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Τετάρτη 4 Μαΐου 2022

Pharmacokinetics of bleomycin sclerotherapy in patients with vascular malformations

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Abstract

Bleomycin, a chemotherapy agent that inhibits synthesis of DNA, has been increasingly utilized in sclerotherapy for patients with vascular malformations. A serious long-term risk of intravenous bleomycin is dose-dependent interstitial pneumonitis. Little is known about absorption and circulating levels of bleomycin when used in sclerotherapy for patients with vascular malformations. This is an Institutional Review Board (IRB)-approved prospective study on patients receiving bleomycin sclerotherapy in the management of vascular malformations. Depending on the type of vascular malformation, bleomycin was administered either in the lumen or interstitial space of the involved lesion. A bleomycin assay measured serum bleomycin plasma concentrations versus time at seven intervals following treatment. Pharmacokinetic parameters were obtained for each participant and included peak plasma concentration (C max), time to reach peak plasma concentration (T max), volume of distribution (V d), elimination half-life (t 1/2), the volume of plasma cleared of the drug per unit time (CL), and total systemic exposure area under the curve (AUC). Fifteen patients were enrolled (5: lymphatic, 4: venous, 6: arteriovenous malformations). Bleomycin was administered interstitially (IS) in 11 patients and intraluminal (IL) in four; median age of 13 years (range: 2–67). Pharmacokinetic analysis revealed terminal elimination half-life (t 1/2λz) of 88.51 (±23.09) and 111.61 (±37.75) minutes for the IS and IL groups, respectively. V d was 4.86 L (±6.74) and 1.55 L (±0.54) for the IS and IL groups, respectively. AUC was 53.9 (±23.45) and 129.17 (±93.57) mg min/L for the IS and IL groups, respectively. There were no statistically significant differences in t 1/2λz, V d, or AUC parameters between groups. Bleomycin is absorbed systemically when used as a sclerosant for vascular malformations when injected either IS or IL.

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Local control of parameningeal rhabdomyosarcoma: An expert consensus guideline from the International Soft Tissue Sarcoma Consortium (INSTRuCT)

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Abstract

The International Soft Tissue Sarcoma Database Consortium (INSTRuCT) consists of a collaboration between the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, the European pediatric Soft Tissue Sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). As part of the larger initiative of INSTRuCT to provide consensus expert opinions for clinical treatment of pediatric soft tissue sarcoma, we sought to provide updated, evidenced-based consensus guidelines for local treatment of parameningeal rhabdomyosarcoma using both existing literature as well as recommendations from the relevant cooperative group clinical trials. Overall, parameningeal rhabdomyosarcoma represents a distinctly challenging disease to treat, given its location near many critical structures in the head and neck, frequently advanced local presentation, and predilection for local failure. Definitive chemoradiation remains the standard treatment approach for parameningeal rhabdo myosarcoma, with surgery often limited to biopsy or salvage therapy for recurrent disease. In this consensus paper, we specifically discuss consensus guidelines and evidence for definitive local management with radiotherapy, with a focus on imaging for radiotherapy planning, dose and timing of radiation, approach for nodal irradiation, various radiation techniques, including proton therapy, and the limited role of surgical resection.

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A novel smartphone‐based intervention targeting sleep difficulties in individuals experiencing psychosis: A feasibility and acceptability evaluation

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Abstract

Objectives

Cognitive Behavioural Therapy (CBT) is an effective psychological intervention for sleep difficulties and has been used successfully in individuals with psychosis. However, access is restricted due to lack of resources and staff training. Delivering CBT for sleep problems using smartphone technology may facilitate wider access. This study aimed to evaluate the feasibility, acceptability and potential usefulness of a guided, smartphone-based CBT intervention targeting sleep disturbance for individuals with psychosis.

Design

Participants with psychosis spectrum diagnoses were recruited to a single-arm, uncontrolled study and engaged with the seven-module programme via smartphone app for six weeks with therapist support.

Method

Feasibility was assessed by rates of referral, recruitment and completion. Acceptability was assessed by app usage, a satisfaction questionnaire and qualitative analysis of participants' semi-structured interview. Pre- and post-intervention assessment of sleep, psychotic experiences, mood, well-being and functioning was conducted. Mean change confidence intervals were calculated and reported as an indication of usefulness.

Results

Fourteen individuals consented to participation, and eleven completed the post-intervention assessment. On average, each participant engaged with 5.6 of 7 available modules. Qualitative feedback indicated the intervention was considered helpful and would be recommended to others. Suggested improvements to app design were provided by participants. Potential treatment benefits were observed for sleep difficulties, and all outcomes considered, except frequency of hallucinatory experiences.

Conclusions

It is feasible and acceptable to deliver therapist-guided CBT for sleep problems by smartphone app for individuals with psychosis. This method provides a low-intensity, accessible intervention, which could be offered more routinely. Further research to determine treatment efficacy is warranted.

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Differences in craniofacial morphology between platybasic and nonplatybasic patients with velopharyngeal dysfunction and control subjects

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Publication date: Available online 28 April 2022

Source: American Journal of Orthodontics and Dentofacial Orthopedics

Author(s): Ariela Nachmani, Muhamed Masalha, Ameen Biadsee, Ben Nageris, Tom Ben-Dov, Firas Kassem

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Medicine, Religion, and the Humanitarian Ethos:

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Abstract
Biographies of Walter B. Cannon (1871-1945) usually present two sides of his life: one, where he was an outstanding man of science in the United States during the so-called "Golden Age of Medicine," and the other, where he was a leading humanitarian activist engaged in myriad causes, notably in the defense of Spanish democracy during the Civil War (1936-1939). However, these biographies fail to take into account that the apparent link between these two sides of his life was his religious conviction.This study summarizes the aims and accomplishments of the American Medical Bureau to Aid the Spanish Democracy (AMBASD) of which Cannon was chair between 1937 and 1939. Then, it examines Cannon's inspirational role on the international relief work with Spanish Republican refugees in France, through the case of the Varsovie Hospital of Toulouse that between 1945 and 1949 was jointly managed by the Unitarian Service Committee (USC) and the Joint An ti-Fascist Refugee Committee (JAFRC), and renamed Varsovie Hospital/Walter B. Cannon Memorial in recognition of the Spanish Republicans' debt for his extraordinary contribution during the Spanish Civil War and beyond. Finally, the article investigates the Unitarian roots of Cannon's humanitarian ethos by exploring the historical relations of this religious movement with science and with many major actors at Harvard University as well as the links of Cannon's relatives to Unitarianism.The analysis reveals Unitarianism's influence on Cannon's views about science, democracy, and liberty, as well as on his remarkable involvement in the medical solidarity movement with the Second Spanish Republic and other similar commitments. In sum, it shows how important is to branch out in our studies of medical and scientific practice to include practitioners' broader social and religious communities in order to understand their motivations, achievements, and behavior.
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Association of comorbidity score with perioperative outcomes following transoral robotic surgery: National analysis

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Abstract

Background

The association of comorbidities with perioperative outcomes after transoral robotic surgery (TORS) is not well-defined in the literature.

Methods

Using the National Cancer Database, 4004 patients with T1-T2 oropharyngeal cancer between 2010 and 2017 were stratified based on their Charlson–Deyo Comorbidity Class (CDCC). Thirty-day unplanned readmissions, 30-day mortality, and 90-day mortality were compared using chi-square test and logistic regression. Hospital length of stay (LOS) was compared using the Kruskal–Wallis test.

Results

LOS was greater for patients with CDCC 2 or 3 compared to CDCC 0 or 1 (p < 0.001). Increasing age and CDCC ≥3 were associated with 30-day mortality (CDCC ≥3: odds ratio [OR] 5.55, 95% confidence interval [CI] 1.59–19.45). CDCC ≥3 (OR 2.61, 95%CI 1.09–6.27) was significantly associated with 30-day readmissions.

Conclusion

This national analysis demonstrates greater rates of unplanned 30-day readmissions, longer hospitalizations, and increased 30- and 90-day mortality after TORS in patients with CDCC ≥3.

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Simulation CT-based radiomics for prediction of response after neoadjuvant chemo-radiotherapy in patients with locally advanced rectal cancer

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To report on the discriminative ability of a simulation Computed Tomography (CT)-based radiomics signature for predicting response to treatment in patients undergoing neoadjuvant chemo-radiation for locally ad...
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Pregnancy Outcome in Women Exposed to Metal Fume in Welding: A Canadian Cohort Study

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Abstract
Objectives
Welding is a physically demanding job that entails exposure to metal fume and particles. There is little information on the effect of welding exposures on the outcome of a pregnancy conceived during a period when a woman was employed as a welder.
Methods
Women welders recruited to the Workers Health in Apprenticeship Trades—Metal and Electrical (WHAT-ME) study were followed-up every 6 months for up to 5 years (January 2011–August 2018), and every pregnancy recorded. At the first 6-month follow-up, a detailed questionnaire was completed for the most recent day in welding, and this information was collected again at each follow-up and also from questionnaires completed during pregnancy. The date of conception was estimated for each pregnancy and the job at that date identified. Exposures to ergonomic factors, work schedule and perceptions of noise, heat and cold were extracted for the job at conception. Exposures t o metals (aluminum, chromium, manganese, and nickel) and particles in welding fume were estimated from previously validated exposure algorithms reflecting the welding process, base metal and consumables of the job at the conception date. The effects of exposures were estimated in multilevel multivariable models allowing for confounding.
Results
There were 242 pregnancies conceived by a welder working in her trade, 87 were before the first follow-up, 3 were after first follow-up but detailed information was not collected, 22 of those potentially included in the assessment group were in-trade but not welding leaving 122 pregnancies in 90 welders for analysis. Of these 91 resulted in a live birth and 31 in a fetal loss (27 miscarriages and 4 stillbirths). Mean birth weight for live births was 3365 g and gestation 39.4 weeks. Final models showed that risk of fetal loss increased with manipulating heavy objects [odds ratio (OR) = 5.13, 95% confidence interval (CI) 2.04–12.92], whole-body vibration (OR = 5.86, 95% CI 1.81–18.92), a higher rating for noise exposure intensity (OR = 1.52, 95% CI 1.24–1.85), and decreased with use of local exhaust ventilation (OR = 0.20, 95% CI 0.03–1.18). Gestation decreased with perceived heat intensity (β = −0.15, 95% CI −0.29 to −0.02) and number of previous pregnancies (β = −0.35, 95% CI −0.65 to −0.05). Birth weight was lower in those reporting whole-body vibration (β = −596 g, 95% CI −924 to −267) and increased with the welder's body mass index (β = 36 g, 95% CI 12–61). Estimates of exposure to metals and particles were unrelated to gestation or birth weight. In a bivariate analysis, allowing for the same welder reporting >1 pregnancy, estimated airborne aluminum exposure (and to a lesser degree exposure to nickel and particles ) was related to greater risk of fetal loss (OR = 1.52, 95% CI 1.04–2.24) but neither aluminum nor the other estimated elements of welding fume added to the final model.
Conclusions
In this group of women actively engaged in welding during the time surrounding conception, the outcome of pregnancy was strongly related to work exposures, particularly vibration (reported in grinding tasks), manipulation of heavy objects, and perceived intensity of noise and heat. The study was unable to show an independent effect of exposure to metal fume constituents.
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Large cell neuroendocrine carcinoma of the floor of mouth and retromolar trigone in association with basaloid squamous cell carcinoma

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Large cell neuroendocrine carcinoma and basaloid squamous cell carcinoma are each rare but aggressive diseases of the head and neck. A case of large cell neuroendocrine carcinoma occurring simultaneously with a basaloid squamous cell carcinoma originating from the oral cavity is described in this report. The diagnosis of these pathologies can be challenging but is important, as staging and treatment recommendations differ from those for oral cavity squamous cell carcinoma. (Source: International Journal of Oral and Maxillofacial Surgery)
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Rivaroxaban population pharmacokinetic and pharmacodynamic modeling

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Rivaroxaban population pharmacokinetic and pharmacodynamic modeling in Iranian patients

A population pharmacokinetic/pharmacodynamic (PKPD) model of rivaroxaban was established in Iranian patients. The model consisted of a one-compartment pharmacokinetic model and a direct link linear equation that described the relationship of rivaroxaban concentration with both prothrombin and activated partial thromboplastin times. The selected model for anti-factor Xa activity consisted of a direct link inhibitory E max model with Hill coefficient. Significant differences were seen in the PKPD model parameters in Iranian patients compared to the values reported in other populations.


Abstract

What is Known and Objective

Although predictable pharmacokinetic and pharmacodynamic of rivaroxaban allow fixed dosing regimens without routine coagulation monitoring, there is still the necessity to monitor and predict the effects of rivaroxaban in specific conditions and different populations. The current study was designed and conducted to analyze the rivaroxaban population pharmacokinetics in Iranian patients and establish a pharmacokinetic/pharmacodynamic model to predict the relationship between rivaroxaban concentration and its anticoagulant activity.

Methods

A sequential nonlinear mixed effect pharmacokinetic/pharmacodynamic modeling method was used to establish the relation between rivaroxaban concentration and anti-factor Xa activity, prothrombin time, and activated partial thromboplastin time (aPTT) as pharmacodynamic biomarkers in a population of sixty-nine Iranian patients under treatment with oral rivaroxaban. Rivaroxaban plasma concentration was quantified by a validated high-performance liquid chromatography-tandem mass spectrometry.

Results and Discussion

The typical population values (inter-individual variability%) of the oral volume of distribution and clearance for a one-compartment model were 61.2 L (21%) and 3.68 L·h−1 (61%), respectively. Creatinine clearance and Child-Turcotte-Pugh score were found to affect the clearance. A direct link linear structural model best fitted the data for both prothrombin time and aPTT. The baseline estimates of aPTT and prothrombin time in the population were 35.0 (15%) and 12.6 (2%) seconds, respectively. The slope of the relationship between apTT, prothrombin time, and rivaroxaban concentration was 0.033 (28%) and 0.018 (54%) s·ml·ng−1, respectively. The selected model for anti-factor Xa activity consisted of a direct link inhibitory E max model with Hill coefficient. The maximum level of inhibition (E max) was 4 IU·ml−1. The concentration of rivaroxaban producing 50% of the maximum inhibitory effect (EC50) was 180 (24%) ng·ml−1, and Hill coefficient (γ) was 1.44 (108%). No covariates showed a statistically significant effect on PT and activated partial thromboplastin time prolonging properties and anti-factor Xa activity.

What is New and Conclusion

Our results confirmed that pharmacokinetic/pharmacodynamic models similar to those of the other studies describe the relationship between the rivaroxaban concentration and its anticoagulant effect in Iranian patients. However, considerable differences were observed in the parameters of the pharmacodynamics–pharmacokinetic models with the results of other reports that can explain the unpredictable effects of rivaroxaban in some patients.

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Pharmacokinetics, safety and efficacy of intra‐articular non‐steroidal anti‐inflammatory drug injections for the treatment of osteoarthritis: A narrative review

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Pharmacokinetics, safety and efficacy of intra-articular non-steroidal anti-inflammatory drug injections for the treatment of osteoarthritis: A narrative review

We provide a comprehensive review on intra-articular (IA) non-steroidal anti-inflammatory drug (NSAID) injections for the treatment of osteoarthritis (OA). We found that single doses of IA NSAIDs provided far less total systemic and synovial exposure compared to a one week course of oral NSAIDs, but maximum concentrations to the synovium with IA administration were much higher. Further, single IA NSAID injections appeared to be safe and efficacious compared to courses of oral NSAIDs or single IA corticosteroids in either small animals, large animals or humans. Further research must be conducted, however, IA NSAIDs could be used as an alternative or adjunct therapy to treat OA related pain, especially for patients that are high risk for corticosteroid related adverse effects.


Abstract

What is known and Objective

Osteoarthritis (OA) is a common cause of joint disease and activity limitation in adults. Common therapies to treat OA-related pain are oral and topical non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular (IA) corticosteroids. However, prolonged courses of oral NSAIDs are associated with systemic adverse effects and repeat IA corticosteroid injections may cause cartilage degeneration. IA NSAIDs may be an alternative therapy possibly minimizing systemic side effects while maintaining efficacy. Therefore, we sought to summarize the pharmacokinetics, safety and efficacy of IA NSAIDs to help providers make a more informed decision on the use of IA NSAIDs.

Methods

We searched the National Library of Medicine Database with terms "intraarticular and nsaid", yielding 1032 results. Only traditional formulations of NSAIDs were considered for inclusion. Animal studies were included if animals were healthy or if the method of arthritis induction was a reasonable model of osteoarthritis. Human studies were included if humans were healthy or if the primary disease studied was osteoarthritis of a large joint. Of 1032 results, 31 research articles met the inclusion criteria and were summarized in this review.

Results and Discussion

We found that single doses of IA NSAIDs provided far less total systemic and synovial exposure compared to a one week course of oral NSAIDs, but maximum concentrations to the synovium with IA administration were much higher. IA NSAIDs had an excellent safety profile in small animals, large animals and humans, although these injections were associated with non-specific cartilage inflammation in healthy animals. In animal models, IA NSAIDs had similar efficacy to PO NSAIDs in treating OA-related pain. In humans, IA NSAIDs had similar efficacy to PO NSAIDS and IA corticosteroids in treating OA-related pain; however, many trials did not have a placebo control and outcome measures were heterogeneous.

What is new and Conclusion

Overall, single doses of IA NSAIDs appear safe and efficacious across animals and humans. The optimal use of IA NSAIDs is still to be determined and further research is needed. However IA NSAIDs may be an additional beneficial therapy to treat OA-related pain. Potential uses may be to augment IA corticosteroids injections, to interrupt multiple IA corticosteroid injections or as an alternative in patients that are high risk for corticosteroid-related adverse events.

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