinib, and the absolute oral bioavailability (F) and fraction absorbed (F a ) using a 14 C microtracer approach., Methods: This was a phase 1 open-label, nonrandomized, fixed sequence, two-period, single-dose study of brepocitinib in healthy male participants. Participants received a single oral 60 mg dose of 14 C brepocitinib (~300 nCi) in Period A, then an unlabelled oral 60 mg dose followed by an intravenous (IV) 30 μg dose of 14 C labelled brepocitinib (~300 nCi) in Period B. Mass balance, pharmacokinetic parameters and safety were assessed., Results: Six participants were enrolled. Brepocitinib was absorbed rapidly following oral administration. In Period A, total recovery of the oral dose was 96.7% ± 6.3% (88.0% ± 8.0% in urine, 8.7% ± 2.1% in faeces). In Period B, a small fraction (6.0% of the oral dose) was recovered unchanged in urine. F and F a were 74.6% (90% confidence interval 67.3%, 82.8%) and 106.9%, respectively. Brepocitinib demonstrated an acceptable safety profile and was well tolerated following oral or oral then IV administrations. No deaths, serious adverse events or discontinuations were reported., Conclusion: Intestinal absorption of brepocitinib was essentially complete after oral administration, with F ~75%. Drug-related material recovery was high, with the majority excreted in urine. The major route of elimination of brepocitinib was renal excretion as metabolites, whereas urinary elimination of unchanged brepocitinib was minor. NCT: NCT03770039., (© 2023 Pfizer Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)