Normal Lung Function and Mortality in World Trade Center Responders and National Health and Nutrition Examination Survey III Participants.

Rationale: Low FEV1 is a biomarker of increased mortality. The association of normal lung function and mortality is not well described. Objectives: To evaluate the FEV1-mortality association among participants with normal lung function. Methods: A total of 10,999 Fire Department of the City of New York (FDNY) responders and 10,901 Third National Health and Nutrition Examination Survey (NHANES III) participants, aged 18-65 years with FEV1 ⩾80% predicted, were analyzed, with FEV1 percent predicted calculated using Global Lung Function Initiative Global race-neutral reference equations. Mortality data were obtained from linkages to the National Death Index. Cox proportional hazards models estimated the association between FEV1 and all-cause mortality, controlling for age, sex, race/ethnicity, smoking history, and, for FDNY, work assignment. Cohorts were followed for a maximum of 20.3 years. Measurements and Main Results: We observed 504 deaths (4.6%) of 10,999 for FDNY and 1,237 deaths (9.4% [weighted]) of 10,901 for NHANES III. Relative to FEV1 ⩾120% predicted, mortality was significantly higher for FEV1 100-109%, 90-99%, and 80-89% predicted in the FDNY cohort. In the NHANES III cohort, mortality was significantly higher for FEV1 90-99% and 80-89% predicted. Each 10% higher predicted FEV1 was associated with 15% (hazard ratio, 0.85; 95% confidence interval, 0.80-0.91) and 23% (hazard ratio, 0.77; 95% confidence interval, 0.71-0.84) lower mortality for FDNY and NHANES III, respectively. Conclusions: In both cohorts, higher FEV1 is associated with lower mortality, suggesting higher FEV1 is a biomarker of better health. These findings demonstrate that a single cross-sectional measurement of FEV1 is predictive of mortality over two decades, even when FEV1 is in the normal range.

Dupilumab in patients with chronic spontaneous urticaria (LIBERTY-CSU CUPID): Two randomized, double-blind, placebo-controlled, phase 3 trials.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a chronic inflammatory disease characterized by recurrent pruritic wheals (hives) and/or angioedema. Patients with CSU could remain symptomatic despite standard-of-care H1 antihistamines (H1-AH) or anti-IgE (omalizumab) treatment. Dupilumab blocks IL-4/IL-13 signaling and is approved for multiple type 2/atopic indications. OBJECTIVE: We conducted two phase 3, randomized, placebo-controlled, double-blind trials comparing dupilumab with placebo in patients with symptomatic CSU despite H1-AH. METHODS: In LIBERTY-CSU CUPID Study A, patients were omalizumab-naive (n = 138, aged ≥6 years). In Study B, patients were omalizumab-intolerant/incomplete responders (n = 108, aged ≥12 years). The primary end point was either change from baseline over 7 days in the Urticaria Activity Score (UAS7) or Itch Severity Score (ISS7) at week 24, with the other as a key secondary end point, depending on regional regulatory requirements. Studies were pooled for safety assessment. RESULTS: In Study A, UAS7 and ISS7 improved with dupilumab versus placebo (difference -8.5 [95% CI, -13.2 to -3.9; P = .0003] and -4.2 [95% CI, -6.6 to -1.8; P = .0005]). In Study B, tested at α = 0.043 after interim analysis, UAS7 improved (difference -5.8 [95% CI, -11.4 to -0.3; P = .0390]), with a numerical trend in ISS7 (difference -2.9 [95% CI, -5.7 to -0.07; nominal P = .0449, not significant]). Pooled safety data were consistent between dupilumab and placebo and with the known dupilumab safety profile. CONCLUSIONS: Dupilumab reduced urticaria activity by reducing itch and hives severity in omalizumab-naive patients with CSU uncontrolled with H1-AH. Although the primary end point for Study B was not met, dupilumab effects were small in patients who were omalizumab-intolerant/incomplete responders.

Does dual oocyte retrieval with continuous FSH administration increase the number of mature oocytes in low responders? An open-label randomized controlled trial.

STUDY QUESTION: Is there an increase in the total number of metaphase II (MII) oocytes between a conventional ovarian stimulation (OS) and a double uninterrupted stimulation? SUMMARY ANSWER: There is no increase in the total number of MII oocytes when comparing one conventional OS to a continuous stimulation with double oocyte aspiration. WHAT IS KNOWN ALREADY: Based on the concept of multiple follicular waves, the combination of two stimulations in the same ovarian cycle has gained interest in patients with a low ovarian reserve. This so-called dual stimulation approach is usually characterized by a discontinuation of FSH administration for ∼5 days and appears to have a favourable impact on the number of retrieved oocytes without affecting the embryo quality or ploidy status. The outcomes of dual uninterrupted OS have not yet been studied. STUDY DESIGN, SIZE, DURATION: This was an open-label randomized controlled trial (RCT) with superiority design, performed in a single tertiary centre. Subjects were randomized with a 1:1 allocation into two groups between October 2019 and September 2021. All patients underwent a conventional stimulation with recombinant FSH. When two or more follicles of 17 mm were present, the final inclusion criterion was assessed; randomization occurred only in the presence of ≤9 follicles of ≥11 mm. In Group A, ovulation was triggered with hCG, and oocyte retrieval (OR) was performed 34-36 h later, followed by a fresh single or double embryo transfer (SET or DET) on Day 3/5. In Group B, ovulation was triggered with GnRH agonist, followed by another OS, without discontinuation of the FSH administration. In the presence of one or more follicles of ≥17 mm, the second stimulation was completed with hCG. A freeze-all strategy (Day 3/5) was applied for both retrievals, followed by transfer of one or two embryos in an artificially prepared frozen-thawed cycle. In the absence of one or more follicles of ≥17 mm after 13 additional days of stimulation, the second cycle was cancelled. All ORs were executed by a senior fertility specialist who was blinded for the first treatment, and all follicles >10 mm were aspirated, according to routine clinical practice. The primary outcome was the total number of MII oocytes. Patients were followed up until all embryos were transferred, or until live birth was achieved. Other secondary outcomes included the number of cumulus-oocyte complexes (COCs), the number of good quality embryos (Day 3/5), the ongoing pregnancy rate, and gonadotropin consumption. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients between 25 and 40 years old, with an anti-Müllerian hormone level of ≤1.5 ng/ml, antral follicle count of ≤6, or ≤5 oocytes after a previous stimulation, were included. At the start, 70 patients were eligible for participation in the trial, of whom 48 patients fulfilled the final inclusion criterium and were randomized. After drop-out of two patients, 23 patients were randomized to a single round of OS (Group A), and 23 patients were randomized to two uninterrupted rounds of OS (Group B). MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were similar between both groups. The cumulative number of COCs and MII oocytes after completion of the second OR was similar in Group A and Group B [5.3 ± 2.7 versus 5.3 ± 3.0 (P = 0.95); 4.1 ± 2.4 versus 4.3 ± 2.7 (P = 0.77)]. Likewise, a comparable number of excellent and good quality embryos was available on Day 3 (3.0 ± 2.0 versus 2.7 ± 2.0; P = 0.63). In Group B, the cancellation rate due to insufficient response to the second round of stimulation was 39.1% (9/23). When focusing on the first stimulation in both groups, there were no significant differences regarding basal FSH, gonadotropin consumption, and the number of preovulatory follicles. After the first OR, the mean number of COC and MII oocytes was significantly higher in Group A (who had hCG triggering), compared to Group B (who had GnRH agonist triggering) [5.3 ± 2.7 versus 3.3 ± 2.2; difference 95% CI (0.54 to 3.45), P = 0.004 and 4.1 ± 2.4 versus 3.0 ± 2.2; difference 95% CI (-0.15 to 2.6), P = 0.05, respectively]. Likewise, the number of excellent and good quality embryos on Day 3 was significantly higher (3.0 ± 2.0 versus 1.9 ± 1.7; P = 0.02) in Group A. LIMITATIONS, REASONS FOR CAUTION: This study was powered to demonstrate superiority for the number of MII oocytes after dual stimulation. Investigating the impact of dual stimulation on pregnancy rates would have required a larger sample size. Furthermore, the heterogeneity in embryo vitrification and transfer policies precluded a correct comparison of embryologic outcomes between both groups. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT investigating the role of continuous stimulation with double aspiration in low responders. Our results show no statistically significant differences in the cumulative number of MII oocytes between one conventional stimulation with fresh ET and two consecutive stimulations with a freeze-only approach. Furthermore, the observed suboptimal oocyte yield after agonist ovulation triggering in low responders in the dual uninterrupted OS group is a reason for concern and further scrutiny, given that previous RCTs have shown similar outcomes in normal and high responders after hCG and GnRH agonist triggers. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by a research grant from Organon. H.T. received honoraria for lectures and presentations from Abbott, Cooper Surgical, Gedeon-Richter, Cook, Goodlife, and Ferring. L.B. received fees for lectures from Merck & Organon and support for attending ESHRE 2023. M.D.V. reports fees for lectures from Ferring, Merck, Organon, IBSA, Gedeon Richter, and Cooper Surgical and support for attending ASRM 2023. S.M. received honoraria for lectures and presentations from Abbott, Cooper Surgical, Gedeon-Richter, IBSA, and Merck. C.B. was on the Advisory board and received consulting fees from Theramex and received honoraria for lectures and presentations from Abbott, Ferring, Gedeon-Richter, IBSA, and Merck. TRIAL REGISTRATION NUMBER: NCT03846544. TRIAL REGISTRATION DATE: 19 February 2019. DATE OF FIRST PATIENT'S ENROLMENT: 28 October 2019.

Double versus single stimulation in young low prognosis patients followed by a fresh embryo transfer: a randomized controlled trial (DUOSTIM-fresh).

STUDY QUESTION: Does double stimulation, followed by a fresh embryo transfer (DUOSTIM fresh) give a higher number of good-quality blastocysts as compared with a single stimulation in young low prognosis patients? SUMMARY ANSWER: Compared to single stimulation, DUOSTIM fresh leads to a significantly higher number of good quality blastocysts, without hindering fresh embryo transfer outcomes. WHAT IS KNOWN ALREADY: DUOSTIM (ovarian stimulation both in the follicular and luteal phase of the same cycle) is an innovative strategy to retrieve a higher number of oocytes in a shorter time frame, thus it is particularly appealing for poor ovarian responders. Three current limitations of dual stimulation are: (i) it is unclear whether outcomes of the second (luteal) wave result from the second stimulation, or a carry-over effect from previous follicular stimulation; (ii) the desynchronization between endometrium and ovaries and, (iii) lack of robust evidence. No previous studies explored DUOSTIM starting from the luteal phase, and with a fresh embryo transfer (DUOSTIM fresh). STUDY DESIGN, SIZE, DURATION: This study is a randomized, controlled, single-center, superiority clinical trial comparing two different ovarian stimulation protocols: a double stimulation cycle versus a single stimulation cycle followed by fresh embryo transfer. The primary outcome was the number of good quality blastocysts obtained, while secondary outcomes included results from fresh embryo transfer (clinical pregnancy, miscarriage). A total of 120 women were enrolled in this study between October 2020 and October 2022, with a 1:1 allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Only young (<40 years old) low prognosis (anti-Müllerian hormone <1.2 ng/ml) patients were recruited in the Reproductive Medicine Department of Dexeus University Hospital. In the investigational group, DUOSTIM fresh, the first stimulation was initiated in the luteal phase (Day 18-21 cycle) followed by a second stimulation 5 days post first oocyte retrieval, initiated in the follicular phase and a fresh embryo transfer of the best blastocyst generated (first or second cycle). The control group performed a follicular phase single stimulation cycle with a fresh embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 107 patients were analyzed, 53 in the investigational (DUOSTIM fresh) and 54 in the control arm (single stimulation). DUOSTIM fresh resulted in a significantly higher number of good quality blastocysts as compared to single stimulation (difference of mean 0.81, 95% CI 0.12-1.49). The mean percentage of cycles with embryo transfer was comparable (62.3% and 51.9%, respectively for double versus single stimulation). No significant differences were found for clinical outcomes following fresh embryo transfer with an ongoing pregnancy rate of 24.5% for DUOSTIM fresh versus 22.2%, for conventional IVF. Of interest comparisons between different stimulation cycles (A: luteal-phase DUOSTIM fresh, B: follicular-phase DUOSTIM fresh, and C: single stimulation) did not demonstrate any significant difference in terms of ovarian response with the mean (SD) number of mature oocytes being (A: 3.3 (2.9), B: 3.4 (3.4), and C: 3.5 (2.9), respectively). LIMITATIONS, REASONS FOR CAUTION: Study sample size was calculated to detect differences on the mean number of good quality blastocysts. Therefore, results for secondary outcomes (embryo transfer rates and clinical pregnancy rates) should be interpreted with caution as exploratory findings that deserve future investigations. WIDER IMPLICATIONS OF THE FINDINGS: Although DUOSTIM fresh results in a higher number of blastocysts as compared with a single stimulation in young low prognosis patients, the decision of performing dual stim should be evaluated with caution, considering that whether this may improve embryo transfers rate and pregnancy outcomes is still unclear. Results on cumulative-live-birth-rate are warranted. STUDY FUNDING/COMPETING INTEREST(S): The study was an investigator-initiated study supported by an unrestricted grant by Organon. N.P.P. has received grants from Merck Serono, Organon, Ferring Pharmaceutical, Theramex, and Besins Healthcare. N.P.P. has received consulting fees from Merck Serono, Organon, Besins Healthcare, and IBSA. N.P.P. has received honoraria for lectures from Merck Serono, Organon, Theramex, Roche Diagnostics, IBSA, Besins Healthcare, and Ferring. A.R. has received Research grants, honoraria for lectures from Merck Serono, MSD/Organon, Ferring Pharmaceuticals, Besins International, IBSA, Guerbet. The other authors declare that there is no conflict of interest to disclose with respect to the content of this article. TRIAL REGISTRATIO NUMBER: NCT04446845. TRIAL REGISTRATION DATE: 25 June 2020. DATE OF FIRST PATIENT'S ENROLMENT: 30 October 2020.

Real-world biologics response and super-response in the International Severe Asthma Registry cohort.

BACKGROUND: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. METHODS: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. RESULTS: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. CONCLUSIONS: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.

Ibuprofen and Other Arylpropionics: The Relevance in Immediate Hypersensitivity Drug Reactions.

BACKGROUND: Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), is the most frequent medication to be involved in hypersensitivity drug reactions (HDRs). Other analgesic/anti-inflammatory drugs in the arylpropionic group are also relevant, albeit to a lesser extent. Ibuprofen is widely consumed by people of all ages, both on medical prescription and over the counter; moreover, it is an organic contaminant of surface waters and foods. While numerous drugs cause HDR, ibuprofen's underlying mechanisms are more intricate and involve both specific immunological and non-immunological mediated reactions. SUMMARY: we concentrate on immediate responses, including urticaria with or without angioedema, anaphylaxis, and angioedema, classifying reactions according to whether they are caused by single or multiple NSAIDs and based on the mechanisms at play. Both groups may experience anaphylaxis, defined as an immediate, severe systemic reaction involving at least two organs, though the frequency and severity can vary. Following this classification, more clinical manifestations can be identified. Diagnosis is partly based on a detailed clinical history, including information about ibuprofen and/or other arylpropionic derivatives involved, the interval between drug intake and symptoms onset, clinical manifestations, number of episodes, and the patient's tolerance or response to other medications - mainly non-chemically related NSAID - both before and after reactions to ibuprofen and/or other arylpropionic drugs. A drug provocation test is frequently necessary to make a diagnosis. KEY MESSAGE: Because ibuprofen is the most widely prescribed NSAID, it is reasonable to assume its role as the leading cause of HDR will only become more important.

Effectiveness of Mepolizumab in Patients with Severe Eosinophilic Asthma with/without Nasal Polyposis: A Real-Life Study.

INTRODUCTION: Asthma is one of the most common chronic diseases and affects around 334 million people worldwide. The estimated prevalence of severe asthma is 3-10% of the asthmatic population. Mepolizumab has demonstrated efficacy in reducing exacerbations, oral corticosteroid use, and improving quality of life, asthma control, and lung function in patients with severe eosinophilic asthma (SEA). Our study aimed to check the response to mepolizumab in a series of severe asthma patients regarding exacerbations, oral corticosteroid use, asthma control, quality of life, and lung function and to compare the response between patients with and without nasal polyps. METHOD: This is a retrospective, multicenter study of RE-ASGRAMUR (Register of Severe Asthma of the Region of Murcia) performed in eight hospitals of the Region of Murcia (Spain) under routine clinical practice conditions. We included patients diagnosed with SEA who completed at least 1 year of treatment with mepolizumab. We analyzed clinical characteristics, drug tolerance, and effectiveness: exacerbations, ACT, miniAQLQ, forced expiratory volume in 1 s (FEV1), and use of oral corticosteroids. We also compared the results between patients with and without nasal polyps. RESULTS: The median of exacerbations before treatment was 3 and decreased to 0 after treatment (mean decrease of 77.4%). The median diary oral prednisone intake was 15 mg before treatment and 5 mg after treatment (mean 56% reduction). We have obtained a significant improvement in other variables: ED visits and hospitalizations, asthma control (ACT), quality of life (miniAQLQ), and lung function (FEV1). Thirty-four out of 70 patients (48.57%) fulfilled the criteria of super-responder, and 17 out of 70 (24.29%) had a complete response. More patients in the group with nasal polyps fulfilled the criteria of super-responder and complete response to mepolizumab. CONCLUSIONS: Mepolizumab is a safe and effective treatment for SEA patients, improving exacerbations, oral corticosteroid intake, asthma control, quality of life, and lung function. In patients with associated nasal polyposis, there is a statistically significant higher proportion of super-responders and complete responders.

Clinical factors associated with unexpected poor or suboptimal response in Poseidon criteria patients.

RESEARCH QUESTION: What clinical factors are associated with 'unexpected' poor or suboptimal responses to IVF ovarian stimulation per POSEIDON's criteria, and which AMH and AFC threshold values distinguish this population? DESIGN: Tri-centre retrospective cohort study (2015-2017) involving first-time IVF and ICSI cycles with conventional ovarian stimulation (≥150 IU/day of FSH). Eligibility criteria included sufficient ovarian reserve markers according to POSEIDON's classification (AMH ≥1.2 ng/ml; AFC ≥5). Ovarian response categories were poor (<4 oocytes), suboptimal (4-9 oocytes) and normal (≥9 oocytes). Primary outcomes included clinical factors associated with an unexpected poor or suboptimal response to conventional ovarian stimulation using logistic regression analyses, and the threshold values of AMH and AFC predicting increased risk of such responses using ROC curves. RESULTS: A total of 7625 patients met the inclusion criteria: 204 (9.3%) were poor and 1998 (90.7%) were suboptimal responders. Logistic regression identified significant clinical predictors for a poor or suboptimal response, including AFC, AMH, total gonadotrophin dose, gonadotrophin type and trigger type (P ≤ 0.02). The ROC curves indicated that AMH 2.87 ng/ml (AUC 0.740) and AFC 12 (AUC 0.826) were the threshold values predicting a poor or suboptimal response; AMH 2.17 ng/ml (AUC 0.741) and AFC 9 (AUC 0.835) predicted a poor response; and AMH 2.97 ng/ml (AUC 0.722) and AFC 12 (AUC 0.801) predicted a suboptimal response. CONCLUSIONS: The threshold values of AMH and AFC predicting 'unexpected' poor or suboptimal response were higher than expected. These findings have critical implications for tailoring IVF stimulation regimens and dosages.

Missingness mechanisms and generalizability of patient reported outcome measures in colorectal cancer survivors - assessing the reasonableness of the "missing completely at random" assumption.

BACKGROUND: Patient-Reported Outcome Measures (PROM) provide important information, however, missing PROM data threaten the interpretability and generalizability of findings by introducing potential bias. This study aims to provide insight into missingness mechanisms and inform future researchers on generalizability and possible methodological solutions to overcome missing PROM data problems during data collection and statistical analyses. METHODS: We identified 10,236 colorectal cancer survivors (CRCs) above 18y, diagnosed between 2014 and 2018 through the Danish Clinical Registries. We invited a random 20% (2,097) to participate in a national survey in May 2023. We distributed reminder e-mails at day 10 and day 20, and compared Initial Responders (response day 0-9), Subsequent Responders (response day 10-28) and Non-responders (no response after 28 days) in demographic and cancer-related characteristics and PROM-scores using linear regression. RESULTS: Of the 2,097 CRCs, 1,188 responded (57%). Of these, 142 (7%) were excluded leaving 1,955 eligible CRCs. 628 (32%) were categorized as initial responders, 418 (21%) as subsequent responders, and 909 (47%) as non-responders. Differences in demographic and cancer-related characteristics between the three groups were minor and PROM-scores only marginally differed between initial and subsequent responders. CONCLUSION: In this study of long-term colorectal cancer survivors, we showed that initial responders, subsequent responders, and non-responders exhibit comparable demographic and cancer-related characteristics. Among respondents, Patient-Reported Outcome Measures were also similar, indicating generalizability. Assuming Patient-Reported Outcome Measures of subsequent responders represent answers by the non-responders (would they be available), it may be reasonable to judge the missingness mechanism as Missing Completely At Random.

Increasing the transplant dose and repeating faecal microbiota transplantation results in the responses of male patients with IBS reaching those of females.

BACKGROUND: Faecal microbiota transplantation (FMT) performed with a proper protocol is a safe treatment for IBS that has high efficacy and durable effects. Females have been reported to respond better than males to FMT. The present study aimed at determining whether increasing the transplant dose or repeating FMT improve the responses of males to FMT. METHODS: This study included 186 IBS patients (131 females and 55 males) who were randomized at a 1:1:1 ratio to receive 90 g of donor faeces once into the large intestine, once into the small intestine or twice into the small intestine. Patients completed five questionnaires that assessed their symptoms and quality of life, and provided faecal samples at baseline and at 3, 6 and 12 months after FMT. The faecal bacterial profile and dysbiosis index were determined using 16S rRNA gene PCR DNA amplification covering variable genes V3-V9. RESULTS: The response rates to FMT at all observation times did not differ significantly between females and males regardless of the transplant administration route or whether it was repeated. Faecal Alistipes levels were higher in females than in males at baseline and increased in both females and males after FMT. In the repeated group, the Alistipes levels did not differ between females and males after FMT. CONCLUSIONS: Increasing the transplant dose and repeating FMT results in the responses of male IBS patients to FMT reaching those of females regardless of the administration route. Alistipes spp. levels appear to play a role in this improvement.www.clinicaltrials.gov (NCT04236843).

"This is it this is our normal" - the voices of family members and first responders experiencing duty-related trauma in Ireland.

BACKGROUND: Compared to other occupational groups, first responders (FR) experience worse mental health outcomes due to duty-related trauma and occupational stressors. Despite their best efforts, they bring this stress home to friends and family. Consequently, FR and their supporters suffer from increased psychosocial difficulties and experience stigma and other barriers to help-seeking. Prior work offers little opportunity for open dialogue and shared understanding of the repercussions of this occupation for all members of the first responder community. In this qualitative study, we aimed to: (i) explore the lived experience of Irish FR and their family members (FM) related to occupational stressors, and (ii) identify opportunities to engage FM with existing organizational supports available for FR. METHODS: Using a community based participatory research (CBPR) approach, we conducted six focus groups involving a total of fourteen participants comprising FR, organizational representatives, and FM. All focus groups were audio recorded, transcribed, and analyzed using reflexive thematic analysis. FINDINGS: FR and FM shared their experiences of both joining and learning to live as members of the FR community in Ireland. Through our analysis, we identified a main theme of 'crossing thresholds', characterizing their transformative learning experiences. This learning experience includes recognizing the consequences of this new role for them as individuals and for their relationships. Participants also shared how they have learned to cope with the consequences of their roles and what they need to better support each other. CONCLUSIONS: FM are often unheard, hidden members of the first responder community in Ireland, highlighting an unmet need for FR organizations to acknowledge FM role in supporting FR and to provide them with the appropriate training and resources required. Training for new recruits needs to move beyond the tokenistic involvement of FM and encourage knowledge sharing among experienced and novice members. Cultural change is required to support help-seeking among FR and foster a sense of peer support and community among families.

Characterization of Codeine Treatment Responders Among Patients with Refractory or Unexplained Chronic Cough: A Prospective Real-World Cohort Study.

PURPOSE: Codeine is a narcotic antitussive often considered for managing patients with refractory or unexplained chronic cough. This study aimed to evaluate the proportion and characteristics of patients who responded to codeine treatment in real-world practice. METHODS: Data from the Korean Chronic Cough Registry, a multicenter prospective cohort study, were analyzed. Physicians assessed the response to codeine based on the timing and degree of improvement after treatment initiation. Follow-up assessments included the Leicester Cough Questionnaire and cough severity visual analog scale at six months. In a subset of subjects, objective cough frequency was evaluated following the initiation of codeine treatment. RESULTS: Of 305 patients, 124 (40.7%) responded to treatments based on anatomic diagnostic protocols, while 181 (59.3%) remained unexplained or refractory to etiological treatments. Fifty-one subjects (16.7%) were classified as codeine treatment responders (those showing a rapid and clear response), 57 (18.7%) as partial responders, and 62 (20.3%) as non-responders. Codeine responders showed rapid improvement in objective cough frequency and severity scores within a week of the treatment. At 6 months, responders showed significantly improved scores in cough scores, compared to non-responders. Several baseline parameters were associated with a more favorable treatment response, including older age, non-productive cough, and the absence of heartburn. CONCLUSIONS: Approximately 60% of chronic cough patients in specialist clinics may require antitussive drugs. While codeine benefits some, only a limited proportion (about 20%) of patients may experience rapid and significant improvement. This underscores the urgent need for new antitussive drugs to address these unmet clinical needs.

Evaluating Airflow Sensor Methods: Precision in Indirect Calorimetry.

This study assesses the impact of three volumetric gas flow measurement methods-turbine (fT); pneumotachograph (fP), and Venturi (fV)-on predictive accuracy and precision of expired gas analysis indirect calorimetry (EGAIC) across varying exercise intensities. Six males (Age: 38 ± 8 year; Height: 178.8 ± 4.2 cm; V ̇ O 2 peak $$ \dot{V}{\mathrm{O}}_2\mathrm{peak} $$ : 42 ± 2.8 mL O2 kg-1 min-1) and 14 females (Age = 44.6 ± 9.6 year; Height = 164.6 ± 6.9 cm; V ̇ O 2 peak $$ \dot{V}{\mathrm{O}}_2\mathrm{peak} $$ = 45 ± 8.6 mL O2 kg-1 min-1) were recruited. Participants completed physical exertion on a stationary cycle ergometer for simultaneous pulmonary minute ventilation ( V ̇ $$ \dot{V} $$ ) measurements and EGAIC computations. Exercise protocols and subsequent conditions involved a 5-min cycling warm-up at 25 W min-1, incremental exercise to exhaustion ( V ̇ O 2 $$ \dot{V}{\mathrm{O}}_2 $$ ramp test), then a steady-state exercise bout induced by a constant Watt load equivalent to 80% ventilatory threshold (80% VT). A linear mixed model revealed that exercise intensity significantly affected V ̇ O 2 $$ \dot{V}{\mathrm{O}}_2 $$ measurements (p < 0.0001), whereas airflow sensor method (p = 0.97) and its interaction with exercise intensity (p = 0.91) did not. Group analysis of precision yielded a V ̇ O 2 $$ \dot{V}{\mathrm{O}}_2 $$ CV % = 21%; SEM = 5 mL O2 kg-1 min-1. Intra- and interindividual analysis of precision via Bland-Altman revealed a 95% confidence interval (CI) precision benchmark of 3-5 mL kg-1 min-1. Agreement among methods decreased at power outputs eliciting V ̇ $$ \dot{V} $$ up to 150 L min-1, indicating a decrease in precision and highlighting potential challenges in interpreting biological variability, training response heterogeneity, and test-retest comparisons. These findings suggest careful consideration of airflow sensor method variance across metabolic cart configurations.

Cross-sectional association between posttraumatic stress and cognition is moderated by pulmonary functioning in world trade center responders.

BACKGROUND: Posttraumatic stress disorder (PTSD) symptomatology and poorer pulmonary function are highly prevalent psychiatric and medical conditions. In the present study, we tested for the individual, additive, and modifying associations of PTSD symptomatology and pulmonary function with cognitive performance. METHODS: In this cross-sectional study, a total of 1,401 World Trade Center (WTC) responders (mean age = 53, SD = 8 years, 92% males) participated in the study. Cogstate assessment measured cognitive performance. PTSD symptomatology was measured using the trauma-specific version of the posttraumatic stress disorder checklist (PCL-17) adapted for the WTC attacks. The 1-second forced expiratory volume and forced vital capacity (FEV1/FVC) ratio was used to measure pulmonary function. Linear regressions with cognitive performance as the outcome were conducted to assess individual, additive, and moderating associations of PTSD symptomatology and pulmonary function. RESULTS: Higher PTSD symptomatology and poorer pulmonary function were negatively associated with cognitive performance. A 10% increase on the FEV1/FVC ratio moderated the association between PTSD symptomatology and cognition, whereby its association with cognition was stronger when PTSD symptomatology was higher (est. = 0.01, 95%CI = 0.004, 0.01, p < 0.001). When stratified by responder type, these associations persisted in trained (est. = 0.01, 95%CI = 0.01, 0.02, p < 0.001), but not in non-trained (est. = 0.004, 95% C.I. = -0.01, 0.02, p = 0.39) responders. CONCLUSIONS: In the presence of higher PTSD, better pulmonary functioning is associated with better cognitive performance. Early intervention efforts to mitigate preventable cognitive decline in high-risk populations should be studied, especially since intervention in one modality may have an impact on others.

"Breaking down in tears, soaked in sweat, and sick from the heat": Media-based composite narratives of first responders working during the 2021 Heat Dome.

BACKGROUND: During the summer of 2021, a deadly, unprecedented multiday Heat Dome engulfed western Canada. As a result of this extreme heat event (EHE), emergency dispatchers received an unparalleled increase in incoming 911 calls for ambulance, police, and fire (as first responders) services to attend to hundreds of heat-vulnerable community members succumbing to the heat. With 103 all-time heat records broken during this EHE and indoor temperatures of nearly 40°C, the first responders attending these calls faced extensive job demands and highly challenging operating conditions. Initial investigations have explored the health system-level impacts; however, little has been done to explore the impact on the first responders themselves. Therefore, this study aimed to improve our understanding of EHEs' impacts on the operational capabilities and health of first responders, specifically police, fire, ambulance, and dispatch services. METHODS: A systematized review and content analysis of media articles published on the 2021 Heat Dome in Canada was conducted (n = 2909), and four media-based composite narratives were developed highlighting police, fire, ambulance, and dispatch services. The Job Demands-Resources (JD-R) model was applied as a theoretical framework for occupational burnout. RESULTS: The media-based composite narratives highlighted that first responders faced record-breaking call volumes, increased mental-health-related claims, and exhaustive heat-related physiological stress. Using the JD-R model as a theoretical framework for occupational burnout, we identified three measures of stressful job demand: work overload (e.g., the surge in call volume, firefighters responding to medical emergencies), emotional demands (e.g., severe medical emergencies, sudden deaths, unresponsive patients, distraught family members), and physical demands (e.g., resuscitation in personal protective equipment, heat-related illness). CONCLUSION: The experiences described underscore the importance of supporting first responders during work in extreme heat conditions. These findings have important implications for addressing rising rates of burnout during and following public health crises, such as EHEs, a problem that is increasingly being recognized as a threat to the Canadian public healthcare system.

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response.

Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.

Exposure to aggression in three contexts of emergency response: A longitudinal examination of the relationship with psychological characteristics of the emergency responder.

Some emergency responders are more often exposed to workplace aggression than others. Victimological theories and previous studies suggest that characteristics of the target may predict exposure to workplace aggression. This paper examines the relationship between negative affect, hostile attribution, dominance, empathy, self-evaluations, and exposure to workplace aggression among emergency responders. Emergency medical workers, firefighters and police officers in the Netherlands filled in a survey during three measurement occasions (6 months apart). Results from the three occupational groups were presented separately. Results suggest that some psychological characteristics are related to exposure to workplace aggression, but that the contribution of these characteristics in the explanation of exposure to workplace aggression is limited. In addition, although differences between occupational groups could not be statistically tested due to differences in the factor structure of exposure to workplace aggression between the three groups of emergency response, differences seem to occur in models between emergency response contexts. Implications and suggestions for future research are discussed.

An evaluation of first responders' intention to refer to post-overdose services following SHIELD training.

BACKGROUND: First responders [law enforcement officers (LEO) and Fire/Emergency Medical Services (EMS)] can play a vital prevention role, connecting overdose survivors to treatment and recovery services. This study was conducted to examine the effect of occupational safety and harm reduction training on first responders' intention to refer overdose survivors to treatment, syringe service, naloxone distribution, social support, and care-coordination services, and whether those intentions differed by first responder profession. METHODS: First responders in Missouri were trained using the Safety and Health Integration in the Enforcement of Laws on Drugs (SHIELD) model. Trainees' intent to refer (ITR) overdose survivors to prevention and supportive services was assessed pre- and post-training (1-5 scale). A mixed model analysis was conducted to assess change in mean ITR scores between pre- and post-training, and between profession type, while adjusting for random effects between individual trainees and baseline characteristics. RESULTS: Between December 2020 and January 2023, 742 first responders completed pre- and post-training surveys. SHIELD training was associated with higher first responders' intentions to refer, with ITR to naloxone distribution (1.83-3.88) and syringe exchange (1.73-3.69) demonstrating the greatest changes, and drug treatment (2.94-3.95) having the least change. There was a significant increase in ITR score from pre- to post-test (ß = 2.15; 95% CI 1.99, 2.30), and LEO-relative to Fire/EMS-had a higher score at pre-test (0.509; 95% CI 0.367, 0.651) but a lower score at post-test (0.148; 95% CI - 0.004, 0.300). CONCLUSION: Training bundling occupational safety with harm reduction content is immediately effective at increasing first responders' intention to connect overdose survivors to community substance use services. When provided with the rationale and instruction to execute referrals, first responders are amenable, and their positive response highlights the opportunity for growth in increasing referral partnerships and collaborations. Further research is necessary to assess the extent to which ITR translates to referral behavior in the field.

Outcomes of adult patients discharged at scene by emergency medical services.

BACKGROUND: The outcomes of patients who call an ambulance but are discharged at scene reflect the safety and quality of emergency medical service (EMS) care. While previous studies have examined the outcomes of patients discharged at scene, none have specifically focused on paramedic-initiated discharge. This study aims to describe the outcomes of adult patients discharged at scene by paramedics and identify factors associated with 72-hour outcomes. METHODS: This was a retrospective data linkage study on consecutive adult EMS patients discharged at scene by paramedics in Victoria, Australia, between 1 January 2015 and 30 June 2019. Multivariable logistic regression was used to investigate factors associated with EMS recontact, ED presentation, hospital admission and serious adverse events (death, cardiac arrest, category 1 triage or intensive care unit admission) within 72 hours of the initial emergency call. RESULTS: There were 375 758 cases of adults discharged at scene following EMS attendance, of which 222 571 (59.2%) were paramedic-initiated decisions. Of these, 6.8% recontacted EMS, 5.0% presented to ED, 2.4% were admitted to hospital and 0.3% had a serious adverse event in the following 72 hours. The odds of EMS recontact were increased in cases related to mental health (adjusted OR (AOR) 1.41 (95% CI 1.33 to 1.49)), among low-income government concession holders (AOR 1.61 (95% CI 1.55 to 1.67)) and in areas of low socioeconomic advantage (AOR 1.19 (95% CI 1.13 to 1.25)). The odds of hospital admission were increased in cases related to infection (AOR 3.14 (95% CI 2.80 to 3.52)) and pain (AOR 1.93 (95% CI 1.75 to 2.14)). The strongest driver of serious adverse events was an abnormal vital sign (AOR 4.81 (95% CI 3.87 to 5.98)). CONCLUSION: The occurrence of hospital admission and adverse events is rare in those discharged at scene, suggesting generally safe decision-making. However, increased attention to elderly, multimorbid patients or patients with infection and pain is recommended, as is further research examining the use of tools to aid paramedic recognition of potential for deterioration.

Seamless Fusion: Multi-Modal Localization for First Responders in Challenging Environments.

In dynamic and unpredictable environments, the precise localization of first responders and rescuers is crucial for effective incident response. This paper introduces a novel approach leveraging three complementary localization modalities: visual-based, Galileo-based, and inertial-based. Each modality contributes uniquely to the final Fusion tool, facilitating seamless indoor and outdoor localization, offering a robust and accurate localization solution without reliance on pre-existing infrastructure, essential for maintaining responder safety and optimizing operational effectiveness. The visual-based localization method utilizes an RGB camera coupled with a modified implementation of the ORB-SLAM2 method, enabling operation with or without prior area scanning. The Galileo-based localization method employs a lightweight prototype equipped with a high-accuracy GNSS receiver board, tailored to meet the specific needs of first responders. The inertial-based localization method utilizes sensor fusion, primarily leveraging smartphone inertial measurement units, to predict and adjust first responders' positions incrementally, compensating for the GPS signal attenuation indoors. A comprehensive validation test involving various environmental conditions was carried out to demonstrate the efficacy of the proposed fused localization tool. Our results show that our proposed solution always provides a location regardless of the conditions (indoors, outdoors, etc.), with an overall mean error of 1.73 m.