Acupressure in Psychotherapy as an Unsinkable Rubber Duck: A reply to.

In a recent publication entitled "Integrating the Manual Stimulation of Acupuncture Points Into Psychotherapy: A Systematic Review with Clinical Recommendations," appearing in this journal, Feinstein (2023) aims to aggregate the evidence on Emotional Freedom Techniques (EFT) across the "hierarchy of evidence." EFT is based on the premise that tapping facilitates alterations in "energy meridians" and that these alterations reduce psychological symptoms or disorders. This commentary addresses several concerns with the Feinstein (2023) review including the pseudoscientific concept of energy meridians, the lack of evidence that tapping on acupressure points is the active ingredient that resolves psychological disorders, serious methodological flaws with EFT research, and the incompatibility of EFT with the ethical practice of psychology. Thus, we disagree with Feinstein's (2023) conclusion that "The body of research on acupoint tapping that has emerged over the past two decades and the increasing quality of the study designs appears promising" (p. 61) and instead argue that EFT represents a pseudoscientific, "unsinkable rubber duck" (i.e., a belief that people continue to hold despite evidence to the contrary).

ChatGPT vs Medical Professional: Analyzing Responses to Laboratory Medicine Questions on Social Media.

BACKGROUND: The integration of ChatGPT, a large language model (LLM) developed by OpenAI, into healthcare has sparked significant interest due to its potential to enhance patient care and medical education. With the increasing trend of patients accessing laboratory results online, there is a pressing need to evaluate the effectiveness of ChatGPT in providing accurate laboratory medicine information. Our study evaluates ChatGPT's effectiveness in addressing patient questions in this area, comparing its performance with that of medical professionals on social media. METHODS: This study sourced patient questions and medical professional responses from Reddit and Quora, comparing them with responses generated by ChatGPT versions 3.5 and 4.0. Experienced laboratory medicine professionals evaluated the responses for quality and preference. Evaluation results were further analyzed using R software. RESULTS: The study analyzed 49 questions, with evaluators reviewing responses from both medical professionals and ChatGPT. ChatGPT's responses were preferred by 75.9% of evaluators and generally received higher ratings for quality. They were noted for their comprehensive and accurate information, whereas responses from medical professionals were valued for their conciseness. The interrater agreement was fair, indicating some subjectivity but a consistent preference for ChatGPT's detailed responses. CONCLUSIONS: ChatGPT demonstrates potential as an effective tool for addressing queries in laboratory medicine, often surpassing medical professionals in response quality. These results support the need for further research to confirm ChatGPT's utility and explore its integration into healthcare settings.

New records of helminth infections in Bothrops atrox Linnaeus, 1758 from Marajó Island-Brazil and a literature review with a check list of helminths infecting Bothrops species (Squamata, Viperidae) in the neotropical region.

Snakes of the genus Bothrops inhabit tropical forests in Central and South America and are important for the biomedical and pharmaceutical industries because of the chemical properties of their venom. They serve as either definitive or intermediate hosts for many parasitic helminths. The Marajó Island (Brazil) is the natural habitat of venomous snakes, Bothrops atrox and Bothrops marajoensis, which are often found around rural and peri-urban areas and are known to bite humans. Samples of helminths parasitizing the oral cavity, subcutaneous tissues, coelomic cavity, and intestine of four B. atrox from Marajó Island (Pará-Brazil) were collected. The specimens studied were taxonomically classified as trematodes of the species Stycholecitha serpentis, nematodes of the genera Eustrongylides and Camallanus and cystacanths of an acanthocephalan of the genus Centrorhynchus. The aims of the present study were: to record helminths found in B. atrox from the Marajó Island; to discuss their role as definitive, intermediate, or paratenic hosts; and to compile a list of helminths that have been recorded in snakes of the genus Bothrops of the Neotropical region.

Risk of Hemorrhagic Transformation after Mechanical Thrombectomy without versus with IV Thrombolysis for Acute Ischemic Stroke: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

BACKGROUND: When treating acute ischemic stroke due to large-vessel occlusion, both mechanical thrombectomy and intravenous (IV) thrombolysis carry the risk of intracerebral hemorrhage. PURPOSE: This study aimed to delve deeper into the risk of intracerebral hemorrhage and its subtypes associated with mechanical thrombectomy with or without IV thrombolysis to contribute to better decision-making in the treatment of acute ischemic stroke due to large-vessel occlusion. DATA SOURCES: PubMed, EMBASE, and Scopus databases were searched for relevant studies from inception to September 6, 2023. STUDY SELECTION: The eligibility criteria included randomized clinical trials or post hoc analysis of randomized controlled trials that focused on patients with acute ischemic stroke in the anterior circulation. After screening 4870 retrieved records, we included 9 studies (6 randomized controlled trials and 3 post hoc analyses of randomized controlled trials) with 3241 patients. DATA ANALYSIS: The interventions compared were mechanical thrombectomy + IV thrombolysis versus mechanical thrombectomy alone, with the outcome of interest being any form of intracerebral hemorrhage and symptomatic intracerebral hemorrhage after intervention. A common definition for symptomatic intracerebral hemorrhage was pooled from various classification systems, and subgroup analyses were performed on the basis of different definitions and anatomic descriptions of hemorrhage. The quality of the studies was assessed using the revised version of Cochrane Risk of Bias 2 assessment tool. Meta-analysis was performed using the random effects model. DATA SYNTHESIS: Eight studies had some concerns, and 1 study was considered high risk. Overall, the risk of symptomatic intracerebral hemorrhage was comparable between mechanical thrombectomy + IV thrombolysis and mechanial thrombectomy alone (risk ratio, 1.24 [95% CI, 0.89-1.72]; P = .20), with no heterogeneity across studies. Subgroup analysis of symptomatic intracerebral hemorrhage showed a non-significant difference between 2 groups based on the National Institute of Neurological Disorders and Stroke (P = .3), the Heidelberg Bleeding Classification (P = .5), the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (P = .4), and the European Cooperative Acute Stroke Study III (P = .7) criteria. Subgroup analysis of different anatomic descriptions of intracerebral hemorrhage showed no difference between the 2 groups. Also, we found no difference in the risk of any intracerebral hemorrhage between two groups (risk ratio, 1.10 [95% CI, 1.00-1.21]; P = .052) with no heterogeneity across studies. LIMITATIONS: There was a potential for performance bias in most studies. CONCLUSIONS: In this systematic review and meta-analysis, the risk of any intracerebral hemorrhage and symptomatic intracerebral hemorrhage, including its various classifications and anatomic descriptions, was comparable between mechanical thrombectomy + IV thrombolysis and mechanical thrombectomy alone.

Timeliness of surgery for early-stage lung cancer: Patient factors and predictors.

Objectives: Time-to-treatment initiation is an important consideration for patients undergoing thoracic surgery for early-stage lung cancer because delays have the potential to adversely affect outcomes. This study seeks to quantify time-to-treatment initiation for patients with clinical stage I lung cancer, explore patient factors and predictors that lead to an increased time-to-treatment initiation, and compare surgeon perception of appropriate time-to-treatment initiation to the results. Methods: Time-to-treatment initiation was determined for patients enrolled in the Mount Sinai Initiative for Early Lung Cancer Research on Treatment study who underwent surgical resection for clinical stage I lung cancer between March 2016 and December 2021. The following dates were determined: (1) date of first suspicious radiologic imaging, (2) date of first biopsy, and (3) date of surgery. A total of 15 thoracic surgeons who participated in the Mount Sinai Initiative for Early Lung Cancer Research on Treatment were assessed on their perception on time-to-treatment initiation. Results: For 638 patients, median time from first suspicious imaging findings to biopsy was 40 days, biopsy to surgery was 37 days, and suspicious imaging to surgery was 84 days. Significant factors that resulted in longer time-to-treatment initiation in the multivariate analysis were African American or Black race (P = .005), vascular disease (P = .01), and median household income less than $75,000 (P = .04). Although the surgeon's perception was that the average time from biopsy to surgery was 28 days, it was longer for 63.5% of participants; surgeon perception of maximum time between diagnosis and surgery was 84 days and longer for 28.7% of participants. Conclusions: Patient factors such as race, income, and comorbidities were found to have differences in time-to-treatment initiation. Delays to surgery exceeded the expectations of thoracic surgeons.

Systemic lupus erythematosus in Aboriginal and Torres Strait Islander peoples in Australia: addressing disparities and barriers to optimising patient care.

The first inhabitants of Australia and the traditional owners of Australian lands are the Aboriginal and Torres Strait Islander peoples. Aboriginal and Torres Strait Islander peoples are two to four times more likely to have systemic lupus erythematosus (SLE) than the general Australian population. Phenotypically, SLE appears distinctive in Aboriginal and Torres Strait Islander peoples and its severity is substantially increased, with mortality rates up to six times higher than in the general Australian population with SLE. In particular, Aboriginal and Torres Strait Islander peoples with SLE have increased prevalence of lupus nephritis and increased rates of progression to end-stage kidney disease. The reasons for the increased prevalence and severity of SLE in this population are unclear, but socioeconomic, environmental, and biological factors are all likely to be implicated, although there are no published studies investigating these factors in Aboriginal and Torres Strait Islander peoples with SLE specifically, indicating an important knowledge gap. In this Review, we summarise the data on the incidence, prevalence, and clinical and biological findings relating to SLE in Aboriginal and Torres Strait Islander peoples and explore potential factors contributing to its increased prevalence and severity in this population. Importantly, we identify health disparities and deficiencies in health-care provision that limit optimal care and outcomes for many Aboriginal and Torres Strait Islander peoples with SLE and highlight potentially addressable goals to improve outcomes.

Conserved and repetitive motifs in an intrinsically disordered protein drive ⍺-carboxysome assembly.

All cyanobacteria and some chemoautotrophic bacteria fix CO2 into sugars using specialized proteinaceous compartments called carboxysomes. Carboxysomes enclose the enzymes Rubisco and carbonic anhydrase inside a layer of shell proteins to increase the CO2 concentration for efficient carbon fixation by Rubisco. In the ⍺-carboxysome lineage, a disordered and highly repetitive protein named CsoS2 is essential for carboxysome formation and function. Without it, the bacteria require high CO2 to grow. How does a protein predicted to be lacking structure serve as the architectural scaffold for such a vital cellular compartment? In this study, we identify key residues present in the repeats of CsoS2, VTG and Y, which are necessary for building functional ⍺-carboxysomes in vivo. These highly conserved and repetitive residues contribute to the multivalent binding interaction and phase separation behavior between CsoS2 and shell proteins. We also demonstrate 3-component reconstitution of CsoS2, Rubisco, and shell proteins into spherical condensates, and show the utility of reconstitution as a biochemical tool to study carboxysome biogenesis. The precise self-assembly of thousands of proteins is crucial for carboxysome formation, and understanding this process could enable their use in alternative biological hosts or industrial processes as effective tools to fix carbon.

Increased PVR Expression on Bone Marrow Macrophages May Promote Resistance to TIGIT Blockade in Multiple Myeloma.

PURPOSE: TIGIT blockade in our ex vivo models of bone marrow (BM) reduced the number of malignant plasma cells (PCs) in only half of patients with multiple myeloma (MM). Here we wanted to investigate whether increased expression of TIGIT ligands may inhibit T cell immune response promoting resistance to TIGIT blockade. EXPERIMENTAL DESIGN: We first characterized the number and phenotype of BM macrophages in the different stages of disease by multi-parameter flow cytometry. We assessed the effect of TIGIT ligands on PC survival performing experiments with ex vivo BM model and analyzed changes in gene expression by using Nanostring technology and real-time PCR. RESULTS: Frequency of BM macrophages was significantly decreased in MM which was accompanied by changes in their immunophenotype. Moreover, we found a higher number of malignant PCs in ex vivo BM cells cultured onto PVR and nectin-2 compared to control, suggesting that both ligands may support PC survival. In addition, presence of PVR, but not nectin-2, overcame the therapeutic effect of TIGIT blockade or exogenous IL-2. Furthermore, presence of exogenous IL-2 increased TIGIT expression on both CD4+ and CD8+ T cells and, indirectly, PVR on BM macrophages. Consistently, PVR reduced the number of cytotoxic T cells and promoted a gene signature with reduced effector molecules. CONCLUSIONS: IL-2 induced TIGIT on T cells in the BM where increased PVR expression resulted in cytotoxic T cell inhibition promoting PC survival and resistance to TIGIT blockade.

Triple Aspiration Versus Conventional Aspiration Techniques: A Randomized In-Vitro Evaluation.

BACKGROUND AND PURPOSE: A single aspiration maneuver using a large volume syringe is a common and effective technique for aspiration thrombectomy. Multiple aspiration cycles using large aspiration syringes has been proposed as a means to improve efficacy over single aspiration. In this study, we sought to investigate the efficacy of a "triple aspiration technique" where a large volume syringe is cycled three times prior to catheter retraction during aspiration thrombectomy. MATERIALS AND METHODS: A 3D-printed adult vasculature was used as a benchtop thrombectomy platform. Fibrin-rich and red blood cell-rich clots were prepared in centrifuge tubes using human plasma, red blood cells, and calcium chloride. Next, clots were placed in the carotid terminus of the model, and the performances of three different aspiration techniques-triple syringe, single syringe, and continuous pump aspiration-were compared in a randomized manner (1:1:1). Outcomes of interest included first-pass efficacy (FPE), complete clot removal (final mTICI 2c/3), the number of thrombectomy attempts to achieve mTICI 2c/3, vacuum pressure, and distal embolization. The distal emboli were detected using a 70-micron cell strainer placed at the outflow of the model and quantified using an image processing algorithm. The vacuum pressures were measured using a pressure transducer (Honeywell, NC, USA). RESULTS: A total of 102 replicates were performed, 34 for each technique. The triple aspiration technique provided a significantly higher rate of FPE than the syringe and pump aspiration techniques (67.6% vs. 41.1%, p= 0.02). Additionally, the triple aspiration technique achieved complete clot removal with a significantly lower number of thrombectomy attempts compared to single syringe aspiration (1.2 ± 0.5 vs. 1.8 ± 0.8, p=0.005). The triple aspiration technique generated significantly higher vacuum pressure than both the single syringe and vacuum pump aspiration (28.3 ± 0.2 vs. 27.2 ± 0.3 (p= 0.002) and 26.2 ± 0.4 (p=0.001), respectively). The differences in complete clot removal and distal embolization parameters were not statistically significantly different across the groups. CONCLUSIONS: Our findings suggest that the triple aspiration technique can improve FPE rates and vacuum pressure in aspiration thrombectomy. Further studies are needed to examine the safety and efficacy of triple aspiration in the clinical setting. ABBREVIATIONS: AcommA = anterior communicating artery; FPE = first pass efficacy; ICA = internal carotid artery; MCA = middle cerebral artery; MT = mechanical thrombectomy; mTICI = modified thrombolysis in cerebral infarction scale; PcommA = posterior communicating artery.

In vitro evaluation of flow diverter performance using a human fibrinogen-based flow model.

OBJECTIVE: Fibrin deposition represents a key step in aneurysm occlusion, promoting endothelization of implants and connective tissue organization as part of the aneurysm-healing mechanism. In this study, the authors introduce a novel in vitro testing platform for flow diverters based on human fibrinogen. METHODS: A flow diverter was deployed in 4 different glass models. The glass models had the same internal parent artery (4 mm) and aneurysm (8 mm) diameters with varying parent artery angulations (paraophthalmic, sidewall, bifurcation, and slightly curved models). The neck size and area were 4 mm and 25 mm2, respectively. Human fibrinogen (330 mg/dl) was circulated within the glass models at varying flow rates (0, 3, 4, and 5 ml/sec) with or without heparin, calcium chloride, and thrombin for as long as 6 hours or until complete fibrin coverage of the flow diverter's neck was achieved. Aneurysm neck coverage was defined as macroscopic fibrin deposition occluding the flow diverters' pores. Flow characteristics after flow diverter deployment were assessed with computational fluid dynamics analysis. The effects of flow rates, heparin, calcium chloride, and thrombin on fibrin deposition rates were tested using 1-way ANOVA and the Tukey test. RESULTS: A total of 84 replicates were performed. Human fibrin did not accumulate on the flow diverter stents under static conditions. The fibrin deposition rate on the aneurysm neck was significantly greater with the 5 ml/sec flow rate as compared to 3 ml/sec for all models. The paraophthalmic model had the highest inflow velocity of 48.7 cm/sec. The bifurcation model had the highest maximum shear stress (SS) and maximum normalized shear stress values at the device cells at 843.3 dyne/cm2 and 35.1 SS/SSinflow, respectively. The fibrin deposition rates of the paraophthalmic and bifurcation models were significantly higher than those of sidewall and slightly curved models for all additive or flow rate comparisons (p = 0.001 for all comparisons). The incorporation of thrombin significantly increased the fibrin deposition rates across all models (p = 0.001 for all models). CONCLUSIONS: Rates of fibrin deposition varied widely across different configurations and additive conditions in this novel in vitro model system. Fibrin accumulation started at the aneurysm inflow zone where flow velocity and shear stress were the highest. The primary factors influencing fibrin deposition included flow velocities, shear stress, and the addition of thrombin at a physiological concentration. Further research is needed to test the clinical utility of fibrinogen-based models for patient-specific aneurysms.

White Matter Hyperintensities and Mild TBI in Post-9/11 Veterans and Service Members.

INTRODUCTION: The neurobehavioral significance of white matter hyperintensities (WMHs) seen on magnetic resonance imaging after traumatic brain injury (TBI) remains unclear, especially in Veterans and Service Members with a history of mild TBI (mTBI). In this study, we investigate the relation between WMH, mTBI, age, and cognitive performance in a large multisite cohort from the Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium. MATERIALS AND METHODS: The neuroimaging and neurobehavioral assessments for 1,011 combat-exposed, post-9/11 Veterans and Service Members (age range 22-69 years), including those with a history of at least 1 mTBI (n = 813; median postinjury interval of 8 years) or negative mTBI history (n = 198), were examined. RESULTS: White matter hyperintensities were present in both mTBI and comparison groups at similar rates (39% and 37%, respectively). There was an age-by-diagnostic group interaction, such that older Veterans and Service Members with a history of mTBI demonstrated a significant increase in the number of WMHs present compared to those without a history of mTBI. Additional associations between an increase in the number of WMHs and service-connected disability, insulin-like growth factor-1 levels, and worse performance on tests of episodic memory and executive functioning-processing speed were found. CONCLUSIONS: Subtle but important clinical relationships are identified when larger samples of mTBI participants are used to examine the relationship between history of head injury and radiological findings. Future studies should use follow-up magnetic resonance imaging and longitudinal neurobehavioral assessments to evaluate the long-term implications of WMHs following mTBI.

Disparities in unintentional drowning fatalities in Texas, USA, 1999-2020.

BACKGROUND: Drowning is the third-leading cause of unintentional injury death worldwide. Although the USA as a whole bears a heavy burden, with approximately 4000 drowning fatalities annually, Texas stands out as a high-risk state for drowning due to its large population, suitable climate for year-round aquatic activities and availability of water-related recreational opportunities. METHODS: Using mortality data from the Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research online database, this retrospective, cross-sectional study overviews the magnitude and patterns of fatal unintentional drownings among Texans from 1999 to 2020. RESULTS: Over the 22-year period, 7737 Texans died from unintentional drowning. An average of 352 drowning deaths occurred annually, with a rate of 1.4 deaths per 100 000 population. The highest proportion of unintentional drownings occurred in natural water settings (eg, lakes, ponds or rivers), accounting for 40% of fatal drownings. Children aged 1-4 years had the highest drowning death rate compared with all other age groups. Male Texans had a drowning death rate three times higher than that of female Texans. Black Texans had a higher drowning death rate than White Texans and Asian or Pacific Islander Texans. CONCLUSIONS: Drowning remains a significant public health issue in Texas. Data on high-risk groups and settings should be used to strengthen drowning prevention efforts and policy initiatives and encourage more research to address the multifaceted factors contributing to drowning.

Similar QALY gain in primary and revision knee arthroplasty: A cost analysis and Markov model.

PURPOSE: The aim of this study is to investigate the cost-effectiveness of revision total knee arthroplasty compared to primary total knee arthroplasty in terms of cost-per-quality-adjusted life year (QALY). METHODS: Data were retrieved for all primary and revision total knee replacement (TKA) procedures performed at a tertiary Swiss hospital between 2006 and 2019. A Markov model was created to evaluate revision risk and we calculated lifetime QALY gain and lifetime procedure costs through individual EuroQol 5 dimension (EQ-5D) scores, hospital costs, national life expectancy tables and standard discounting processes. Cost-per-QALY gain was calculated for primary and revision procedures. RESULTS: EQ-5D data were available for 1343 primary and 103 revision procedures. Significant QALY gains were seen following surgery in all cases. Similar, but significantly more QALYs were gained following primary TKA (PTKA) (5.67 ± 3.98) than following revision TKA (RTKA) (4.67 ± 4.20). Cost-per-QALY was €4686 for PTKA and €10,364 for RTKA. The highest average cost-per-QALY was seen in two-stage RTKA (€12,292), followed by one-stage RTKA (€8982). CONCLUSION: RTKA results in a similar QALY gain as PTKA. The costs of achieving health gain are two to three times higher in RTKA, but both procedures are highly cost-effective. LEVEL OF EVIDENCE: Economic level II.

A Translation-Independent Directed Evolution Strategy to Engineer Aminoacyl-tRNA Synthetases.

Using directed evolution, aminoacyl-tRNA synthetases (aaRSs) have been engineered to incorporate numerous noncanonical amino acids (ncAAs). Until now, the selection of such novel aaRS mutants has relied on the expression of a selectable reporter protein. However, such translation-dependent selections are incompatible with exotic monomers that are suboptimal substrates for the ribosome. A two-step solution is needed to overcome this limitation: (A) engineering an aaRS to charge the exotic monomer, without ribosomal translation; (B) subsequent engineering of the ribosome to accept the resulting acyl-tRNA for translation. Here, we report a platform for aaRS engineering that directly selects tRNA-acylation without ribosomal translation (START). In START, each distinct aaRS mutant is correlated to a cognate tRNA containing a unique sequence barcode. Acylation by an active aaRS mutant protects the corresponding barcode-containing tRNAs from oxidative treatment designed to damage the 3'-terminus of the uncharged tRNAs. Sequencing of these surviving barcode-containing tRNAs is then used to reveal the identity of the aaRS mutants that acylated the correlated tRNA sequences. The efficacy of START was demonstrated by identifying novel mutants of the Methanomethylophilus alvus pyrrolysyl-tRNA synthetase from a naïve library that enables incorporation of ncAAs into proteins in living cells.

Large-scale CRISPR screen reveals context-specific genetic regulation of retinal ganglion cell regeneration.

Many genes are known to regulate retinal regeneration following widespread tissue damage. Conversely, genes controlling regeneration following limited cell loss, per degenerative diseases, are undefined. As stem/progenitor cell responses scale to injury levels, understanding how the extent and specificity of cell loss impact regenerative processes is important. Here, transgenic zebrafish enabling selective retinal ganglion cell (RGC) ablation were used to identify genes that regulate RGC regeneration. A single cell multiomics-informed screen of 101 genes identified seven knockouts that inhibited and eleven that promoted RGC regeneration. Surprisingly, 35 of 36 genes known/implicated as being required for regeneration following widespread retinal damage were not required for RGC regeneration, and seven even enhanced regeneration kinetics, including proneural factors neurog1, olig2, and ascl1a. Mechanistic analyses revealed ascl1a disruption increased the propensity of progenitor cells to produce RGCs; i.e., increased "fate bias". These data demonstrate plasticity in how Müller glia can convert to a stem-like state and context-specificity in how genes function during regeneration. Increased understanding of how the regeneration of disease-relevant cell types is specifically controlled will support the development of disease-tailored regenerative therapeutics.

Single-modulator, dual comb serrodyne spectroscopy.

Dual optical frequency comb spectroscopy allows for high speed, broadband measurements without any moving parts. Here, we combine differential chirp downconversion to probe large spectral bandwidths and serrodyne modulation to separate the positive and negative sidebands in a single modulator. As an initial demonstration, we apply this approach to measure a sharp cavity resonance to illustrate the system performance. We then measure methane transitions in the near-infrared and compare the resulting spectra to models based upon the current spectroscopic databases. The serrodyne method has lower hardware requirements compared to many existing approaches, and its simplicity enables a high degree of mutual coherence between the two combs. Further, this method is readily amenable to chip-scale photonic integration.

A Systematic Overview of Contraindications and Special Warnings for Biologic and Targeted Synthetic Disease Modifying Antirheumatic Drugs: Establishing a Framework to Create a "Safety Checklist".

BACKGROUND/AIM: The purpose of this review is to provide an overview of the contraindications, special warnings, and boxed warnings with the aim to establish a framework to create a prescription safety checklist for a class of drugs or disease indication. This study covers biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs). METHODS: We identified contraindications, boxed warnings, and special warnings provided by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The study included b/tsDMARDs approved for treating rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (SpA), and juvenile idiopathic arthritis (JIA) within the drug-classes anti-CD20, tumor necrosis factor inhibitors (TNFi), interleukin-1 inhibitors (IL-1i), cytotoxic T-lymphocyte-associated protein (CTLA) 4, interleukin-12/23 inhibitors (IL-12/23i), interleukin 6 receptor inhibitors (IL-6Ri), Janus kinase inhibitors (JAKi), phosphodiesterase 4 inhibitors (PDE4i), interleukin-17 inhibitors (IL-17i), and interleukin-23 inhibitors (IL-23i). RESULTS: All drug classes, except PDE4i, had contraindications and/or warnings related to infections, including tuberculosis. A warning about herpes zoster was listed for anti-CD20, IL-1i, IL-6Ri, and JAKi, while a warning about hepatitis reactivation was listed for anti-CD20, TNFi, IL-1i, CTLA4-Ig, IL-6Ri, and JAKi. Malignancy risk was mentioned for all drug classes except PDE4i, IL-17i, and IL-23i. Other warnings included demyelinating disease (TNFi, CTLA4-Ig, and IL-6Ri), heart failure (anti-CD20 and TNFi), major adverse cardiac events (JAKi and IL-12/23) and venous thromboembolism (JAKi), hyperlipidemia (IL-6Ri and JAKi), liver impairment (TNFi, IL-1i, IL-6Ri, and JAKi), kidney impairment (IL-1i, JAKi, and PDE4i), inflammatory bowel disease (IL-17i), gastrointestinal perforation (IL-6Ri, JAKi), cytopenia (anti-CD20, TNFi, IL-1i, IL-6Ri, JAKi), and depression (PDE4i). Contraindications and warnings appeared to increase with the passage of time since the drug's approval. CONCLUSION: This review provides an overview to establish the framework to create an easily accessible and actionable prescription safety checklist from individual medical product prescription information provided by regulatory medical authorities.

Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance.

Receptor tyrosine kinases (RTKs) control stem cell maintenance vs. differentiation decisions. Casitas B-lineage lymphoma (CBL) family ubiquitin ligases are negative regulators of RTKs, but their stem cell regulatory roles remain unclear. Here, we show that Lgr5+ intestinal stem cell (ISC)-specific inducible Cbl-knockout (KO) on a Cblb null mouse background (iDKO) induced rapid loss of the Lgr5 Hi ISCs with transient expansion of the Lgr5 Lo transit-amplifying population. LacZ-based lineage tracing revealed increased ISC commitment toward enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro, Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single-cell RNA sequencing in organoids identified Akt-mTOR (mammalian target of rapamycin) pathway hyperactivation upon iDKO, and pharmacological Akt-mTOR axis inhibition rescued the iDKO defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine-tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.