Dose Changes Research Articles

Changes in DOM and alum doses for two rivers of contrasting catchments after intense wildfires

ABSTRACT The dynamics of dissolved organic matter (DOM) in two river waters were investigated after their catchments had been severely burnt in the 2019/2020 Australian wildfires. Shortly after these wildfires, dissolved organic carbon (DOC) concentrations were recorded at high levels (∼19 and 30 mg/L) and these became much lower (up to ∼80% less) in the following winter when river flows had increased. Satellite imagery-based data indicated up to 95% of catchment areas burnt and up to ∼50% subsequent vegetation recoveries after 2 years. Shifts in burn index values for the burnt areas coincided with DOC concentration variations. The specific colour of waters increased up to 40% as daily river flows increased, indicating higher input of humic content from the burnt catchments. Chlorophyll a was detected at the highest levels in the waters soon after the fires when river flows were lowest. Enhanced alum doses were predicted using two feed-forward models; one based on DOC and turbidity data and the other based on UV@254 nm, colour, and turbidity. The doses predicted using the two models showed high correlations (r > 0.9) and were highest for waters directly after the fires. These models were developed for diverse source waters including those impacted by extreme climate events.

Variability of solar UV radiation in the northern mountains of the Czech Republic, 2020–2021

Solar ultraviolet (UV) radiation has a crucial role in many atmospheric processes and a huge impact on living organisms. Its main positive effect is the synthesis of vitamin D, but it also causes problems such as sunburn, skin cancer or eye cataracts. In the mountains, high doses of UV frequently occur due to a specific combination of atmospheric and geographical factors such as a high ground reflection as a consequence of a large number of days with snow cover, or a lower concentration of atmospheric pollutants in comparison to lowland urban regions. This study used measurements of erythemal UV radiation from two high altitude areas: the Hrubý Jeseník Mountains (Vysoká hole meteorological station, 1 464 m a.s.l.) and the Giant Mountains (Luční bouda meteorological station, 1 413 m a.s.l.) in the Czech Republic, during 2020 and 2021. We evaluated the daily and monthly changes in erythemal dose and UV index. The maximum daily dose of 5.0 kJ.m-2 (8.9 of UV index) was measured on 28 June 2020 at Vysoká hole. The maximal UV index of 10.1 was observed at Luční bouda on 5 July 2020, while the maximum daily dose of 4.9 kJ.m-2 occurred on 14 June 2021. The main factors that caused changes in solar UV radiation were the amount of cloud cover as well as the total ozone column.

Plasma Renin: A Useful Marker for Mineralocorticoid Adjustment in Patients With Primary Adrenal Insufficiency.

Renin is a marker of blood volume. There is no consensus on the validity of plasma renin measurement for adjusting mineralocorticoid (MC) substitution in patients with primary adrenal insufficiency (PAI). This work aimed to investigate if plasma renin could be used to adjust MC substitution in patients with PAI. A total of 150 patients with at least one measurement of plasma renin followed for PAI at 2 tertiary expert centers between 2008 and 2022 were retrospectively included. As supraphysiological hydrocortisone might have additional MC activity, we integrated the individual hydrocortisone dose to obtain the MC equivalent dose (Eq-MC). Renin less than 20 mIU/L was considered oversubstituted, renin between 20 and 60 mIU/L as correctly substituted, and renin over 60 mIU/L as undersubstituted. The mean dose of fludrocortisone was 82.3 ± 46 μg/day. Plasma renin was abnormal in 56.7% of cases (7 patients oversubstituted and 78 patients undersubstituted). Abnormalities in electrolyte levels were observed in only 12.7% of patients. Plasma renin correlated negatively with sodium (P < .01) and systolic blood pressure (P = .026), and positively with potassium (P < .01). Doses changes in Eq-MC had a statistically significant effect on renin levels (P = .0037), with an increase of MC dose correlating with a decrease in renin level and vice versa; no correlation was observed using electrolytes or blood pressure. Plasma renin correlates with electrolytes and blood pressure. While dose changes significantly alter renin levels, electrolytes and blood pressure do not, suggesting that renin may provide more information about MC replacement therapy than electrolytes and blood pressure.

Linear energy transfer dependent variation in viability and proliferation along the Bragg peak curve in sarcoma and normal tissue cells

Objective.The energy deposition of photons and protons differs. It depends on the position in the proton Bragg peak (BP) and the linear energy transfer (LET) leading to a variable relative biological effectiveness (RBE). Here, we investigate LET dependent alterations on metabolic viability and proliferation of sarcoma and endothelium cell lines following proton irradiation in comparison to photon exposure.Approach.Using a multi-step range shifter, each column of a 96-well plate was positioned in a different depth along four BP curves with increasing intensities. The high-throughput experimental setup covers dose, LET, and RBE changes seen in a treatment field. Photon irradiation was performed to calculate the RBE along the BP curve. Two biological information out of one experiment were extracted allowing a correlation between metabolic viability and proliferation of the cells.Main results.The metabolic viability and cellular proliferation were column-wise altered showing a depth-dose profile. Endothelium cell viability recovers within 96 h post BP irradiation while sarcoma cell viability remains reduced. Highest RBE values were observed at the BP distal fall-off regarding proliferation of the sarcoma and endothelial cells.Significance.The high-throughput experimental setup introduced here (I) covers dose, LET, and RBE changes seen in a treatment field, (II) measures short-term effects within 48 h to 96 h post irradiation, and (III) can additionally be transferred to various cell types without time consuming experimental adaptations. Traditionally, RBE values are calculated from clonogenic cell survival. Measured RBE profiles strongly depend on physical characteristics such as dose and LET and biological characteristics for example cell type and time point. Metabolic viability and proliferation proofed to be in a similar effect range compared to clonogenic survival results. Based on limited data of combined irradiation with doxorubicin, future experiments will test combined treatment with systemic therapies applied in clinics e.g. cyclin-dependent inhibitors.

A multi-centre, tolerability study of a cannabidiol-enriched Cannabis Herbal Extract for chronic headaches in adolescents: The CAN-CHA protocol

Introduction Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents. Methods and analysis Youth, parents, and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2–0.4 mg/kg of CBD per day and escalating monthly up to 0.8–1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE. Discussion This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials. Trial registration CAN-CHA trial is registered with ClinicalTrials.gov with a number of register NCT05337033.

Evaluation of voriconazole therapeutic drug monitoring in malignant hematology patients.

Malignant hematology (MH) patients are susceptible to invasive fungal infections due to prolonged neutropenia and immunosuppressive therapies, which may require voriconazole therapy. Although voriconazole therapeutic drug monitoring (TDM) is common, evidence describing this practice is limited. The primary objective of this study was to describe the current practice of voriconazole TDM in MH patients at the Princess Margaret Cancer Centre (PM). A retrospective chart review was conducted for MH inpatients initiated on voriconazole at PM between November 1st, 2019 and November 13th, 2020. Data regarding voriconazole doses, levels, dose changes, and adverse effects were collected. The primary endpoint was the proportion of patients with initial voriconazole levels within therapeutic range (1-5 mg/L). Fifty-six patients were included in the study. The most common reason for starting voriconazole was possible invasive fungal infection (44 patients, 78.6%). Fifty-one patients (91.1%) received a loading dose of voriconazole, averaging 386.5 ± 78.5 mg. The average maintenance dose was 242.1 ± 45.7 mg. An average of 2.6 ± 2.9 levels were drawn per patient with an average level of 3.2 ± 2.4 mg/L. Forty-one patients (73.2%) had an initial voriconazole level within therapeutic range and 90 out of 145 total levels (62.1%) were within therapeutic range. There were 52 dose modifications made; 31 (60.8%) doses adjusted, 12 (23.5%) doses held, and 9 (17.6%) doses discontinued. For the 31 dose adjustments, 26 (83.9%) had a level redrawn and 17 (65.4%) of those levels were within therapeutic range. Twenty-three (41.1%) patients developed adverse effects, 8 (34.8%) of which were associated with supratherapeutic levels. Of these 23 patients, 19 (33.9%) experienced transaminitis, 3 (5.4%) experienced both transaminitis and neurotoxicity, and 1 (1.8%) experienced photopsia. Overall, 41 (73.2%) patients achieved an initial voriconazole level within therapeutic range. Of these 41 patients, 30 (73.2%) remained within therapeutic range for the duration of their inpatient voriconazole therapy. These findings suggest that the current practice of voriconazole TDM at our institution is yielding largely positive results, but still has room for improvement.

A drug mix and dose decision algorithm for individualized type 2 diabetes management

Pharmacotherapy guidelines for type 2 diabetes (T2D) emphasize patient-centered care, but applying this approach effectively in outpatient practice remains challenging. Data-driven treatment optimization approaches could enhance individualized T2D management, but current approaches cannot account for drug-specific and dose-dependent variations in safety and efficacy. We developed and evaluated an AI Drug mix and dose Advisor (AIDA) for glycemic management, using electronic medical records from 107,854 T2D patients in the SingHealth Diabetes Registry. Given a patient’s medical profile, AIDA leverages a predict-then-optimize approach to identify the minimal drug mix and dose changes required to optimize glycemic control, subject to clinical knowledge-based guidelines. On unseen data from large internal, external, and temporal validation sets, AIDA recommendations were estimated to improve post-visit glycated hemoglobin (HbA1c) by an average of 0.40–0.68% over standard of care (P < 0.0001). In qualitative evaluations on 60 diverse cases by a panel of three endocrinologists, AIDA recommendations were mostly rated as reasonable and precise. Finally, AIDA’s ability to account for drug-dose specifics offered several advantages over competing methods, including greater consistency with practice preferences and clinical guidelines for practical but effective options, indication-based treatments, and renal dosing. As AIDA provides drug-dose recommendations to improve outcomes for individual T2D patients, it could be used for clinical decision support at point-of-care, especially in resource-limited settings.

Mycophenolate Mofetil and New-Onset Systemic Lupus Erythematosus

Anti-double-stranded DNA (dsDNA) antibody has been reported to have a close relationship with systemic lupus erythematosus (SLE) flares and participates in the pathogenesis of lupus nephritis (LN) as well as causing damage to other organs. However, whether early use of mycophenolate mofetil (MMF) could prevent SLE flares is not clear. To assess the efficacy and safety of MMF plus prednisone and hydroxychloroquine sulfate compared with prednisone and hydroxychloroquine sulfate alone in patients with SLE. This investigator-initiated, multicenter, observer-blinded randomized clinical trial enrolled 130 participants aged 18 to 65 years and was conducted in 3 hospitals across China. Treatment-naive patients with newly diagnosed SLE, a high titer of anti-dsDNA antibody, and no major organ involvement were included. The study was started September 1, 2018, and the follow-up was completed September 30, 2021. Data were analyzed from December 1, 2021, to March 31, 2022. Patients were randomized 1:1 to receive oral prednisone (0.5 mg/kg/d) and hydroxychloroquine sulfate (5 mg/kg/d) (control group) or prednisone (0.5 mg/kg/d) and hydroxychloroquine sulfate (5 mg/kg/d) plus MMF (500 mg twice daily) (MMF group) for 96 weeks. The primary outcome was the proportion of patients presenting with flares according to the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Flare Index. The secondary outcomes included the proportion with lupus low disease activity state at week 96, 36-Item Short Form Health Survey scores before and after treatment, proportion of adverse events (AEs), and changes in SLEDAI-2000 scores and prednisone doses. Among 130 randomized patients (mean [SD] age, 34.5 [12.5] years; 112 [86.2%] women), 119 (91.5%) completed the follow-up. The risk of severe flare was significantly lower in the MMF group (7 of 65 [10.8%]) vs the control group (18 of 65 [27.7%]) (relative risk [RR], 0.39 [95% CI, 0.17-0.87]; P = .01). Additionally, 1 of 65 patients in the MMF group (1.5%) and 9 of 65 in the control group (13.8%) manifested LN (RR, 0.11 [95% CI, 0.01-0.85]; P = .008). Most common serious study drug-related AEs were infections (20 of 65 [30.8%] in the control group and 22 of 65 [33.8%] in the MMF group). The findings of this randomized clinical trial suggest that MMF may reduce the rate of severe flare and lower the incidence of LN in patients with new-onset SLE and a high titer of anti-dsDNA antibody without major organ involvement. Chinese Clinical Trial Registry: ChiCTR1800017540.

Novel evidence of CNV deletion in KCTD13 related to the severity of isolated hypospadias in Chinese population.

CNV in KCTD13 has been identified to influence androgen receptor function via its changes in gene dosage, which might contribute to hypospadias. However, there is lack of population-level evidence to assess the contribution of KCTD13 CNV to hypospadias. 349 isolated hypospadias patients were recruited and their genotyping was performed using real-time qPCR. We use Database of Genomic Variants (DGV) and CNV calls from SNP-array intensity data in 1,008 Chinese healthy men as reference. 11.17% of patients were identified to have KCTD13 CNV deletion, significantly higher than 0.05% in DGV (P < 0.001), but no cases found to have CNV duplication. Meanwhile, no CNV calls encompassing KCTD13 region were detected in Chinese healthy men. Incidence of KCTD13 CNV deletion was significantly increased with the severity of hypospadias, P _trend = 9.00 × 10-6. Compared to distal hypospadias, ORs for the proximal and midshaft were 10.07 (2.91-34.84) and 6.08 (1.69-21.84) respectively. In addition, the association between genital characteristics (stretched penile length and glans width) and KCTD13 CNV showed no significance in hypospadias children (P > 0.05). We demonstrate KCTD13 CNV deletion is strongly associated with hypospadias and its severity, but duplication is not, characterizing KCTD13 genetic variation in more detail than previously described.

Assessing antidepressant exposure and response using UK electronic health record data

Objective and ApproachMany people do not respond to antidepressants and our poor mechanistic understanding of antidepressant response has hampered efforts to personalise treatment. Understanding how and when antidepressants work at an individual level requires real-world antidepressant exposure and response data, at scale. To date, studies have rarely had access to sufficiently detailed clinical data at the scales needed to derive such phenotypes and track them longitudinally. Indeed, many studies use research-based measures and phenotypes that are not commonly used in clinical settings, making translation to clinically-applicable tools difficult. This study aims to develop novel measures of antidepressant treatment exposure and response by capitalising on the variety and volume of UK clinical records. We identify cases of depression from national primary and secondary care records, and derive longitudinal antidepressant treatment episodes from national community dispensing data. ResultsFocusing on the Generation Scotland cohort (N = 21,000), we describe common antidepressant treatment trajectories and identify changes in medication, dose and strength. We examine the frequency of drug switching, augmentation, and drug stability, contrasting these to other UK linked cohorts. We also describe the demographic characteristics of those defined as treatment resistant and those identified as in drug maintenance. ConclusionsLinked electronic records provide the opportunity to track antidepressant exposure and response longitudinally. Changes in treatment can provide new measures that help to better understand treatment resistance and maintenance. ImplicationsBy better tracking antidepressant response, the present study helps inform mechanistic research to understand treatment effectiveness and ultimately to develop personalised treatments.

Riboflavin as a Coloring Agent of Tablets Affects the Photostability of Manidipine after the Change of Dosage Forms

Manidipine (MP) is widely used for reducing high blood pressure. Calslot® (CALS) tablets, which are the original MP medicines, and their generic medicines have been used for patients in clinical situations. The authors hypothesized that the photodegradability of MP drug substance in CALS tablets might be enhanced when the tablets were photo-exposed after the change of the dosage form by the presence of riboflavin (RF), which is utilized as a coloring agent and a well-known photosensitizer. The present study clarified that RF enhanced the photodegradation of MP when the powders and the suspensions of CALS tablets were ultraviolet light (UV) irradiated. The addition of RF to the suspension of MP standard substances also promoted MP photodegradation along with the increase of the generation rate of its main photoproduct, benzophenone. Finally, the authors performed the photostabilization of MP suspensions based on the addition of quercetin (QU), which is one of polyphenols and has both the antioxidative potency and the UV filtering potency. It is summarized that QU has a protective potency for MP’s own photodegradation, and it partially suppresses the photocatalytic effect of RF. Further studies focused on the photochemical behaviors of utilized additives for medicines are needed for their safe use.

RING1 missense variants reveal sensitivity of DNA damage repair to H2A monoubiquitination dosage during neurogenesis

Polycomb repressive complex 1 (PRC1) modifies chromatin through catalysis of histone H2A lysine 119 monoubiquitination (H2AK119ub1). RING1 and RNF2 interchangeably serve as the catalytic subunit within PRC1. Pathogenic missense variants in PRC1 core components reveal functions of these proteins that are obscured in knockout models. While Ring1a knockout models remain healthy, the microcephaly and neuropsychiatric phenotypes associated with a pathogenic RING1 missense variant implicate unappreciated functions. Using an in vitro model of neurodevelopment, we observe that RING1 contributes to the broad placement of H2AK119ub1, and that its targets overlap with those of RNF2. PRC1 complexes harboring hypomorphic RING1 bind target loci but do not catalyze H2AK119ub1, reducing H2AK119ub1 by preventing catalytically active complexes from accessing the locus. This results in delayed DNA damage repair and cell cycle progression in neural progenitor cells (NPCs). Conversely, reduced H2AK119ub1 due to hypomorphic RING1 does not generate differential expression that impacts NPC differentiation. In contrast, hypomorphic RNF2 generates a greater reduction in H2AK119ub1 that results in both delayed DNA repair and widespread transcriptional changes. These findings suggest that the DNA damage response is more sensitive to H2AK119ub1 dosage change than is regulation of gene expression.

Implementation of a pharmacist-guided pharmacogenomics dosing service at a rural NCI-designated comprehensive cancer center.

The goal of pharmacogenetic testing is to identify genetic variants with significant implications on drug safety and efficacy. Several professional organizations and institutions have demonstrated the value of pharmacist involvement in the implementation of pharmacogenomic services. Therefore, we aimed to establish a pharmacist-guided model for interpretation of pharmacogenetic results for all oncology patients seen at the Dartmouth Cancer Center (DCC) in Lebanon, NH. A pilot of a pharmacist-guided pharmacogenomics dosing service was implemented at the DCC. Pharmacy services included review of results from a next generation sequencing panel for DPYD, TPMT, NUDT15, and UGT1A1 variants. The pharmacist wrote a note in the electronic health record (EHR) detailing actionable drug-gene interactions and drug-dosing guidance, which was then routed to the treating oncologist. Outcomes collected included highlighting actionable mutations and defining pharmacist interventions. In addition, time spent formulating and documenting patient-specific drug-dosing recommendations was collected. From February 2024 through May 2024, a total of 71 patients with pharmacogenetic results, provided by the clinical molecular laboratory at Dartmouth Health, were reviewed by the pharmacist. The majority of patients tested were diagnosed with a malignancy of gastrointestinal origin. Twenty-one patients were found to have actionable variants in at least one of the four genes evaluated, and five of the 21 identified patients had active treatment plans for which dose changes were then implemented. Implementation of a pharmacist-guided pharmacogenomics based dosing service aided in optimizing drug therapy and has positioned Dartmouth Health for further expansion of pharmacogenomics and personalized patient care.

Effects of electron density force to 1.0 and fill to 1.0 on VMAT treatment plans for lung SBRT.

The aim of this study is to determine the effect of forcing and filling the electron density (ED) to 1.0 of the planning target volume (PTV) overdose distribution in lung SBRT treatment leading to shortening patient treatment time and increasing patient comfort by reducing MU/fraction due to ED manipulation effect. In this study, 36 lung SBRT plans of 12 suitable patients who prescribed a total dose of 50Gy in five fractions were generated with Monaco v.5.10 TPS using the Monte Carlo (MC) algorithm and volumetric modulated arc therapy (VMAT) technique by PTV ED values forcing as well as filling to 1.0 and comparatively assessed. The first group of plans was created by using the patient's original ED, second and third groups of plans were reoptimized by forcing and filling the ED of PTV to 1.0, respectively, therefore acquiring a new dose distribution which lead to comparatively assessment the effects of changes in ED on PTV and OAR doses. Assessment of treatment plans revealed that mean MU/fx numbers were decreased by 76% and 75.25% between Groups 1 and 2, Groups 1 and 3, respectively. The number of segments was also reduced in Group 1 by up to 15% compared with Groups 2 and 3. Maximum HI and CI differences for PTV between Groups 1 and 2 were less than 1% and Groups 1 and 3 were 1.5% which indicates all 3 group plans were comparable in terms of dose distribution within PTV. Forcing and filling the ED of PTV to 1.0 strategy has provided reduced a number of segments and MU/fx without a significant change in PTV mean and maximum doses, thereby decreasing treatment time and patient discomfort during treatment. This process should be considered in line of a potential number of patients as well as prescribed dose and MU/fx numbers.

Improved Clinical Outcomes with the Combination Therapy of a Glucagon-like Peptide-1 Receptor Agonists and a Sodium-glucose Cotransporter-2 Inhibitor in Overweight/Obese People with Type 2 Diabetes: Real-world Evidence from the Indian Subcontinent.

Type 2 diabetes (T2D) mellitus is increasing exponentially in India, with overweight/obesity being prime contributors. This study aimed at assessing the clinical impact of the combination therapy of a glucagon-like peptide-1 receptor agonist (GLP-1RA) injection (inj.) and a sodium-glucose cotransporter-2 inhibitor (SGLT-2i) in overweight/obese patients from the Indian subcontinent. In two real-world evidence (RWE) studies (RWE1 and 2), we retrospectively observed the effect of the combination therapy of a GLP-1RA, injection dulaglutide (DU) 1.5 mg/week, and an SGLT-2i, canagliflozin (CAN) 100 mg/day at weeks 16, 32, and 52 on HbA1c, body weight (weight), systolic blood pressure (SBP), lipids, change in doses of antidiabetic agents (ADA) and antihypertensive agents (AHA) in overweight/obese Asian Indian subjects with T2D, who had suboptimal glycemic control. A total of 95 T2D patients [51 males (M), 44 females (F)] completed the two RWE studies. In RWE 1, 40 patients (20 M/20 F), mean [standard deviation (SD)] age 49.4 (10.7) years (Y), weight 92.6 (6.6) kg, body mass index (BMI) 30.6 (2.3) kg/m2, duration of T2D 8.1 (3.2) Y, completed the study. At week 32, the mean (SD) reduction in A1c (%) was -1.3% [8.4 (0.7) to 7.1 (0.3); p < 0.01] and mean (SD) weight (kg) loss was -5.5 [92.6 (6.6) to 87.9 (7.02); p < 0.00001]. This group was then followed up until week 52. In RWE 2, 55 patients (31 M/24 F), age 51 (5.8) Y, weight 92.6 ± 3.4 kg, BMI 31.1 ± 2.1 kg/m2, SBP 142.4 ± 3.9 mm Hg, estimated glomerular filtration rate (eGFR) 62 ± 5 mL/minute/1.73 m2, with 8.4 ± 3.3 Y duration of diabetes met the inclusion criteria. In 71% of subjects, A1c decreased by -1.4% [8.5 ± 0.4 to 7.1 ± 0.2; p < 0.0001] at week 16 and was 6.8 ± 0.3 (p = 0.0002) in 18% at week 32. A statistically significant (SS) improvement in glycemic control, weight, and improvement in cardiovascular (CV) risk factors was observed with the GLP-1RA/SGLT-2i combination, which was well tolerated.

Prevalence of actionable pharmacogenetic variants and high-risk drug prescriptions: A Swiss hospital-based cohort study.

Drug type and dosing recommendation have been designed and optimized based on average response in the general population. Yet, there is significant inter-individual variability in drug response, which results in treatment inefficacy or adverse drug reactions in a subset of patients. This is partly due to genetic factors that typically affect drug metabolism or clearance. To verify the relevance and applicability of international pharmacogenetic guidelines in the Swiss population, we genotyped 1533 patients from a hospital-based biobank who received at least 30 different drugs, as documented in their electronic health record. We then assessed the prevalence of clinically actionable variants in 13 high-risk pharmacogenes. We compared the allele frequencies obtained in the hospital-based cohort with those of a Swiss population-based cohort of 4791 individuals. The prevalence of clinically actionable variants was comparable between the two cohorts, with most study participants (97.3%) carrying at least one actionable pharmacogenetic variant. We then assessed the frequency of high-risk prescriptions due to actionable gene-drug interactions and observed that 31% of patients in the hospital-based cohort were prescribed at least one drug for which they carried a high-risk variant, and for which international guidelines recommend a change of drug or dosage. Our analysis confirms the high prevalence of actionable pharmacogenetic variants in the Swiss population. It also shows that a substantial minority of patients are exposed to drugs for which they carry potentially problematic variants. Implementing a genetically informed approach to drug prescribing could have a positive impact on the quality of healthcare delivery.

Orlando Veterans Affairs stratification tool for opioid risk mitigation (STORM) very high risk interdisciplinary team review: A brief report

BackgroundCompared to the general population, Veterans Health Administration (VHA) patients have higher rates of mental illness, chronic pain, and substance use disorders (SUD), conditions that increase risk for opioid-related adverse events. VHA developed the Stratification Tool for Opioid Risk Mitigation (STORM) and mandated case reviews by an interdisciplinary team (IDT) for patients identified as very high risk, a process implemented and led by clinical pharmacist practitioners at the Orlando Veterans Affairs Healthcare System (OVAHCS) in 2018. ObjectiveTo evaluate and describe the implementation and process for IDT reviews of patients identified as very high risk by the STORM clinical decision support tool at OVAHCS. MethodsA single center, retrospective, observational chart review was conducted. Veterans reviewed by the STORM IDT between January and September 2018 were reviewed for change in Morphine Equivalent Daily Dose (MEDD), naloxone, nonopioid analgesics, medications for SUD, benzodiazepines, engagement with clinical services (e.g., mental health, SUD, and pain clinic), and overdose or suicide attempts in the year prior versus the year after IDT review. The frequency of follow-up IDT reviews was evaluated. ResultsSeventeen patients were identified. Four were excluded due to nonopioid related death within 12 months after review. The average baseline MEDD was 82.2 mg (range 10–496 mg) and average 12 months after review was 7.5 mg (range 0 – 67.5 mg), a decrease of 74.7 mg, or 90.9% reduction. An increase in medications for SUD (3 patients; 23%), SUD engagement (3 to 6 patients), and urine drug tests was observed (79% increase). Benzodiazepine use decreased by 50%. ConclusionThis report provides insight on the IDT case review process at OVAHCS, a process that may vary widely across facilities. A reduction in MEDD, increase in SUD treatment, and improved risk mitigation was observed. The central role of clinical pharmacy and expanded process for continued follow-up warrants further study.

Use of real-time electronic extremity dosimeters for monitoring and optimisation of radiopharmacy technique

Radiopharmacy staff members are subject to extremity radiation doses, particularly to the fingertips. Dosemeters, such as, thermoluminescent detectors (TLDs) are currently used for monitoring fingertip doses. This study aimed to use real-time dosemeters to monitor radiopharmacy extremity doses to identify specific procedural steps associated with higher fingertip doses and, subsequently, reduce dose through promotion of optimised radiation protection practises. Five radiopharmacy operators were monitored using an ED3 active extremity dosemeter with a detector attached to each tip of the index fingers. Dose rate and accumulated dose data were matched to the handled radioactivity data, of99mTc-labelled radiopharmaceuticals only, with the dose per activity (μSv MBq-1) calculated for each step. Once baseline dose data was established, an educational session identified technique adjustments toward improved radiation protection. A subsequent monitored session was undertaken with the dose data compared to quantify changes in operator doses. Radiopharmacy steps which significantly contributed to extremity doses were identified. The average accumulated dose per activity across all procedural steps for the99mTc-labelled radiopharmaceuticals for all operators before the educational session was 0.042 ± 0.045μSv MBq-1and 0.042 ± 0.041μSv MBq-1(n= 89) for non-dominant and dominant index fingertips, respectively, and 0.030 ± 0.044μSv MBq-1and 0.031 ± 0.032μSv MBq-1(n= 97), respectively, afterwards. Overall, there was an average 40.7% reduction in the total extremity dose received after the educational session. Real-time electronic extremity dosemeters for monitoring radiopharmacy extremity dose presented as a useful tool for incorporation into radiation protection education and training, towards optimised radiopharmacy technique.

Real-World Effectiveness of Mepolizumab in Severe Asthma: Results from the Multi-country, Self-controlled Nucala Effectiveness Study (NEST).

The Nucala Effectiveness Study (NEST) assessed the effectiveness of mepolizumab in patients with severe asthma (SA) in countries previously underrepresented in real-world studies. A multi-country, bi-directional, self-controlled, observational cohort study conducted in Colombia, Chile, India, Türkiye, Saudi Arabia, United Arab Emirates, Kuwait, Oman, and Qatar. Historical and/or prospective data from patients with SA were assessed 12months pre- and post-mepolizumab initiation. incident rate ratio (IRR) of clinically significant exacerbations (CSEs). Key secondary endpoints: healthcare resource utilisation (HCRU), oral corticosteroid (OCS) use, lung function and symptom control (Asthma Control Test [ACT] scores). Overall, 525 patients with SA burden pre-initiation (geometric mean blood eosinophil count [BEC] 490.7 cells/µl; 31.4% prior biologic use; 37.3% obese) received at least one dose of mepolizumab 100mg subcutaneously. Post-initiation, a significant reduction in CSEs was observed (76% [p < 0.001]; IRR [95% confidence interval] 0.24 [0.19-0.30]); 72.0% of patients had no CSEs. Mepolizumab treatment led to a reduction in OCS use (52.8% pre-initiation vs. 16.6% post-initiation) and a mean (standard deviation [SD]) change in OCS dose of -18.1 (20.7) mg post-initiation; 36.1% of patients became OCS-free. Fewer patients were hospitalised post-initiation (22.5% pre-initiation vs. 6.9% post-initiation). Improvements in mean (SD) forced expiratory volume in 1s (62.8 [20.2]% pre-initiation vs. 73.0 [22.7]% post-initiation) and ACT scores (15.0% pre-initiation vs. 64.5% of patients post-initiation with well-controlled asthma) were observed. Proportion of patients with BEC ≥ 500 cells/µl decreased from 84.4% pre-initiation to 18.1% post-initiation. Mepolizumab was effective in reducing the burden of SA by significantly reducing CSEs, reducing OCS use and HCRU, and improving lung function and asthma control, which could translate to improvements in health-related quality of life in patients with SA and high OCS dependency in the countries studied. A graphical abstract is available with this article.

Structural regulation and property balancing of ethylene‐propylene‐diene monomer‐based oil‐absorbing expandable rubber modified with flexible α‐olefins

AbstractTo regulate the comprehensive performance of ethylene‐propylene‐diene monomer (EPDM)‐based oil‐absorbing expandable rubber, a series of irradiated α‐olefin‐EPDM7001 rubbers (EOR7001‐X‐Y) are prepared. The influence of the carbon chain length and content of α‐olefins on the structure and properties of the rubber is systematically investigated. Results show that EOR7001‐X‐Y possesses a cross‐linked network structure, and its gel fraction decreases gradually with the increase in carbon chain length and content of α‐olefins. The incorporation of α‐octadecene successfully creates micro‐nanoscale porous structures within the rubber matrix, providing favorable conditions for oil absorption. The introduction of α‐olefins and changes in irradiation dose do not significantly affect the thermal stability of EPDM7001 rubber. The tensile strength slightly reduces, while elongation at break significantly increases, improving the deformation capability. EOR7001‐18‐20 demonstrates exceptional resistance to aging and withstands external forces even after oil absorption. This study supports the development of high‐performance oil‐absorbing expandable rubber.