Global Ring Study to Investigate the Comparability of Total Assay Performance of Commercial Claudin 18 Antibodies for Evaluation in Gastric Cancer.

Claudin 18.2 (CLDN18.2), the dominant isoform of CLDN18 in gastric tissues, is a highly specific tight junction protein of the gastric mucosa with variably retained expressions in gastric and gastroesophageal junction cancers. Additionally, CLDN18.2-targeted treatment with zolbetuximab, in combination with chemotherapy, has recently been assessed in 2 phase-III studies of patients with HER2-negative, locally advanced, unresectable, or metastatic gastric or gastroesophageal junction adenocarcinoma. These trials used the investigational VENTANA CLDN18 (43-14A) RxDx immunohistochemistry (IHC) assay on the Ventana BenchMark platform to identify patients eligible for CLDN18.2-targeted treatment. We report the findings of a global ring study evaluating the analytical comparability of concordance of the results of 3 CLDN18 antibodies (Ventana, LSBio, and Novus) stained on 3 IHC-staining platforms (Ventana, Dako, and Leica). A tissue microarray (TMA), comprising 15 gastric cancer cases, was stained by 27 laboratories across 11 countries. Each laboratory stained the TMAs using at least 2 of the 3 evaluated CLDN18 antibodies. Stained TMAs were assessed and scored using an agreed IHC-scoring algorithm, and the results were collated for statistical analysis. The data confirmed a high level of concordance for the VENTANA CLDN18 (43-14A; Ventana platform only) and LSBio antibodies on both the Dako and Leica platforms, with accuracy, precision, sensitivity, and specificity rates all reaching a minimum acceptable ≥85% threshold and good-to-excellent levels of concordance as measured by Cohen's kappa coefficient. The Novus antibody showed the highest level of variability against the reference central laboratory results for the same antibody/platform combinations. It also failed to meet the threshold for accuracy and sensitivity when used on either the Dako or Leica platform. These results demonstrated the reliability of IHC testing for CLDN18 expression in gastric tumor samples when using commercially available platforms with an appropriate methodology and primary antibody selection.

An analysis of nutrient facts labels of pediatric multi-vitamin and mineral supplements: Is there a risk of overexposure?

BACKGROUND: Voluntary and mandatory fortification of pediatric foods, along with widespread consumption of dietary supplements have resulted in an increased proportion of children with excessive micronutrient intake. AIM: This study aimed to analyze the proportion of pediatric dietary supplements that exceed the Recommended Dietary Allowance (RDA) and Tolerable Upper Limit for the individual micronutrients. We further identified the proportion of supplements with large amounts of micronutrients that were marketed through child-friendly and parent-geared promotional language and graphics on the packaging. METHODS: The nutrient facts label on pediatric supplement packages sold by three large retail pharmacy chains was analyzed for micronutrient content. Labels were examined for the presence of trademarked or generic cartoon characters and parent-geared health promotional statements. RESULTS: More than a third and almost a fifth of the samples contained vitamin A and niacin respectively in amounts equivalent to or above the established tolerable upper limit for one- to three-year-old children. A major proportion of these supplements had child-friendly and parent-targeted promotional language on the package. CONCLUSION: The potential for pediatric supplements as a source for excessive micronutrient consumption underscores the need for parents and health care professionals to use nutrition labels as a valuable tool to prevent micronutrient toxicity.

An interactive web application for exploring human plasma and fibroblast metabolomics data from patients with inborn errors of metabolism.

Metabolomic profiling is instrumental in understanding the systemic and cellular impact of inborn errors of metabolism (IEMs), monogenic disorders caused by pathogenic genomic variants in genes involved in metabolism. This study encompasses untargeted metabolomics analysis of plasma from 474 individuals and fibroblasts from 67 subjects, incorporating healthy controls, patients with 65 different monogenic diseases, and numerous undiagnosed cases. We introduce a web application designed for the in-depth exploration of this extensive metabolomics database. The application offers a user-friendly interface for data review, download, and detailed analysis of metabolic deviations linked to IEMs at the level of individual patients or groups of patients with the same diagnosis. It also provides interactive tools for investigating metabolic relationships and offers comparative analyses of plasma and fibroblast profiles. This tool emphasizes the metabolic interplay within and across biological matrices, enriching our understanding of metabolic regulation in health and disease. As a resource, the application provides broad utility in research, offering novel insights into metabolic pathways and their alterations in various disorders.

Gift of time: learning together to embed a palliative approach to care in long-term care.

BACKGROUND: Embedding a Palliative Approach to Care (EPAC) is a model that helps shift the culture in long-term care (LTC) so that residents who could benefit from palliative care are identified early. Healthcare Excellence Canada supported the implementation of EPAC in seven teams from across Canada between August 2018 and September 2019. OBJECTIVE: To identify effective strategies for supporting the early identification of palliative care needs to improve the quality of life of residents in LTC. INTERVENTION: Training methods on the EPAC model included a combination of face-to-face education (national and regional workshops), online learning (webinars and access to an online platform) and expert coaching. Each team adapted EPAC based on their organisational context and jurisdictional requirements for advance care planning. MEASURES: Teams tracked their progress by collecting monthly data on the number of residents who died, date of their most recent goals of care (GOCs) conversation, location of death and number of emergency department (ED) transfers in the last 3 months of life. Teams also shared their implementation strategies including successes, barriers and lessons. RESULTS: Implementation of EPAC required leadership support and dedicated time for changing how palliative care is perceived in LTC. Based on 409 resident deaths, 89% (365) had documented GOC conversations; 78% (318) had no transfers to the ED within the last 3 months of life; and 81% (333) died at home. A monthly review of the results showed that teams were having earlier GOC conversations with residents. Teams also reported improvements in the quality of care provided to residents and their families. CONCLUSION: EPAC was successfully adapted and adopted to the organisational contexts of homes participating in the collaborative.

Clinical Exome Studies Have Inconsistent Coverage.

BACKGROUND: Exome sequencing has become a commonly used clinical diagnostic test. Multiple studies have examined the diagnostic utility and individual laboratory performance of exome testing; however, no previous study has surveyed and compared the data quality from multiple clinical laboratories. METHODS: We examined sequencing data from 36 clinical exome tests from 3 clinical laboratories. Exome data were compared in terms of overall characteristics and coverage of specific genes and nucleotide positions. The sets of genes examined included genes in Consensus Coding Sequence (CCDS) (n = 17723), a subset of genes clinically relevant to epilepsy (n = 108), and genes that are recommended for reporting of secondary findings (n = 57; excludes X-linked genes). RESULTS: The average exome nucleotide coverage (≥20×) of each laboratory varied at 96.49% (CV = 3%), 96.54% (CV = 1%), and 91.68% (CV = 4%), for laboratories A, B, and C, respectively. For CCDS genes, the average number of completely covered genes varied at 12184 (CV = 29%), 11687 (CV = 13%), and 5989 (CV = 37%), for laboratories A, B, and C, respectively. With smaller subsets of genes related to epilepsy and secondary findings, the CV revealed low consistency, with a maximum CV seen in laboratory C for both epilepsy genes (CV = 60%) and secondary findings genes (CV = 71%). CONCLUSIONS: Poor consistency in complete gene coverage was seen in the clinical exome laboratories surveyed. The degree of consistency varied widely between the laboratories.

A Canadian Cohort Study to Evaluate the Outcomes Associated with a Multicenter Initiative to Reduce Antipsychotic Use in Long-Term Care Homes.

OBJECTIVES: To evaluate the impact of a multicenter intervention to reduce potentially inappropriate antipsychotic use in Canadian nursing homes at the individual and facility levels. DESIGN: Longitudinal, population-based cohort study to evaluate the Canadian Foundation for Healthcare Improvement's Spreading Healthcare Innovations Initiative to reduce potentially inappropriate antipsychotic use in 6 provinces/territories. SETTING AND PARTICIPANTS: Adults in nursing homes in 6 provinces/territories in Canada between 2014 and 2016. The sample involved 4927 residents in 45 intervention homes and 122,570 residents in 1193 control homes in the first quarter of the study. MEASURES: Assessment data based on the Resident Assessment Instrument 2.0 were used in both settings to track antipsychotic use and to obtain risk-adjusters for a quality indicator on potentially inappropriate use. INTERVENTION: Quality improvement teams in participating organizations were provided with education, training, and support to implement localized strategies intended to reduce antipsychotic medication use in residents without diagnosis of psychosis. RESULTS: At the resident level, we found that the odds of remaining on potentially inappropriate antipsychotics were 0.75 in intervention compared with control homes after adjusting for age, sex, aggressive behavior, and cognition. These findings were evident within the pooled Canadian data as well as within provinces. At the facility level, the intervention homes had greater improvements in risk-adjusted quality indicator performance than the control homes, and this was true for the worst, median, and best-performing homes at baseline. There was no major change in the quality indicator for worsening of behavior symptoms. CONCLUSIONS/IMPLICATIONS: The Canadian Foundation for Healthcare Improvement intervention was associated with a reduction in potentially inappropriate antipsychotic use at both the individual and facility levels of analysis. This improvement in performance was independent of secular trends toward reduced antipsychotic use in participating provinces. This suggests that substantial improvements in medication use may be achieved through targeted, collaborative quality improvement initiatives in long-term care.

Commentary.

Due to the ongoing nature of the COVID-19 pandemic, I have decided to print the following commentary to help provide another alternative for reducing potential exposure to and incidental transmission of SARS-CoV-2 during the provision of anesthesia for dentistry. -Kyle J. Kramer, Editor-in-Chief.

Patient-Reported Impact of Symptoms in Myotonic Dystrophy Type 2 (PRISM-2).

OBJECTIVE: To determine the frequency and relative importance of the most life-affecting symptoms in myotonic dystrophy type 2 (DM2) and to identify the factors that have the strongest association with these symptoms. METHODS: We conducted a cross-sectional study of adult patients with DM2 from a National Registry of DM2 Patients to assess the prevalence and relative importance of 310 symptoms and 21 symptomatic themes. Participant responses were compared by age categories, sex, educational attainment, employment status, and duration of symptoms. RESULTS: The symptomatic themes with the highest prevalence in DM2 were the inability to do activities (94.4%), limitations with mobility or walking (89.2%), hip, thigh, or knee weakness (89.2%), fatigue (89.2%), and myotonia (82.6%). Participants identified the inability to do activities and fatigue as the symptomatic themes that have the greatest overall effect on their lives. Unemployment, a longer duration of symptoms, and less education were associated with a higher average prevalence of all symptomatic themes (p < 0.01). Unemployment, a longer duration of symptoms, sex, and increased age were associated with a higher average effect of all symptomatic themes among patients with DM2 (p < 0.01). CONCLUSIONS: The lives of patients with DM2 are affected by a variety of symptoms. These symptoms have different levels of significance and prevalence in this population and vary across DM2 subgroups in different demographic categories.

An examination of product packaging marketing strategies used to promote pediatric multivitamins.

The purpose of this study was to describe the nature of marketing strategies for multivitamin and multimineral (MVM) supplement packaging and to assess the extent to which these supplements are marketed as food products. A cross-sectional study of children's supplement packaging was conducted. Descriptive statistics identified common marketing practices. Websites of the three largest retail chain pharmacies in the United States and MVM manufacturers were accessed. The study's sample consisted of packaging for 52 children's MVM supplements. Child-targeted marketing included reference to trademarked characters on 42.3% of MVM packaging (n = 22). More than 80% of the sample (n = 42) listed fruity flavors and almost all packaging included descriptive words related to the MVMs' shape and/or flavor (88.5%, n = 46). Nearly one-fifth of the packaging (n = 10) pictured a food item. With respect to parent-targeted promotional language, almost 83% of the supplement packages (n = 43) included text on the support of bodily structure/function. More than half of the sample (53.8%, n = 28) had promotional language related to dietary practice (e.g. organic, gluten-free). Pediatricians can play a role in ensuring that parents are aware of (1) possible risks associated with MVM overconsumption, and (2) the importance of deriving vitamins and minerals from a balanced diet. Given the high number of exposures to pediatric MVMs among youth and established influence of food marketing on shaping children's perceptions and behaviors, further research is necessary to determine the extent to which children's MVMs are marketed as a food product and perceived as such by children.

Patient-identified disease burden in facioscapulohumeral muscular dystrophy.

INTRODUCTION: The multitude of symptoms associated with facioscapulohumeral muscular dystrophy (FSHD) disease burden are of varying importance. The extent of these symptoms and their cumulative effect on the FSHD population is unknown. METHODS: We conducted interviews with adult FSHD patients to identify which symptoms have the greatest effect on their lives. Each interview was recorded, transcribed, coded, and analyzed using a qualitative framework technique, triangulation, and a three-investigator consensus approach. RESULTS: One thousand three hundred seventy-five quotes were obtained through 20 patient interviews. Two hundred fifty-one symptoms of importance were identified representing 14 themes of FSHD disease burden. Symptoms associated with mobility impairment, activity limitation, and social role limitation were most frequently mentioned by participants. CONCLUSIONS: There are multiple themes and symptoms, some previously underrecognized, that play a key role in FSHD disease burden.

Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1).

OBJECTIVE: To determine the most critical symptoms in a national myotonic dystrophy type 1 (DM1) population and to identify the modifying factors that have the greatest effect on the severity of these symptoms. METHODS: We performed a cross-sectional study of 278 adult patients with DM1 from the national registry of patients with DM1 between April and August 2010. We assessed the prevalence and relative significance of 221 critical DM1 symptoms and 14 disease themes. These symptoms and themes were chosen for evaluation based on prior interviews with patients with DM1. Responses were categorized by age, CTG repeat length, gender, and duration of symptoms. RESULTS: Participants with DM1 provided symptom rating survey responses to address the relative frequency and importance of each DM1 symptom. The symptomatic themes with the highest prevalence in DM1 were problems with hands or arms (93.5%), fatigue (90.8%), myotonia (90.3%), and impaired sleep or daytime sleepiness (87.9%). Participants identified fatigue and limitations in mobility as the symptomatic themes that have the greatest effect on their lives. We found an association between age and the average prevalence of all themes (p < 0.01) and between CTG repeat length and the average effect of all symptomatic themes on participant lives (p < 0.01). CONCLUSIONS: There are a wide range of symptoms that significantly affect the lives of patients with DM1. These symptoms, some previously underrecognized, have varying levels of importance in the DM1 population and are nonlinearly dependent on patient age and CTG repeat length.

Open-label trial of recombinant human insulin-like growth factor 1/recombinant human insulin-like growth factor binding protein 3 in myotonic dystrophy type 1.

OBJECTIVE: To evaluate the safety and tolerability of recombinant human insulin-like growth factor 1 (rhIGF-1) complexed with IGF binding protein 3 (rhIGF-1/rhIGFBP-3) in patients with myotonic dystrophy type 1 (DM1). DESIGN: Open-label dose-escalation clinical trial. SETTING: University medical center. PARTICIPANTS: Fifteen moderately affected ambulatory participants with genetically proven myotonic dystrophy type 1. INTERVENTION: Participants received escalating dosages of subcutaneous rhIGF-1/rhIGFBP-3 for 24 weeks followed by a 16-week washout period. MAIN OUTCOME MEASURES: Serial assessments of safety, muscle mass, muscle function, and metabolic state were performed. The primary outcome variable was the ability of participants to complete 24 weeks receiving rhIGF-1/ rhIGFBP-3 treatment. RESULTS: All participants tolerated rhIGF-1/rhIGFBP-3. There were no significant changes in muscle strength or functional outcomes measures. Lean body muscle mass measured by dual-energy x-ray absorptiometry increased by 1.95 kg (P < .001) after treatment. Participants also experienced a mean reduction in triglyceride levels of 47 mg/dL (P = .002), a mean increase in HDL levels of 5.0 mg/dL (P = .03), a mean reduction in hemoglobin A(1c) levels of 0.15% (P = .03), and a mean increase in testosterone level (in men) of 203 ng/dL (P = .002) while taking rhIGF-1/rhIGFBP-3. Mild reactions at the injection site occurred (9 participants), as did mild transient hypoglycemia (3), lightheadedness (2), and transient papilledema (1). CONCLUSIONS: Treatment with rhIGF-1/rhIGFBP-3 was generally well tolerated in patients with myotonic dystrophy type 1. Treatment with rhIGF-1/rhIGFBP-3 was associated with increased lean body mass and improvement in metabolism but not increased muscle strength or function. Larger randomized controlled trials would be needed to further evaluate the efficacy and safety of this medication in patients with neuromuscular disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00233519.

Increased ipsilateral whole breast vascularity as measured by contrast-enhanced magnetic resonance imaging in patients with breast cancer.

BACKGROUND: Tumor-induced neovessel formation identified by gadolinium-enhanced magnetic resonance imaging (MRI) is a commonly used marker for breast malignancy. The purpose of this study was to assess possible differences in whole-breast vascularity as measured by contrast-enhanced MRI in the ipsilateral and contralateral breasts of patients with unilateral breast malignancies. METHODS: Gadolinium-enhanced MRI of the breast using a Siemens 1.0-T scanner with dedicated breast coil was performed on 22 consecutive patients with histologically confirmed unilateral breast carcinoma. Whole-breast vascularity of the breast containing the carcinoma was estimated as increased, decreased, or similar compared with the contralateral unaffected breast. Breast vascularity was then correlated to clinical factors including tumor size, histology, multifocality, nodal involvement, and patient age and menopausal status. RESULTS: Twenty patients had infiltrating carcinomas, and 2 patients had ductal carcinoma in situ. Four were multifocal. Fifteen of 22 patients demonstrated clear evidence of increased whole-breast vascularity in the ipsilateral breast containing the primary breast cancer compared with the contralateral breast. Although there was no clear correlation between the presence of increased whole-breast vascularity in the cancer-bearing breast with tumor size, histology, grade, mammographic appearance, or patient age and menopausal status, increased vascularity was present in 3 of 4 patients with multifocal disease and in 4 of 5 patients with metastatic disease in the axillary nodes. CONCLUSIONS: Measurable increases in whole-breast vascularity can be identified by contrast-enhanced MRI and appear with increased frequency in the cancer-bearing breast. These findings suggest that factors other than tumor size and histology may influence development of macroscopic vessels during tumor progression and may be indicative of angiogenic tumor biology.

Real-time reporting drives the race toward zero.

LifeCare Hospitals of Pittsburgh is a 155-bed freestanding, Acute Long Term Care Hospital, one of 333 nationwide. Patients with complex care needs who are recovering from acute events, postsurgical interventions, and multiple comorbidities stay an average of 25 days. Like other hospitals, reducing medication errors is a focus of the quality improvement program. Provision of a safe environment is tantamount to achieving quality patient outcomes. Creative solutions to the problem of medication errors are needed. Healthcare executives need effective strategies to engage care providers in solving problems in the course of work and in a nonpunitive environment. Over the period of 1 year, medication errors reaching patients at LifeCare decreased by 50% through culture changes, rapid learning cycles, and strong support from the hospital's leaders.

Serum mepivacaine concentrations after intraoral injection in young children.

The authors measured plasma concentrations of mepivacaine in 36 children from the ages of 2 to 5 years who received dental care under light general anesthesia. The subjects were randomly assigned to receive either 2 percent mepivacaine hydrochloride with 1:20,000 levonordefrin or 3 percent mepivacaine hydrochloride without vasoconstrictor. The volume of anesthetic injected depended on the planned procedures for each patient. Blood samples (3 mL) were drawn from an intravenous line before and 5, 10, 20, 30, 45, and 60 minutes after mepivacaine injection. The serum was collected and analyzed by gas-liquid chromatography. Mean serum concentrations, normalized to a dose of 1 mg/kg body weight, reached a peak of 0.67 +/- 0.42 microgram/mL (mean +/- SD) after 3 percent mepivacaine and 0.63 +/- 0.21 microgram/mL after 2 percent mepivacaine with levonordefrin. Levonordefrin had no significant effect on the plasma concentrations. However, because of the higher concentration of mepivacaine in the 3 percent formulation, it was potentially 1.5 times as toxic (P < 0.002) on a volume basis. Statistical analysis also suggested that the maximum recommended dose of 3 mg/lb could result in potentially toxic blood concentrations in a small percentage of pediatric patients. The authors conclude that 3 percent mepivacaine should not be used when relatively large volumes of local anesthetic must be administered to small children and recommend that the maximum dose of mepivacaine not exceed 5 mg/kg.