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Global aviation operations contribute to anthropogenic climate change via a complex set of processes that lead to a net surface warming. Of importance are aviation emissions of carbon dioxide (CO2), nitrogen oxides (NOx), water vapor, soot and sulfate aerosols, and increased cloudiness due to contrail formation. Aviation grew strongly over the past decades (1960-2018) in terms of activity, with revenue passenger kilometers increasing from 109 to 8269 billion km yr-1, and in terms of climate change impacts, with CO2 emissions increasing by a factor of 6.8 to 1034 Tg CO2 yr-1. Over the period 2013-2018, the growth rates in both terms show a marked increase. Here, we present a new comprehensive and quantitative approach for evaluating aviation climate forcing terms. Both radiative forcing (RF) and effective radiative forcing (ERF) terms and their sums are calculated for the years 2000-2018. Contrail cirrus, consisting of linear contrails and the cirrus cloudiness arising from them, yields the largest positive net (warming) ERF term followed by CO2 and NOx emissions. The formation and emission of sulfate aerosol yields a negative (cooling) term. The mean contrail cirrus ERF/RF ratio of 0.42 indicates that contrail cirrus is less effective in surface warming than other terms. For 2018 the net aviation ERF is +100.9 milliwatts (mW) m-2 (5-95% likelihood range of (55, 145)) with major contributions from contrail cirrus (57.4 mW m-2), CO2 (34.3 mW m-2), and NOx (17.5 mW m-2). Non-CO2 terms sum to yield a net positive (warming) ERF that accounts for more than half (66%) of the aviation net ERF in 2018. Using normalization to aviation fuel use, the contribution of global aviation in 2011 was calculated to be 3.5 (4.0, 3.4) % of the net anthropogenic ERF of 2290 (1130, 3330) mW m-2. Uncertainty distributions (5%, 95%) show that non-CO2 forcing terms contribute about 8 times more than CO2 to the uncertainty in the aviation net ERF in 2018. The best estimates of the ERFs from aviation aerosol-cloud interactions for soot and sulfate remain undetermined. CO2-warming-equivalent emissions based on global warming potentials (GWP* method) indicate that aviation emissions are currently warming the climate at approximately three times the rate of that associated with aviation CO2 emissions alone. CO2 and NOx aviation emissions and cloud effects remain a continued focus of anthropogenic climate change research and policy discussions.

Projections of global mean temperature changes (ΔT) in the future are associated with intrinsic uncertainties. Much climate policy discourse has been guided by "current knowledge" of the ΔTs uncertainty, ignoring the likely future reductions of the uncertainty, because a mechanism for predicting these reductions is lacking. By using simulations of Global Climate Models from the Coupled Model Intercomparison Project Phase 5 ensemble as pseudo past and future observations, we estimate how fast and in what way the uncertainties of ΔT can decline when the current observation network of surface air temperature is maintained. At least in the world of pseudo observations under the Representative Concentration Pathways (RCPs), we can drastically reduce more than 50% of the ΔTs uncertainty in the 2040 s by 2029, and more than 60% of the ΔTs uncertainty in the 2090 s by 2049. Under the highest forcing scenario of RCPs, we can predict the true timing of passing the 2 °C (3 °C) warming threshold 20 (30) years in advance with errors less than 10 years. These results demonstrate potential for sequential decision-making strategies to take advantage of future progress in understanding of anthropogenic climate change.

International trade is a vital component of the global economy. However, to realise sustainable benefits of international trade, a national’s external trade policy must identify the non-tariff barriers (NTB) and tariff barriers that hinder small business from participating in international trade and enhance their growth. Though NTBs are largely believed to restrict trade, there is evidence suggesting that NTBs facilitates trade, and provide small businesses a chance to participate in international trade and grow. Therefore, the purpose of this study is to examine the relationship between NTBs and sales growth of small business in Tanzania. This study applied correlational design to analyze quantitative data quantitative collected from managers/owners of small businesses selected using stratified sampling technique. The data was gathered using structured questionnaire from 240 managers/owners of small businesses in Temeke and Ubungo districts of Dar es Salaam City. The quantitative data were analyzed using descriptive and multiple linear regression model to ascertain the relationship between NTBs and sales growth of small business. The findings of this study indicate that, three variables of technical barriers to trade, namely, quality management certification, sanitary and phytosanitary and packaging and labelling have positive and significant association with sales growth of small business, while custom procedures has negative and significant link with sales growth of small business. On the contrary, certificate of origin and product certification were found to have non-significant relationship with sales growth of small business.

Importance of 4Cs of marketing mix on voluntary tax compliance has been acknowledged. However, contrary to its importance, the body of literature has paint little attention regarding 4Cs of marketing mix in relation to the voluntary tax compliance. Therefore, the purpose of this study was to analyse the influence of the 4 Cs of marketing mix on voluntary tax compliance among small taxpayers. This study applied explanatory cross-sectional survey design to collect and analyse both quantitative and qualitative data. The quantitative data were collected from small business managers/owners who were selected using systematic random sampling technique, while qualitative data were collected from three TRA officers selected purposively. The quantitative data was gathered using structured questionnaire from 240 managers/owners of small businesses in Dodoma City. The quantitative data were analysed using descriptive statistics and binary logistic regression model, while qualitative data were analysed using content analysis. The findings of this study indicate that, satisfaction of customer needs and wants, convenience of tax compliance and communication between TRA and tax-payers have positive and significant association with voluntary tax compliance. However, cost of tax compliance has negative and significant effect on voluntary tax compliance. The findings of the study bring knowledge contribution by adding in the body of empirical literature on tax compliance the effect of 4Cs of marketing mix on the voluntary tax compliance among small tax-payers. Based on findings this study recommends to TRA to review tax compliance procedures and documentations so as to identify all unnecessary to be removed.

Oral Diseases (2011) , 291-297 Osteonecrosis of the jaw is a serious complication of bisphosphonate treatment for which the pathophysiology is unknown. The purpose of this study was to investigate whether in vivo zoledronic acid (ZA) induces alterations in cell proliferation, apoptosis, and matrix metalloproteinases (MMPs) expression in oral mucosal epithelial cells. One-year-old dogs were either untreated (control group) or given high doses of intravenous ZA (ZA group) for 3 months. The doses of ZA were equivalent to those given to cancer patients, yet were administered two times more frequently (every 2 weeks). Mucosal tissues were assessed immunohistochemically for cell proliferation (proliferating cell nuclear antigen, PCNA), matrix metalloproteinase (MMP) expression, and apoptosis (caspase 3 and TUNEL). There were no significant differences between the groups with respect to PCNA, MMP-2, MMP-14, and TUNEL positive cells. However, the expression of MMP-9 was significantly higher in the control group than in the ZA group ( P < 0.05), whereas the expression of caspase 3 was significantly lower in the control group than in the ZA group ( P < 0.05). These results suggest that high doses of ZA resulted in higher levels of apoptosis and lower levels of MMP-9 in the oral epithelial cells supporting the idea of bisphosphonate treatment affects the oral mucosa. [ABSTRACT FROM AUTHOR]

The FGF23 coreceptor αKlotho (αKL) is expressed as a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as an endoproteolytic cleavage product of mKL (cKL). Previously, a patient with increased plasma cKL as the result of a translocation [t(9;13)] in the αKLOTHO (KL) gene presented with rickets and a complex endocrine profile, including paradoxically elevated plasma FGF23, despite hypophosphatemia. The goal of this study was to test whether cKL regulates phosphate handling through control of FGF23 expression. To increase cKL levels, mice were treated with an adeno-associated virus producing cKL. The treated groups exhibited dose-dependent hypophosphatemia and hypocalcemia, with markedly elevated FGF23 (38 to 456 fold). The animals also manifested fractures, reduced bone mineral content, expanded growth plates, and severe osteomalacia, with highly increased bone Fgf23 mRNA (>150 fold). cKL activity in vitro was specific for interactions with FGF23 and was FGFR dependent. These results demonstrate that cKL potently stimulates FGF23 production in vivo, which phenocopies the KL translocation patient and metabolic bone syndromes associated with elevated FGF23. These findings have important implications for the regulation of αKL and FGF23 in disorders of phosphate handling and biomineralization. [ABSTRACT FROM AUTHOR]

Study Design: This retrospective study included patients who underwent primary one-level minimally invasive (MIS) transforaminal lumbar interbody fusion (TLIF) for degenerative lumbar spine conditions., Objective: To identify early predictors of failing to achieve the Oswestry Disability Index (ODI) minimum clinically important difference (MCID) one-year post-surgery., Summary of Background Data: Early identification of patients at risk of failing to achieve ODI-MCID is crucial for early intervention and improved postoperative counseling. Currently, no specific thresholds guide patient follow-up for optimal recovery., Methods: The assessment included demographic information, surgical details, and patient-reported outcome measures (PROMs). PROMs were collected postoperatively at 2-, 6-, and 12-week time points, as well as at 6- and 12-months., Results: The study included 166 patients, with 34% failing to achieve ODI-MCID at one year. Early VAS back and leg scores were found to be significant predictors of ODI-MCID achievement. The optimal thresholds identified were 2.25 for early VAS back and 4.25 for early VAS leg. A rerun regression identified the thresholds as independent predictors of ODI-MCID, with odds ratios of 0.31 for both measures., Conclusion: VAS back and leg score thresholds at 6-12 weeks can predict ODI-MCID achievement one year after MIS TLIF. Patients exceeding the identified thresholds may be at risk of failing ODI-MCID and should be monitored closely., Level of Evidence: Level 3., Competing Interests: Conflicts of Interest: Sheeraz Qureshi has the following disclosures: AMOpportunities: Other financial or material support; Annals of Translational Medicine: Editorial or governing board; Association of Bone and Joint Surgeons: Board or committee member; Cervical Spine Research Society: Board or committee member; Contemporary Spine Surgery: Editorial or governing board; Globus Medical: IP royalties; Paid consultant; Paid presenter or speaker; Hospital Special Surgery Journal: Editorial or governing board; HS2, LLC: Stock or stock Options; International Society for the Advancement of Spine Surgery (ISASS) - Program Committee member: Board or committee member; Lifelink.com: Other financial or material support; Lumbar Spine Research Society: Board or committee member; Minimally Invasive Spine Study Group: Board or committee member; North American Spine Society: Board or committee member; Simplify Medical, Inc.: Other financial or material support; Society of Minimally Invasive Spine Surgery (SMISS) - Program Committee member: Board or committee member; Spinal Simplicity: Other financial or material support; SpineGuard, Inc.: Paid consultant; Stryker: IP royalties; Paid consultant; Surgalign: Paid consultant; Tissue Differentiation Intelligence: Stock or stock Options; Viseon, Inc.: Paid consultant; Research support; Clinical Spine Surgery: Editorial or governing board Sravisht Iyer has the following disclosures: Globus Medical: Paid presenter or speaker; Stryker: Paid presenter or speaker; Vertebral Columns/International Society for the Advancement of Spine Surgery (ISASS): Editorial or governing board; HS2, LLC: Ownership/Equity/Investment; Innovasis: Research Support (either personally or through institution), (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Quasi-brittle fracture mechanics is used to evaluate fracture of human cortical bone in aging. The approach is demonstrated using cortical bone bars extracted from one 92-year-old human male cadaver. In-situ fracture mechanics experiments in a 3D X-ray microscope are conducted. The evolution of the fracture process zone is documented. Fully developed fracture process zone lengths at peak load are found to span about three osteon diameters. Crack deflection and arrest at cement lines is a key process to build extrinsic toughness. Strength and toughness are found as size-dependent, not only for laboratory-scale experimental specimens but also for the whole femur. A scaling law for the length fracture process zone is used. Then, size-independent, tissue fracture properties are calculated. Linear elastic fracture mechanics applied to laboratory beam specimens underestimates the tissue toughness by 60%. Tissue fracture properties are used to predict the load capacity of the femur in bending within the range of documented data. The quasi-brittle fracture mechanics approach allows for the assessment of the combined effect of bone quantity and bone quality on fracture risk. However, further work is needed considering a larger range of subjects and in the model validation at the organ length scale., Competing Interests: Declaration of competing interest We declare no conflict of interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: A clinical trial of Epidiolex ® , the only US FDA-approved cannabis-derived consumer product (CDP), discovered an interaction with an immunosuppressant (tacrolimus) that led to drug toxicity, highlighting the unique intersection of prescription and commonly unregulated consumer products., Objective: We aimed to identify if similar drug-drug interactions (DDIs) are occurring among the consumer CDP market, even though they cannot be identified through trials., Methods: We searched Reddit for subreddits related to CDPs or health, resulting in 63,561,233 posts. From these, we identified 190 posts discussing both immunosuppressants and CDPs. Two blinded investigators evaluated the following. (1) Was there a concern about a potential DDI between consumer CDPs and immunosuppressants? (2) Was there a unique adverse event attributed to a DDI between consumer CDPs and immunosuppressants?, Results: Of these, 66 posts (35%) expressed concern about a potential DDI, such as "Hey, my partner wants to try my edibles … she's on Prograf [tacrolimus] and wants to talk to a stoner who's had a heart transplant." Four posts (2%) reported a unique DDI, such as "I have clinical results that are semi-anecdotal, showing the coordination to my halting substance use … It's the CBD. Shot my prograf to 30 at like 4 mg." Two of the four reported DDIs are similar to those first reported for Epidiolex. The remaining two reported DDIs include a potential cannabidiol (CBD)/sirolimus or delta-9-tetrahydrocannabinol (THC)/sirolimus interaction and a THC/tacrolimus interaction, both resulting in drug toxicity., Conclusion: This case study is the first to report on DDIs involving consumer CDPs, including both CBD and THC products, as well as a broader class of immunosuppressants. This demonstrates the risks associated with using consumer CDPs alongside prescription medications while highlighting the need for development of increased surveillance to monitor consumer CDPs for drug safety signals, as well as comprehensive regulations that take into account the unique characteristics of the consumer marketplace., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Context: This article focuses on 4 small local health departments (LHDs) that were in the process of seeking Public Health Accreditation Board (PHAB) reaccreditation or Pathways Recognition using PHAB Standards & Measures Version 2022., Objective: The objective of this study was to explore the experiences of 4 small LHDs related to Quality Improvement (QI) and Performance Management (PM) in their pursuit of PHAB reaccreditation or Pathways Recognition., Design: A team of researchers conducted 22 qualitative interviews with health department leaders and staff. Findings relative to QI/PM represent an embedded case study since they were part of a larger investigation., Setting: The research team conducted interviews remotely with health departments located in the West and Midwest., Participants: Participants included adults at least 18 years old and employed in 1 of 4 health departments., Main Outcome Measures: Emergent themes from this qualitative investigation included using QI/PM tracking systems, building staff buy-in for QI/PM, integrating QI/PM into daily work, and advice for other health departments regarding QI/PM., Results: Participants suggested that tracking systems helped them manage QI/PM processes. Staff buy-in for QI/PM was strengthened by building a sense of ownership of the process and connecting improvement processes to outcomes. Health departments integrated QI/PM into daily work by leadership modeling and communicating expectations. Advice for other health departments included finding a QI system that was easy to follow and recognizing the role of QI/PM in improving performance to better support the wellbeing of the community., Conclusions: QI/PM are important tools for health department effectiveness. Participants affirmed that the primary purposes of QI/PM are to enhance internal processes and improve community health outcomes. Study findings demonstrate how 4 small health departments integrated QI/PM into their public health practice., Competing Interests: The authors declare they have no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Patients with chronic kidney disease (CKD) report high pain levels, but reduced renal clearance eliminates many analgesic options; therefore, 30-50% of CKD patients have chronic opioid prescriptions. Opioid use in CKD is associated with higher fracture rates. Opioids may directly alter bone turnover directly through effects on bone cells and indirectly via increasing inflammation. We hypothesized that continuous opioid exposure would exacerbate the high bone turnover state of CKD and be associated with elevated measures of inflammation. Male C57Bl/6J mice after 8 weeks of adenine-induced CKD (AD) and non-AD controls (CON) had 14-day osmotic pumps (0.25-µL/hr release) containing either saline or 50-mg/mL oxycodone (OXY) surgically implanted in the subscapular region. After 2 weeks, all AD mice had elevated blood urea nitrogen, parathyroid hormone, and serum markers of bone turnover compared to controls with no effect of OXY. Immunohistochemical staining of the distal femur showed increased numbers of osteocytes positive for the mu opioid and for toll-like receptor 4 (TLR4) due to OXY. Osteocyte protein expression of tumor necrosis factor-α (TNF-α) and RANKL were higher due to both AD and OXY so that AD + OXY mice had the highest values. Trabecular osteoclast-covered surfaces were also significantly higher due to both AD and OXY, resulting in AD + OXY mice having 4.5-fold higher osteoclast-covered surfaces than untreated CON. These data demonstrate that opioids are associated with a pro-inflammatory state in osteocytes which increases the pro-resorptive state of CKD., (© 2024. The Author(s).)

Chronic heavy alcohol consumption is a risk factor for low trauma bone fracture. Using a non-human primate model of voluntary alcohol consumption, we investigated the effects of 6 months of ethanol intake on cortical bone in cynomolgus macaques (Macaca fascicularis). Young adult (6.4 ± 0.1 years old, mean ± SE) male cynomolgus macaques (n = 17) were subjected to a 4-month graded ethanol induction period, followed by voluntary self-administration of water or ethanol (4 % w/v) for 22 h/d, 7 d/wk. for 6 months. Control animals (n = 6) consumed an isocaloric maltose-dextrin solution. Tibial response was evaluated using densitometry, microcomputed tomography, histomorphometry, biomechanical testing, and Raman spectroscopy. Global bone response was evaluated using biochemical markers of bone turnover. Monkeys in the ethanol group consumed an average of 2.3 ± 0.2 g/kg/d ethanol resulting in a blood ethanol concentration of 90 ± 12 mg/dl in longitudinal samples taken 7 h after the daily session began. Ethanol consumption had no effect on tibia length, mass, density, mechanical properties, or mineralization (p > 0.642). However, compared to controls, ethanol intake resulted in a dose-dependent reduction in intracortical bone porosity (Spearman rank correlation = -0.770; p < 0.0001) and compared to baseline, a strong tendency (p = 0.058) for lower plasma CTX, a biochemical marker of global bone resorption. These findings are important because suppressed cortical bone remodeling can result in a decrease in bone quality. In conclusion, intracortical bone porosity was reduced to subnormal values 6 months following initiation of voluntary ethanol consumption but other measures of tibia architecture, mineralization, or mechanics were not altered., Competing Interests: Declaration of competing interest The authors have nothing to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Bisphosphonates are widely used in equine athletes to reduce lameness associated with skeletal disorders. Widespread off-label use has led to concern regarding potential negative effects on bone healing, but little evidence exists to support or refute this., Objectives: To investigate the influence of clinically relevant doses of tiludronate on bone remodelling and bone healing., Study Design: Randomised, controlled in vivo experiments., Methods: Each horse had a single tuber coxae biopsied (Day 0), then were divided into a treatment (IV tiludronate) or control (IV saline) group. Treatments were administered 30 and 90 days following initial biopsy. Biopsy of the tuber coxae was repeated on Day 60 to evaluate bone healing following a single treatment. Oxytetracycline was administered on Days 137 and 147 to label bone formation. The contralateral tuber coxae was biopsied on Day 150 to evaluate effects of repeated treatment. Bone biopsies were evaluated with micro-computed tomography and/or dynamic histomorphometry using standard techniques., Results: Nineteen horses completed the study, with no complications following the biopsies and treatments. No significant differences in the trabecular bone parameters or bone formation rate were observed between treatment groups., Main Limitations: The use of a first-generation bisphosphonate may mean some effects of these drugs are underrepresented using this model. The results pertain to the tuber coxae and may not reflect injury or the healing response that occurs in long bones in training or racing., Conclusions: In this model, tiludronate did not affect normal bone remodelling in the horse, despite repeat dosages., (© 2024 The Author(s). Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

Importance: Despite growing interest in psychedelics, there is a lack of routine population-based surveillance of psychedelic microdosing (taking "subperceptual" doses of psychedelics, approximately one-twentieth to one-fifth of a full dose, over prolonged periods). Analyzing Google search queries can provide insights into public interest and help address this gap., Objective: To analyze trends in public interest in microdosing in the US through Google search queries and assess their association with cannabis and psychedelic legislative reforms., Design, Setting, and Participants: In this cross-sectional study, a dynamic event-time difference-in-difference time series analysis was used to assess the impact of cannabis and psychedelic legislation on microdosing search rates from January 1, 2010, to December 31, 2023. Google search rates mentioning "microdosing," "micro dosing," "microdose," or "micro dose" within the US and across US states were measured in aggregate., Exposure: Enactment of (1) local psychedelic decriminalization laws; (2) legalization of psychedelic-assisted therapy and statewide psychedelic decriminalization; (3) statewide medical cannabis use laws; (4) statewide recreational cannabis use laws; and (5) all cannabis and psychedelic use restricted., Main Outcome and Measures: Microdosing searches per 10 million Google queries were measured, examining annual and monthly changes in search rates across the US, including frequency and nature of related searches., Results: Searches for microdosing in the US remained stable until 2014, then increased annually thereafter, with a cumulative increase by a factor of 13.4 from 2015 to 2023 (7.9 per 10 million to 105.6 per 10 million searches, respectively). In 2023, there were 3.0 million microdosing searches in the US. Analysis at the state level revealed that local psychedelic decriminalization laws were associated with an increase in search rates by 22.4 per 10 million (95% CI, 7.5-37.2), statewide psychedelic therapeutic legalization and decriminalization were associated with an increase in search rates by 28.9 per 10 million (95% CI, 16.5-41.2), statewide recreational cannabis laws were associated with an increase in search rates by 40.9 per 10 million (95% CI, 28.6-53.3), and statewide medical cannabis laws were associated with an increase in search rates by 11.5 per 10 million (95% CI, 6.0-16.9). From August through December 2023, 27.0% of the variation in monthly microdosing search rates between states was explained by differences in cannabis and psychedelics legal status., Conclusion and Relevance: This cross-sectional study found that state-led legislative reforms on cannabis and psychedelics were associated with increased public interest in microdosing psychedelics.