Using genetic association data to guide drug discovery and development: Review of methods and applications.

Evidence on the validity of drug targets from randomized trials is reliable but typically expensive and slow to obtain. In contrast, evidence from conventional observational epidemiological studies is less reliable because of the potential for bias from confounding and reverse causation. Mendelian randomization is a quasi-experimental approach analogous to a randomized trial that exploits naturally occurring randomization in the transmission of genetic variants. In Mendelian randomization, genetic variants that can be regarded as proxies for an intervention on the proposed drug target are leveraged as instrumental variables to investigate potential effects on biomarkers and disease outcomes in large-scale observational datasets. This approach can be implemented rapidly for a range of drug targets to provide evidence on their effects and thus inform on their priority for further investigation. In this review, we present statistical methods and their applications to showcase the diverse opportunities for applying Mendelian randomization in guiding clinical development efforts, thus enabling interventions to target the right mechanism in the right population group at the right time. These methods can inform investigators on the mechanisms underlying drug effects, their related biomarkers, implications for the timing of interventions, and the population subgroups that stand to gain the most benefit. Most methods can be implemented with publicly available data on summarized genetic associations with traits and diseases, meaning that the only major limitations to their usage are the availability of appropriately powered studies for the exposure and outcome and the existence of a suitable genetic proxy for the proposed intervention.

Robust use of phenotypic heterogeneity at drug target genes for mechanistic insights: Application of cis-multivariable Mendelian randomization to GLP1R gene region.

Phenotypic heterogeneity at genomic loci encoding drug targets can be exploited by multivariable Mendelian randomization to provide insight into the pathways by which pharmacological interventions may affect disease risk. However, statistical inference in such investigations may be poor if overdispersion heterogeneity in measured genetic associations is unaccounted for. In this work, we first develop conditional F statistics for dimension-reduced genetic associations that enable more accurate measurement of phenotypic heterogeneity. We then develop a novel extension for two-sample multivariable Mendelian randomization that accounts for overdispersion heterogeneity in dimension-reduced genetic associations. Our empirical focus is to use genetic variants in the GLP1R gene region to understand the mechanism by which GLP1R agonism affects coronary artery disease (CAD) risk. Colocalization analyses indicate that distinct variants in the GLP1R gene region are associated with body mass index and type 2 diabetes (T2D). Multivariable Mendelian randomization analyses that were corrected for overdispersion heterogeneity suggest that bodyweight lowering rather than T2D liability lowering effects of GLP1R agonism are more likely contributing to reduced CAD risk. Tissue-specific analyses prioritized brain tissue as the most likely to be relevant for CAD risk, of the tissues considered. We hope the multivariable Mendelian randomization approach illustrated here is widely applicable to better understand mechanisms linking drug targets to diseases outcomes, and hence to guide drug development efforts.

Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches.

Mendelian randomization and colocalization are two statistical approaches that can be applied to summarized data from genome-wide association studies (GWASs) to understand relationships between traits and diseases. However, despite similarities in scope, they are different in their objectives, implementation, and interpretation, in part because they were developed to serve different scientific communities. Mendelian randomization assesses whether genetic predictors of an exposure are associated with the outcome and interprets an association as evidence that the exposure has a causal effect on the outcome, whereas colocalization assesses whether two traits are affected by the same or distinct causal variants. When considering genetic variants in a single genetic region, both approaches can be performed. While a positive colocalization finding typically implies a non-zero Mendelian randomization estimate, the reverse is not generally true: there are several scenarios which would lead to a non-zero Mendelian randomization estimate but lack evidence for colocalization. These include the existence of distinct but correlated causal variants for the exposure and outcome, which would violate the Mendelian randomization assumptions, and a lack of strong associations with the outcome. As colocalization was developed in the GWAS tradition, typically evidence for colocalization is concluded only when there is strong evidence for associations with both traits. In contrast, a non-zero estimate from Mendelian randomization can be obtained despite only nominally significant genetic associations with the outcome at the locus. In this review, we discuss how the two approaches can provide complementary information on potential therapeutic targets.

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Intra-arterial Fractional Flow Reserve Measurements Provide an Objective Assessment of the Functional Significance of Peripheral Arterial Stenoses.

OBJECTIVE: Peripheral arterial stenoses (PAS) are commonly investigated with duplex ultrasound (DUS) and angiography, but these are not functional tests. Fractional flow reserve (FFR), a pressure based index, functionally assesses the ischaemic potential of coronary stenoses, but its utility in PAS is unknown. FFR in the peripheral vasculature in patients with limb ischaemia was investigated. METHODS: Patients scheduled for angioplasty and or stenting of isolated iliac and superficial femoral artery stenoses were recruited. Resting trans-lesional pressure gradient (Pd/Pa) and FFR were measured after adenosine provoked hyperaemia using an intra-arterial 0.014 inch flow and pressure sensing wire (ComboWire XT, Philips). Prior to revascularisation, exercise ABPI (eABPI) and DUS derived peak systolic velocity ratio (PSVR) of the index lesion were determined. Calf muscle oxygenation was measured using blood oxygenation level dependent cardiovascular magnetic resonance prior to and after revascularisation. RESULTS: Forty-one patients (32, 78%, male, mean age 65 ± 11 years) with 61 stenoses (iliac 32; femoral 29) were studied. For lesions < 80% stenosis, resting Pd/Pa was not influenced by the degree of stenosis (p = .074); however, FFR was discriminatory, decreasing as the severity of stenosis increased (p = .019). An FFR of < 0.60 was associated with critical limb threatening ischaemia (area under the curve [AUC] 0.87; 95% CI 0.75 - 0.95), in this study performing better than angiographic % stenosis (0.79; 0.63 - 0.89), eABPI (0.72; 0.57 - 0.83), and PSVR (0.65; 0.51 - 0.78). FFR correlated strongly with calf oxygenation (rho, 0.76; p < .001). A greater increase in FFR signalled resolution of symptoms and signs (ΔFFR 0.25 ± 0.15 vs. 0.13 ± 0.09; p = .009) and a post-angioplasty and stenting FFR of > 0.74 predicted successful revascularisation (combined sensitivity and specificity of 95%; AUC 0.98; 0.91 - 1.00). CONCLUSION: This pilot study demonstrates that FFR can objectively measure the functional significance of PAS that compares favourably with visual and DUS based assessments. Its role as a quality control adjunct that confirms optimal vessel patency after angioplasty and or stenting also merits further investigation.

Unveiling piperazine-quinoline hybrids as potential multi-target directed anti-Alzheimer's agents: design, synthesis and biological evaluation.

Multi-target directed ligands (MTDLs) have recently been popularized due to their outstanding efficacy in combating the complicated features of Alzheimer's disease. This study details the synthesis of piperazine-quinoline-based MTDLs through a multicomponent Petasis reaction, targeting multiple factors such as AChE, BuChE, metal chelation to restore metal dyshomeostasis, and antioxidant activity. Some of the synthesized compounds exhibited notable inhibitory activity against AChE and BuChE enzymes at specific concentrations. Among the synthesized compounds compound (95) containing a 4-chloroaniline moiety and a 4-methoxybenzyl group displayed the most promising inhibitory activities against AChE (IC50 3.013 µM) and BuChE (IC50 = 3.144 µM). Compound (83) featuring 2-methoxyaniline and 4-fluorobenzyl substituents, exhibited the highest BuChE inhibition (IC50 1.888 µM). Notably, compound (79) demonstrated 93-times higher selectivity for BuChE over AChE. Molecular docking and molecular dynamics simulations were also performed to explore the binding modes and stability of these compounds with the AChE amd BuChE proteins. Further, kinetics study was performed against AChE for comounds (83 and 95) which indicated mixed inhibition of the enzyme by these compounds, Amongs the synthesized compounds, nine compounds were assessed for their antioxidant activity, displaying significant antioxidant properties with IC50 values ranging from 156 µM to 310 µM. Moreover, all the compounds demonstrated metal chelating tendency with Cu+2, Zn+2, Fe+2, Fe+3 and Al+3. This study provides insights into the design of novel MTDLs, highlighting compound (95) as a potential candidate for combating Alzheimer's disease.

Bacteriophages as a potential substitute for antibiotics: A comprehensive review.

Over the years, the administration of antibiotics for the purpose of addressing bacterial infections has become increasingly challenging due to the increased prevalence of antimicrobial resistance exhibited by various strains of bacteria. Multidrug-resistant (MDR) bacterial species are rising due to the unavailability of novel antibiotics, leading to higher mortality rates. With these conditions, there is a need for alternatives in which phage therapy has made promising results. Phage-derived endolysins, phage cocktails, and bioengineered phages are effective and have antimicrobial properties against MDR and extensively drug-resistant strains. Despite these, it has been observed that phages can give antimicrobial activity to more than one bacterial species. Thus, phage cocktail against resistant strains provides broad spectrum treatment and magnitude of effectivity, which is many folds higher than antibiotics. Many commercially available endolysins such as Staphefekt SA.100, Exebacase (CF-301), and N-Rephasin®SAL200 are used in biofilm penetration and treating plant diseases. The role of CMP1 phage endolysin in transgenic tomato plants in preventing Clavibacter michiganensis infection and the effectiveness of phage in protecting Atlantic salmon from vibriosis have been reported. Furthermore, phage-derived endolysin therapy, such as TSPphg phage exogenous treatment, can aid in disrupting cell walls, leading to bacterial cell lysis. As animals in aquaculture and slaughterhouses are highly susceptible to bacterial infections, effective phage therapy instead of antibiotics can help treat poultry animals, preserve them, and facilitate disease-free trade. Using bioengineered phages and phage cocktails enhances the effectiveness by providing a broad spectrum of phages and target specificity. Research is currently being conducted on clinical trials to confirm the efficacy of engineered phages and phage cocktails in humans. Although obtaining commercial approval may be time-consuming, it will be beneficial in the postantibiotic era. This review provides an overview of the significance of phage therapy as a potential alternative to antibiotics in combating resistant bacterial strains and its application to various fields and emphasizes the importance of safeguarding and ensuring treatment efficacy.

Computational Exploration of Naturally Occurring Flavonoids as TGF-ß Inhibitors in Breast Cancer: Insights from Docking and Molecular Dynamics Simulations and In-vitro Cytotoxicity Study.

Breast cancer is a global health concern, demanding innovative treatments. Targeting the Transforming Growth Factor-beta (TGF-ß) signaling pathway, pivotal in breast cancer, is a promising approach. TGF-ß inhibits proliferation via G1 phase cell cycle arrest, acting as a suppressor initially, but in later stages, it promotes progression by enhancing motility, invasiveness, and metastasis formation. This study explores naturally occurring flavonoids' interactions with TGF-ß. Using molecular docking against the protein's crystal structure (PDB Id: 1PY5), Gossypin showed the highest docking score and underwent molecular dynamics simulation, revealing complex flexibility and explaining how flavonoids impede TGF-ß signaling in breast cancer. ADMET predictions adhered to Lipinski's rule of Five. Insights into flavonoid-TGF-ß binding offer a novel angle for breast cancer treatment. Flavonoids having a good docking score like gossypin, morin, luteolin and taxifolin shown potent cytotoxic effect on breast cancer cell line, MCF-7. Understanding these interactions could inspire flavonoid-based therapies targeting TGF-ß to halt breast cancer growth. These findings pave the way for personalized, targeted breast cancer therapies, offering hope against this formidable disease.

Eco-friendly approaches to 1,3,4-oxadiazole derivatives: A comprehensive review of green synthetic strategies.

This review article offers an environmentally benign synthesis of 1,3,4-oxadiazole derivatives, with a focus on sustainable methodologies that have minimal impact on the environment. These derivatives, known for their diverse applications, have conventionally been associated with synthesis methods that utilize hazardous reagents and produce significant waste, thereby raising environmental concerns. The green synthesis of 1,3,4-oxadiazole derivatives employs renewable substrates, nontoxic catalysts, and mild reaction conditions, aiming to minimize the environmental impact. Innovative techniques such as catalyst-based, catalyst-free, electrochemical synthesis, green-solvent-mediated synthesis, grinding, microwave-mediated synthesis, and photosynthesis are implemented, providing benefits in terms of scalability, cost-effectiveness, and ease of purification. This review emphasizes the significance of sustainable methodologies in the synthesis of 1,3,4-oxadiazole and boots for continued exploration in this research domain.

Emerging green synthetic routes for thiazole and its derivatives: Current perspectives.

This review article provides an overview of the green synthesis of thiazole derivatives, emphasizing sustainable and environmentally friendly methodologies. Thiazole derivatives possess significant value and find diverse applications across various fields. However, conventional synthesis methods often involve hazardous reagents and generate substantial waste, posing environmental concerns. The green synthesis of thiazole derivatives employs renewable starting materials, nontoxic catalysts, and mild reaction conditions to minimize environmental impact. Innovative techniques such as microwave irradiation, ultrasound synthesis, green solvents, a green catalyst-based approach, and mechanochemistry-mediated synthesis are employed, offering advantages in terms of scalability, cost-effectiveness, and purification simplicity. The resulting thiazole derivatives exhibit comparable or enhanced biological activities, showcasing the feasibility and practicality of green synthesis in drug discovery. This review paper underscores the importance of sustainable approaches in functional molecular synthesis and encourages further research in this domain.

Untargeted metabolomics-based identification of bioactive compounds from Mangifera indica L. seed extracts in drug discovery through molecular docking and assessment of their anticancer potential.

BACKGROUND: Mangifera indica L. (mango), a medicinal plant rich in biologically active compounds, has potential to be used in disease-preventing and health-promoting products. The present investigation reveals and uncovers bioactive metabolites with remarkable therapeutic efficiency from mango (family: Anacardiaceae) seeds. RESULTS: Biological activity was determined by antimicrobial, antioxidant and anticancer assays, and metabolite profiling was performed on gas chromatography coupled to quadrupole time-of-flight mass spectrometry (GC-QTOF-MS) and liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) platforms. Validation of active metabolites was carried out by in silico molecular docking (Molinspiration Cheminformatics Server and PASS). Extracted and identified metabolites were screened; 54 compounds associated with various groups were selected for the in silico interaction study. CONCLUSIONS: Molecular docking revealed lead molecules with a potential binding energy score, efficacy and stable modulation with a selected protein domain. Investigation, directed by in vitro and in silico analysis, confirms mango seeds as an excellent source of potential metabolites as a therapeutic agent. © 2024 Society of Chemical Industry.

Recent advances in Bacillus-mediated plant growth enhancement: a paradigm shift in redefining crop resilience.

The Bacillus genus has emerged as an important player in modern agriculture, revolutionizing plant growth promotion through recent advances. This review provides a comprehensive overview of the critical role Bacillus species play in boosting plant growth and agricultural sustainability. Bacillus genus bacteria benefit plants in a variety of ways, according to new research. Nitrogen fixation, phosphate solubilization, siderophore production, and the production of growth hormones are examples of these. Bacillus species are also well-known for their ability to act as biocontrol agents, reducing phytopathogens and protecting plants from disease. Molecular biology advances have increased our understanding of the complex interplay between Bacillus species and plants, shedding light on the genetic and metabolic underpinnings of these interactions. Furthermore, novel biotechnology techniques have enabled the development of Bacillus-based biofertilizers and biopesticides, providing sustainable alternatives to conventional chemical inputs. Apart from this, the combination of biochar and Bacillus species in current biotechnology is critical for improving soil fertility and encouraging sustainable agriculture through enhanced nutrient retention and plant growth. This review also emphasizes the Bacillus genus bacteria's ability to alleviate environmental abiotic stresses such as drought and salinity, hence contributing to climate-resilient agriculture. Moreover, the authors discuss the challenges and prospects associated with the practical application of Bacillus-based solutions in the field. Finally, recent advances in Bacillus-mediated plant growth promotion highlight their critical significance in sustainable agriculture. Understanding these improvements is critical for realizing the full potential of Bacillus genus microorganisms to address current global food production concerns.

Disentangling the effects of traits with shared clustered genetic predictors using multivariable Mendelian randomization.

When genetic variants in a gene cluster are associated with a disease outcome, the causal pathway from the variants to the outcome can be difficult to disentangle. For example, the chemokine receptor gene cluster contains genetic variants associated with various cytokines. Associations between variants in this cluster and stroke risk may be driven by any of these cytokines. Multivariable Mendelian randomization is an extension of standard univariable Mendelian randomization to estimate the direct effects of related exposures with shared genetic predictors. However, when genetic variants are clustered, due to being located in a single genetic region, a Goldilocks dilemma arises: including too many highly-correlated variants in the analysis can lead to ill-conditioning, but pruning variants too aggressively can lead to imprecise estimates or even lack of identification. We propose multivariable methods that use principal component analysis to reduce many correlated genetic variants into a smaller number of orthogonal components that are used as instrumental variables. We show in simulations that these methods result in more precise estimates that are less sensitive to numerical instability due to both strong correlations and small changes in the input data. We apply the methods to demonstrate the most likely causal risk factor for stroke at the chemokine gene cluster is monocyte chemoattractant protein-1.

Effect of Thoracic Surgery Regionalization on 1- and 3-Year Survival after Cancer Esophagectomy.

OBJECTIVE: The aim of this study was to investigate whether our previously reported improvements in short-term cancer esophagectomy outcomes after large-scale regionalization in the United States translated to longer-term survival benefit. BACKGROUND: Regionalization is associated with better early postoperative outcomes following cancer esophagectomy; however, data regarding its effect on long-term survival are mixed. METHODS: We retrospectively reviewed 461 patients undergoing cancer esophagectomy before (2009-2013, N = 272) and after (2014-2016, N = 189) regionalization. Kaplan-Meier curves and chi-square tests were used to describe 1- and 3-year survival in each era. Hierarchical logistic regression models examined the adjusted effect of regionalization on mortality. RESULTS: Compared to pre-regionalization patients, post-regionalization patients had significantly higher 1-year survival (83.1% vs 73.9%, P = 0.02) but not 3-year survival (52.9% vs 58.2%, P = 0.26).Subgroup analysis by cancer stage revealed that 1-year survival benefit was only significant among mid-stage (IIB-IIIB) patients, whereas differences in 3-year survival only approached significance among early-stage (IA-IIA) patients.In multivariable analysis, only regionalization was a predictor of lower mortality at 1 year [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.29-1.00], and only thoracic specialty at 3years (OR 0.62, 95% CI 0.38-0.99). Older age, more advanced stage, and complications were associated with higher 1- and 3-year mortality. Comorbidity, minimally invasive approach, surgeon volume, facility volume, and neoadjuvant treatment were not significant in this model. CONCLUSIONS: Regionalization was associated with improved 1-year survival after cancer esophagectomy, independent of factors such as morbidity or volume in our adjusted models. This survival benefit did not persist at 3 years, likely due to the aggressive nature of the disease.

Conditional inference in cis-Mendelian randomization using weak genetic factors.

Mendelian randomization (MR) is a widely used method to estimate the causal effect of an exposure on an outcome by using genetic variants as instrumental variables. MR analyses that use variants from only a single genetic region (cis-MR) encoding the protein target of a drug are able to provide supporting evidence for drug target validation. This paper proposes methods for cis-MR inference that use many correlated variants to make robust inferences even in situations, where those variants have only weak effects on the exposure. In particular, we exploit the highly structured nature of genetic correlations in single gene regions to reduce the dimension of genetic variants using factor analysis. These genetic factors are then used as instrumental variables to construct tests for the causal effect of interest. Since these factors may often be weakly associated with the exposure, size distortions of standard t-tests can be severe. Therefore, we consider two approaches based on conditional testing. First, we extend results of commonly-used identification-robust tests for the setting where estimated factors are used as instruments. Second, we propose a test which appropriately adjusts for first-stage screening of genetic factors based on their relevance. Our empirical results provide genetic evidence to validate cholesterol-lowering drug targets aimed at preventing coronary heart disease.

Venous Thromboembolism Prophylaxis in Pediatric Inflammatory Bowel Disease Patients Hospitalized With a Central Line.

OBJECTIVES: Patients hospitalized with inflammatory bowel disease (IBD) have increased risk of venous thromboembolism (VTE). The aim of this study was to determine whether the adoption of a VTE protocol would change rates of medical VTE prophylaxis (low molecular weight heparin) in patients with IBD and a central venous catheter (CVC), while subsequently decreasing the incidence of VTE in this population. METHODS: A protocol for VTE prophylaxis in IBD was established in March of 2018. Every patient hospitalized with an IBD flare and central venous access from March 2013 to March 2020 was identified. Study data, including patient demographics, rates of Doppler ultrasound (US), and rates of VTE were collected using International Classification of Diseases (ICD)-10 codes, CPT codes, and chart review retrospectively. Determination of an IBD flare was based on physician global assessment. Groups were compared with independent-sample t tests and chi-squared tests. RESULTS: A total of 313 hospitalizations across 187 different patients were identified that met criteria including IBD and central venous access. VTE prophylaxis increased from 5.24% (n = 12) prior to the intervention to 63.10% (n = 53) after the intervention [chi-square (1, N = 313) = 125.0192, P < 0.001]. Rate of Doppler US increased from 9.17% (n = 21) prior to the intervention to 17.86% (n = 15) after the intervention [chi-square (1, N = 313) = 4.5562, P < 0.05]. Diagnosis of VTE increased from 0.87% (n = 2) prior to the intervention to 7.14% (n = 6) after the intervention [chi-square (1, N = 313) = 9.6992, P < 0.01]. There were no significant differences in the demographic characteristics pre- versus post-intervention. CONCLUSIONS: Rates of Doppler US and VTE prophylaxis use increased significantly after implementation of a VTE protocol. Rates of VTE diagnosis also increased, though we suspect this may be due to missed diagnoses prior to implementation of the protocol and increased risk awareness after the protocol was established.

Use, Durability, and Risks for Discontinuation of Initial and Subsequent Biologics in a Large Pediatric-Onset IBD Cohort.

BACKGROUND: Biologic medications are recommended for treatment of moderately-to-severely active Crohn disease (CD) or ulcerative colitis (UC) in children. However, many patients require sequential biologic treatment because of nonresponse or loss of response to the initial biologic. METHODS: We analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation. RESULTS: Of 17,649 patients with IBD [CD: 12,410 (70%); UC: 5239 (30%)], 7585 (43%) were treated with a biologic agent before age 18 (CD: 50%; UC: 25%). Biologic treatment was more likely for CD than UC (odds ratio, 3.0; 95% CI: 2.8-3.2; P < 0.0001). First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab). Probability of remaining on the first biologic was significantly higher in CD than UC ( P < 0.0001). First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%). In univariate analysis, factors associated with discontinuation of first and/or second biologics in CD include colonic-only disease, corticosteroid use, upper gastrointestinal tract involvement, and clinical and biochemical markers of severe disease. Biologic durability improved with later induction date. CONCLUSIONS: Treatment with biologic medications is common in pediatric IBD. Patients with CD are more likely to receive biologics, receive biologics earlier in disease course, and remain on the first biologic longer than patients with UC. Multiple factors may predict biologic durability in children with IBD.

Association of Surgical Timing with Outcomes in Early Stage Lung Cancer.

BACKGROUND: Optimal time to surgery for lung cancer is not well established. We aimed to assess whether time to surgery correlates with outcomes. METHODS: We assessed patients 18-84 years old who were diagnosed with stage I/II lung cancer at our integrated healthcare system from 2009 to 2019. Time to surgery was defined to start with disease confirmation (imaging or biopsy) prior to the surgery scheduling date. Outcomes of unplanned return to care within 30 days of lung cancer surgery, all-cause mortality, and disease recurrence were compared based on time to surgery before and after 2, 4, and 12 weeks. RESULTS: Of 2861 included patients, 70% were over 65 years old and 61% were female. Time to surgery occurred in 1-2 weeks for 6%, 3-4 weeks for 31%, 5-12 weeks for 58%, and 13-26 weeks for 5% of patients. Patients with time to surgery > 4 (vs. ≤ 4) weeks had greater risk of both death (hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.00-1.39) and recurrence (HR 1.33, 95% CI 1.10-1.62). Associations were not statistically significant when dichotomizing time to surgery at 2 or 12 weeks for death (2 week HR 1.23, 95% CI 0.93-1.64; 12 week HR 1.35, 95% CI 0.97-1.88) and recurrence (2 week HR 1.54, 95% CI 0.85-2.80; 12 week HR 2.28, 95% CI 0.80-6.46). CONCLUSIONS: Early stage lung cancer patients with time to surgery within 4 weeks experienced lower rates of recurrence. Optimal time to surgical resection may be shorter than previously reported.

A retrospective review of single-position prone lateral lumbar interbody fusion cases: early learning curve and perioperative outcomes.

PURPOSE: The objective of this study was to discuss our experience performing LLIF in the prone position and report our complications. METHODS: A retrospective chart review was conducted that included all patients who underwent single- or multi-level single-position pLLIF alone or as part of a concomitant procedure by the same surgeon from May 2019 to November 2022. RESULTS: A total of 155 patients and 250 levels were included in this study. Surgery was most commonly performed at the L4-L5 level (n = 100, 40%). The most common preoperative diagnosis was spondylolisthesis (n = 74, 47.7%). In the first 30 cases, 3 surgeries were aborted to an MIS TLIF. Complications included 3 unintentional ALL ruptures (n = 3/250, 1.2%), and 1 malpositioned implant impinging on the contralateral foramen requiring revision (n = 1/250, 0.4%), which all occurred within the first 30 cases. Out of 147 patients with more than 6-week follow-ups, there were 3 cases of femoral nerve palsy (n = 3/147, 2.0%). Two cases of femoral nerve palsy improved to preoperative strength by the 6th week postoperatively, while one improved to 4/5 preoperative strength by 1 year. There were no cases of bowel perforation or vascular injury. CONCLUSION: Our single-surgeon experience demonstrates the initial learning curve when adopting pLLIF. Thereafter, we experienced reproducibility in our technique and large improvements in our operative times, and complication profile. We experienced no technical complications after the 30th case. Further studies will include long-term clinical and radiographic outcomes to understand the complete utility of this approach.