Characterization of the in vitro metabolic profile of nazartinib in HLMs using UPLC-MS/MS method: In silico metabolic lability and DEREK structural alerts screening using StarDrop software.

The orally given, irreversible, third-generation inhibitor of the epidermal growth factor receptor (EGFR), known as Nazartinib (EGF816), is now undergoing investigation in Phase II clinical trials conducted by Novartis for Non-Small Cell Lung Cancer. The primary aim of the current research was to establish a rapid, specific, environmentally friendly, and highly versatile UPLC-MS/MS methodology for the determination of nazartinib (NZT) levels in human liver microsomes (HLMs). Subsequently, same approach was used to examine the metabolic stability of NZT. The UPLC-MS/MS method employed in HLMs was validated as stated in the bioanalytical method validation criteria outlined by the US- FDA. The evaluation of the metabolic stability of NZT and the identification of potentially structural alarms were performed using the StarDrop software package that includes the P450 and DEREK software. The calibration curve for NZT showed a linearity in the range from 1 to 3000 ng/mL. The inter-day accuracy and precision exhibited a range of values between -4.33 % and 4.43 %, whereas the intra-day accuracy and precision shown a range of values between -2.78 % and 7.10 %. The sensitivity of the developed approach was verified through the determination of a LLOQ of 0.39 ng/mL. The intrinsic clearance and in vitro half-life of NZT were assessed to be 46.48 mL/min/kg and 17.44 min, respectively. In our preceding inquiry, we have effectively discerned the bioactivation center, denoted by the carbon atom between the unsaturated conjugated system and aliphatic linear tertiary amine. In the context of computational software, making minor adjustments or substituting the dimethylamino-butenoyl moiety throughout the drug design process may increase the metabolic stability and safety properties of new synthesized derivatives. The efficiency of utilizing different in silico software approaches to conserve resources and reduce effort was proved by the outcomes attained from in vitro incubation experiments and the use of NZT in silico software.

An ultra-fast green ultra-high-performance liquid chromatography-tandem mass spectrometry method for estimating the in vitro metabolic stability of zotizalkib in human liver microsomes.

Zotizalkib (ZTK, TPX-0131) is a fourth-generation highly effective inhibitor of wild-type anaplastic lymphoma kinase (ALK) and ALK-resistant mutations that can penetrate the central nervous system. It exhibited greater potency compared to all five officially approved ALK inhibitors. The aim of this study was to develop a rapid, accurate, eco-friendly, and highly sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for measuring the concentration of ZTK in human liver microsomes (HLMs). The validation aspects of the current UHPLC-MS/MS methodology in the HLMs were conducted in accordance with the bioanalytical method validation standards specified by the US Food and Drug Administration. ZTK and encorafenib were separated using an Agilent C8 column (Eclipse Plus) and an isocratic mobile phase. The calibration curve for the developed ZTK exhibited a linear relationship within the concentration range of 1-3000 ng/mL. The results from the Analytical Green-ness Metric Approach program (0.76) suggested that the created method demonstrated a significant degree of environmental sustainability. The in vitro half-life (t1/2) and intrinsic clearance (Clint) of ZTK were determined to be 15.79 min and 51.35 mL/min/kg, respectively that suggests the ZTK exhibits characteristics similar to those of a medication with a high extraction ratio. These approaches are crucial for the progress of novel pharmaceutical development, especially in improving metabolic stability.

An ultra-fast ultra-high-performance liquid chromatography-tandem mass spectrometry method for estimating the in vitro metabolic stability of palbociclib in human liver microsomes: In silico study for metabolic lability, absorption, distribution, metabolism, and excretion features, and DEREK alerts screening.

Palbociclib (Ibrance; Pfizer) was approved for the management of metastatic breast cancer characterized by hormone receptor-positive/human epidermal growth factor receptor 2 negative status. The objective of this study was to create a fast, precise, environmentally friendly, and highly sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry approach for quantifying palbociclib (PAB) in human liver microsomes with the application for assessing metabolic stability. The validation features were performed in agreement with the bioanalytical method validation standards outlined by the US Food and Drug Administration. The StarDrop software (WhichP450 and DEREK modules) was used in screening the metabolic lability and structural alerts of PAB. The separation of PAB and encorafenib (as an internal standard) was achieved on a C8 column, employing an isocratic mobile phase. The inter-day and intra-day accuracy and precision ranged from -6.00% to 4.64% and from -2.33% to 3.13%, respectively. The constructed calibration curve displayed a linearity in the range of 1-3000 ng/mL. The sensitivity of the established approach was proven by the lower limit of quantification of 0.73 ng/mL. The Analytical GREEness calculator results revealed the high level of greenness of the developed method. The PAB's metabolic stability (t1/2 of 18.5 min and a moderate clearance (Clint) of 44.8 mL/min/kg) suggests a high extraction ratio medication that matched the WhichP450 software results.

Enhanced power grid performance through Gorilla Troops Algorithm-guided thyristor controlled series capacitors allocation.

This article introduces an innovative application of the Enhanced Gorilla Troops Algorithm (EGTA) in addressing engineering challenges related to the allocation of Thyristor Controlled Series Capacitors (TCSC) in power grids. Drawing inspiration from gorilla group behaviors, EGTA incorporates various methods, such as relocation to new areas, movement towards other gorillas, migration to specific locations, following the silverback, and engaging in competitive interactions for adult females. Enhancements to EGTA involve support for the exploitation and the exploration, respectively, through two additional strategies of periodic Tangent Flight Operator (TFO), and Fitness-based Crossover Strategy (FCS). The paper initially evaluates the effectiveness of EGTA by comparing it to the original GTA using numerical CEC 2017 single-objective benchmarks. Additionally, various recent optimizers are scrutinized. Subsequently, the suitability of the proposed EGTA for the allocation of TCSC apparatuses in transmission power systems is assessed through simulations on two IEEE power grids of 30 and 57 buses, employing various TCSC apparatus quantities. A comprehensive comparison is conducted between EGTA, GTA, and several other prevalent techniques in the literature for all applications. According to the average attained losses, the presented EGTA displays notable reductions in power losses for both the first and second systems when compared to the original GTA. Specifically, for the first system, the proposed EGTA achieves reductions of 1.659 %, 2.545 %, and 4.6 % when optimizing one, two, and three TCSC apparatuses, respectively. Similarly, in the second system, the suggested EGTA achieves reductions of 6.096 %, 7.107 %, and 4.62 %, respectively, when compared to the original GTA's findings considering one, two, and three TCSC apparatuses. The findings underscore the superior effectiveness and efficiency of the proposed EGTA over both the original GTA and several other contemporary systems.

CT Pulmonary Angiogram Clinical Pretest Probability Tool: Impact on Emergency Department Utilization.

OBJECTIVE: Currently, computed tomographic pulmonary angiogram (CTPA) for evaluating acute pulmonary embolism (PE) in Emergency Departments (EDs) is overused and with low yields. The goal of this study is to assess the impact of an evidence-based clinical decision support (CDS) tool, aimed at optimizing appropriate use of CTPA for evaluating PE. METHODS: The study was performed at EDs in a large healthcare system and included 9 academic and community hospitals. The primary outcome was the percent difference in utilization (number of CTPA performed/number of ED visits) and secondary outcome was yield (percentage of CTPA positive for acute PE), comparing 12 months before (6/1/2021-5/31/2022) vs. 12 months after (6/1/2022-5/31/2023) a system-wide implementation of the CDS. Univariate and multivariable analyses using logistic regression were performed to assess factors associated with diagnosis of acute PE. Statistical process control (SPC) charts were used to assess monthly trends in utilization and yield. RESULTS: Among 931,677 visits to Emergency Departments, 28,101 CTPAs were performed on 24,675 patients. 14,825 CTPAs were performed among 455,038 visits (3.26%) pre-intervention; 13,276 among 476,639 visits (2.79%) post-intervention, a 14.51% relative decrease in CTPA utilization (chi-square, p<0.001). CTPA yield remained unchanged (1371/14825=9.25% pre- vs. 1184/13276=8.92% post-intervention; chi-square, p=0.34). Patients with COVID diagnosis prior to CTPA had higher probability of acute PE. SPC charts demonstrated seasonal variation in utilization (Friedman test, p=0.047). DISCUSSION: Implementing a CDS based on validated decision rules was associated with a significant reduction in CTPA utilization. The change was immediate and sustained for 12 months post-intervention.

A CYP11A1 homozygous exonic variant inducing an alternative splicing, frameshift and truncation in a family with congenital adrenal hyperplasia.

Background: Congenital adrenal hyperplasia (CAH) is a heterogeneous group of adrenal steroidogenesis disorders with variable degrees of glucocorticoid, mineralocorticoid and sex steroid deficiencies. CYP11A1 gene encodes the mitochondrial cholesterol side-chain cleavage enzyme (P450scc), which initiates the first reaction in steroidogenesis by converting cholesterol to pregnenolone. Variants in this gene are extremely rare but associated with severe forms of CAH due to its early and critical function in various steroid biosynthesis pathways. Here, we report a CYP11A1 exonic homozygous variant that, although exonic in location, affects splicing by creating an additional aberrant splicing site with frameshift and truncation of the gene. Patients and methods: The proband is a 23-year old 46,XY patient raised as a girl. She was a product of normal pregnancy for first-degree relative parents. Soon after birth, she had vomiting, dehydration, hypotension, hyponatremia and hyperkalemia. She was started on glucocorticoids and mineralocorticoids with prompt recovery. Apart from a chronic need for these medications, her neonatal and childhood history was unremarkable. She sought medical advice at age 19 years for delayed puberty with primary amenorrhea and lack of breast development. On evaluation, she had normal external female genitalia, no breast development, undescended testes and absent uterus and ovaries. Her hormonal evaluation revealed very low estrogen, testosterone, cortisol, aldosterone, 17-hydroxyprogesterone, and androstenedione levels. ACTH, LH, FSH and renin were very high consistent with primary gonadal and adrenal failure. Her parents are healthy first-degree cousins. She has three sisters, all with 46,XX karyotype. One of them is clinically and biochemically normal while the other two sisters have normal female phenotype, normal uterus and ovaries, similar hormonal profile to the proband but different karyotype (46,XX) and absence of undescended testes. gDNA was used for whole exome sequencing (WES). Sanger sequencing was performed to confirm the detected variant and its segregation with the disease. Results: WES identified a homozygous missense variant in CYP11A1 changing the second nucleotide (GCG > GTG) at position 189 in exon 3 and resulting in a change of Alanine to Valine (p.Ala189Val). This variant was confirmed by PCR and Sanger sequencing. It was found in a homozygous form in the proband and her two affected sisters and in a heterozygous form in the unaffected sister. In-silico analysis predicted this variant to create a new splicing site with frameshift and truncation of the gene transcript. This was confirmed by isolation of RNA, cDNA synthesis, gel electrophoresis and sequencing. Conclusion: We describe a family with a very rare form of CAH due to a CYP11A1 variant leading to creation of a new splice site, frameshift and premature truncation of the protein.

False-negative 99mTc-sestamibi scans: factors and outcomes in primary hyperparathyroidism.

Primary hyperparathyroidism has emerged as a prevalent endocrine disorder in clinical settings, necessitating in most cases, surgical intervention for the removal of the diseased gland. This condition is characterised by overactivity of the parathyroid glands, resulting in excessive parathyroid hormone production and subsequent disturbances in calcium homeostasis. The primary mode of management is surgical treatment, relying on the accurate localisation of the pathological parathyroid gland. Precise identification is paramount to ensuring that the surgical intervention effectively targets and removes the diseased gland, alleviating the hyperfunctioning state. However, localising the gland becomes challenging, as discrepancies between the clinical manifestation of active parathyroid and radiological identification are common. Based on our current knowledge, to date, no comprehensive review has been conducted that considers all factors collectively. This comprehensive review delves into the factors contributing to false-negative 99mTc-sestamibi scans. Our research involved an exhaustive search in the PubMed database for hyperparathyroidism, with the identified literature meticulously filtered and reviewed by the authors. The results highlighted various factors, including multiple parathyroid diseases, nodular goitre, mild disease, or the presence of an ectopic gland that causes discordance. Hence, a thorough consideration of these factors is crucial during the diagnostic workup of hyperparathyroidism. Employing intraoperative PTH assays can significantly contribute to a successful cure of the disease, thereby providing a more comprehensive approach to managing this prevalent endocrine disorder.

Transnasal Transsphenoidal Approach for a Nine-Year-Old Child With Pituitary Apoplexy: A Case Report.

Pituitary apoplexy is a rare but potentially life-threatening condition of sudden hemorrhage or infarction within the pituitary gland that results in symptoms of acute onset such as severe headache, visual impairment, and hormonal deficiencies. Though more common in adults, the same criteria for diagnostic and management dilemmas apply to pediatric cases. We present the case of a nine-year-old boy presenting with acute-onset severe headache and significant visual deterioration suggestive of pituitary apoplexy. An emergency MRI was performed, which showed a hemorrhagic sellar and suprasellar mass compressing the optic chiasm. Given the severe visual symptoms in this case, emergency surgical intervention was indicated. Decompression and gross total resection of the tumor were successfully attained using the endoscopic transnasal transsphenoidal approach by a multidisciplinary team. After the surgery, there was a significant improvement in the visual field, especially regarding the right eye's nasal hemifield, and the motor strength and consciousness remained stable. This case underscores the importance of early diagnosis and expedited surgical management in pediatric pituitary apoplexy. The transnasal transsphenoidal approach is practical for maximal decompression of the optic apparatus and reduces the risk of long-term visual deficits. In addition, it points out the need for coordinated, multidisciplinary treatment with the participation of neurosurgeons, endocrinologists, and pediatricians both for immediate and long-term consequences, including potential hormonal deficiencies. The report emphasizes the need for vigilance and prompt intervention in pediatric presentations, unlike the index case, for better outcomes and to avoid permanent morbidity.

Radiation sensor based on a 1D-periodic structure infiltrated by (B-co-MP) a conjugated copolymer.

In this study, a novel gamma-ray radiation sensor has been developed depending on a 1D photonic crystal (1D-PhC). Based on porous silicon (PSi) layer that has been penetrated by a conjugated copolymer (B-co-MP) which consists of BEHP-PPV and MEH-PPV, with a fractional ratio of 60:40. The suggested method for the development of the dosimeter is based on the shift of photonic band-gap to shorter wavelengths, where exposure to gamma-ray radiation at doses ranging from 0 to 20 kGy alters the refractive index of the (B-co-MP) copolymer. The fitted experimental data, the equation of Bruggeman effective medium, and the transfer matrix method (TMM) are the main axes in the framework of the current theoretical approach. The collected data shows that, within the visible range, the suggested sensor's sensitivity (224 nm/RIU) is high and stable over a 0-20 kGy applied-dose range. Also, we compared these results with previous research.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early Alzheimer's disease (AD) pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify cerebrospinal fluid  (CSF) biomarkers for AD-related central nervous system (CNS) pathophysiologic changes using tissue and fluids with early pathology, free of post mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-42/40, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights seven core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking. HIGHLIGHTS: AD CSF biomarkers correlate with CNS pathology and transcriptomic changes. Seven proteins correlate with CNS pathology and gene expression changes. Inflammatory and neuronal gene expression changes correlate with YKL-40 and NPTXR, respectively. CSF metabolomic analysis identifies pathways that correlate with biopsy data. Fatty acid metabolic pathways correlate with ß-amyloid pathology.

Significant Association of PD-L1 With CD44 Expression and Patient Survival: Avenues for Immunotherapy and Cancer Stem Cells Downregulation in Pancreatic Cancers.

Background: Pancreatic cancers are known for their aggressive nature. This aggressiveness may be attributed to the presence of cancer stem cells (CSCs), which promote relapse, metastasis, and resistance to chemotherapy. Targeting CSCs is essential to reverse this aggressiveness in pancreatic malignancies. Literature highlights the association of PD-L1 expression with CSCs in various cancers, suggesting immunotherapy as a promising therapeutic approach. This study is aimed at investigating the potential of immunotherapy in pancreatic cancers by examining its association with selected CSC marker expression. Method: A retrospective cohort study was conducted involving 56 patients with confirmed diagnoses of pancreatic cancers at Aga Khan University Hospital from January 2015 to October 2022. After exclusions, based on refusal to provide consent or incomplete follow-up data, 38 patients were enrolled in the study. Immunohistochemistry was performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue samples to assess the expression of CSC markers (CD133, CD44, and L1CAM) and immune checkpoint inhibitor marker (PD-L1). Statistical analysis was employed to determine associations between marker expression, clinical factors, and overall survival. Results: The study revealed that 86.8% of pancreatic cancer cases exhibited positive PD-L1 expression. Moreover, a significant association of PD-L1 expression was observed with the presence of CD44 protein (p = 0.030), as well as with the overall survival of patients (p = 0.023). Conclusion: Our findings show a significant association of PD-L1 with CD44 marker expression as well as patient survival. This research shows the potential to serve as the foundation for investigating the efficacy of immunotherapy in reducing CD44-expressing CSCs in pancreatic cancer, potentially enhancing patient outcomes.

Propofol vs Midazolam As the Initial Sedation Strategy for Mechanically Ventilated Patients: A Single-Center Experience From Saudi Arabia.

Background Propofol and midazolam are the most common sedative agents used in critical settings. Propofol and midazolam might have different mortality rates after sedation administration. Some studies mention that propofol is associated with a lower mortality rate than midazolam in mechanically ventilated patients, but other studies have contradicting results. This study aims to compare the 28-day mortality of propofol versus midazolam for patients undergoing mechanical ventilation in the National Guard Hospital Health Affairs (NGHA)-Western Region (WR). Methods A retrospective chart review was conducted at (NGHA-WR) from March 2016 to July 2022. The inclusion criteria were those mechanically ventilated patients aged 18 years or older who were admitted to ICU, where they were given either propofol or midazolam as the initial sedative agent. Those who signed DNR (Do Not Resuscitate) or were contraindicated to sedation, such as allergy, were excluded from the study. Data were retrospectively retrieved and obtained from the Hospital Information System (HIS-BestCare, Saudi-Korean Health Informatics Company, Riyadh, Saudi Arabia) and the Office of Data Intelligence. Results There is a significant difference between the type of sedation and the 28-day mortality rate. Midazolam was associated with higher rates of mortality - 104 (47.93%) when compared to propofol - three (14.29%). Also, patients who used midazolam had longer durations of ICU stay compared to propofol, with a mean number of 19.23 days vs 7.55 days, respectively. Conclusion There is a significant difference regarding the 28-day mortality between patients who were given propofol or midazolam as an initial sedative agent for mechanical ventilation ≥ 24 hours. Moreover, the use of propofol is associated with fewer days of being intubated or being in ICU when compared to midazolam.

Sitosterolemia With Two Heterozygous Variants Including a Novel Mutation c.1800T>A in the ABCG5 Gene: A Case Report of a Rare Condition in a Young Saudi Girl.

Sitosterolemia is a rare autosomal recessively inherited lipid disorder characterized by an accumulation and deposition of phytosterols in various tissues with decreased biliary excretion leading to various complications. We report a case of a three-year-old Saudi girl who exhibited xanthomas and elevated cholesterol levels. Initially, she was misdiagnosed with familial hypercholesterolemia, but subsequent testing of the low-density lipoprotein receptor gene by next-generation sequencing ruled out this condition. Two heterozygous variants were identified in the ABCG5 gene through a whole exome sequencing study. These variants, namely c.1336C>T and c.1800T>A, have been characterized as pathogenic and likely pathogenic, respectively, with the latter being a novel mutation associated with sitosterolemia. The patient responded positively to treatment with ezetimibe, resulting in controlled cholesterol levels and decreased xanthoma size.

Outcomes of biological therapy in patients with severe asthma with chronic rhinosinusitis in Saudi Arabia: patients with nasal polyps versus those without nasal polyps.

BACKGROUND: This study's purposes were to evaluate the impact of biological therapies on outcomes in patients with severe asthma (SA) and chronic rhinosinusitis (CRS) and to compare these effects among those with NP (CRSwNP) versus those without NP (CRSsNP) in the "real-world" setting in Saudi Arabian patients. METHODS: From March to September 2022, a retrospective observational cohort study was undertaken at the severe asthma clinics of the Armed Forces Hospital-Southern Region (AFHSR) and King Khalid University Hospital, Abha, Saudi Arabia, to delineate the effects of dupilumab therapy. Outcomes were assessed, including clinical outcomes, FEV1, and laboratory findings before and one year after dupilumab. Post-therapy effects were compared between CRSwNP and CRSsNP. RESULTS: Fifty subjects were enrolled, with a mean age of 46.56. There were 27 (54%) females and 23(46%) males. Significant improvements in clinical parameters (frequency of asthma exacerbations and hospitalizations, the use of OCs, anosmia, SNOTT-22, and the ACT), FEV1, and laboratory ones (serum IgE and eosinophilic count) were observed 6 and 12 months after using dupilumab (p < 0.001), respectively. However, after 12 months of dupilumab therapy, there were no significant differences between those with and without NP with regards to clinical (anosmia, ACT, and OCs use), laboratory (eosinophilic count, serum IgE level) parameters, and FEV1%. CONCLUSIONS: Patients with CRS experienced significant improvements in clinical, FEV1, and laboratory outcomes after dupilumab therapy. However, these improvements were not maintained when comparing CRSwNP with CRSsNP. There were no significant differences between those with and without NP regarding ACT and OCs use or laboratory (eosinophilic count, serum IgE level) parameters. Further prospective multicenter studies are warranted.

Posaconazole-hemp seed oil loaded nanomicelles for invasive fungal disease.

Invasive fungal infections (IFI) pose a significant health burden, leading to high morbidity, mortality, and treatment costs. This study aims to develop and characterize nanomicelles for the codelivery of posaconazole and hemp seed oil for IFI via the oral route. The nanomicelles were prepared using a nanoprecipitation method and optimized through the Box Behnken design. The optimized nanomicelles resulted in satisfactory results for zeta potential, size, PDI, entrapment efficiency, TEM, and stability studies. FTIR and DSC results confirm the compatibility and amorphous state of the prepared nanomicelles. Confocal laser scanning microscopy showed that the optimized nanomicelles penetrated the tissue more deeply (44.9µm) than the suspension (25µm). The drug-loaded nanomicelles exhibited sustained cumulative drug release of 95.48 ± 3.27% for 24 h. The nanomicelles showed significant inhibition against Aspergillus niger and Candida albicans (22.4 ± 0.21 and 32.2 ± 0.46 mm, respectively). The pharmacokinetic study on Wistar rats exhibited a 1.8-fold increase in relative bioavailability for the nanomicelles compared to the suspension. These results confirm their therapeutic efficacy and lay the groundwork for future research and clinical applications, providing a promising synergistic antifungal nanomicelles approach for treating IFIs.

Effectiveness of SNAPPS Implementation in the Family Medicine Residency Program in Erbil: A Randomized Controlled Trial.

Background and objectives There is a crucial need to embrace modern methodologies for enhancing medical education in disciplines such as Family Medicine. The study introduces the SNAPPS (Summarize, Narrow, Analyze, Probe, Plan, and Select) model, a six-step mnemonic representing a learner-centered case presentation approach that streamlines fact reporting while encouraging clinical reasoning, aiming to evaluate the effectiveness of the SNAPPS method as compared to the traditional model of case presentation in Family Medicine outpatient clinics and to gain insights into how students and preceptors perceive it. Methods A randomized controlled trial was conducted in Family Medicine outpatient clinics in Erbil, Iraq, from March 15, 2023, to August 30, 2023. Using convenience sampling, all Family Medicine board residents (n=30) in Erbil and six preceptors from the Community and Family Medicine department/College of Medicine/Hawler Medical University were randomly assigned into two groups by using the RAND function in Microsoft Excel (Microsoft Corporation, Redmond, Washington, United States). The SNAPPS method was introduced to the SNAPPS group employing approved tools and methods, while no intervention was needed in the control group. Subsequently, 30 cases were presented in each group with a total of 60 case presentations; the case presentations served as the units for data analysis. Feedback and data were gathered after each presentation using validated data recording sheets. Results The study showed a significant advantage for the SNAPPS group over the control group in terms of time efficiency, number of basic clinical attributes covered, and justified diagnoses (P value < 0.001). In the SNAPPS group, 90% of the students sought clarification and information, surpassing 30% in the control group (P-value < 0.001). Almost all SNAPPS group students (96.7%) discussed case-related topics, compared to 43.3% in the controls (P-value<0.001). The SNAPPS group received superior overall ratings from both preceptors and students. Conclusion The SNAPPS method enhances clinical diagnostic reasoning in Family Medicine outpatient clinics. It is time-efficient and encourages students to articulate uncertainties, pose questions, and identify case-related topics for self-study.

First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumors.

RATIONALE OF THE TRIAL: Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors. TRIAL DESIGN: The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of 16 patients. IMA202 consists of autologous genetically modified cytotoxic CD8+ T cells expressing a T cell receptor (TCR), which is specific for a nine amino acid peptide derived from MAGEA1. Eligible patients underwent leukapheresis, T cells were isolated, transduced with lentiviral vector carrying MAGEA1-specific TCR and following lymphodepletion (fludarabine/cyclophosphamide), infused with a median of 1.4×109 specific T cells (range, 0.086×109-2.57×109) followed by interleukin 2. SAFETY OF IMA202: No DLT was observed. The most common grade 3-4 adverse events were cytopenias, that is, neutropenia (81.3%), lymphopenia (75.0%), anemia (50.0%), thrombocytopenia (50.0%) and leukopenia (25.0%). 13 patients experienced cytokine release syndrome, including one grade 3 event. Immune effector cell-associated neurotoxicity syndrome was observed in two patients and was grade 1 in both. EFFICACY OF IMA202: Of the 16 patients dosed, 11 (68.8%) patients had stable disease (SD) as their best overall response (Response Evaluation Criteria in Solid Tumors V.1.1). Five patients had initial tumor shrinkage in target lesions and one patient with SD experienced continued shrinkage in target lesions for 3 months in total but had to be classified as progressive disease due to progressive non-target lesions. IMA202 T cells were persistent in peripheral blood for several weeks to months and were also detectable in tumor tissue. Peak persistence was higher in patients who received higher doses. CONCLUSION: In conclusion, IMA202 had a manageable safety profile, and it was associated with biological and potential clinical activity of MAGEA1-targeting genetically engineered TCR-T cells in a poor prognosis, multi-indication solid tumor cohort. TRIAL REGISTRATION NUMBERS: NCT04639245, NCT05430555.