A Randomized Trial of Two Remote Health Care Delivery Models on the Uptake of Genetic Testing and Impact on Patient-Reported Psychological Outcomes in Families With Pancreatic Cancer: The Genetic Education, Risk Assessment, and Testing (GENERATE) Study.

BACKGROUND & AIMS: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes. METHODS: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3 months postintervention. RESULTS: A total of 424 families were randomized, including 601 participants (n = 296 Arm 1; n = 305 Arm 2), 90% of whom completed genetic testing (Arm 1 [87%]; Arm 2 [93%], P = .014). Arm 1 participants were significantly less likely to complete genetic testing compared with Arm 2 participants (adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). Among participants who completed patient-reported psychological outcomes questionnaires (Arm 1 [n = 194]; Arm 2 [n = 206]), the intervention did not affect mean anxiety, depression, or cancer worry scores. CONCLUSIONS: Remote genetic education and testing can be a successful and complementary option for delivering genetics care. (Clinicaltrials.gov, number NCT03762590).

Simplified and more sensitive criteria for identifying individuals with pathogenic CDH1 variants.

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome most often caused by pathogenic variants in CDH1. The International Gastric Cancer Linkage Consortium (IGCLC) recently updated its criteria for genetic testing. The purpose of this study was to estimate the sensitivity of IGCLC's 2020 criteria for identifying carriers of CDH1 pathogenic variants and to formulate a new set of criteria that is simpler and more sensitive. METHODS: Medical histories of 112 CDH1 mutation carriers, identified predominantly by multigene panel testing, and their 649 family members were reviewed. The percentage of subjects fulfilling the IGCLC 2015 and 2020 criteria was calculated, once without making any assumptions about unavailable pathology, and once assuming gastric cancer to be diffuse when pathology was unavailable. For comparison, we calculated the percentage of subjects who fulfilled our proposed criteria. RESULTS: When making no assumptions about missing pathology, a small (19%) and equal percentage of CDH1 mutation carriers fulfilled the IGCLC 2015 and 2020 criteria. When assuming unspecified gastric cancer to be diffuse, 45 out of 112 (40%) subjects met the 2015 criteria and 53 out of 112 (47%) met the 2020 criteria. Eighty-seven per cent (97/112) fulfilled our proposed criteria. CONCLUSION: In consecutive cases, mostly unselected for clinical criteria of HDGC, the IGCLC 2020 criteria are, at best, marginally more sensitive than previous iterations, but they are also more cumbersome. Unavailable cancer pathology reports are a real-world obstacle to their proper application. Our proposed Yale criteria both address this issue and offer significantly greater sensitivity than the IGCLC 2020 criteria.

Point mutation I634A in the glucocorticoid receptor causes embryonic lethality by reduced ligand binding.

The glucocorticoid (GC) receptor (GR) is essential for normal development and in the initiation of inflammation. Healthy GRdim/dim mice with reduced dimerization propensity due to a point mutation (A465T) at the dimer interface of the GR DNA-binding domain (DBD) (here GRD/D) have previously helped to define the functions of GR monomers and dimers. Since GRD/D retains residual dimerization capacity, here we generated the dimer-nullifying double mutant GRD+L/D+L mice, featuring an additional mutation (I634A) in the ligand-binding domain (LBD) of GR. These mice are perinatally lethal, as are GRL/L mice (these mice have the I634A mutation but not the A465T mutation), displaying improper lung and skin formation. Using embryonic fibroblasts, high and low doses of dexamethasone (Dex), nuclear translocation assays, RNAseq, dimerization assays, and ligand-binding assays (and Kd values), we found that the lethal phenotype in these mice is due to insufficient ligand binding. These data suggest there is some correlation between GR dimerization potential and ligand affinity. We conclude that even a mutation as subtle as I634A, at a position not directly involved in ligand interactions sensu stricto, can still influence ligand binding and have a lethal outcome.

Nutritional problems of patients with COVID-19 receiving dietetic treatment in primary care.

BACKGROUND: The nutritional problems of patients who are hospitalised for COVID-19 are becoming increasingly clear. However, a large group of patients have never been hospitalised and also appear to experience persistent nutritional problems. The present study describes the nutritional status, risk of sarcopaenia and nutrition-related complaints of patients recovering from COVID-19 receiving dietetic treatment in primary care. METHODS: In this retrospective observational study, data were collected during dietetic treatment by a primary care dietitian between April and December 2020. Both patients who had and had not been admitted to the hospital were included at their first visit to a primary care dietitian. Data on nutritional status, risk of sarcopaenia and nutrition-related complaints were collected longitudinally. RESULTS: Data from 246 patients with COVID-19 were collected. Mean ± SD age was 57 ± 16 years and 61% of the patient population was female. At first consultation, two thirds of patients were classified as overweight or obese (body mass index >25 kg m-2 ). The majority had experienced unintentional weight loss because of COVID-19. Additionally, 55% of hospitalised and 34% of non-hospitalised patients had a high risk of sarcopaenia. Most commonly reported nutrition-related complaints were decreased appetite, shortness of breath, changed or loss of taste and feeling of being full. Nutrition-related complaints decreased after the first consultation, but remained present over time. CONCLUSIONS: In conclusion, weight changes, risk of sarcopaenia and nutrition-related complaints were prevalent in patients with COVID-19, treated by a primary care dietitian. Nutrition-related complaints improved over time, but remained prevalent until several months after infection.

Relative contribution of molecular mechanisms to cumulative ligand-mediated downregulation of GRα.

Central to the pharmacological use of glucocorticoids (GCs) is the availability of the glucocorticoid receptor alpha (GRα). However, chronic GC therapy often results in the ligand-mediated downregulation of the GRα, and the subsequent development of an acquired GC resistance. While studies have demonstrated the dimerization-dependent downregulation of GRα, as well as the molecular mechanisms through which ligand-mediated downregulation occurs, little is known regarding the relative contribution of these molecular mechanisms to the cumulative ligand-mediated downregulation of the receptor, especially within an endogenous system. Thus, to probe this, the current study evaluates the conformational-dependent regulation of GRα protein using mouse embryonic fibroblast (MEF) cells containing either wild type GRα (MEFwt) or the dimerization deficient GRα mutant (MEFdim) and inhibitors of transcription, translation, and proteasomal degradation. Results show that the promotion of GRα dimerization increases the downregulation of the receptor via two main mechanisms, proteasomal degradation of the receptor protein, and downregulation of GRwt mRNA transcripts. In contrast, when receptor dimerization is restricted these two mechanisms play a lesser role and results suggest that stabilization of GRα protein by non-coding RNAs may potentially be the major regulatory mechanism. Together, these findings clarify the relative contribution of the molecular mechanisms involved in ligand-mediated downregulation of GRα and provides pharmacological targets for the development of GRα ligands with a more favourable therapeutic index.

Histopathological characteristics are instrumental to distinguish monomorphic from polymorphic maculopapular cutaneous mastocytosis in children.

BACKGROUND: Mastocytosis is characterized by the accumulation of mast cells (MCs) in the skin or other organs, and can manifest at any age. A significant number of paediatric mastocytosis cases persist after puberty. In particular, monomorphic maculopapular cutaneous mastocytosis (mMPCM) is often persistent and associated with systemic mastocytosis. However, clinical differentiation of MPCM from polymorphic (p)MPCM can be difficult. AIM: To identify histopathological features that can help to distinguish mMPCM from other subtypes of paediatric mastocytosis. METHODS: This was a retrospective study using skin biopsies from patients with any subtype of mastocytosis. The localization and density of the MC infiltrate, MC morphology and expression of aberrant markers were evaluated and correlated with clinical characteristics. RESULTS: In total, 33 biopsies were available for evaluation from 26 children [(10 with mMPCM, 5 with mastocytoma, 3 with diffuse cutaneous mastocytosis (DCM), 8 with pMPCM)] and 7 adults with MPCM. The MC number was increased in all patients, but was higher in children than adults (P < 0.01). The presence of mMPCM was associated with sparing of the papillary dermis from MC infiltration, whereas MC density in the papillary dermis was highest in pMPCM and DCM (P < 0.01). The positive predictive value of the presence of a reticular MC infiltrate for mMPCM was 72.7% (95% CI 51.4-87.0), and the negative predictive value was 83.3% (95% CI 42.2-97.2). There were no relevant differences in the expression of CD2, CD25 or CD30 between the different subtypes. CONCLUSION: Skin histopathology might enhance the phenotypical differentiation of mMPCM from other subtypes in children, thereby increasing the accuracy of one's prognosis.

ALEX versus ISAC multiplex array in analyzing food allergy in atopic children.

ALEX multiplex array is a relatively new multiplex allergy test which analyses more than 120 allergen extracts and 170 molecular components. ISAC is the most used and studied multiplex array to date, offering 112 molecular components. In ten atopic children with multiple food allergies good agreement was observed between ALEX and ISAC sIgE results for nearly all shared food components. Presence of larger number of allergens in ALEX could help clinicians to improve personalized dietary advice. However more positive sensitizations with unknown clinical relevance were found by ALEX, potentially increasing clinical complexity. Pediatric allergists should be aware of this, especially in young atopic children with (severe) eczema who have not introduced all sorts of food yet.

How Do Presenting Symptoms and Outcomes Differ by Race/Ethnicity Among Hospitalized Patients With Coronavirus Disease 2019 Infection? Experience in Massachusetts.

BACKGROUND: Population-based literature suggests severe acute respiratory syndrome coronavirus 2 infection may disproportionately affect racial/ethnic minorities; however, patient-level observations of hospitalization outcomes by race/ethnicity are limited. Our aim in this study was to characterize coronavirus disease 2019 (COVID-19)-associated morbidity and in-hospital mortality by race/ethnicity. METHODS: This was a retrospective analysis of 9 Massachusetts hospitals including all consecutive adult patients hospitalized with laboratory-confirmed COVID-19. Measured outcomes were assessed and compared by patient-reported race/ethnicity, classified as white, black, Latinx, Asian, or other. Student t test, Fischer exact test, and multivariable regression analyses were performed. RESULTS: A total of 379 patients (aged 62.9 ± 16.5 years; 55.7% men) with confirmed COVID-19 were included (49.9% white, 13.7% black, 29.8% Latinx, 3.7% Asian), of which 376 (99.2%) were insured (34.3% private, 41.2% public, 23.8% public with supplement). Latinx patients were younger, had fewer cardiopulmonary disorders, were more likely to be obese, more frequently reported fever and myalgia, and had lower D-dimer levels compared with white patients (P < .05). On multivariable analysis controlling for age, gender, obesity, cardiopulmonary comorbidities, hypertension, and diabetes, no significant differences in in-hospital mortality, intensive care unit admission, or mechanical ventilation by race/ethnicity were found. Diabetes was a significant predictor for mechanical ventilation (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.11-3.23), while older age was a predictor of in-hospital mortality (OR, 4.18; 95% CI, 1.94-9.04). CONCLUSIONS: In this multicenter cohort of hospitalized COVID-19 patients in the largest health system in Massachusetts, there was no association between race/ethnicity and clinically relevant hospitalization outcomes, including in-hospital mortality, after controlling for key demographic/clinical characteristics. These findings serve to refute suggestions that certain races/ethnicities may be biologically predisposed to poorer COVID-19 outcomes.

State of the art: the role of citrulline as biomarker in patients with chemotherapy- or graft-versus-host-disease-induced mucositis.

PURPOSE OF REVIEW: Serum or plasma citrulline levels are used as biomarker for a broad spectrum of intestinal functions. During high-dose chemotherapy, citrulline levels are decreased due to mucositis, a common side effect of chemotherapy. This may decrease intestinal function and result in diarrhea. In this review, most recent studies investigating citrulline as biomarker for intestinal function are discussed, with focus on patients with oncological diseases, specifically hematological malignancies with chemotherapy- or Graft-versus-Host-disease (GVHD)-induced mucositis. RECENT FINDINGS: Citrulline has recently been widely studied in relation to intestinal function and various clinical conditions. It seems therefore a promising noninvasive biomarker in clinical practice for more than intestinal function alone. The association between citrulline levels and intestinal function in patients with hematological malignancies, with or without mucositis remains unclear, as no other parameters of intestinal function for this purpose were assessed. SUMMARY: In conclusion, citrulline seems to be a promising noninvasive biomarker for various intestinal conditions in general, and potentially for intestinal function in patients with chemotherapy- or GVHD-induced mucositis. It is unclear from recent literature whether high fecal volume or diarrhea as side effect, results in impaired intestinal function and severe malabsorption and if citrulline biomarkers can be useful to detect this.

Operative Intervention Does Not Change Pain Perception in Patients With Diabetic Foot Ulcers.

Researchers investigated pain perception in patients with diabetic foot ulcers (DFUs) by analyzing pre- and postoperative physical function (PF), pain interference (PI), and depression domains of the Patient-Reported Outcome Measurement Information System (PROMIS). They hypothesized that 1) because of painful diabetic peripheral neuropathy (DPN), a majority of patients with DFUs would have high PROMIS PI scores unchanged by operative intervention, and 2) the initially assessed PI, PF, and depression levels would be correlated with final outcomes. Seventy-five percent of patients with DFUs reported pain, most likely because of painful DPN. Those who reported high PI and low PF were likely to report depression. PF, PI, and depression levels were unchanged after operative intervention or healing of DFUs.

Indulgent Foods Can Paradoxically Promote Disciplined Dietary Choices.

As obesity rates continue to rise, interventions promoting healthful choices will become increasingly important. Here, participants ( N = 79) made binary choices between familiar foods; some trials contained a common consequence that had a constant probability of receipt regardless of the participant's choice. We theorized-on the basis of simulations using a value-normalization model-that indulgent common consequences potentiated disciplined choices by shaping other options' perceived healthfulness and tastiness. Our experimental results confirmed these predictions: An indulgent common consequence more than doubled the rate of disciplined choices. We used eye-gaze data to provide insights into the underlying mechanisms, finding that an indulgent common consequence biased eye gaze toward healthful foods. Furthermore, attention toward the common consequence predicted individual differences in behavioral bias. Results were replicated across two independent samples receiving distinct goal primes. These results demonstrate that introducing an irrelevant indulgent food can alter processing of healthier items-and thus promote disciplined choices.

Small percentage of anaphylactic reactions treated with epinephrine during food challenges in Dutch children.

BACKGROUND: Severe allergic reactions, including anaphylaxis, occur during oral food challenges (OFCs) and the first-line treatment of anaphylaxis is epinephrine. OBJECTIVE: To evaluate the percentage of anaphylactic reactions treated with epinephrine during OFCs and to identify associated factors for the administration of epinephrine. METHODS: Children who underwent an OFC with peanut, hazelnut, cow's milk, hen's egg, or cashew nut from 2005 through 2015 in the Netherlands were evaluated. Children with reactions meeting the criteria for anaphylaxis according to the European Academy of Allergy and Clinical Immunology guidelines for food allergy and anaphylaxis were included. Children with an anaphylactic reaction treated with vs without epinephrine were compared. Possible factors associated with the administration of epinephrine, such as age, sex, symptoms consistent with asthma, history of an allergic reaction to the tested allergen, and symptom types during the anaphylactic reaction, were evaluated using logistic regression analysis. RESULTS: Eighty-three children in clinical and research settings (43% boys; median age, 7 years; range, 1-17) who met the criteria for anaphylaxis were included in this study. Thirty-two of 83 children (39%) with anaphylaxis were treated with epinephrine. Respiratory symptoms during the OFC were treated significantly more often with epinephrine than gastrointestinal symptoms (P = .01). CONCLUSION: Only 39% of children with anaphylaxis, according to the guideline criteria, were treated with epinephrine during the OFC and most of these children had respiratory symptoms. There is need for an easy-to-use international guideline for the treatment of allergic symptoms during OFCs.

A comparison of 24 chemicals in the six-well bacterial reverse mutation assay to the standard 100-mm Petri plate bacterial reverse mutation assay in two laboratories.

The bacterial reverse mutation assay (Ames) is a fundamental genetic toxicology test, and efforts to miniaturize the regulatory GLP version are essential in assessing genotoxic liabilities earlier in the drug development pipeline. Two versions of the Ames were compared: the six-well (miniaturized) plate and the standard 100-mm plate test at two different laboratories. Of twenty-four chemicals tested, a subset of six chemicals was tested in the six-well test only and the remaining eighteen were evaluated in both versions of the test. The plate incorporation procedure was used with one Escherichia coli and four different Salmonella strains. The six-well test uses the same plating procedure and evaluation methods as the standard Ames assay in 100-mm plates, but the smaller format requires 20% of the test chemical. Additionally, the six-well test uses a limit concentration of 1000 µg/well versus the standard Petri plate test limit concentration of 5000 µg/plate. Testing across the two formats resulted in 100% concordance in overall mutagenicity judgement and 94% concordance across all tester strains and conditions. Known mutagenic positive control chemicals were correctly detected as positive in both formats. The overall conclusion is that the six-well assay results are concordant with the standard assay format in this evaluation and could be a reliable alternative.

Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 µg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication.

Management around invasive procedures in mastocytosis: An update.

OBJECTIVE: Mastocytosis is a chronic hematologic disorder that is characterized by the accumulation of aberrant mast cells and typically involves the skin and/or bone marrow. Patients with mastocytosis are at increased risk of anaphylaxis. Based on theoretical assumptions, medical procedures requiring general anesthesia or radiocontrast media are deemed hazardous for patients with mastocytosis. The objective of this article is to provide a comprehensive overview of the actual risk of iatrogenic anaphylaxis and provide recommendations for daily practice. DATA SOURCES: Various scientific search engines were used (eg, PubMed and Medline). STUDY SELECTIONS: Because of the paucity of high-level studies on this topic, all available evidence was considered, including case reports. RESULTS: Reliable data on the incidence of iatrogenic anaphylaxis in mastocytosis are lacking. However, although the incidence as reported in (retrospective) cohort studies is higher than in the general population, it is still lower than commonly anticipated, with an incidence of 5.4% in 1 study. Adequate premedication and avoidance of certain physical stimuli can further decrease this risk by 10-fold. The role of drugs as elicitors of anaphylaxis is perhaps overestimated, and physical stimuli are at least as important in inducing release of mast cell mediators. CONCLUSION: This article provides practical recommendations for the management of invasive procedures in patients with mastocytosis based on current knowledge of this topic.