Locoregional recurrence in studies of primary systemic therapy in early invasive breast cancer.

INTRODUCTION: The use of primary systemic therapy (PST) in early invasive breast cancer is routine but there are concerns about risk of locoregional recurrence. METHODS: We conducted a systematic literature review to identify studies of locoregional treatment and recurrence in patients with early invasive breast cancer who received non-endocrine PST. RESULTS: We identified 112 studies (18 prospective trials and 94 non-interventional studies). The use of surgery and radiotherapy after PST was recorded in 65 (58 %) and 50 (45 %) of studies respectively. 66 (59 %) studies reported locoregional recurrence. Cumulative 5-year locoregional recurrence risks varied from 1 % to 23 %. Locoregional recurrence was higher in patients under the age of 40, those who did not achieve a pathological complete remission after PST, had ER-negative or HER2 negative tumours, were recorded to have inoperable disease before PST, and did not have radiotherapy. LRR rates in these studies have not fallen over the overall calendar period of patient enrollment (1999-2016). CONCLUSION: The recording of locoregional treatments and outcomes is suboptimal in studies of PST and efforts to improve this are required. In the absence of randomised evidence, our findings may help to inform care and guideline development. We were unable to exclude concern that the use of PST is associated with a higher than desired risk of locoregional recurrence.

Systematized Serendipity: Fishing Expeditions for Anesthetic Drugs and Targets.

Most of science involves making observations, forming hypotheses, and testing those hypotheses, to form valid conclusions. However, a distinct, longstanding, and very productive scientific approach does not follow this paradigm; rather, it begins with a screen through a random collection of drugs or genetic variations for a particular effect or phenotype. Subsequently, the identity of the drug or gene is determined, and only then are hypotheses formed and the more standard scientific method employed. This alternative approach is called forward screening and includes methods such as genetic mutant screens, small molecule screens, metabolomics, proteomics, and transcriptomics. This review explains the rational for forward screening approaches and uses examples of screens for mutants with altered anesthetic sensitivities and for novel anesthetics to illustrate the methods and impact of the approach. Forward screening approaches are becoming even more powerful with advances in bioinformatics aided by artificial intelligence.

Implementing a pharmacogenomic-driven algorithm to guide antiplatelet therapy among Caribbean Hispanics: a non-randomised clinical trial.

OBJECTIVES: To assess whether genotype-guided selection of oral antiplatelet drugs using a clinical decision support (CDS) algorithm reduces the rate of major adverse cardiovascular and cerebrovascular events (MACCEs) among Caribbean Hispanic patients, after 6 months. DESIGN: An open-label, multicentre, non-randomised clinical trial. SETTING: Eight secondary and tertiary care hospitals (public and private) in Puerto Rico. PARTICIPANTS: 300 Caribbean Hispanic patients on clopidogrel, both genders, underwent percutaneous coronary intervention (PCI) for acute coronary syndromes, stable ischaemic heart disease and documented extracardiac vascular diseases. INTERVENTIONS: Patients were separated into standard-of-care (SoC) and genotype-guided (pharmacogenetic (PGx)-CDS) groups (150 each) and stratified by risk scores. Risk scores were calculated based on a previously developed CDS risk prediction algorithm designed to make actionable treatment recommendations for each patient. Individual platelet function, genotypes, clinical and demographic data were included. Ticagrelor was recommended for patients with a high-risk score ≥2 in the PGx-CDS group only, the rest were kept or de-escalated to clopidogrel. The intervention took place within 3-5 days after PCI. Adherence medication score was also measured. PRIMARY AND SECONDARY OUTCOMES: The occurrence rate of MACCEs (primary) and bleeding episodes (secondary). Statistical associations between patient time free of events and predictor variables (ie, treatment groups, risk scores) were tested using Kaplan-Meier survival analyses and Cox proportional-hazards regression models. RESULTS: The genotype-guided group had a clinically lower but not significantly different risk of MACCEs compared with the SoC group (8.7% vs 10.7%, p=0.56; HR=0.56). Among high-risk score patients, genotype-driven guidance of antiplatelet therapy showed superiority over SoC in reducing MACCE incidence 6 months postcoronary stenting (adjusted HR=0.104; p< 0.0001). CONCLUSIONS: The potential benefit of implementing our PGx-CDS algorithm to significantly reduce the incidence rate of MACCEs in post-PCI Caribbean Hispanic patients on clopidogrel was observed exclusively among high-risk patients, with apparently no evident effect in other patient groups. TRIAL REGISTRATION NUMBER: NCT03419325.

Apicoplast-derived isoprenoids are essential for biosynthesis of GPI protein anchors, and consequently for egress and invasion in Plasmodium falciparum.

Glycophosphatidylinositol (GPI) anchors are the predominant glycoconjugate in Plasmodium parasites, enabling modified proteins to associate with biological membranes. GPI biosynthesis commences with donation of a mannose residue held by dolichol-phosphate at the endoplasmic reticulum membrane. In Plasmodium dolichols are derived from isoprenoid precursors synthesised in the Plasmodium apicoplast, a relict plastid organelle of prokaryotic origin. We found that treatment of Plasmodium parasites with apicoplast inhibitors decreases the synthesis of isoprenoid and GPI intermediates resulting in GPI-anchored proteins becoming untethered from their normal membrane association. Even when other isoprenoids were chemically rescued, GPI depletion led to an arrest in schizont stage parasites, which had defects in segmentation and egress. In those daughter parasites (merozoites) that did form, proteins that would normally be GPI-anchored were mislocalised, and when these merozoites were artificially released they were able to attach to but not invade new red blood cells. Our data provides further evidence for the importance of GPI biosynthesis during the asexual cycle of P. falciparum, and indicates that GPI biosynthesis, and by extension egress and invasion, is dependent on isoprenoids synthesised in the apicoplast.

Treatment outcomes of vulvar and vaginal melanoma at an NCCN institution between 1993 and 2021.

Background: Vulvar melanoma and vaginal melanoma are rare and difficult to treat. We describe the last three decades in a cohort predominantly treated surgically with adjuvant therapy. Methods: All new patients between 1993 and 2021 followed until 2024. Collection of demographic and oncologic data allowed comparisons and Kaplan-Meier method was used to evaluate overall survival (OS) and progression free survival (PFS) stratified by adjuvant therapy type, diagnosis before and after 2011, and between vulvar and vaginal melanomas. Results: Consultation for 63/72 patients (87.5 %) were for primary treatment. Most patients had vulvar melanoma (50/72, 69.4 %), received surgery (65/72, 90.3 %), and adjuvant treatment (40/72, 55.6 %) with immunotherapy, chemotherapy, and/or targeted therapy. Median survival for 63 patients presenting for primary treatment was 54.2 months, and 9/13 patients who were disease free after five years later received adjuvant immunotherapy. Survival did not vary by adjuvant therapy type or diagnosis after 2011 but was significantly less for vaginal melanoma. Following recurrence seven patients experienced complete response including three patients receiving combined nivolumab with ipilimumab and two nivolumab alone experienced. Conclusions: Survival was not significantly different by adjuvant therapy type or after 2011. Most patients who were disease-free five years after surgery had received adjuvant therapy. Seven patients experienced complete responses to therapy after recurrence of whom five received immune checkpoint inhibitors. Although survival is not improved as in cutaneous melanomas by immune checkpoint inhibitors, signal continues for the use of immune checkpoint inhibitors in gynecologic melanomas.

Comparing adaptations from blood flow restriction exercise training using regulated or unregulated pressure systems: A systematic review and meta-analysis.

OBJECTIVE: No study has examined outcomes derived from blood flow restriction exercise training interventions using regulated compared with unregulated blood flow restriction pressure systems. Therefore, we used a systematic review and meta-analyses to compare the chronic adaptations to blood flow restriction exercise training achieved with regulated and unregulated blood flow restriction pressure systems. DATA SOURCES: The electronic database search included using the tool EBSCOhost and other online database search engines. The search included Medline, SPORTDiscus, CINAHL, Embase and SpringerLink. METHODS: Included studies utilised chronic blood flow restriction exercise training interventions greater than two weeks duration, where blood flow restriction was applied using a regulated or unregulated blood flow restriction pressure system, and where outcome measures such as muscle strength, muscle size or physical function were measured both pre- and post-training. Studies included in the meta-analyses used an equivalent non-blood flow restriction exercise comparison group. RESULTS: Eighty-one studies were included in the systematic review. Data showed that regulated (n = 47) and unregulated (n = 34) blood flow restriction pressure systems yield similar training adaptations for all outcome measures post-intervention. For muscle strength and muscle size, this was reaffirmed in the included meta-analyses. CONCLUSION: This review indicates that practitioners may achieve comparable training adaptations with blood flow restriction exercise training using either regulated or unregulated blood flow restriction pressure systems. Therefore, additional factors such as device quality, participant comfort and safety, cost and convenience are important factors to consider when deciding on appropriate equipment to use when prescribing blood flow restriction exercise training.

Thermomechanical Processing for Improved Mechanical Properties of HT9 Steels.

Thermomechanical processing (TMP) of ferritic-martensitic (FM) steels, such as HT9 (Fe-12Cr-1MoWV) steels, involves normalizing, quenching, and tempering to create a microstructure of fine ferritic/martensitic laths with carbide precipitates. HT9 steels are used in fast reactor core components due to their high-temperature strength and resistance to irradiation damage. However, traditional TMP methods for these steels often result in performance limitations under irradiation, including embrittlement at low temperatures (<~430 °C), insufficient strength and toughness at higher temperatures (>500 °C), and void swelling after high-dose irradiation (>200 dpa). This research aimed to enhance both fracture toughness and strength at high temperatures by creating a quenched and tempered martensitic structure with ultrafine laths and precipitates through rapid quenching and unconventional tempering. Mechanical testing revealed significant variations in strength and fracture toughness depending on the processing route, particularly the tempering conditions. Tailored TMP approaches, combining rapid quenching with limited tempering, elevated strength to levels comparable to nano-oxide strengthened ferritic alloys while preserving fracture toughness. For optimal properties in high-Cr steels for future reactor applications, this study recommends a modified tempering treatment, i.e., post-quench annealing at 500 °C or 600 °C for 1 h, possibly followed by a brief tempering at a slightly higher temperature.

Multiple metal exposures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study.

BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival and exposure sources. METHODS: Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. ORs and HRs for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected single-nucleotide polymorphisms. RESULTS: Plasma and urine samples from 454 ALS and 294 control participants were analysed. Elevated levels of individual metals, including copper, selenium and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.37, CI=1.20-1.58, p<0.001; urine, HR=1.44, CI=1.23-1.67, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures were associated with measured plasma and urine metals. CONCLUSION: Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.

Tranexamic Acid in Patients Undergoing Liver Resection: The HeLiX Randomized Clinical Trial.

Importance: Tranexamic acid reduces bleeding and blood transfusion in many types of surgery, but its effect in patients undergoing liver resection for a cancer-related indication remains unclear. Objective: To determine whether tranexamic acid reduces red blood cell transfusion within 7 days of liver resection. Design, Setting, and Participants: Multicenter randomized clinical trial of tranexamic acid vs placebo conducted from December 1, 2014, to November 8, 2022, at 10 hepatopancreaticobiliary sites in Canada and 1 site in the United States, with 90-day follow-up. Participants, clinicians, and data collectors were blinded to allocation. A volunteer sample of 1384 patients undergoing liver resection for a cancer-related indication met eligibility criteria and consented to randomization. Interventions: Tranexamic acid (1-g bolus followed by 1-g infusion over 8 hours; n = 619) or matching placebo (n = 626) beginning at induction of anesthesia. Main Outcomes and Measures: The primary outcome was receipt of red blood cell transfusion within 7 days of surgery. Results: The primary analysis included 1245 participants (mean age, 63.2 years; 39.8% female; 56.1% with a diagnosis of colorectal liver metastases). Perioperative characteristics were similar between groups. Red blood cell transfusion occurred in 16.3% of participants (n = 101) in the tranexamic acid group and 14.5% (n = 91) in the placebo group (odds ratio, 1.15 [95% CI, 0.84-1.56]; P = .38; absolute difference, 2% [95% CI, -2% to 6%]). Measured intraoperative blood loss (tranexamic acid, 817.3 mL; placebo, 836.7 mL; P = .75) and total estimated blood loss over 7 days (tranexamic acid, 1504.0 mL; placebo, 1551.2 mL; P = .38) were similar between groups. Participants receiving tranexamic acid experienced significantly more complications compared with placebo (odds ratio, 1.28 [95% CI, 1.02-1.60]; P = .03), with no significant difference in venous thromboembolism (odds ratio, 1.68 [95% CI, 0.95-3.07]; P = .08). Conclusions and Relevance: Among patients undergoing liver resection for a cancer-related indication, tranexamic acid did not reduce bleeding or blood transfusion but increased perioperative complications. Trial Registration: ClinicalTrials.gov Identifier: NCT02261415.

How to: assess patient suitability for unlicensed phage therapy in the United Kingdom.

BACKGROUND: Bacteriophage (phage) therapy is a promising alternative antimicrobial approach which has the potential to transform the way we treat bacterial infections. The antibiotic resistance crisis is driving renewed interest in phage therapy. There are currently no licenced phage therapy medicinal products and phage therapy is used in small but growing patient numbers on an unlicensed basis. OBJECTIVES: This article provides guidelines on the assessment of patient suitability for unlicensed phage therapy for clinicians in the United Kingdom. SOURCES: This article builds on Health Improvement Scotland's recommendation for the consideration of phage therapy in difficult-to-treat infection and the experience of the author group who have collectively assessed the suitability of 30 patients for phage therapy. CONTENT: In the UK, unlicensed medicines, including phages, may be considered to meet special clinical needs. The use of unlicensed medicines is governed by national legislation and local NHS Trust policies. Phages can be used in any NHS Trust and decisions about suitability should be made via existing local clinical management pathways. This article sets out guidelines to support local clinical teams in the assessment of patient suitability for phage therapy. Clinical and microbiological considerations are presented, including allergy and pregnancy.

Larger colony sizes favoured the evolution of more worker castes in ants.

The size-complexity hypothesis is a leading explanation for the evolution of complex life on earth. It predicts that in lineages that have undergone a major transition in organismality, larger numbers of lower-level subunits select for increased division of labour. Current data from multicellular organisms and social insects support a positive correlation between the number of cells and number of cell types and between colony size and the number of castes. However, the implication of these results is unclear, because colony size and number of cells are correlated with other variables which may also influence selection for division of labour, and causality could be in either direction. Here, to resolve this problem, we tested multiple causal hypotheses using data from 794 ant species. We found that larger colony sizes favoured the evolution of increased division of labour, resulting in more worker castes and greater variation in worker size. By contrast, our results did not provide consistent support for alternative hypotheses regarding either queen mating frequency or number of queens per colony explaining variation in division of labour. Overall, our results provide strong support for the size-complexity hypothesis.

ResMAP-a saturation mutagenesis platform enabling parallel profiling of target-specific resistance-conferring mutations in Plasmodium.

New and improved drugs are required for the treatment and ultimate eradication of malaria. The efficacy of front-line therapies is now threatened by emerging drug resistance; thus, new tools to support the development of drugs with a lower propensity for resistance are needed. Here, we describe the development of a RESistance Mapping And Profiling (ResMAP) platform for the identification of resistance-conferring mutations in Plasmodium drug targets. Proof-of-concept studies focused on interrogating the antimalarial drug target, Plasmodium falciparum lysyl tRNA synthetase (PfKRS). Saturation mutagenesis was used to construct a plasmid library encoding all conceivable mutations within a 20-residue span at the base of the PfKRS ATP-binding pocket. The superior transfection efficiency of Plasmodium knowlesi was exploited to generate a high coverage parasite library expressing PfKRS bearing all possible amino acid changes within this region of the enzyme. The selection of the library with PfKRS inhibitors, cladosporin and DDD01510706, successfully identified multiple resistance-conferring substitutions. Genetic validation of a subset of these mutations confirmed their direct role in resistance, with computational modeling used to dissect the structural basis of resistance. The application of ResMAP to inform the development of resistance-resilient antimalarials of the future is discussed. IMPORTANCE: An increase in treatment failures for malaria highlights an urgent need for new tools to understand and minimize the spread of drug resistance. We describe the development of a RESistance Mapping And Profiling (ResMAP) platform for the identification of resistance-conferring mutations in Plasmodium spp, the causative agent of malaria. Saturation mutagenesis was used to generate a mutation library containing all conceivable mutations for a region of the antimalarial-binding site of a promising drug target, Plasmodium falciparum lysyl tRNA synthetase (PfKRS). Screening of this high-coverage library with characterized PfKRS inhibitors revealed multiple resistance-conferring substitutions including several clinically relevant mutations. Genetic validation of these mutations confirmed resistance of up to 100-fold and computational modeling dissected their role in drug resistance. We discuss potential applications of this data including the potential to design compounds that can bypass the most serious resistance mutations and future resistance surveillance.

Persistent species relationships characterize migrating bird communities across stopover sites and seasons.

Global migrations of diverse animal species often converge along the same routes, bringing together seasonal assemblages of animals that may compete, prey on each other, and share information or pathogens. These interspecific interactions, when energetic demands are high and the time to complete journeys is short, may influence survival, migratory success, stopover ecology, and migratory routes. Numerous accounts suggest that interspecific co-migrations are globally distributed in aerial, aquatic, and terrestrial systems, although the study of migration to date has rarely investigated species interactions among migrating animals. Here, we test the hypothesis that migrating animals are communities engaged in networks of ecological interactions. We leverage over half a million records of 50 bird species from five bird banding sites collected over 8 to 23 y to test for species associations using social network analyses. We find strong support for persistent species relationships across sites and between spring and fall migration. These relationships may be ecologically meaningful: They are often stronger among phylogenetically related species with similar foraging behaviors and nonbreeding ranges even after accounting for the nonsocial contributions to associations, including overlap in migration timing and habitat use. While interspecific interactions could result in costly competition or beneficial information exchange, we find that relationships are largely positive, suggesting limited competitive exclusion at the scale of a banding station during migratory stopovers. Our findings support an understanding of animal migrations that consist of networked communities rather than random assemblages of independently migrating species, encouraging future studies of the nature and consequences of co-migrant interactions.

Prenatal Dexamethasone Programs Autonomic Dysregulation in Female Rats.

Autonomic dysfunction is associated with cardiovascular and neurological disease, including hypertension, heart failure, anxiety, and stress-related disorders. Prior studies demonstrated that late gestation exposure to dexamethasone (DEX) resulted in female-biased increases in stress-responsive mean arterial pressure (MAP) and heart rate (HR), suggesting a role for glucocorticoid-mediated programming of autonomic dysfunction. The present study investigated the influence of sympathetic (SYM) or parasympathetic (PS) blockade on cardiovascular function in male and female rat offspring of mothers injected with DEX in utero (gestation days [GD]18-21). At 11-12-weeks of age, MAP, HR, and heart rate variability (HRV) were evaluated at baseline and in response to SYM antagonists (α 1 -adrenoceptor + ß 1 -adrenoceptor), a PS (muscarinic) antagonist, or saline (SAL). To assess stress-responsive function, rats were exposed to acute restraint. Tyrosine hydroxylase was measured in adrenals and left ventricle, and gene expression for the ß 1 adrenergic receptor was measured in left ventricle. Maternal DEX injection reduced basal HRV in male and female offspring. SYM blockade attenuated increases in stress-responsive HR and MAP. PS blockade elevated stress-responsive HR and MAP to a greater extent in Vehicle females. SYM and PS blockade produced equivalent effects on HR and MAP responses in male offspring, regardless of maternal treatment. Based on these findings, we suggest that maternal DEX injection disrupted autonomic regulation of cardiovascular function in females, resulting in a shift toward greater SYM input and less input from PS. Future studies will investigate whether changes in autonomic function are mediated by changes in central autonomic circuitry. New and Noteworthy: These studies use pharmacological antagonists to characterize the nature of the autonomic dysregulation induced in female offspring exposed to the synthetic glucocorticoid, dexamethasone, in utero . The female offspring of dams injected with dexamethasone in late gestation show a reduction in vulnerability to parasympathetic blockade and an increase in responses to acute restraint stress even in the presence of sympathetic blockade. This suggests that late gestation dexamethasone disrupts the normal development of the autonomic function in females leading to a shift in the sympathovagal balance.

Surgical window of opportunity trial reveals mechanisms of response and resistance to navtemadlin (KRT-232) in patients with recurrent glioblastoma.

We investigated the effectiveness of navtemadlin (KRT-232) in treating recurrent glioblastoma. A surgical window-of-opportunity trial ( NCT03107780 ) was conducted on 21 patients to determine achievable drug concentrations within tumor tissue and examine mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact. Sequencing of three recurrent tumors revealed an absence of TP53 -inactivating mutations, indicating alternative mechanisms of resistance. In patient-derived GBM models, the lower range of clinically achieved navtemadlin concentrations induced partial tumor cell death as monotherapy. However, combining navtemadlin with temozolomide increased apoptotic rates while sparing normal bone marrow cells in vitro, which in return underwent reversible growth arrest. These results indicate that clinically achievable doses of navtemadlin generate significant pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy is a route to durable survival benefits. Statement of significance: Tissue sampling during this clinical trial allowed us to assess mechanisms of response and resistance associated with navtemadlin treatment in recurrent GBM. We report that clinically achievable doses of navtemadlin induce pharmacodynamic effects in tumor tissue, and suggest combinations with standard-of-care chemotherapy for durable clinical benefit.

A multidisciplinary team and patient perspective on omission of surgery after neoadjuvant systemic therapy for early breast cancer: A European Society of Surgical Oncology (ESSO) Research Academy survey.

BACKGROUND: Surgical de-escalation aims to reduce morbidity without compromising oncological outcomes. Trials to de-escalate breast cancer (BC) surgery among exceptional responders after neoadjuvant systemic therapy (NST) are ongoing. Combined patient and clinician insights on this strategy are unknown. METHODS: The European Society of Surgical Oncology Young Surgeons Alumni Club (EYSAC) performed an online survey to evaluate the perspective of multidisciplinary teams (MDTs) on omission of surgery ("no surgery") following complete response to NST for early BC. The aim was to identify MDT considerations and perceived barriers to omission of BC surgery. Patient insights were obtained through a focused group discussion (FGD) with four members of the patient advocacy group, Guiding Researchers and Advocates to Scientific Partnerships (GRASP). RESULTS: The MDT survey had 248 responses, with 229 included for analysis. Criteria for a "no surgery" approach included: patient's tumor and nodal status before (39.7 %) and after (45.9 %) NST and comorbidities (44.3 %). The majority chose standard surgery for hypothetical cases with a complete response to NST. Barriers for implementation were lack of definitive trials (55.9 %), "no surgery" not being discussed in MDTs (28.8 %) and lack of essential diagnostic or therapeutic options (24 %). Patients expressed communication gaps about BC surgery, lack of trust regarding accuracy of imaging, fear of regret and psychosocial burden of choosing less extensive surgery. CONCLUSIONS: Before accepting "no surgery" after complete response to NST, MDTs and patients need level 1 evidence from clinical trials, access to standard diagnostic modalities and treatments. Patient's fear of regretting less surgery need to be acknowledged and addressed.

Cost-effectiveness analysis design for interventions to prevent children's oral disease.

Introduction: In 2015, the National Institute of Dental and Craniofacial Research (NIDCR) launched the Multidisciplinary Collaborative Research Consortium to Reduce Oral Health Disparities in Children, supporting four randomized trials testing strategies to improve preventive care. A Coordinating Center provides scientific expertise, data acquisition and quality assurance services, safety monitoring, and final analysis-ready datasets. This paper describes the trials' economic analysis strategies, placing these strategies within the broader context of contemporary economic analysis methods. Methods: The Coordinating Center established a Cost Collaborative Working Group to share information from the four trials about the components of their economic analyses. Study teams indicated data sources for their economic analysis using a set of structured tables. The Group meets regularly to share progress, discuss challenges, and coordinate analytic approaches. Results: All four trials will calculate incremental cost-effectiveness ratios; two will also conduct cost-utility analyses using proxy diseases to estimate health state utilities. Each trial will consider at least two perspectives. Key process measures include dental services provided to child participants. The non-preference-weighted Early Childhood Oral Health Impact Scale (ECOHIS) will measure oral health-related quality of life. All trials are measuring training, implementation, personnel and supervision, service, supplies, and equipment costs. Conclusions: Consistent with best practices, all four trials have integrated economic analysis during their planning stages. This effort is critical since poor quality or absence of essential data can limit retrospective analysis. Integrating economic analysis into oral health preventive intervention research can provide guidance to clinicians and practices, payers, and policymakers.

Percentage Predicted Peak Oxygen Consumption in People With Fontan Circulation: A Rapid Systematic Scoping Review and Validation Study.

BACKGROUND: Peak oxygen consumption (peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$) is routinely measured in people who have congenital heart disease and is reported as a percentage of predicted value, based upon age- and sex-matched normative reference values (NRVs). This study aimed to identify which NRVs are being used, assess whether NRVs are being applied appropriately, and evaluate if recommended NRVs are valid when applied to people with congenital heart disease. METHODS AND RESULTS: A systematic scoping review identified studies that reported peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ percentage of predicted value in people with congenital heart disease. A modified risk of bias tool evaluated the included studies. Forty-five studies reported peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ percentage of predicted value, and only 21 (47%) studies described or provided a reference on how their percentage of predicted value was calculated. The most cited NRVs were from Wasserman (n=12) and Cooper and Weiler-Ravell (n=7). Risk of bias analysis judged 63% of studies as having some concerns. The NRVs recommended by the American Heart Association were applied to participants with a Fontan circulation (n=70; aged 26.5±6.4 years; 59% women) to examine validity. Predicted peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ values from the Wasserman NRV was not significantly associated to measured peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ values (men: b=0.31, R2≤0.01; women: b=0.07, R2=0.02). CONCLUSIONS: Numerous NRVs have been applied to individuals with congenital heart disease and are often poorly reported and inappropriately matched to participants. The Wasserman NRV was the most cited but showed poor validity when applied to a Fontan cohort.

Reliability of MR Enterography Features for Describing Fibrostenosing Crohn Disease.

Background Clinical decision making and drug development for fibrostenosing Crohn disease is constrained by a lack of imaging definitions, scoring conventions, and validated end points. Purpose To assess the reliability of MR enterography features to describe Crohn disease strictures and determine correlation with stricture severity. Materials and Methods A retrospective study of patients with symptomatic terminal ileal Crohn disease strictures who underwent MR enterography at tertiary care centers (Cleveland Clinic: September 2013 to November 2020; Mayo Clinic: February 2008 to March 2019) was conducted by using convenience sampling. In the development phase, blinded and trained radiologists independently evaluated 26 MR enterography features from baseline and follow-up examinations performed more than 6 months apart, with no bowel resection performed between examinations. Follow-up examinations closest to 12 months after baseline were selected. Reliability was assessed using the intraclass correlation coefficient (ICC). In the validation phase, after five features were redefined, reliability was re-estimated in an independent convenience sample using baseline examinations. Multivariable linear regression analysis identified features with at least moderate interrater reliability (ICC ≥0.41) that were independently associated with stricture severity. Results Ninety-nine (mean age, 40 years ± 14 [SD]; 50 male) patients were included in the development group and 51 (mean age, 45 years ± 16 [SD]; 35 female) patients were included in the validation group. In the development group, nine features had at least moderate interrater reliability. One additional feature demonstrated moderate reliability in the validation group. Stricture length (ICC = 0.85 [95% CI: 0.75, 0.91] and 0.91 [95% CI: 0.75, 0.96] in development and validation phase, respectively) and maximal associated small bowel dilation (ICC = 0.74 [95% CI: 0.63, 0.80] and 0.73 [95% CI: 0.58, 0.87] in development and validation group, respectively) had the highest interrater reliability. Stricture length, maximal stricture wall thickness, and maximal associated small bowel dilation were independently (regression coefficients, 0.09-3.97; P < .001) associated with stricture severity. Conclusion MR enterography definitions and scoring conventions for reliably assessing features of Crohn disease strictures were developed and validated, and feature correlation with stricture severity was determined. © RSNA, 2024 Supplemental material is available for this article. See also the article by Rieder and Ma et al in this issue. See also the editorial by Galgano and Summerlin in this issue.