Association between patient activation level and functional outcomes in older adults with hip fractures.

BACKGROUND: Hip fractures can significantly impact older adults' mobility and function. Effective rehabilitation is crucial to help them regain independence and quality of life. However, little is known about the association between patient activation and hip fracture rehabilitation. This study aims to assess the association between the PAM-13 scores and the level of physical function, mobility, and activities of daily living in older adults following a hip fracture rehabilitation program. METHOD: An exploratory outcome study from a cluster-randomized stepped-wedge clinical controlled trial. Two hundred thirty-nine patients were classified into four Patient Activation Measure-Levels (PAM-13) according to their PAM-13 scores, reflecting their confidence and preparedness to manage their health. Level 1 represents the lowest level of confidence. The patient's mobility, function, and daily activities were evaluated at discharge and after 12 and 24 weeks. RESULTS: The cohort had a median age of 78; 67% were female, and 50% lived alone. There were no significant differences in demographics between the PAM-Levels. PAM-Level 1 patients had longer hospital stays and lower mobility scores than PAM-Level 4 patients. However, all patients improved over time, and higher initial PAM levels resulted in better outcomes. PAM-Level 1 patients improved in Time Up and Go score from a median score of 54 seconds to 14 seconds at 24 weeks, while PAM-Level 4 patients improved from 26 to 9 seconds. CONCLUSION: Our study found an association between PAM levels and functional outcomes in hip fracture rehabilitation. Patients with higher activation levels had better mobility and functional outcomes.

Timing and dosage of intrapartum prophylactic penicillin for preventing early-onset group B streptococcal disease: assessing maternal and umbilical cord blood concentration.

OBJECTIVE: Timing of administration of antibiotics and concentrations in maternal blood and the umbilical cord blood are important prerequisites for optimal intrapartum antibiotic prophylaxis (IAP) of neonatal early-onset group B streptococcus (GBS) disease. This cohort study aimed to explore penicillin concentrations in mothers and infants at birth in relation to time elapsed from administration to delivery and to the minimal inhibitory concentration (MIC) for GBS. MAIN OUTCOME MEASURES: Penicillin G concentrations in maternal and umbilical cord blood in relation to time and dose from administration to time of delivery. RESULTS: In 44 mother-infant dyads, median maternal penicillin G concentration was 0.2 mg/L (IQR 0-0.8 mg/L; range 0-1.6 mg/L). Median infant penicillin G concentration was 1.2 mg/L (IQR 0.5-5.0 mg/L; range 0-12.7 mg/L). In all infants (N=38) born less than 4 hours after the latest IAP administration, penicillin G concentrations far exceeded MIC (0.125 mg/L), even after short time intervals between IAP administration and birth. The highest plasma concentrations were reached in umbilical cord blood within 1 hour from IAP administration to birth.For 44 mother-infant dyads, maternal concentrations were very low compared with their infants'; particularly, very high concentrations were seen in the 20 infants with only one dose of IAP. CONCLUSION: High concentrations of penicillin G were found in umbilical cord blood of infants born less than 4 hours after IAP administration, well above the MIC for GBS.

Outcome of pregnancy oral glucose tolerance test and preterm birth.

BACKGROUND: Gestational diabetes is associated with adverse outcomes such as preterm birth (<37 weeks). However, there is no international consensus on screening criteria or diagnostic levels for gestational diabetes, and it is unknown whether body mass index (BMI) or obesity modifies the relation between glucose level and preterm birth. METHODS: We studied a pregnancy cohort restricted to two Danish regions from the linked Danish Medical Birth Register to study associations between glucose measurements from the 2-hour post-load 75-gram oral glucose tolerance test (one-step approach) and preterm birth from 2004-2018. In Denmark, gestational diabetes screening is a targeted strategy for mothers with identified risk factors. We used Poisson regression to estimate rate ratios (RR) of preterm birth with z-standardized glucose measurements. We assessed effect measure modification by stratifying analyses and testing for heterogeneity. RESULTS: Among 11,337 pregnancies (6.2% delivered preterm), we observed an adjusted preterm birth RR of 1.2 (95% CI: 1.1-1.3) for a 1 standard deviation glucose increase of 1.4 mmol/L from the mean 6.7 mmol/L. There was evidence for effect measure modification by obesity, e.g., adjusted RR for non-obese (BMI <30): 1.2 (95%CI: 1.1-1.3) vs. obese (BMI ≥30): 1.3 (95%CI: 1.2-1.5), P=0.05 for heterogeneity. CONCLUSIONS: Among mothers screened for gestational diabetes, increased glucose levels, even those below the diagnostic level for gestational diabetes in Denmark, were associated with increased preterm birth risk. Obesity (BMI ≥30) may be an effect measure modifier, not just a confounder, of the relation between blood glucose and preterm birth risk.

Informal care after hip fracture: prospective cohort.

BACKGROUND: Hip fracture is very common and it has life-shattering consequences for older persons. After discharge the older persons need help with even basic everyday activities from formal and informal caregivers. In Scandinavia formal care are well-developed however the presence of informal caregivers likely reflect on the amount of formal care and wears on the informal caregivers. This study explore how often and how much informal care (IC) older persons receive after hip fracture. METHOD: We contacted 244 community-dwelling older persons every two weeks the first twelve weeks after discharge after hip fracture and asked them if they received care from family and/or friends and how much. We used non-parametric statistics and level of significance was 95%. RESULTS: The proportion of older persons receiving IC was 90% and the median amount of IC was 32 hours (IQR 14-66). The number of older persons who received IC was highest the first four weeks after discharge and so was the amount of hours of IC. The older persons that were high-dependence on IC received a median of 66 (IQR 46-107) hours compared to the low-dependent of 11 hours (IQR 2-20). CONCLUSION: IC is very frequent, especially the first two to four weeks after discharge. The median IC was 32 hours from discharge to the 12-week follow-up. However, this figure tended to rise for persons with, among other, reduced functionality and those residing with a partner. IMPLICATIONS: With respect to local differences, the findings in this study are likely applicable to other Scandinavian countries. We strongly suggest that the variation in older person need for informal caregiver be given consideration in the prioritisation of resources. TRIAL REGISTRATION: This prospective cohort study of informal care, was part of a cluster-randomised stepped-wedge clinical controlled trial. Written consent was obtained required by regional ethics committee S-20200070. Data was collected in accordance with the Danish Data Protection Agency (20-21854).

Treatment of nausea in hospitalized patients with acute illness.

Evidence suggests that available antiemetics are equal to intravenous fluid treatment against acute nausea of other causes than motion sickness, pregnancy, anaesthesia, chemo- or radiation therapy. Each antiemetic is associated with adverse effects, which include movement disorders, sedation, and QT prolongation. Intravenous fluid and treatment directed against underlying pathology is recommended as a first-line treatment against nausea in these patients. If an antiemetic is clinically warranted, ondansetron has the most favourable ratio between side effects and price, as argued in this review.

COVID-19 severity in patients with chronic lymphocytic leukemia treated with venetoclax: a single-center observational cohort study.

Patients with chronic lymphocytic leukemia (CLL) are at high risk of developing severe COVID-19. The present study was undertaken to elucidate COVID-19 related morbidity and mortality in CLL patients treated with venetoclax. We present a single-center study of 108 patients with small lymphocytic lymphoma or CLL treated with venetoclax. Primary outcome was 30-day COVID-19 mortality. Secondary outcomes included COVID-19 severity and hospitalization rate. Forty-eight (44%) patients had PCR-verified SARS-COV-2 between March 2020 and January 2023. Thirty-six patients (75%) presented with asymptomatic/mild COVID-19 and 12 (25%) with severe/critical disease. The hospitalization rate was 46% with a 30-day mortality rate of only 4% and severe comorbidities as the primary cause of death. COVID-19 severity and mortality were similar before and during the Omicron era. High CIRS-scores (P < 0.02) and thrombocytopenia (P < 0.01) were more frequent in patients with severe/critical disease. In real-world data, most venetoclax treated patients presented with mild COVID-19. Hospitalization and mortality rates were low compared to data of general CLL populations. Our data indicate that venetoclax was a safe treatment option for CLL patients during the pandemic.

Influence of Low-Density Lipoprotein Cholesterol Levels on NSAID-Associated Cardiovascular Risks After Myocardial Infarction: A Population-Based Cohort Study.

Aim: To examine whether low-density lipoprotein cholesterol (LDL-C) levels influence the cardiovascular risk associated with non-aspirin non-steroidal anti-inflammatory drug (NSAID) use after myocardial infarction (MI). Methods: Using Danish health registries, we conducted a population-based cohort study of all adult patients with first-time MI during 2010-2020 with an LDL-C value before discharge. Based on the latest LDL-C value, we categorized patients into a low and a high LDL-C group (<3.0 vs ≥3.0 mmol/L). We used time varying Cox regression to compute hazard ratios (HRs) with 95% confidence intervals of the association between NSAID use and a major adverse cardiovascular event (MACE: recurrent MI, ischemic stroke, and all-cause death). Results: We followed 50,573 patients for a median of 3.1 years. While exposed, 521 patients experienced a MACE: 312 in the low LDL-C group and 209 in the high LDL-C group. The HRs for MACE comparing NSAID use with non-use were 1.21 (1.11-1.32) overall, 1.19 (1.06-1.33) in the low LDL-C group, and 1.23 (1.07-1.41) in the high LDL-group. The HRs for recurrent MI and ischemic stroke were comparable between the LDL-C subgroups. The HRs for all-cause death were 1.22 (1.07-1.39) in the low LDL-C group and 1.54 (1.30-1.83) in the high LDL-C group. Changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L showed consistent results. Conclusion: In patients with MI, LDL-C levels did not influence the increased risk of MACE associated with NSAID use, but might influence the association between NSAID use and all-cause death.

Semaglutide (Ozempic®) Use in Denmark 2018 Through 2023 ‒ User Trends and off-Label Prescribing for Weight Loss.

Purpose: A surge in the use of semaglutide injection (Ozempic®) approved to treat type 2 diabetes (T2D) has led to a global supply shortage. We investigated contemporary user rates and clinical characteristics of semaglutide (Ozempic®) users in Denmark, and the extent of "off-label" prescribing for weight loss. Patients and Methods: Nationwide population-based cross-sectional study based on linked health registries January 2018 through December 2023. All adults who received a first prescription of semaglutide once weekly (Ozempic®) were included. We examined quarterly rates of new users and total user prevalences, using other glucagon-like peptide-1 receptor agonists and weight loss medications as comparison. We also investigated user characteristics including T2D, glucose control, comedications, and cardiorenal disease. Results: The new user rate of semaglutide (Ozempic®) remained stable at approximately 4 per 1000 adult person-years between 2019 and 2021 and then accelerated, peaking at 10 per 1000 in the first quarter of 2023 after which it declined sharply. User prevalence increased to 91,626 users in Denmark in 2023. The proportion of semaglutide (Ozempic®) new users who had a record of T2D declined from 99% in 2018 to only 67% in 2022, increasing again to 87% in 2023. Among people with T2D who initiated semaglutide (Ozempic®) in 2023, 52% received antidiabetic polytherapy before initiation, 39% monotherapy, and 8% no antidiabetic therapy. Most T2D initiators had suboptimal glucose control, with 83% having an HbA1c ≥48 mmol/mol and 68% ≥53 mmol/mol despite use of antidiabetic medication, and 29% had established atherosclerotic cardiovascular disease or kidney disease. Conclusion: The use of semaglutide (Ozempic®) in Denmark has increased dramatically. Although not approved for weight loss without T2D, one-third of new users in 2022 did not have T2D. Conversely, most initiators with T2D had a clear medical indication for treatment intensification, and "off-label" use can only explain a minor part of the supply shortage.

Determination of cortisol cut-off limits and steroid dynamics in the ACTH stimulation test: a comparative analysis using Roche Elecsys Cortisol II immunoassay and LC-MS/MS.

PURPOSE: Measurement of cortisol concentrations is method dependent. The study aimed to establish assay-specific cut-off limits for cortisol after adrenocorticotropic hormone (ACTH) stimulation, comparing Roche Elecsys Cortisol II immunoassay to liquid chromatography-mass spectrometry (LC-MS/MS), and to assess the impact of patient characteristics, estrogen containing oral contraceptives as well as relation to other adrenocortical steroid hormone dynamics. METHODS: One hundred healthy participants underwent a 250 µg ACTH-test, with plasma samples analyzed using ElecsysCortI, ElecsysCortII, and LC-MS/MS. Cortisone, corticosterone, 17-OH-progesterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone were additionally analyzed with LC-MS/MS. Cut-off limit for a normal cortisol response to the ACTH-test was defined as: 2.5th percentile-1.96 × SE. RESULTS: ElecsysCort II measured cortisol concentrations 21% (95% CI: 19-22%) lower than ElecsysCort I. Cut-off limits for cortisol 30 and 60 min after ACTH were 426 and 485 nmol/L (ElecsysCort II) and 411 and 470 nmol/L (LC-MS/MS). Cut-offs were unaffected by gender, or body-composition. The ACTH-test resulted in significantly increased adrenocortical steroid hormones, except for decreased cortisone concentrations (both sexes), and decreased testosterone in men (1.9 nmol/L, 95% CI: 1.3-2.5). Testosterone was increased in women (0.07 nmol/L, 95% CI: 0.02-0.13). CONCLUSION: ElecsysCort II has high analytical performance and yields significantly lower cortisol concentrations than prior polyclonal immunoassays. This clinically relevant difference underscores the necessity for revised cut-off limits for improved diagnostic precision. Suggested 30-minute cortisol cutoff limits are 411 nmol/L (LC-MS/MS) and 426 nmol/L (ElecsysCort II). Adrenocortical steroids increased upon ACTH stimulation, except for cortisone in both sexes and testosterone in men, both of which decreased.

Encounters with public and professional understandings of Down syndrome: A qualitative study of parents' experiences.

BACKGROUND: The meanings of neurodevelopmental conditions are socially and culturally defined. We explored how parents of a child with Down syndrome experienced public and professional understandings of Down syndrome. METHOD: Qualitative interviews with 25 parents of a child with Down syndrome living in Denmark. From a reflexive thematic analysis, we developed themes describing understandings (i.e., attitudes or perceptions) of Down syndrome. RESULTS: The parents experienced that the Down syndrome diagnosis acted as a 'label'; this had perceived positive and negative consequences for the child. The parents felt others understood Down syndrome as severe and undesirable. This attitude was tied to the existence of prenatal screening. Finally, to the parents, professional support for their child expressed an understanding of children with Down syndrome as valued individuals. CONCLUSIONS: Parents encountered ambiguous understandings of Down syndrome. This should be recognised by professionals who may shape such understandings.

Efficacy of intravenous high-dose methotrexate in preventing relapse to the central nervous system in R-CHOP(-like)-treated, high-risk, diffuse large B-cell lymphoma patients and its effect on mortality: a systematic review and meta-analysis.

CNS relapse in patients with diffuse large B-cell lymphoma (DLBCL) carries a dismal prognosis with most clinical guidelines recommending CNS prophylaxis to patients deemed at high risk for CNS relapse. However, results from observational studies investigating the effect of CNS prophylaxis have yielded conflicting results. OBJECTIVES: To evaluate: 1) whether addition of prophylactic intravenous HD-MTX reduces the risk of CNS relapse in high-risk DLBCL patients treated with R-CHOP or similar and 2) whether HD-MTX prophylaxis confers an overall survival benefit, irrespective of CNS relapse. METHODS: A systematic search of MEDLINE/PubMed and EMBASE on DLBCL patients at high risk of CNS relapse treated with R-CHOP or similar receiving HD-MTX as intervention and a comparator arm receiving no prophylaxis and/or IT prophylaxis. Risk of Bias was estimated using the ROBINS-I tool and the quality of the evidence by the GRADE approach. Finally, a meta-analysis based on the systematic review was conducted. RESULTS: A total of 1812 studies were screened. No RCT's were identified. Seven observational studies comprising 1661 patients met inclusion criteria. We found a statistically non-significant relative risk of 0.54 [0.27-1.07, 95% CI] of CNS relapse for patients receiving HD-MTX vs. controls. The meta-analysis investigating mortality demonstrated a relative risk of death of 0.70 [0.44-1.11, 95% CI] for HD-MTX treated vs. controls. The overall risk of bias was adjudged as "serious" and the quality of the evidence was rated as low. CONCLUSION: Our data indicate that HD-MTX does not prevent, or at best, only slightly reduces the risk of CNS relapse and confers no survival benefit.

Preterm Birth Following Active Surveillance vs Loop Excision for Cervical Intraepithelial Neoplasia Grade 2.

Importance: Active surveillance for cervical intraepithelial neoplasia grade 2 (CIN2) is being implemented in many high-income countries due to the association of excisional treatment with preterm birth. However, it is unknown whether active surveillance results in lower risk of preterm birth given that cervical dysplasia itself is associated with higher risk of preterm birth. Objective: To compare the preterm birth risk between women with CIN2 undergoing active surveillance or immediate loop electrosurgical excision procedure (LEEP). Design, Setting, and Participants: This historical population-based cohort study included women with a first-time diagnosis of CIN2 and a subsequent singleton birth from 1998 to 2018 in Denmark. Women with prior CIN grade 3 or greater or LEEP were excluded. Data were collected from 4 Danish health care registries. Analyses were conducted from October 2022 to June 2023. Exposure: Women were categorized into active surveillance (cervical biopsy and/or cytology) or immediate LEEP based on their first cervical sample after CIN2 diagnosis. The active surveillance group was further subdivided based on whether a delayed LEEP was performed within 28 months from CIN2 diagnosis. Main Outcomes and Measures: Risk of preterm birth (<37 + 0 weeks) was assessed and relative risks (RRs) were calculated using modified Poisson regression. Analyses used inverse probability treatment weighting of the propensity scores to adjust for age, parity, calendar year, index cytology, and smoking. Results: A total of 10 537 women with CIN2 and a singleton birth were identified; 4430 (42%) underwent active surveillance and 6107 (58%) were treated with immediate LEEP. For both groups, most were aged 23 to 29 years at CIN2 diagnosis (3125 [70%] and 3907 [64%], respectively). Overall, 869 births (8.2%) were preterm. The risk of preterm birth was comparable between active surveillance and immediate LEEP (RR, 1.03; 95% CI, 0.90-1.18). However, for women undergoing delayed LEEP after active surveillance (1539 of the active surveillance group [35%]), the risk of preterm birth was higher than for women treated with immediate LEEP (RR, 1.29; 95% CI, 1.08-1.55). Conclusions and relevance: In this cohort study of women with CIN2, the risk of preterm birth was comparable between active surveillance and immediate LEEP. However, delayed LEEP was associated with 30% higher risk of preterm birth than immediate LEEP. Thus, risk stratification at CIN2 diagnosis is important to identify women with increased risk of delayed LEEP.

Neutralizing IgG4 antibodies are a biomarker of sustained efficacy after peanut oral immunotherapy.

BACKGROUND: Clinical efficacy of oral immunotherapy (OIT) has been associated with the induction of blocking antibodies, particularly those capable of disrupting IgE-allergen interactions. Previously, we identified mAbs to Ara h 2 and structurally characterized their epitopes. OBJECTIVE: We investigated longitudinal changes during OIT in antibody binding to conformational epitopes and correlated the results with isotype and clinical efficacy. METHODS: We developed an indirect inhibitory ELISA using mAbs to block conformational epitopes on immobilized Ara h 2 from binding to serum immunoglobulins from peanut-allergic patients undergoing OIT. We tested the functional blocking ability of mAbs using passive cutaneous anaphylaxis in mice with humanized FcεRI receptors. RESULTS: Diverse serum IgE recognition of Ara h 2 conformational epitopes are similar before and after OIT. Optimal inhibition of serum IgE occurs with the combination of 2 neutralizing mAbs (nAbs) recognizing epitopes 1.2 and 3, compared to 2 nonneutralizing mAbs (non-nAbs). After OIT, IgG4 nAbs, but not IgG1 or IgG2 nAbs, increased in sustained compared to transient outcomes. Induction of IgG4 nAbs occurs after OIT only in those with sustained efficacy. Murine passive cutaneous anaphylaxis after sensitization with pooled human sera is significantly inhibited by nAbs compared to non-nAbs. CONCLUSIONS: Serum IgE conformational epitope diversity remains unchanged during OIT. However, IgG4 nAbs capable of uniquely disrupting IgE-allergen interactions to prevent effector cell activation are selectively induced in OIT-treated individuals with sustained clinical efficacy. Therefore, the induction of neutralizing IgG4 antibodies to Ara h 2 are clinically relevant biomarkers of durable efficacy in OIT.

Use of medication in pregnancy on the rise: Study on 1.4 million Danish pregnancies from 1998 to 2018.

INTRODUCTION: Maternal demographics have evolved, and more women than ever enter pregnancy with preexisting comorbidity and with potentially complex medication exposure, including polypharmacy (concomitant intake of multiple medications). This study aims to describe the evolution of medication use in pregnancy in Denmark from 1998 to 2018 with special focus on polypharmacy, patterns of use, and underlying demographics. MATERIAL AND METHODS: A Danish nationwide historical registry study based on all clinically recognized pregnancies with a gestation ≥10 weeks between 1998 and 2018. Medication use was estimated by redemption of prescriptions during pregnancy. RESULTS: Among a total of 1 402 327 clinically recognized pregnancies, redemption of at least one prescription medication during pregnancy increased from 56.9% in 1998 to 63.3% in 2018, coinciding with an increased use of polypharmacy (from 24.8% in 1998 to 35.2% in 2018). The prevalence of pregnant women who used medications for chronic conditions increased more than the prevalence of women treated for occasional or short-time conditions. Redemption of one or multiple prescription medications during pregnancy was mostly seen among pregnant women ≥35 years of age. However, pregnant women <25 years old exhibited the largest increase in medication use during the study period. CONCLUSIONS: Medication use in general, and polypharmacy in particular, increased from 1998 to 2008, possibly as the result of an increased prevalence of pregnant women with chronic conditions requiring pharmacological treatment. Notably, a marked maternal age-based discrepancy in usage pattern was observed, highlighting the need for further research in this area. The rise in the prevalence of polypharmacy during pregnancy underscores the need for pharmacovigilance to monitor adverse effects. Future studies should investigate the patterns of polypharmacy and the accompanying maternal and fetal risks.

Heparan sulfate selectively inhibits the collagenase activity of cathepsin K.

Cathepsin K (CtsK) is a cysteine protease with potent collagenase activity. CtsK is highly expressed by bone-resorbing osteoclasts and plays an essential role in resorption of bone matrix. Although CtsK is known to bind heparan sulfate (HS), the structural details of the interaction, and how HS regulates the biological functions of CtsK, remains largely unknown. In this report, we discovered that HS is a multifaceted regulator of the structure and function of CtsK. Structurally, HS forms a highly stable complex with CtsK and induces its dimerization. Co-crystal structures of CtsK with bound HS oligosaccharides reveal the location of the HS binding site and suggest how HS may support dimerization. Functionally, HS plays a dual role in regulating the enzymatic activity of CtsK. While it preserves the peptidase activity of CtsK by stabilizing its active conformation, it inhibits the collagenase activity of CtsK in a sulfation level-dependent manner. These opposing effects can be explained by our finding that the HS binding site is remote from the active site, which allows HS to specifically inhibit the collagenase activity without affecting the peptidase activity. At last, we show that structurally defined HS oligosaccharides effectively block osteoclast resorption of bone in vitro without inhibiting osteoclast differentiation, which suggests that HS-based oligosaccharide might be explored as a new class of selective CtsK inhibitor for many diseases involving exaggerated bone resorption.

DNA polymerase λ Loop1 variant yields unexpected gain-of-function capabilities in nonhomologous end-joining.

DNA polymerases lambda (Polλ) and mu (Polµ) are X-Family polymerases that participate in DNA double-strand break (DSB) repair by the nonhomologous end-joining pathway (NHEJ). Both polymerases direct synthesis from one DSB end, using template derived from a second DSB end. In this way, they promote the NHEJ ligation step and minimize the sequence loss normally associated with this pathway. The two polymerases differ in cognate substrate, as Polλ is preferred when synthesis must be primed from a base-paired DSB end, while Polµ is required when synthesis must be primed from an unpaired DSB end. We generated a Polλ variant (PolλKGET) that retained canonical Polλ activity on a paired end-albeit with reduced incorporation fidelity. We recently discovered that the variant had unexpectedly acquired the activity previously unique to Polµ-synthesis from an unpaired primer terminus. Though the sidechains of the Loop1 region make no contact with the DNA substrate, PolλKGET Loop1 amino acid sequence is surprisingly essential for its unique activity during NHEJ. Taken together, these results underscore that the Loop1 region plays distinct roles in different Family X polymerases.

Feasibility of Constant Work Rate Testing to Detect Exercise-Induced Laryngeal Obstruction.

INTRODUCTION: Exercise-induced laryngeal obstruction (EILO) is a condition in which laryngeal structures inappropriately obstruct the upper airway during exercise. The standard diagnostic test for EILO is the continuous laryngoscopy during exercise (CLE) test, usually performed with an incremental work rate protocol regardless of the nature of the triggering event. Typically, laryngeal obstruction occurs only briefly at the end of an incremental test, near peak work capacity. We aimed to investigate constant work rate (CWR) protocols for CLE testing to expand diagnostic test modalities and improve the understanding of EILO. METHODS: In this prospective, self-controlled feasibility study, 10 patients with EILO performed both an incremental and a CWR CLE test at 70%, 80%, and 90% of maximal exercise capacity. Laryngoscopic video data were recorded and compared, and we evaluated the ability of CWR to reproduce the symptoms and laryngeal obstruction seen in incremental testing. RESULTS: In 70%-90% of cases, CWR testing induced at least the same severity of obstruction as incremental testing and CLE scores remained comparable across test modalities. CWR at 70% allowed observation of laryngeal obstruction for a significantly longer duration than in incremental testing (158 s; 95% confidence interval, 25-291 s; P = 0.027). Dyspnea intensity appeared higher during CWR testing compared with incremental testing. CONCLUSIONS: Submaximal CWR CLE testing is feasible and able to induce EILO equivalent to the standard incremental CLE test. This is the first step toward tailored CLE exercise protocols, and further studies are now needed to establish the utility of CWR in clinical and research settings.

Correction: Migraine and risk of premature myocardial infarction and stroke among men and women: A Danish population-based cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1004238.].

Defining the cross-reactivity between peanut allergens Ara h 2 and Ara h 6 using monoclonal antibodies.

In peanut allergy, Arachis hypogaea 2 (Ara h 2) and Arachis hypogaea 6 (Ara h 6) are two clinically relevant peanut allergens with known structural and sequence homology and demonstrated cross-reactivity. We have previously utilized X-ray crystallography and epitope binning to define the epitopes on Ara h 2. We aimed to quantitatively characterize the cross-reactivity between Ara h 2 and Ara h 6 on a molecular level using human monoclonal antibodies (mAbs) and structural characterization of allergenic epitopes. We utilized mAbs cloned from Ara h 2 positive single B cells isolated from peanut-allergic, oral immunotherapy-treated patients to quantitatively analyze cross-reactivity between recombinant Ara h 2 (rAra h 2) and Ara h 6 (rAra h 6) proteins using biolayer interferometry and indirect inhibitory ELISA. Molecular dynamics simulations assessed time-dependent motions and interactions in the antibody-antigen complexes. Three epitopes-conformational epitopes 1.1 and 3, and the sequential epitope KRELRNL/KRELMNL-are conserved between Ara h 2 and Ara h 6, while two more conformational and three sequential epitopes are not. Overall, mAb affinity was significantly lower to rAra h 6 than it was to rAra h 2. This difference in affinity was primarily due to increased dissociation of the antibodies from rAra h 6, a phenomenon explained by the higher conformational flexibility of the Ara h 6-antibody complexes in comparison to Ara h 2-antibody complexes. Our results further elucidate the cross-reactivity of peanut 2S albumins on a molecular level and support the clinical immunodominance of Ara h 2.