Blood Stored In EDTA Tubes Provides Accurate Peanut Basophil Activation Test Results For 48 hours.

BACKGROUND: The peanut basophil activation test (BAT) has demonstrated excellent diagnostic accuracy with heparinized blood, but its clinical utility is limited by the short stability of samples stored in this anticoagulant. OBJECTIVE: Using EDTA anticoagulated blood, these investigations determined if Peanut BAT sample stability can be extended to 2 days, the minimum stability requirement for diagnostic tests currently offered through American reference laboratories. METHODS: Peanut non-allergic control (NAC), peanut IgE sensitized (PS), and peanut allergic (PA) children aged 6 months through 17 years were recruited from members of Kaiser Permanente Southern California. EDTA anti-coagulated blood samples were collected from participants, shipped to a centralized laboratory, and stored at 4oC for peanut BAT testing 1 and 2 days later. RESULTS: Peanut BAT results for 23 unblinded participants were used to establish sample rejection and interpretation criteria that were subsequently validated in a prospective double-blind study involving 112 additional children (39-NAC, 36-PS, 37-PA). Of 105 blinded blood samples tested on each study day, 88 (84%) day-1 and 90 (86%) day-2 peanut BAT results were considered interpretable, with diagnostic accuracies of 95.5% and 94.4%, respectively. Moreover, all interpretable PA results were considered positive (100% sensitivity). CONCLUSION: Using EDTA anti-coagulated blood samples collected remotely, 1 and 2 days before testing, study results highlight the favorable diagnostic performance characteristics of the peanut BAT and provide further evidence that the test could be readily operationalized for clinical use by interested commercial reference laboratories.

Nanopore occlusion: A biophysical mechanism for bipolar cancellation in cell membranes.

Extraordinarily large but short electric field pulses are reported by many experiments to cause bipolar cancellation (BPC). This unusual cell response occurs if a first pulse is followed by a second pulse with opposite polarity. Possibly universal, BPC presently lacks a mechanistic explanation. Multiple versions of the "standard model" of cell electroporation (EP) fail to account for BPC. Here we show, for the first time, how an extension of the standard model can account for a key experimental observation that essentially defines BPC: the amount of a tracer that enters a cell, and how tracer influx can be decreased by the second part of a bipolar pulse. The extended model can also account for the recovery of BPC wherein the extent of BPC is diminished if the spacing between the first and second pulses is increased. Our approach is reverse engineering, meaning that we identify and introduce an additional biophysical mechanism that allows pore transport to change. We hypothesize that occluding molecules from outside the membrane enter or relocate within a pore. Significantly, the additional mechanism is fundamental and general, involving a combination of partitioning and hindrance. Molecules near the membrane can enter pores to block transport of tracer molecules while still passing small ions (charge number ±1) that govern electrical behavior. Our extension of the standard model accounts for key BPC behavior.

Unique Familial MLL(KMT2A)-Rearranged Precursor B-Cell Infant Acute Lymphoblastic Leukemia in Non-twin Siblings.

BACKGROUND: Infant acute lymphoblastic leukemia (ALL) has never occurred in families except for the ∼100% concordant cases in monozygous twins attributed to twin-to-twin metastases. We report the first kindred with infant ALL in non-twin siblings. The siblings were diagnosed with MLL-rearranged (MLL-R) ALL 26 months apart. The second affected sibling had an unaffected dichorionic monozygous co-twin. Both had fatal outcomes. PROCEDURES: Translocations were characterized by karyotype, FISH, multiplex FISH, and MLL breakpoint cluster region (bcr) Southern blot analysis. Breakpoint junctions and fusion transcripts were cloned by PCR. TP53 mutation and NADPH quinone oxidorecuctase 1 (NQO1) C609T analyses were performed, and pedigree history and parental occupations were ascertained. The likelihood of chance occurrence of infant ALL in non-twin siblings was computed based on a binomial distribution. Zygosity was determined by single nucleotide polymorphism (SNP) array. RESULTS: The translocations were not related or vertically transmitted. The complex karyotype of the proband's ALL had chromosome 2, 3, 4, and 11 abnormalities causing a 5'-MLL-AFF1-3' fusion and a non-productive rearrangement of 3'MLL with a chromosome 3q intergenic region. The affected twin's ALL exhibited a simple t(4;11). The complex karyotype of the proband's ALL suggested a genotoxic insult, but no exposure was identified. There was no germline TP53 mutation. The NQO1 C609T risk allele was absent. The likelihood of infant ALL occurring in non-twin siblings by chance alone is one in 1.198 × 10(9) families. CONCLUSIONS: Whether because of a deleterious transplacental exposure, novel predisposition syndrome, or exceedingly rare chance occurrence, MLL-R infant ALL can occur in non-twin siblings. The discordant occurrence of infant ALL in the monozygous twins was likely because they were dichorionic.

Estimated Effectiveness of the BNT162b2 XBB Vaccine Against COVID-19.

Importance: Data describing the early additional protection afforded by the recently recommended BNT162b2 XBB vaccine (Pfizer-BioNTech; 2023-2024 formulation) are limited. Objective: To estimate the association between receipt of the BNT162b2 XBB vaccine and medically attended COVID-19 outcomes among US adults 18 years and older. Design, Setting, and Participants: This test-negative case-control study was performed to estimate the effectiveness of the BNT162b2 XBB vaccine against COVID-19-associated hospitalization and emergency department (ED) or urgent care (UC) encounters among adults in the Kaiser Permanente Southern California health system between October 10, 2023, and December 10, 2023. Cases were those presenting with an acute respiratory illness and who had a positive SARS-CoV-2 polymerase chain reaction test; controls had an acute respiratory illness but tested negative for SARS-CoV-2. Exposure: The primary exposure was receipt of the BNT162b2 XBB vaccine compared with not receiving an XBB vaccine of any kind, regardless of prior COVID-19 vaccination or SARS-CoV-2 infection history. Receipt of prior (non-XBB) versions of COVID-19 vaccines was also compared with being unvaccinated to estimate remaining protection from older vaccines. Main Outcomes and Measures: Analyses for cases and controls were conducted separately for COVID-19 hospital admissions and ED/UC encounters. Adjusted odds ratios and 95% CIs were estimated from multivariable logistic regression models that were adjusted for patient demographic and clinical characteristics. Estimation of vaccine effectiveness was calculated as 1 - odds ratio × 100%. Results: Among 2854 cases and 15 345 controls (median [IQR] age, 56 [37-72] years; 10 658 [58.6%] female), adjusted estimation of effectiveness of the BNT162b2 XBB vaccine received a median of 34 days prior vs not having received an XBB vaccine of any kind was 62% (95% CI, 32%-79%) against COVID-19 hospitalization and 58% (95% CI, 48%-67%) for ED/UC visits. Compared with being unvaccinated, those who had received only older versions of COVID-19 vaccines did not show statistically significant reduced risk of COVID-19 outcomes, including hospital admission. Conclusions and Relevance: Findings of this case-control study reaffirm current recommendations for broad age-based use of annually updated COVID-19 vaccines given that (1) the BNT162b2 XBB vaccine provided statistically significant additional protection against a range of COVID-19 outcomes and (2) older versions of COVID-19 vaccines offered little, if any, long-term protection, including against hospital admission, regardless of the number or type of prior doses received.

Effectiveness and durability of mRNA-1273 BA.4/BA.5 bivalent vaccine (mRNA-1273.222) against SARS-CoV-2 BA.4/BA.5 and XBB sublineages.

Emerging SARS-CoV-2 sublineages continue to cause serious COVID-19 disease, but most individuals have not received any COVID-19 vaccine for >1 year. Assessment of long-term effectiveness of bivalent COVID-19 vaccines against circulating sublineages is important to inform the potential need for vaccination with updated vaccines. In this test-negative study at Kaiser Permanente Southern California, sequencing-confirmed BA.4/BA.5- or XBB-related SARS-CoV-2-positive cases (September 1, 2022 to June 30, 2023), were matched 1:3 to SARS-CoV-2-negative controls. We assessed mRNA-1273 bivalent relative (rVE) and absolute vaccine effectiveness (VE) compared to ≥2 or 0 doses of original monovalent vaccine, respectively. The rVE analysis included 20,966 cases and 62,898 controls. rVE (95%CI) against BA.4/BA.5 at 14-60 days and 121-180 days was 52.7% (46.9-57.8%) and 35.5% (-2.8-59.5%) for infection, and 59.3% (49.7-67.0%) and 33.2% (-28.2-68.0%) for Emergency Department/Urgent Care (ED/UC) encounters. For BA.4/BA.5-related hospitalizations, rVE was 71.3% (44.9-85.1%) and 52.0% (-1.2-77.3%) at 14-60 days and 61-120 days, respectively. rVE against XBB at 14-60 days and 121-180 days was 48.8% (33.4-60.7%) and -3.9% (-18.1-11.3%) for infection, 70.7% (52.4-82.0%) and 15.7% (-6.0-33.2%) for ED/UC encounters, and 87.9% (43.8-97.4%) and 57.1% (17.0-77.8%) for hospitalization. VE and subgroup analyses (age, immunocompromised status, previous SARS-CoV-2 infection) results were similar to rVE analyses. rVE of mRNA-1273 bivalent vaccine against BA.4/BA.5 and XBB infections, ED/UC encounters, and hospitalizations waned over time. Periodic revaccination with vaccines targeting emerging variants may be important in reducing COVID-19 morbidity and mortality.

Prediction of persistent chronic cough in patients with chronic cough using machine learning.

Introduction: The aim of this study was to develop and validate prediction models for risk of persistent chronic cough (PCC) in patients with chronic cough (CC). This was a retrospective cohort study. Methods: Two retrospective cohorts of patients 18-85 years of age were identified for years 2011-2016: a specialist cohort which included CC patients diagnosed by specialists, and an event cohort which comprised CC patients identified by at least three cough events. A cough event could be a cough diagnosis, dispensing of cough medication or any indication of cough in clinical notes. Model training and validation were conducted using two machine-learning approaches and 400+ features. Sensitivity analyses were also conducted. PCC was defined as a CC diagnosis or any two (specialist cohort) or three (event cohort) cough events in year 2 and again in year 3 after the index date. Results: 8581 and 52 010 patients met the eligibility criteria for the specialist and event cohorts (mean age 60.0 and 55.5 years), respectively. 38.2% and 12.4% of patients in the specialist and event cohorts, respectively, developed PCC. The utilisation-based models were mainly based on baseline healthcare utilisations associated with CC or respiratory diseases, while the diagnosis-based models incorporated traditional parameters including age, asthma, pulmonary fibrosis, obstructive pulmonary disease, gastro-oesophageal reflux, hypertension and bronchiectasis. All final models were parsimonious (five to seven predictors) and moderately accurate (area under the curve: 0.74-0.76 for utilisation-based models and 0.71 for diagnosis-based models). Conclusions: The application of our risk prediction models may be used to identify high-risk PCC patients at any stage of the clinical testing/evaluation to facilitate decision making.

Risk Factors for Persistent Chronic Cough During Consecutive Years: A Retrospective Database Analysis.

BACKGROUND: The identification of patients at high risk for diseases provides clinicians essential information to better manage such patients. Persistent chronic cough (PCC) is a condition with high clinical burden and limited knowledge of the risk factors that drive the persistent symptoms. OBJECTIVE: To understand the risk factors of PCC in patients with CC diagnosed by specialists. METHODS: In this retrospective study, adults aged 18 to 85 years diagnosed with CC by a pulmonologist, allergist, otolaryngologist, or gastroenterologist in the period 2011 to 2016 were identified. PCC was defined by another CC code or at least 2 cough events at least 8 weeks but no more than 4 months apart in each of the 2 consecutive years beginning 1 year after the original CC diagnosis. Unadjusted and adjusted risk ratios with 95% CI for patient characteristics at baseline in relationship to PCC were estimated by Poisson regression models with robust error variance. RESULTS: Of the adults with CC, 3270 (27.4%) had PCC and 5302 (44.5%) did not have CC during follow-up; 3341 (28.1%) had CC in only 1 follow-up year and were excluded from the analysis. Compared with patients without PCC, patients with PCC were noted to have significantly increased adjusted risk ratios for the following baseline features: (1) demographic characteristics (elderly, females, and less educated); (2) comorbidities (chronic obstructive pulmonary disease, chronic sinusitis, bronchiectasis, pulmonary fibrosis, hypertension, depression, and cough complications); (3) medication dispensed (inhaled corticosteroids/long-acting beta-agonists, leukotriene modifiers, nasal corticosteroids, nasal short-acting muscarinic antagonists, proton pump inhibitors, antitussives with narcotics, and neuromodulators); and (4) specialist care, particularly with pulmonologists. CONCLUSIONS: Knowledge of the independent risk factors associated with PCC should aid clinicians in identifying such patients and improve their management.

The Natural History of NAFLD, a Community-Based Study at a Large Health Care Delivery System in the United States.

Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. However, the natural history of NAFLD is incomplete. This is a retrospective cohort study of patients identified with NAFLD by diagnosis codes in a large, community-based health care delivery system. The objectives were (1) to follow patients from initial NAFLD presentation through progression to cirrhosis and/or decompensated cirrhosis to liver cancer, liver transplant, and death for up to 10 years; and (2) to conduct disease progression analysis restricted to patients with NAFLD identified as having diabetes at baseline. A total of 98,164 patients with full NAFLD and 26,488 with diabetes were divided into three baseline prevalent states: (1) no cirrhosis, (2) compensated cirrhosis, and (3) decompensated cirrhosis. In baseline patients without cirrhosis, annual rates of compensated cirrhosis, decompensated cirrhosis, and death were 0.28%, 0.31%, and 0.63% per year, respectively. With baseline compensated cirrhosis, the annual rates of decompensation and death were 2.4% and 6.7% per year. Finally, in those with decompensated cirrhosis at baseline, the death rate was 8.0% per year. In those without cirrhosis and with cirrhosis at baseline, the rates of liver cancer and death were increased approximately 2-fold in the diabetic subpopulation compared with the full NAFLD cohort. Age and comorbidities increased with increasing disease severity. Cox proportional hazards regression analysis showed that cirrhosis was strongly associated with death and liver cancer, and that diabetes was associated with a significant increase in the hazard of both liver cancer and death (2.56 [2.04-3.20] and 1.43 [1.35-1.52]), respectively. Conclusion: The findings of this community-based study further our understanding of the natural history of NAFLD and demonstrate that diabetes is a major factor in the progression of this disease.

Patient-Reported Burden of Chronic Cough in a Managed Care Organization.

BACKGROUND: The burden of chronic cough (CC) requires better understanding. OBJECTIVE: To determine the severity, health status, and health care resource utilization among patients with CC identified by electronic health records on 2 visits separated by ≥1 year. METHODS: Information on cough-related burden was collected through survey from patients with CC, including validated questionnaires (the cough health status Leicester Cough Questionnaire [LCQ], the cough hypersensitivity Hull Airway Reflux Questionnaire [HARQ], and the Cough Quality of Life Questionnaire [CQLQ]), CC-associated respiratory and gastrointestinal comorbidities, and treatment responses. Spearman correlation coefficients were reported to examine the associations among the LCQ, HARQ, and CQLQ. Patient demographics and patient-reported CC features were compared between males and females, and among ethnic groups using Robust Poisson regression models. RESULTS: The survey was completed by 565 patients who were 64.8 ± 12.6 years, 75.8% female, and 60.4% white. CC duration was 8.6 ± 10.5 years with an average weekly severity of 5.3 ± 2.3 (maximum 10). The LCQ score was 11.3 ± 3.9 (maximum 21). The HARQ score was 33.3 ± 13.6 (normal ≤13). The CQLQ score was 56.9 ± 17.5 (maximum 112, worse with higher scores). The Spearman rank correlations were high between the LCQ and HARQ (-0.65), the LCQ and CQLQ (-0.80), and the HARQ and CQLQ (0.69). Patients with CC-associated respiratory and gastrointestinal comorbidities generally showed similar results regarding the above questionnaires. Treatment responses were suboptimal. Women compared with men and non-whites compared with whites reported significantly worse cough severity and poorer LCQ, HARQ, and CQLQ scores. CONCLUSIONS: CC is self-reported as a burdensome condition, particularly in women and non-white minorities, which markedly affects daily living with inadequate response to treatments.

Identifying Ectopic Pregnancy in a Large Integrated Health Care Delivery System: Algorithm Validation.

BACKGROUND: Surveillance of ectopic pregnancy (EP) using electronic databases is important. To our knowledge, no published study has assessed the validity of EP case ascertainment using electronic health records. OBJECTIVE: We aimed to assess the validity of an enhanced version of a previously validated algorithm, which used a combination of encounters with EP-related diagnostic/procedure codes and methotrexate injections. METHODS: Medical records of 500 women aged 15-44 years with membership at Kaiser Permanente Southern and Northern California between 2009 and 2018 and a potential EP were randomly selected for chart review, and true cases were identified. The enhanced algorithm included diagnostic/procedure codes from the International Classification of Diseases, Tenth Revision, used telephone appointment visits, and excluded cases with only abdominal EP diagnosis codes. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall performance (Youden index and F-score) of the algorithm were evaluated and compared to the validated algorithm. RESULTS: There were 334 true positive and 166 true negative EP cases with available records. True positive and true negative EP cases did not differ significantly according to maternal age, race/ethnicity, and smoking status. EP cases with only one encounter and non-tubal EPs were more likely to be misclassified. The sensitivity, specificity, PPV, and NPV of the enhanced algorithm for EP were 97.6%, 84.9%, 92.9%, and 94.6%, respectively. The Youden index and F-score were 82.5% and 95.2%, respectively. The sensitivity and NPV were lower for the previously published algorithm at 94.3% and 88.1%, respectively. The sensitivity of surgical procedure codes from electronic chart abstraction to correctly identify surgical management was 91.9%. The overall accuracy, defined as the percentage of EP cases with correct management (surgical, medical, and unclassified) identified by electronic chart abstraction, was 92.3%. CONCLUSIONS: The performance of the enhanced algorithm for EP case ascertainment in integrated health care databases is adequate to allow for use in future epidemiological studies. Use of this algorithm will likely result in better capture of true EP cases than the previously validated algorithm.

The effect of lowering the prostate-specific antigen normal cutoff on referral rates to urology.

BACKGROUND: Routine prostate cancer screening is controversial, yet the use of prostate-specific antigen (PSA) for screening is likely to continue. Our hospital laboratory decreased the cutoff for normal PSA to 2.5 ng/mL on July 2, 2007, based on the National Comprehensive Screening Network recommendations. The purpose of this study was to determine if referral rates to urology increased after this change. METHODS: We queried our electronic health records to obtain the number of total screening PSA and abnormal PSA and subsequent referrals to urology in the 20-month periods before and after the change in PSA cutoff. RESULTS: There was no significant difference between the percentage of total screening PSA that resulted in a referral to urology after the change than before (7 of 199 [3.5%] vs 8 of 113 [7.1%]; P = .16). The percentage of abnormal PSA (as defined in the respective time periods) that were referred to urology actually decreased after the change (7 of 29 [24.1%] vs 6 of 10 [60.0%]; P = .04); however, when considering only PSA >4.0 ng/mL in each time period, there was no difference in percentage of referrals between the 2 periods. CONCLUSIONS: Contrary to expectations, lowering the cutoff for normal PSA did not increase referrals to urology.

Resetting behavior in a model of bursting in secretory pituitary cells: distinguishing plateaus from pseudo-plateaus.

We study a recently discovered class of models for plateau bursting, inspired by models for endocrine pituitary cells. In contrast to classical models for fold-homoclinic (square-wave) bursting, the spikes of the active phase are not supported by limit cycles of the frozen fast subsystem, but are transient oscillations generated by unstable limit cycles emanating from a subcritical Hopf bifurcation around a stable steady state. Experimental time courses are suggestive of such fold-subHopf models because the spikes tend to be small and variable in amplitude; we call this pseudo-plateau bursting. We show here that distinct properties of the response to attempted resets from the silent phase to the active phase provide a clearer, qualitative criterion for choosing between the two classes of models. The fold-homoclinic class is characterized by induced active phases that increase towards the duration of the unperturbed active phase as resets are delivered later in the silent phase. For the fold-subHopf class of pseudo-plateau bursting, resetting is difficult and succeeds only in limited windows of the silent phase but, paradoxically, can dramatically exceed the native active phase duration.

Prospective study of carboplatin-based chemotherapy for pediatric germ cell tumors.

BACKGROUND: Survival of pediatric patients with malignant germ cell tumors has improved dramatically with the use of cisplatin-based chemotherapy, though patients are at high risk of significant long-term complications. In a prospective study, carboplatin was substituted for cisplatin in an attempt to minimize nephro- and oto-toxicities, while achieving excellent disease-free survival. PROCEDURE: All consecutive patients with malignant germ cell tumors at The Children's Hospital of Philadelphia were treated between 1989 and 1998. After pathologic confirmation of disease and pretreatment evaluation of pulmonary, renal, and otologic function, patients received etoposide 150 mg/m(2) days 1, 2, 3; carboplatin 600 mg/m(2) day 2; and bleomycin 10 mg/m(2) day 3 for at least four courses. RESULTS: Twenty-three patients were entered for study, and were available for evaluation. All patients achieved either a complete or partial remission following therapy with surgery and chemotherapy. With a median of 58 months of follow-up, overall survival is 91% and event-free survival is 87%. Therapy was given as an outpatient, and well tolerated, with 20 admissions for fever and neutropenia. Ototoxicity and nephrotoxicity, when evaluated, have been extremely limited. Three patients, all with stage III disease, have relapsed; one of these remains alive and disease free. CONCLUSIONS: Carboplatin can successfully substitute for cisplatin during the treatment of pediatric germ cell tumors without sacrificing response or survival. Long-term effects, especially nephrotoxicity and ototoxicity, were rare or mild among the small number of patients evaluated. Carboplatin appears to be a safe and efficacious alternative in the treatment of germ cell tumors, and should be considered as primary therapy for pediatric patients.