Exploratory immunogenicity outcomes of peanut oral immunotherapy: Findings from the PALISADE trial.

BACKGROUND: Immunoglobulin E (IgE) and immunoglobulin G4 (IgG4) to peanut and its components may influence the clinical reactivity to peanut. Allergen-specific immunotherapy is known for modifying both IgE and IgG4. Peanut oral immunotherapy may influence these serological parameters. METHODS: Exploratory analyses of serological data from participants receiving peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) and placebo in the double-blind, randomized, phase 3 PALISADE trial were conducted to evaluate potential relationships between peanut-specific and peanut component-specific (Ara h 1, Ara h 2, Ara h 3, Ara h 6, Ara h 8, and Ara h 9) IgE and IgG4 levels and clinical outcomes. RESULTS: A total of 269 participants (PTAH, n = 202; placebo, n = 67) were analyzed. No relationship was observed between specific IgE and IgG4 levels at screening and maximum tolerated peanut protein dose during screening or response status during exit double-blind placebo-controlled food challenge (DBPCFC). In PTAH-treated participants, no relationship was observed between IgE and IgG4 levels at screening and maximum symptom severity during exit DBPCFC. Postscreening ratios (ie, postscreening/screening) in the PTAH group were significant at the end of updosing and exit visit for most components. Postscreening changes in specific IgE levels were more pronounced with PTAH versus placebo for most components. CONCLUSIONS: Specific IgE and IgG4 levels at screening are not correlated with screening or exit DBPCFC results, and are not predictive of clinical response to PTAH. Peanut (Arachis hypogaea) allergen powder-dnfp contains the relevant and immunodominant allergens, inducing immunological changes with the treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02635776.

Novel Application of a Dynamic, In-room Survey Platform to Measure Surgical Team Satisfaction.

OBJECTIVE: To elucidate the potential usage of continuous feedback regarding team satisfaction and correlations with operative performance and patient outcomes. BACKGROUND: Continuous, actionable assessment of teamwork quality in the operating room (OR) is challenging. This work introduces a novel, data-driven approach to prospectively and dynamically assess health care provider satisfaction with teamwork in the OR. METHODS: Satisfaction with teamwork quality for each case was assessed utilizing a validated prompt displayed on HappyOrNot Terminals placed in all ORs, with separate panels for circulators, scrub nurses, surgeons, and anesthesia providers. Responses were cross-referenced with OR log data, team familiarity indicators, efficiency parameters, and patient safety indicator events through continuous, semiautomated data marts. Deidentified responses were analyzed through logistic regression modeling. RESULTS: Over a 24-week period, 4123 responses from 2107 cases were recorded. The overall response rate per case was 32.5%. Greater scrub nurse specialty experience was strongly associated with satisfaction (odds ratio: 2.15, 95% CI: 1.53-3.03, P < 0.001). Worse satisfaction was associated with longer than expected procedure time (odds ratio: 0.91, 95% CI: 0.82-1.00, P = 0.047), nighttime (0.67, 95% CI: 0.55-0.82, P < 0.001), and add-on cases (0.72, 95% CI: 0.60-0.86, P < 0.001). Higher material costs (22%, 95% CI: 6-37, P = 0.006) were associated with greater team satisfaction. Cases with superior teamwork ratings were associated with a 15% shorter length of hospital stay (95% CI: 4-25, P = 0.006). CONCLUSIONS: This study demonstrates the feasibility of a dynamic survey platform to report actionable health care provider satisfaction metrics in real-time. Team satisfaction is associated with modifiable team variables and some key operational outcomes. Leveraging qualitative measurements of teamwork as operational indicators may augment staff engagement and measures of performance.

Primary Care Continuity, Frequency, and Regularity Associated With Medicare Savings.

Importance: Reducing Medicare expenditures is a key objective of Medicare's transition to value-based reimbursement models. Improving access to primary care is an important way to reduce expenditures, yet less is known about how visits should be organized to maximize savings. Objective: To examine the association between Medicare savings and primary care visit patterns. Design, Setting, and Participants: This retrospective cohort study used data from a 5% sample of traditional Medicare claims from 2016 to 2019. Participants had at least 3 primary care visits with at least 180 days between the first and the last visit, were not enrolled in Medicare Advantage, did not have end-stage kidney disease, and were not institutionalized. Data were analyzed from June 2022 to April 2023. Exposures: Primary care visit patterns: visit frequency, regularity, continuity of care. Main Outcomes and Measures: Savings in Medicare expenditures; risk-adjusted Medicare expenditures, number of emergency department (ED) visits, and hospitalizations. Results: Among 504 471 beneficiaries (298 422 [59.16%] women; mean [SD] age, 74.26 [10.41] years), temporally regular visits with higher continuity were associated with the highest savings. For these patients, the savings increased with increasing visit frequencies, with peak savings observed at higher visit frequencies as clinical complexity increased. As regularity and continuity decreased, the association between savings and visit frequencies progressively inverted. The group with a regular and highly continuous pattern was associated with greater savings (175.87%; 95% CI, 167.40% to 184.33%; P < .001), lower risk-adjusted expenditures (-16.61%; 95% CI, -16.73% to -16.48%; P < .001), fewer risk-adjusted ED visits (-40.49%; 95% CI, -40.55% to -40.43%; P < .001), and fewer risk-adjusted hospitalizations (-53.32%; 95% CI, -53.49% to -53.14%; P < .001) compared with the irregular noncontinuous group. Conclusions and Relevance: In this cohort study, savings in Medicare expenditures and improvements in acute care utilization were associated with visit frequency, regularity, and continuity in primary care in an interrelated fashion such that optimization of primary care visit patterns along each axis were associated with the largest improvement in outcomes. Demonstrating the magnitude and interdependence of these associations is useful for health care professionals and policymakers as Medicare continues its transition to value-based reimbursement models.

Distinct trajectories distinguish antigen-specific T cells in peanut-allergic individuals undergoing oral immunotherapy.

BACKGROUND: Despite similar clinical symptoms, peanut-allergic (PA) individuals may respond quite differently to the same therapeutic interventions. OBJECTIVE: This study aimed to determine whether inherent qualities of cell response at baseline could influence response to peanut oral immunotherapy (PnOIT). METHODS: We first performed ex vivo T-cell profiling on peanut-reactive CD154+CD137+ T (pTeff) cells from 90 challenge-confirmed PA individuals. We developed a gating strategy for unbiased assessment of the phenotypic distribution of rare pTeff cells across different memory CD4+ T-cell subsets to define patient immunotype. In longitudinal samples of 29 PA participants enrolled onto the IMPACT trial of PnOIT, we determined whether patient immunotype at baseline could influence response to PnOIT. RESULTS: Our data emphasize the heterogeneity of pTeff cell responses in PA participants with 2 mutually exclusive phenotypic entities (CCR6-CRTH2+ and CCR6+CRTH2-). Our findings lead us to propose that peanut allergy can be classified broadly into at least 2 discrete subtypes, termed immunotypes, with distinct immunologic and clinical characteristics that are based on the proportion of TH2A pTeff cells. PnOIT induced elimination of TH2A pTeff cells in the context of the IMPACT clinical trial. Only 1 PA patient with a low level of TH2A pTeff cells at baseline experienced long-lasting benefit of remission after PnOIT discontinuation. CONCLUSION: Dividing PA patients according to their individual peanut-specific T-cell profile may facilitate patient stratification in clinical settings by identifying which immunotypes might respond best to different therapies.

Participant characteristics and safety outcomes of peanut oral immunotherapy in the RAMSES and ARC011 trials.

BACKGROUND: Clinical trials (PALISADE [ARC003], ARTEMIS [ARC010]) proving efficacy and safety of peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) have used double-blind, placebo-controlled food challenges (DBPCFCs) to screen for eligibility and to evaluate efficacy. In routine clinical practice, individuals with peanut allergy do not always undergo food challenges to confirm diagnosis or determine candidacy for treatment. OBJECTIVE: To describe PTAH safety and tolerability in participants selected by clinical history and peanut sensitization parameters not undergoing DBPCFCs during trials and to compare findings with previously published data. METHODS: RAMSES (ARC007) was a 6-month, phase 3, randomized, double-blind, placebo-controlled trial in children aged 4 to 17 years with physician-confirmed peanut allergy. ARC011 was the subsequent 6-month follow-on maintenance PTAH study. The primary end point for RAMSES and ARC011 was the frequency of treatment-emergent adverse events (AEs). We descriptively compared baseline characteristics and safety outcomes from RAMSES and ARC011 to participants undergoing DBPCFCs in phase 3 PALISADE and ARTEMIS trials. RESULTS: In 506 patients randomized to study treatment, baseline characteristics appeared balanced among groups. Proportion of participants with at least 1 AE was 55% for PTAH vs 33.9% for placebo during initial dose escalation and 98.8% vs 94.0% during updosing, respectively. Most participants with AEs had mild or moderate events. The most common AEs were gastrointestinal. Comparisons to pooled PALISADE and ARTEMIS data revealed higher baseline median peanut-specific immunoglobulin E and skin prick test values for RAMSES participants. Safety outcomes during trial periods were comparable. CONCLUSION: Safety data from clinically selected children with peanut allergy receiving PTAH do not seem different from those in phase 3 trials requiring DBPCFC to enter trials.

A High-Fidelity Model to Predict Length-of-Stay in the Neonatal Intensive Care Unit (NICU).

Having an interpretable dynamic length-of-stay (LOS) model can help hospital administrators and clinicians make better decisions and improve the quality of care. The widespread implementation of electronic medical record (EMR) systems has enabled hospitals to collect massive amounts of health data. However, how to integrate this deluge of data into healthcare operations remains unclear. We propose a framework grounded in established clinical knowledge to model patients' lengths-of-stay. In particular, we impose expert knowledge when grouping raw clinical data into medically meaningful variables, which summarize patients' health trajectories. We use dynamic predictive models to output patients' remaining lengths-of-stay (RLOS), future discharges, and census probability distributions based on their health trajectories up to the current stay. Evaluated with large-scale EMR data, the dynamic model significantly improves predictive power over the performance of any model in previous literature and remains medically interpretable.

Oral desensitization therapy for peanut allergy induces dynamic changes in peanut-specific immune responses.

BACKGROUND: The PALISADE study, an international, phase 3 trial of peanut oral immunotherapy (POIT) with AR101, resulted in desensitization in children and adolescents who were highly allergic to peanut. An improved understanding of the immune mechanism induced in response to food allergen immunotherapy would enable more informed and effective therapeutic strategies. Our main purpose was to examine the immunological changes in blood samples from a subset of peanut-allergic individuals undergoing oral desensitization immunotherapy with AR101. METHODS: Blood samples obtained as part of enrollment screening and at multiple time points during PALISADE study were used to assess basophil and CD4+ T-cell reactivity to peanut. RESULTS: The absence of clinical reactivity to the entry double-blinded placebo-controlled peanut challenge (DBPCFC) was accompanied by a significantly lower basophil sensitivity and T-cell reactivity to peanut compared with DBPCFC reactors. At baseline, peanut-reactive TH2A cells were observed in many but not all peanut-allergic patients and their level in peripheral blood correlates with T-cell reactivity to peanut and with serum peanut-specific IgE and IgG4 levels. POIT reshaped circulating peanut-reactive T-cell responses in a subset-dependent manner. Changes in basophil and T-cell responses to peanut closely paralleled clinical benefits to AR101 therapy and resemble responses in those with lower clinical sensitivity to peanut. However, no difference in peanut-reactive Treg cell frequency was observed between groups. CONCLUSION: Oral desensitization therapy with AR101 leads to decreased basophil sensitivity to peanut and reshapes peanut-reactive T effector cell responses supporting its potential as an immunomodulatory therapy.

Updating the CoFAR Grading Scale for Systemic Allergic Reactions in Food Allergy.

BACKGROUND: Immunotherapy is promising as an efficacious treatment for food allergy. Other food allergy treatments are also under development. However, adverse allergic events during treatment, as well as during oral food challenges, are common and reporting is not standardized. OBJECTIVE: A more nuanced grading scale is needed to create a comprehensive and universal system to categorize adverse events and their severity for food allergy clinical trials. METHODS: Starting with the 2012 Consortium for Food Allergy Research (CoFAR) Grading Scale and the World Allergy Organization Grading System, we developed the CoFAR Grading Scale for Systemic Allergic Reactions, Version 3.0, in collaboration with industry partners with expert opinion. RESULTS: The revised CoFAR Grading Scale for Systemic Allergic Reactions has 5 levels of increasing severity, ranging from generalized urticaria, localized angioedema, rhinitis, and abdominal pain (grade 1) to death (grade 5). Systemic reactions are further categorized within each grade by relevant organ system. Mild, single-system reactions are differentiated from mild, multisystem reactions. Lower respiratory tract symptoms are graded on the basis of response to therapy; those that are refractory to standard treatment (eg, requiring >3 doses of intramuscular epinephrine, continuous intravenous epinephrine infusion, and continuous albuterol nebulization) and respiratory compromise requiring mechanical ventilation are classified as grade 4, life-threatening reactions. CONCLUSIONS: Universal and consistent use of the revised CoFAR Grading Scale beyond the CoFAR centers would allow for better data aggregation and safety comparisons in clinical trials for food allergy.

Safety of peanut (Arachis hypogaea) allergen powder-dnfp in children and teenagers with peanut allergy: Pooled summary of phase 3 and extension trials.

BACKGROUND: Peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; previously known as AR101) is a daily oral immunotherapy approved to mitigate allergic reactions after accidental peanut exposure in peanut-allergic individuals aged 4-17 years. OBJECTIVE: We sought to comprehensively summarize the PTAH safety profile for up to ∼2 years of treatment. METHODS: Safety and adverse event (AE) data from participants aged 4-17 years from 3 controlled, phase 3 and 2 open-label extension trials were pooled and assessed. RESULTS: Of the 944 individuals receiving ≥1 PTAH dose, median exposure was ∼49 weeks; most participants experienced ≥1 treatment-related AE (TRAE; n = 853; 90.4%). A total of 829 participants experienced TRAEs with a maximum severity of mild (497, 52.6%) or moderate (332, 35.2%); 24 participants (2.5%) experienced TRAEs graded as severe. Overall, 80 participants (9.5%) discontinued as a result of AEs; most experienced gastrointestinal symptoms and discontinued during the first 6 months. When adjusted for exposure, AEs and TRAEs occurred at a rate of 76.4 and 58.7 events per participant-year of exposure (PYE), respectively, during updosing; AEs and TRAEs decreased to 23.0 and 14.2, respectively, during 300 mg maintenance. Overall, exposure-adjusted rates of systemic allergic reactions were 0.12 events/PYE (mild), 0.11 events/PYE (moderate), and 0.01 events/PYE (severe [anaphylaxis]). CONCLUSION: The safety profile of PTAH was consistent across trials, manageable, and improved over time. AEs were predominantly mild to moderate, and all grades declined in frequency with continued treatment. These data can be used to facilitate shared decision-making discussions with patients and families considering treatment with PTAH.

Open-label follow-on study evaluating the efficacy, safety, and quality of life with extended daily oral immunotherapy in children with peanut allergy.

BACKGROUND: The benefit of daily administration of Peanut (Arachis hypogaea) Allergen Powder-dnfp (PTAH)-formerly AR101-has been established in clinical trials, but limited data past the first year of treatment are available. This longitudinal analysis aimed to explore the impact of continued PTAH therapeutic maintenance dosing (300 mg/day) on efficacy, safety/tolerability, and food allergy-related quality of life. METHODS: We present a subset analysis of PALISADE-ARC004 participants (aged 4-17 years) who received 300 mg PTAH daily for a total of ~1.5 (Group A, n = 110) or ~2 years (Group B, n = 32). Safety assessments included monitoring the incidence of adverse events (AEs), accidental exposures to food allergens, and adrenaline use. Efficacy was assessed by double-blind, placebo-controlled food challenge (DBPCFC); skin prick testing; peanut-specific antibody assays; and Food Allergy Quality of Life Questionnaire (FAQLQ) and Food Allergy Independent Measure (FAIM) scores. RESULTS: Continued maintenance with PTAH increased participants' ability to tolerate peanut protein: 48.1% of completers in Group A (n = 50/104) and 80.8% in Group B (n = 21/26) tolerated 2000 mg peanut protein at exit DBPCFC without dose-limiting symptoms. Immune biomarkers showed a pattern consistent with treatment-induced desensitization. Among PTAH-continuing participants, the overall and treatment-related exposure-adjusted AE rate decreased throughout the intervention period in both groups. Clinically meaningful improvements in FAQLQ and FAIM scores over time suggest a potential link between increased desensitization as determined by the DBPCFC and improved quality of life. CONCLUSIONS: These results demonstrate that daily PTAH treatment for peanut allergy beyond 1 year leads to an improved safety/tolerability profile and continued clinical and immunological response.

Using data from food challenges to inform management of consumers with food allergy: A systematic review with individual participant data meta-analysis.

BACKGROUND: Eliciting doses (EDs) (eg, ED01 or ED05 values, which are the amounts of allergen expected to cause objective symptoms in 1% and 5% of the population with an allergy, respectively) are increasingly being used to inform allergen labeling and clinical management. These values are generated from food challenge, but the frequency of anaphylaxis in response to these low levels of allergen exposure and their reproducibility are unknown. OBJECTIVE: Our aim was to determine (1) the rate of anaphylaxis in response to low-level peanut exposure and (2) the reproducibility of reaction thresholds (and anaphylaxis) at food challenge. METHODS: We conducted a systematic review and individual participant data meta-analysis of studies that reported at least 50 individuals with peanut allergy reacting to peanut at double-blind, placebo-controlled food challenge (DBPCFC) and were published between January 2010 and September 2020. Risk of bias was assessed by using National Institute for Clinical Excellence methodologic checklists. RESULTS: A total of 19 studies were included (covering a total of 3151 participants, 534 of whom subsequently underwent further peanut challenge). At individual participant data meta-analysis, 4.5% (95% CI, 1.9% to 10.1%) of individuals reacted to 5 mg or less of peanut protein with anaphylaxis (moderate heterogeneity [I2 = 57%]). Intraindividual thresholds varied by up to 3 logs, although this variation was limited to a half-log change in 71.2% (95% CI, 56.2% to 82.6%) of individuals. In all, 2.4% (95% CI, 1.1% to 5.0%) of patients initially tolerated 5 mg of peanut protein but then reacted to this dose at subsequent challenge (low heterogeneity [I2 = 16%]); none developed anaphylaxis. CONCLUSION: Around 5% of individuals reacting to an ED01 or ED05 level of exposure to peanut might develop anaphylaxis in response to that dose. This equates to 1 and 6 anaphylaxis events per 2500 patients exposed to an ED01 or ED05 dose, respectively, in the broader population of individuals with peanut allergy.

Efficacy and safety of oral immunotherapy with AR101 in European children with a peanut allergy (ARTEMIS): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Peanut allergy is the leading cause of food-related anaphylaxis. Current management options can negatively affect food allergy-related quality of life. We aimed to investigate the efficacy of an investigational oral biologic drug (AR101). METHODS: The AR101 Trial in Europe Measuring Oral Immunotherapy Success in peanut-allergic children (ARTEMIS) trial was a multicentre, double-blind, randomised, placebo-controlled phase 3 trial done at 18 hospitals in Ireland, France, Germany, Italy, Spain, Sweden, and the UK. Children and adolescents with peanut allergy, aged 4-17 years, who developed dose-limiting symptoms to 300 mg or less peanut protein (equivalent to approximately one peanut kernel) during a double-blind placebo-controlled food challenge test at study entry were enrolled. Participants were randomly assigned (3:1) to receive daily doses of either AR101 oral immunotherapy (AR101 group) or a taste-masked placebo (placebo group). All participants, investigators, and care providers were masked to treatment allocation until the study was completed. Doses were increased every 2 weeks over 6 months until a dose of 300 mg was reached and maintained for 3 months. The primary endpoint was the proportion of participants in the intention-to-treat or safety population (defined as those participants who had been randomly assigned and had received at least one dose of the assigned drug) who could consume a single dose of 1000 mg (cumulative dose 2043 mg) peanut protein without developing dose-limiting allergic symptoms at an exit double-blind placebo-controlled food challenge after 9 months of treatment. Additional endpoints included safety (ie, the frequency and severity of adverse events) and changes in food allergy-related quality of life, assessed by use of age-appropriate Food Allergy Quality of Life Questionnaires (FAQLQs) and the Food Allergy Independent Measure (FAIM). The study is registered with ClinicalTrials.gov, NCT03201003, and is completed. FINDINGS: Between June 12, 2017, and Feb 15, 2018, 227 patients were screened, of whom 175 were randomly assigned to the AR101 group (n=132) and the placebo group (n=43). All primary and secondary endpoints were met. 77 (58%) of 132 participants in the AR101 group tolerated 1000 mg peanut protein at the exit food challenge versus one (2%) of 43 participants in the placebo group (AR101-placebo treatment difference 56·0% [95% CI 44·1-65·2], p<0·0001). Adverse events were reported by almost all participants. The maximum severity of adverse events reported was mild or moderate for most participants who received AR101 (mild, 66 [50%] of 132 participants; moderate, 63 [48%]; and severe, one [1%]) or placebo (mild, 24 [56%] of 43 participants; moderate, 18 [42%]; severe, none). Participants aged 8-12 years in the AR101 group reported improvements that exceeded the minimum clinically important difference between the two groups across all FAQLQ domains. Additionally, participants in the AR101 group and their caregivers reported improvements that exceeded the minimum clinically important difference in FAIM domains related to the perceived likelihood and outcomes of a severe allergic reaction. INTERPRETATION: AR101 oral immunotherapy treatment led to rapid desensitisation to peanut protein, with a predictable safety profile that improved with treatment, and an associated improvement in self-reported and caregiver-reported food allergy-related quality of life. These patient-oriented outcomes provide invaluable data to help physicians, patients, and caregivers make informed, shared decisions on the management of peanut allergy. FUNDING: Aimmune Therapeutics.

Thousands Of Lives Could Be Saved In The US During The COVID-19 Pandemic If States Exchanged Ventilators.

It is thought that there are not enough mechanical ventilators in the United States for every patient who may need one during the novel coronavirus disease (COVID-19) pandemic. However, there has been no analysis that measures the potential magnitude of the problem or proposes a solution. In this article I combine the pandemic forecasting model used by the federal government with estimates of ventilator availability from the literature to assess the expected shortage under various scenarios. I then propose that the federal government organize a national effort for ventilators to be exchanged between states to take advantage of the intertemporal differences in demand peaks. I evaluate versions of this proposal, including use of the national stockpile, to estimate the potentially substantial number of lives that could be saved. In the absence of other viable solutions, the government should begin this effort in earnest, or else make preparations for such coordination should the country face another pandemic in the future.

Latiglutenase Treatment for Celiac Disease: Symptom and Quality of Life Improvement for Seropositive Patients on a Gluten-Free Diet.

BACKGROUND: Celiac disease (CD) is a widespread autoimmune disease triggered by dietary gluten that can lead to severe gastrointestinal symptoms. Because there is no available treatment other than a lifelong gluten-free diet, many patients continue to experience chronic symptoms. AIM: In this analysis we report on the efficacy of latiglutenase, an orally administered enzyme treatment, for improving multiple gluten-induced symptoms and consequent quality of life (QOL) due to inadvertent gluten consumption. METHODS: This analysis is based on data from the CeliAction study of symptomatic patients (ALV003-1221; NCT01917630). Patients were treated with latiglutenase or placebo for 12 weeks and instructed to respond to a symptom diary daily and to multiple QOL questionnaires at weeks 0, 6, and 12 of the treatment periods as secondary endpoints. The results were stratified by serostatus. RESULTS: 398 patients completed the 12-week CDSD study. In seropositive, but not seronegative, CD patients a statistically significant and dose-dependent improvement was seen in the severity and frequency of abdominal pain, bloating, tiredness, and constipation. In subjects receiving 900 mg latiglutenase, improvements (p-values) in the severity of these symptoms for week 12 were 58% (0.038), 44% (0.023), 21% (0.164), and 104% (0.049) respectively, relative to placebo-dosed subjects. The reduction in symptoms trended higher for more symptomatic patients. Similar results were observed for the QOL outcome measures. CONCLUSIONS: Although this study was not powered to definitively establish the benefit of latiglutenase in seropositive CD patients, such patients appear to show symptomatic and QOL benefit from using latiglutenase with meals.

Measuring Change In Small Intestinal Histology In Patients With Celiac Disease.

Small intestinal histologic abnormalities in celiac disease include atrophy of the intestinal villi, hypertrophy of the crypts and lymphocytic infiltration of intraepithelial spaces and lamina propria. These findings are central to diagnosis and their severity and change over time are valuable to monitor disease course and response to therapy. Subjective methods to grade celiac disease histological severity include the Marsh-Oberhuber and Corazza-Villanacci systems. Quantitative histology uses villus height (Vh), crypt depth (Cd), and intra-epithelial lymphocyte count (per 100 enterocytes) to provide objective measures of histologic changes including Vh:Cd ratio. Here we examine the available literature regarding these methodologies and support the use of quantitative histology as the preferred method for accurately and reproducibly demonstrating change of relevant histologic end points over time. We also propose a Quantitative-Mucosal Algorithmic Rules for Scoring Histology (Q-MARSH) system to partially align quantitative histology results with the traditional Marsh, Marsh-Oberhuber, and Corazza-Villanacci systems. Q-MARSH can provide a standardized, objective, and quantitative histology scoring system for use as a clinical or research application.

A clinical pathway for heart failure reduces admissions from the ED without increasing congestion in the ED.

BACKGROUND: A multidisciplinary team at a major academic medical center established an Acutely Decompensated Heart Failure Clinical Pathway (ADHFCP) program to reduce inpatient readmission rates among patients with heart failure which, among several interventions, included an immediate consultation from a cardiologist familiar with an ADHFCP patient when the patient presented at the Emergency Department (ED). This study analyzed how that program impacted utilization of services in the ED and its subsequent effect on rates of admission from the ED and on disposition times. METHODS: ADHFCP inpatient visits were retrospectively risk stratified and matched with non-program inpatient visits to create a control group. A Cox survival model analyzed the ADHFCP's impact on patients' likelihood to visit the ED. Multivariable ANOVA evaluated the impact of the program on the patients' likelihood of being admitted when presenting at the ED. The ADHFCP's impact on bed-to-disposition time in the ED was evaluated by Wilcoxon's rank-sum test, as were doses of diuretics administered in the ED. RESULTS: The survival analysis showed no impact of the ADHFCP on patients' likelihood of visiting the ED, but ADHFCP patients presenting to the ED were 13.1 (95% CI: 3.6-22.6) percentage points less likely to be admitted. There was no difference in bed-to-disposition times, but ADHFCP patients received diuretics more frequently and at higher doses. CONCLUSIONS: Improved communication between cardiologists and ED physicians through the establishment of an explicit pathway to coordinate the care of heart failure patients may decrease that population's likelihood of admission without increasing ED disposition times.

A B-Cell Gene Signature Correlates With the Extent of Gluten-Induced Intestinal Injury in Celiac Disease.

BACKGROUND & AIMS: Celiac disease (CeD) provides an opportunity to study autoimmunity and the transition in immune cells as dietary gluten induces small intestinal lesions. METHODS: Seventy-three celiac disease patients on a long-term, gluten-free diet ingested a known amount of gluten daily for 6 weeks. A peripheral blood sample and intestinal biopsy specimens were taken before and 6 weeks after initiating the gluten challenge. Biopsy results were reported on a continuous numeric scale that measured the villus-height-to-crypt-depth ratio to quantify gluten-induced intestinal injury. Pooled B and T cells were isolated from whole blood, and RNA was analyzed by DNA microarray looking for changes in peripheral B- and T-cell gene expression that correlated with changes in villus height to crypt depth, as patients maintained a relatively healthy intestinal mucosa or deteriorated in the face of a gluten challenge. RESULTS: Gluten-dependent intestinal damage from baseline to 6 weeks varied widely across all patients, ranging from no change to extensive damage. Genes differentially expressed in B cells correlated strongly with the extent of intestinal damage. A relative increase in B-cell gene expression correlated with a lack of sensitivity to gluten whereas their relative decrease correlated with gluten-induced mucosal injury. A core B-cell gene module, representing a subset of B-cell genes analyzed, accounted for the correlation with intestinal injury. CONCLUSIONS: Genes comprising the core B-cell module showed a net increase in expression from baseline to 6 weeks in patients with little to no intestinal damage, suggesting that these individuals may have mounted a B-cell immune response to maintain mucosal homeostasis and circumvent inflammation. DNA microarray data were deposited at the GEO repository (accession number: GSE87629; available: https://www.ncbi.nlm.nih.gov/geo/).