Safety Assessment Research Articles

Use of the DTRAX Posterior Cervical Facet Joint Fusion and Distraction Device: A Case Series Including 50 Patients

Objective: This retrospective study aimed to assess the efficacy, safety, and feasibility of the DTRAX system for posterior cervical facet fusion in cervical degenerative pathology.Methods: A retrospective analysis of 50 cases involving DTRAX for posterior cervical facet fusion between January 2017 and January 2022. Patient selection criteria, surgical techniques, outcome measures, and data analysis methods were defined.Results: Among the 50 patients included in this study, 21 were women (42%) and 29 were men (58%). Fusion levels varied, with 36 patients undergoing fusion at a single level (72%), 12 at 2 levels (24%), and 2 at 3 levels (4%), totalling 132 implants. The average age was 44.26 years; most patients presented with neck pain, and 23 also reported arm pain (46%). Discharge within 24 hours was common. Pseudoarthrosis was the leading indication (32%), followed by foraminal stenosis (28%) and failed prosthetic implants (24%). Postoperatively, significant reductions in neck and radicular pain were observed, with visual analogue scale scores decreasing steadily over 12 months (p<0.001). Functional improvements, measured by Neck Disability Index scores, were sustained, with a slight increase at 6 and 12 months (p<0.001). The fusion rates at 6 and 12 months were 88% and 96%, respectively. Complications were infrequent, including transient paraesthesia (2%), anterior revision surgery for foraminal stenosis (2%), and suboptimal implant positioning (4%).Conclusion: Favourable clinical and functional outcomes, high fusion rates, and relatively low complication rates were observed with the DTRAX system. Further studies are needed for validation and long-term assessment of efficacy and safety.

Unveiling the Contamination Patterns of Neonicotinoid Insecticides: Detection, Distribution, and Risk Assessment in Panax notoginseng across Plant Parts.

This study analyzed neonicotinoid insecticides (NEOs) and metabolite (m-NEOs) residues in 136 Panax notoginseng samples via ultra-performance liquid chromatography-tandem mass spectrometry. Imidacloprid was the most detected NEO (88.24% of samples), ranging from 1.50 to 2850 μg/kg. To the best of our knowledge, some novel NEOs were detected in P. notoginseng for the first time. NEO clustering patterns varied among plant parts, with higher contamination in leaves and flowers. Fourteen NEO/m-NEOs, including cycloxaprid and acetamiprid, showed site-specific behavior, indicating the possibility of using multiple NEOs simultaneously during planting, resulting in formation of distinct metabolites in different plant parts. Transfer rates in decoction and infusion ranged from 10.06 to 32.33%, reducing residues postprocessing. Dietary risk assessment showed low hazard quotients (HQa: 7.05 × 10-7 to 2.09 × 10-2; HQc: 3.74 × 10-7 to 2.38 × 10-3), but risk-ranking scores indicated potential hazards with imidacloprid and acetamiprid in flowers and leaves. The findings are expected to promote safety assessment and distribution research of NEOs in plants.

Safety Assessment of Sedation Services in Radiology at Shaukat Khanum Memorial Cancer Hospital and Research Center, Peshawar

Objective: The purpose of this retrospective observational study was to evaluate the safety of newly started sedation services in the department of Radiology Shaukat Khanum Memorial Cancer Hospital and Research Center Peshawar, Pakistan. Methods: Medical record of the patients who underwent sedation for different types of imaging studies at Shaukat Khanum Memorial Cancer Hospital, Peshawar center were retrospectively reviewed to evaluate the safety outcome of sedation. Process variables included preoperative assessment, obtaining informed consent acquisition, confirmation of nulla per os (NPO) status, monitoring during the procedure, post-anesthetic care unit (PACU) handover, and discharge instructions. The monitored complications included instances of cardiac arrest, respiratory arrest, hypoxia, apnea and vomiting. Results: No major adverse events, such as respiratory or cardiovascular arrest, were observed among the patients in our study. A limited number of cases experienced minor events, specifically hypoxia and apnea, all of which were effectively addressed through simple maneuvers. However, one patient with previously undiagnosed obstructive sleep apnea encountered upper airway obstruction, necessitating the discontinuation of the procedure. Subsequently, all patients were safely discharged to their homes from the recovery area. Conclusion: Sedation in Radiology department can be safely performed by adhering to a structured approach aligned with hospital policies and procedures. doi: https://doi.org/10.12669/pjms.40.8.9326 How to cite this: Mansoor F. Safety Assessment of Sedation Services in Radiology at Shaukat Khanum Memorial Cancer Hospital and Research Center, Peshawar. Pak J Med Sci. 2024;40(8):---------. doi: https://doi.org/10.12669/pjms.40.8.9326 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

WAVE SPECTRUM ANALYSIS FOR OPERATIONAL OFFSHORE PLATFORM IN MALAYSIA WATER

As an ageing platform has passed its design life of 20 to 30 years, it is crucial to identify wether it is still fit for operation based on the current environmental behaviour, particularly due to the wave impact. Hence, an analytical approach of wave spectrum analysis between the wave behaviour and offshore structural response will be conducted. The aim is to verify the stability and safety of ageing offshore platforms with the current wave behaviour based on identifying wave characteristics, developing a normalized wave energy spectral density, and analyzing the natural frequency of offshore structural response. The methodology includes data collection from structural dynamic monitoring assessments, wave spectrum development using empirical models, and evaluation of offshore platform stability. The results will provide insights into platform stability, resonance risks, and safety assessment of ageing offshore platforms in Malaysian waters. The findings will contribute to recommendations for modifications or improvements to ensure the safety and integrity of offshore platforms in the specific region.

Safety of the express freight train running over a long-span bridge

PurposeExpress freight transportation is in rapid development currently. Owing to the higher speed of express freight train, the deformation of the bridge deck worsens the railway line condition under the action of wind and train moving load when the train runs over a long-span bridge. Besides, the blunt car body of vehicle has poor aerodynamic characteristics, bringing a greater challenge on the running stability in the crosswind.Design/methodology/approachIn this study, the aerodynamic force coefficients of express freight vehicles on the bridge are measured by scale model wind tunnel test. The dynamic model of the train-long-span steel truss bridge coupling system is established, and the dynamic response as well as the running safety of vehicle are evaluated.FindingsThe results show that wind speed has a significant influence on running safety, which is mainly reflected in the over-limitation of wheel unloading rate. The wind speed limit decreases with train speed, and it reduces to 18.83 m/s when the train speed is 160 km/h.Originality/valueThis study deepens the theoretical understanding of the interaction between vehicles and bridges and proposes new methods for analyzing similar engineering problems. It also provides a new theoretical basis for the safety assessment of express freight trains.

The role of HSE risk assessments in mitigating occupational hazards and infectious disease spread: A public health review

The intercession of Health, Safety, and Environmental (HSE) risk assessments with public health strategy is crucial in mitigating occupational hazards and controlling the spread of infectious diseases. This review examines the role of Health, Safety, and Environment (HSE) risk assessments in mitigating occupational hazards and controlling the spread of infectious diseases, with a focus on public health implications. The study highlights the importance of comprehensive risk assessments in identifying and managing workplace hazards, including both physical and psychosocial risks. It discusses the integration of advanced technologies, such as artificial intelligence and big data analytics, to enhance the predictive capabilities of HSE risk assessments. The review also explores the necessity of ethical considerations in the application of these technologies, emphasizing transparency, privacy, and accountability. Furthermore, it underscores the importance of coordinated efforts between industries and public health authorities, especially in the context of infectious disease outbreaks like COVID-19. Policy recommendations include the development of robust regulations, the promotion of industry-public health collaboration, and the provision of support for small and medium-sized enterprises. The review identifies gaps in current research and suggests future directions, such as longitudinal studies on the effectiveness of HSE interventions and the inclusion of psychosocial factors in risk assessments. By addressing these gaps and implementing the proposed recommendations, policymakers and industry stakeholders can significantly enhance workplace safety and health standards, ultimately protecting workers and promoting public health resilience.

Assessment of Metabolic and Bariatric Surgery Safety in Patients with Advanced Liver Fibrosis.

The well-established relationship between obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) is a key etiological factor in the development of liver cirrhosis. Bariatric surgery is an effective treatment for weight loss in patients with moderate-to-severe obesity, also playing a role in controlling MASLD. However, surgical safety in patients with advanced fibrosis remains to be established. This study aimed to evaluate the safety and repercussions of bariatric surgery according to fibrosis stage. Patients undergoing bariatric surgery who had an intraoperative liver biopsy were retrospectively evaluated. Preoperative and postoperative data were collected from medical records, and results were stratified according to fibrosis stage into early fibrosis (no fibrosis or stages 1 and 2) and advanced fibrosis (stages 3 and 4). The study included 1185 patients: 1129 with early fibrosis and 56 with advanced fibrosis. The advanced fibrosis group had higher percentage of men (35.7% vs 21.6%, p = 0.014) and of people with diabetes (42.9% vs 16.5%, p < 0.001) and hypertension (57.1% vs 41.4%, p = 0.012). Patients with advanced fibrosis also required longer hospitalizations (4.64 vs 4.06days, p < 0.001) and were more frequently admitted to the intensive care unit (7.1% vs 2.9%, p = 0.038). The groups did not differ significantly in other outcomes. There were no deaths in either group. Bariatric surgery proved to be safe, with similar complication rates in patients with advanced fibrosis and in those with early fibrosis.

Assessment of Efficacy and Safety of Mangifera indica Extract (Stadice®) for Cognitive Function: A Randomized, Double-Blind, Placebo-Controlled Study

Assessment of Efficacy and Safety of Mangifera indica Extract (Stadice®) for Cognitive Function: A Randomized, Double-Blind, Placebo-Controlled Study

Preclinical Safety Assessment of the EBS-LASV Vaccine Candidate against Lassa Fever Virus

There are currently no prophylactic vaccines licensed to protect against Lassa fever caused by Lassa virus (LASV) infection. The Emergent BioSolutions (EBS) vaccine candidate, EBS-LASV, is being developed for the prevention of Lassa fever. EBS-LASV is a live-attenuated recombinant Vesicular Stomatitis Virus (rVSV)-vectored vaccine encoding the surface glycoprotein complex (GPC) from LASV and has two attenuating vector modifications: a gene shuffle of the VSV N gene and a deletion of the VSV G gene. Preclinical studies were performed to evaluate EBS-LASV’s neurovirulence potential following intracranial (IC) injection and to determine the biodistribution and vector replication following intramuscular (IM) inoculation in mice. In addition, the potential EBS-LASV toxicity was assessed using repeated-dose IM EBS-LASV administration to rabbits. All mice receiving the IC injection of EBS-LASV survived, while mice administered the unattenuated control vector did not. The vaccine was only detected in the muscle at the injection site, draining lymph nodes, and the spleen over the first week following IM EBS-LASV injection in mice, with no detectable plasma viremia. No toxicity was observed in rabbits receiving a three-dose regimen of EBS-LASV. These studies demonstrate that EBS-LASV is safe when administered to animals and supported a first-in-human dose-escalation, safety, and immunogenicity clinical study.

Crack propagation process and lifetime prediction method of concrete-rock interface under constant loading

This study investigated the crack propagation processes and established the lifetime prediction methods of the concrete-rock interfaces under constant loading. Firstly, the constant loading tests were performed under three-point bending loading on the composite concrete-rock beams with three kinds of interfaces, i.e. natural, 4 × 4, and 7 × 7 interfaces, and under three constant load levels, i.e. initial cracking load, 80% and 97% of the peak loads. Then, the clip gauge method and digital image correlation method were employed to detect the crack lengths under constant loading. Finally, the effects of constant load levels on fracture properties of the concrete-rock interfaces were analyzed and the crack propagation processes under constant loading were discussed. The results indicated that the clip gauge method was an available and accurate method to detect the crack lengths of the concrete-rock interfaces under constant loading. Crack propagation processes and crack mouth opening processes under constant loading exhibited the three-stage feature, i.e. deceleration stage, uniform stage and acceleration stage. In addition, the logarithms of the constant loading lifetimes showed an approximate linear relationship with the logarithms of the crack mouth uniform opening rates, and a quantitative relationship was established by using the linear regression analysis to establish the lifetime prediction methods. This study proposed a practical method to predict the service life of concrete structure-bedrock interface. When the crack mouth uniform opening stage was recognized, the lifetime of concrete structure-bedrock interface in service can be predicted by substituting the crack mouth uniform opening rate into the pre-established prediction model. This study can provide the theoretical support for the safety assessment of the concrete structure-bedrock interface in service.

Pharmacokinetic, bioequivalence, and safety assessments of two brands of 30-mg nifedipine controlled-release formulations in Chinese healthy subjects.

This study aimed to analyze the pharmacokinetic (PK) characteristics, safety, and bioequivalence (BE) of a test (T) preparation of a nifedipine controlled-release tablet and the reference (R) drug (Adalat GTIS) in Chinese study participants in the context of fasting and postprandial states. An open-label, single-center, randomized, single-dose, two-period study was designed including two separate arms, one with administration under fasting conditions and one with administration under postprandial conditions (high-fat, high-calorie breakfast). After oral administration, the nifedipine concentrations in plasma were quantitatively analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) at regular intervals. Primary PK parameters, including the area under the concentration curve from 0 to infinity (AUC0-∞), the area under the concentration profile from 0 to the last measurable concentration time (AUC0-t), and maximal measured plasma concentration (Cmax) were log-transformed with BE limits of 80-125% to evaluate BE. All adverse events (AEs) were wholly supervised. The PK profiles of the T and R formulations were comparable to each other under both fasting and postprandial conditions. The 90% confidence intervals (CIs) of the AUC0-∞, AUC0-t, and Cmax were 92.69-106.06%, 93.32-107.05%, and 99.53-116.71%, respectively, under the fasting state. The 90% CIs of the AUC0-∞, AUC0-t, and Cmax were 105.05-117.40%, 105.43-117.82%, and 102.66-116.30%, respectively, in the postprandial arm. 47 cases of drug-associated AEs were noted in the entire research. Under both the fasting and postprandial states, the two nifedipine controlled-release formulations were bioequivalent and safe in healthy Chinese subjects.

Long-Term Stability Analysis and Structural Safety Assessment of Tunnel Surrounding Rock in Carbonaceous Slate Formation

Long-Term Stability Analysis and Structural Safety Assessment of Tunnel Surrounding Rock in Carbonaceous Slate Formation

A paradigm for the contextual safety assessment of agricultural microbes: a closer look at Klebsiella variicola

Adopting a risk assessment paradigm that is contextualized and strain-specific will be critical to enabling the continued development and safe use of microbes, particularly bacteria, in numerous industries and applications. An overly simplistic approach of labeling bacterial species as either harmful or beneficial is ill-suited for the complexities of their interactions with hosts and other microbes, where the lines between friend, foe, and innocent bystander are often unclear. Many such nuanced relationships have been described in human microbiome studies, illustrating the inherent challenges of defining bacterial safety. Any effective risk assessment framework must take into account bacterial niche and environment, fitness, host health, route and extent of exposure, and strain characterization. Klebsiella variicola, a diazotrophic soil bacterium isolated around the world, has been the subject of increasing interest on both environmental and clinical fronts, and has been used commercially as a biofertilizer on millions of farm acres. Here we review its population structure, relevance in clinical and environmental settings, and use as a biofertilizer in light of the risk assessment framework described.

Accelerating evidence synthesis for safety assessment through ClinicalTrials.gov platform: a feasibility study

BackgroundStandard systematic review can be labor-intensive and time-consuming meaning that it can be difficult to provide timely evidence when there is an urgent public health emergency such as a pandemic. The ClinicalTrials.gov provides a promising way to accelerate evidence production.MethodsWe conducted a search on PubMed to gather systematic reviews containing a minimum of 5 studies focused on safety aspects derived from randomized controlled trials (RCTs) of pharmacological interventions, aiming to establish a real-world dataset. The registration information of each trial from eligible reviews was further collected and verified. The meta-analytic data were then re-analyzed by using 1) the full meta-analytic data with all trials and 2) emulated rapid data with trials that had been registered and posted results on ClinicalTrials.gov, under the same synthesis methods. The effect estimates of the full meta-analysis and rapid meta-analysis were then compared.ResultsThe real-world dataset comprises 558 meta-analyses. Among them, 56 (10.0%) meta-analyses included RCTs that were not registered in ClinicalTrials.gov. For the remaining 502 meta-analyses, the median percentage of RCTs registered within each meta-analysis is 70.1% (interquartile range: 33.3% to 88.9%). Under a 20% bias threshold, rapid meta-analyses conducted through ClinicalTrials.gov achieved accurate point estimates ranging from 77.4% (using the MH model) to 83.1% (using the GLMM model); 91.0% to 95.3% of these analyses accurately predicted the direction of effects.ConclusionsUtilizing the ClinicalTrials.gov platform for safety assessment with a minimum of 5 RCTs holds significant potential for accelerating evidence synthesis to support urgent decision-making.

Experimental Research on Thermal-Venting Characteristics of the Failure 280 Ah LiFePO4 Battery: Atmospheric Pressure Impacts and Safety Assessment

Experimental Research on Thermal-Venting Characteristics of the Failure 280 Ah LiFePO4 Battery: Atmospheric Pressure Impacts and Safety Assessment

Safety and Efficacy of Staged, Bilateral Focused Ultrasound Thalamotomy in Essential Tremor

Unilateral magnetic resonance-guided focused ultrasound ablation of ventralis intermedius nucleus of the thalamus for essential tremor reduces tremor on 1 side, but untreated contralateral or midline symptoms remain limiting for some patients. Historically, bilateral lesioning produced unacceptable risks and was supplanted by deep brain stimulation; increasing acceptance of unilateral focused ultrasound lesioning has led to interest in a bilateral option. To evaluate the safety and efficacy of staged, bilateral focused ultrasound thalamotomy. This prospective, open-label, multicenter trial treated patients with essential tremor from July 2020 to October 2021, with a 12-month follow-up, at 7 US academic medical centers. Of 62 enrolled patients who had undergone unilateral focused ultrasound thalamotomy at least 9 months prior to enrollment, 11 were excluded and 51 were treated. Eligibility criteria included patient age (22 years and older), medication refractory, tremor severity (Clinical Rating Scale for Tremor [CRST] part A score ≥2 for postural or kinetic tremor), and functional disability (CRST part C score ≥2 in any category). A focused ultrasound system interfaced with magnetic resonance imaging allowed real-time alignment of thermography maps with anatomy. Subthreshold sonications allowed target interrogation for efficacy and off-target effects before creating an ablation. Tremor/motor score (CRST parts A and B) at 3 months for the treated side after treatment was the primary outcome measure, and secondary assessments for efficacy and safety continued to 12 months. The mean (SD) population age was 73 (13.9) years, and 44 participants (86.3%) were male. The mean (SD) tremor/motor score improved from 17.4 (5.4; 95% CI, 15.9-18.9) to 6.4 (5.3; 95% CI, 4.9 to 7.9) at 3 months (66% improvement in CRST parts A and B scores; 95% CI, 59.8-72.2; P < .001). There was significant improvement in mean (SD) postural tremor (from 2.5 [0.8]; 95% CI, 2.3 to 2.7 to 0.6 [0.9]; 95% CI, 0.3 to 0.8; P < .001) and mean (SD) disability score (from 10.3 [4.7]; 95% CI, 9.0-11.6 to 2.2 [2.8]; 95% CI, 1.4-2.9; P < .001). Twelve participants developed mild (study-defined) ataxia, which persisted in 6 participants at 12 months. Adverse events (159 of 188 [85%] mild, 25 of 188 [13%] moderate, and 1 severe urinary tract infection) reported most commonly included numbness/tingling (n = 17 total; n = 8 at 12 months), dysarthria (n = 15 total; n = 7 at 12 months), ataxia (n = 12 total; n = 6 at 12 months), unsteadiness/imbalance (n = 10 total; n = 0 at 12 months), and taste disturbance (n = 7 total; n = 3 at 12 months). Speech difficulty, including phonation, articulation, and dysphagia, were generally mild (rated as not clinically significant, no participants with worsening in all 3 measures) and transient. Staged, bilateral focused ultrasound thalamotomy significantly reduced tremor severity and functional disability scores. Adverse events for speech, swallowing, and ataxia were mostly mild and transient. ClinicalTrials.gov Identifier NCT04112381.

Efficacy and safety of insulin glargine 300 U/mL in people with type 2 diabetes in China: The INITIATION study.

To evaluate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) in people with suboptimally controlled type 2 diabetes (T2D) in China. INITIATION (NCT05002933) was a prospective, interventional, multicentre, single-arm, phase IV study conducted in China. Individuals with suboptimally controlled T2D who were insulin naïve or switching from another basal insulin (insulin experienced) were included. The primary endpoint was the change in HbA1c from baseline to week 24. Safety assessments included hypoglycaemia and adverse events (AEs). In total, 568 participants were enrolled and 562 initiated Gla-300 treatment (189 in the insulin-naïve subgroup; 373 in the insulin-experienced subgroup). At week 24, the mean ± standard error (SE) change in HbA1c from baseline was -0.91% ± 0.05% (-9.9 ± 0.5 mmol/mol; P < .0001). Significant HbA1c reductions were also observed in the insulin-naïve (mean ± SE change: -1.38% ± 0.09% [-15.1 ± 1.0 mmol/mol]) and insulin-experienced (-0.68% ± 0.05% [-7.4 ± 0.5 mmol/mol]) subgroups (both P < .0001). During the 24-week treatment period, the incidence of confirmed hypoglycaemia (plasma glucose ≤ 3.9 mmol/L) was 39.7% for all hypoglycaemia and 13.3% for nocturnal hypoglycaemia; the incidence of severe hypoglycaemia was low (0.5%). Overall, treatment-emergent AEs (TEAEs) were reported in 126 participants (22.4%), with no serious treatment-related TEAEs. Gla-300 was effective in improving glycaemic control and had a relatively low risk of hypoglycaemia in people with suboptimally controlled T2D who were insulin naïve or switching from another basal insulin in China.

A case study to address the limitation of accident scenario identifications with respect to diverse manual responses

Probabilistic safety assessment (PSA) is a tool for securing the operational safety of nuclear power plants. One unique benefit of PSA is to identify accident scenarios leading to undesirable consequences. Since these accident scenarios result from highly complicated combinations of automatic and manual responses, a huge number of simulations are generally required with a precise thermal-hydraulic (TH) code. Therefore, current PSA typically reduces the number of TH code runs by focusing on limited numbers of safety-critical components with reasonable engineering assumptions. Nevertheless, it has been pointed out that the current catalog of accident scenarios in PSA may be insufficient to some extent. In order to corroborate this claim, in this work, 14,348,907 simulation conditions were randomly generated after combining 79 manual responses identified from the emergency operating procedure of a steam generator tube rupture (SGTR) event in a reference nuclear power plant. Results show that about 14.7 % of the simulations correspond to an undesirable consequence pertaining to the SGTR. Accordingly, in terms of enhancing the quality of PSA results, the results of this study support that it is inevitable to develop a promising way to reduce the amount of computational resources required by large numbers of TH code runs.

Critical Review of Hydrogen Safety Assessment Tools: Indian Perspective

Critical Review of Hydrogen Safety Assessment Tools: Indian Perspective

A Comparative Clinical Pharmacology Analysis of FDA-Approved Targeted Covalent Inhibitors vs. Reversible Inhibitors in Oncology.

Targeted covalent inhibitors (TCIs) are an emerging class of anticancer therapeutics. TCIs are designed to selectively engage their targeted proteins via covalent warheads. From the drug development standpoint, the covalent inhibition mechanism is anticipated to elicit the following theoretical benefits: (i) an extended duration of therapeutic action that is determined by the target protein turnover rate and not necessarily by drug half-life, (ii) a lower therapeutic dose owing to greater pharmacological potency, (iii) lower risk of off-target binding and associated adverse events, and (iv) reduced drug-drug interaction (DDI) liability due to high selectivity and low dose. Elucidating the clinical relevance of these expected benefits requires an integrated assessment of pharmacokinetics (PK), efficacy, safety, and DDI data. In this review, we compared the clinical pharmacology attributes of FDA-approved oncology TCIs within the last 10 years against their reversible inhibitor (RI) counterparts. Our findings indicated that (i) PK half-lives of TCIs were typically shorter and (ii) at their respective recommended clinical doses per drug label, the molar unbound steady state areas under the concentration-time curve (AUCss) of TCIs were lower than those of RIs, but with longer clinically observed durations of response. However, (iii) there was no conclusive evidence supporting improved clinical safety profiles for TCIs, and (iv) DDI perpetrator profiles appeared to be similar between TCIs and RIs. The overall clinical pharmacology comparison of TCI vs. RI surveyed in this paper suggested that at least two of the four forecasted clinical benefits were achieved by TCIs.