Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study.

BACKGROUND: A standard of care and optimal duration of therapy have not been established for patients with multiply relapsed or refractory follicular lymphoma. The aim of this study was to evaluate epcoritamab, a novel CD3 × CD20 bispecific antibody, in the third-line and later setting of follicular lymphoma. METHODS: EPCORE NHL-1 is a multicohort, single-arm, phase 1-2 trial conducted at 88 sites across 15 countries. Here, we report the primary analysis of patients with relapsed or refractory follicular lymphoma in the phase 2 part of the trial, which included the pivotal (dose expansion) cohort and the cycle 1 optimisation cohort. Eligible patients were aged 18 years or older, had relapsed or refractory CD20+ follicular lymphoma (grade 1-3A), an Eastern Cooperative Oncology Group performance status of up to 2, and had received at least two previous lines of therapy (including an anti-CD20 monoclonal antibody and an alkylating agent or lenalidomide). Patients were treated with subcutaneous epcoritamab 48 mg in 28-day cycles: weekly in cycles 1-3, biweekly in cycles 4-9, and every 4 weeks until disease progression or unacceptable toxicity. To mitigate the risk and severity of cytokine release syndrome, in the pivotal cohort, cycle 1 consisted of a step-up dosing regimen of a 0·16-mg priming dose on day 1 and a 0·80-mg intermediate dose on day 8, followed by subsequent 48-mg full doses and prophylactic prednisolone 100 mg; in the cycle 1 optimisation cohort, a second intermediate dose of 3 mg on day 15, adequate hydration, and prophylactic dexamethasone 15 mg were evaluated during cycle 1 to further reduce risk and severity of cytokine release syndrome. Primary endpoints were independently reviewed overall response rate for the pivotal cohort and the proportion of patients with grade 2 or worse and any-grade cytokine release syndrome for the cycle 1 optimisation cohort. Analyses were done in all enrolled patients who had received at least one dose of epcoritamab. This study is registered with ClinicalTrials.gov, NCT03625037, and is ongoing. FINDINGS: Between June 19, 2020, and April 21, 2023, 128 patients (median age 65 years [IQR 55-72]; 49 [38%] female and 79 [62%] male) were enrolled and treated in the pivotal cohort (median follow-up 17·4 months [IQR 9·1-20·9]). The overall response rate was 82·0% (105 of 128 patients; 95% CI 74·3-88·3), with a complete response rate of 62·5% (80 of 128; 95% CI 53·5-70·9). The most common grade 3-4 treatment-emergent adverse event was neutropenia in 32 (25%) of 128 patients. Grade 1-2 cytokine release syndrome was reported in 83 (65%) of 128 patients; grade 3 cytokine release syndrome was reported in two (2%). Immune effector cell-associated neurotoxicity syndrome was reported in eight (6%) of 128 patients (five [4%] grade 1; three [2%] grade 2). Between Oct 25, 2022, and Jan 8, 2024, 86 patients (median age 64 years [55-71]; 37 [43%] female and 49 [57%] male) were enrolled and treated in the cycle 1 optimisation cohort. The incidence of cytokine release syndrome was 49% (42 of 86 patients; eight [9%] grade 2; none of grade 3 or worse), with no reported immune effector cell-associated neurotoxicity syndrome. INTERPRETATION: Epcoritamab monotherapy showed clinically meaningful activity in patients with multiply relapsed or refractory follicular lymphoma, and had a manageable safety profile. FUNDING: Genmab and AbbVie.

Patient Preferences for Treatment in Relapsed/Refractory Acute Leukemia in the United Kingdom: A Discrete Choice Experiment.

Background: Acute leukemia is a cancer of the white blood cells which progresses rapidly and aggressively. There are two types: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The latter has a rare subtype: acute promyelocytic leukemia (APL). For some patients, following first-line treatment, remission is not achieved ("refractory disease"), and for others the leukemia returns after achieving remission ("relapse"). For these individuals, outcomes are typically poor. It is, therefore, important to understand patients' treatment priorities in this context. Methods: Building upon formative qualitative research, an online survey containing a discrete choice experiment (DCE) was designed to explore patients' treatment preferences in the relapsed/refractory setting. The DCE attributes were mode of administration; quality of life during treatment; chance of response; duration of response; and quality of life during response. Each respondent completed twelve scenarios containing two hypothetical treatments. Participants were eligible if they lived in the United Kingdom and had a diagnosis of acute leukemia. The data were analysed using a latent class model. Results: A total of 95 patients completed the survey. The latent class analysis identified two classes. For both, chance of response was the most important attribute. For class 1, every attribute was important, whereas for class 2, the only important attributes were quality of life (during treatment and response) and chance of response. A greater proportion of respondents would fall into class 1 overall, and those with ALL or APL and those more recently diagnosed were more likely to be in class 2. Conclusion: Our results indicate that patients are strongly concerned about the chance of response, as well as quality of life (to a lesser extent), when faced with different treatment options in the relapsed/refractory setting. However, there is significant preference heterogeneity within the patient population, and other treatment characteristics also matter to many.

Oxytocin Receptors on Calvarial Periosteal Innervation: Therapeutic Target for Post-Traumatic Headache?

OBJECTIVE: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)-a densely innervated tissue layer covering the calvarial skull-has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH. METHODS: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia. RESULTS: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model-an effect that was preventable by the administration of an OTR antagonist. CONCLUSION: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.

Views of emergency care providers in providing healthcare for asylum seekers and refugees.

BACKGROUND: The number of asylum seekers awaiting decisions on their claims in the UK has more than tripled since 2014. How we meet international obligations to provide appropriate healthcare to asylum seekers and refugees (ASRs) is therefore an increasingly important issue. The views of frontline healthcare workers are vital to ensure the development of sustainable and effective health policy when it comes to caring for this group. METHOD: A single-centre qualitative study in the form of semistructured interviews was conducted at the Queen Elizabeth University Hospital ED in Glasgow, Scotland, between January and March 2023. Volunteering ED care providers (EDCPs)-doctors and nurses-working in the ED were interviewed and the data analysed and presented through a thematic analytical framework. RESULTS: 12 semistructured interviews were conducted-6 doctors and 6 nurses. Analysis revealed four themes: (1) 'staff attitudes' highlighted in particular the positive views of the participants in providing care for ASRs; (2) 'presentation patterns' revealed significant variations in opinion, with one-third of participants, for example, believing there was no difference in presentations compared with the general population; (3) 'challenges to optimal care' outlines multiple subthemes which impact care including the unique challenge of the ED triage system; and (4) 'transition in care' discusses participant concerns regarding arranging safe and appropriate follow-up for ASR patients. Ethical dilemmas in providing care, as highlighted in previous studies, did not feature heavily in discussions in this study. CONCLUSION: This study provides an insight into the views of EDCPs in providing care to ASRs in the ED. Study findings can potentially contribute to the development of ED-specific guidelines as well as inform wider health policy and provide a focus and direction for further research.

Surface-normal illuminated pseudo-planar Ge-on-Si avalanche photodiodes with high gain and low noise.

Germanium-on-Silicon (Ge-on-Si) avalanche photodiodes (APDs) are of considerable interest as low intensity light detectors for emerging applications. The Ge absorption layer detects light at wavelengths up to ≈ 1600 nm with the Si acting as an avalanche medium, providing high gain with low excess avalanche noise. Such APDs are typically used in waveguide configurations as growing a sufficiently thick Ge absorbing layer is challenging. Here, we report on a new vertically illuminated pseudo-planar Ge-on-Si APD design utilizing a 2 µm thick Ge absorber and a 1.4 µm thick Si multiplication region. At a wavelength of 1550 nm, 50 µm diameter devices show a responsivity of 0.41 A/W at unity gain, a maximum avalanche gain of 101 and an excess noise factor of 3.1 at a gain of 20. This excess noise factor represents a record low noise for all configurations of Ge-on-Si APDs. These APDs can be inexpensively manufactured and have potential integration in silicon photonic platforms allowing use in a variety of applications requiring high-sensitivity detectors at wavelengths around 1550 nm.

A Longer Life or a Quality Death? A Discrete Choice Experiment to Estimate the Relative Importance of Different Aspects of End-of-Life Care in the United Kingdom.

Background. Advocates argue that end-of-life (EOL) care is systematically disadvantaged by the quality-adjusted life-year (QALY) framework. By definition, EOL care is short duration and not primarily intended to extend survival; therefore, it may be inappropriate to value a time element. The QALY also neglects nonhealth dimensions such as dignity, control, and family relations, which may be more important at EOL. Together, these suggest the QALY may be a flawed measure of the value of EOL care. To test these arguments, we administered a stated preference survey in a UK-representative public sample. Methods. We designed a discrete choice experiment (DCE) to understand public preferences over different EOL scenarios, focusing on the relative importance of survival, conventional health dimensions (especially physical symptoms and anxiety), and nonhealth dimensions such as family relations, dignity, and sense of control. We used latent class analysis to understand preference heterogeneity. Results. A 4-class latent class multinomial logit model had the best fit and illustrated important heterogeneity. A small class of respondents strongly prioritized survival, whereas most respondents gave relatively little weight to survival and, generally speaking, prioritized nonhealth aspects. Conclusions. This DCE illustrates important heterogeneity in preferences within UK respondents. Despite some preferences for core elements of the QALY, we suggest that most respondents favored what has been called "a good death" over maximizing survival and find that respondents tended to prioritize nonhealth over conventional health aspects of quality. Together, this appears to support arguments that the QALY is a poor measure of the value of EOL care. We recommend moving away from health-related quality of life and toward a more holistic perspective on well-being in assessing EOL and other interventions. Highlights: Advocates argue that some interventions, including but not limited to end-of-life (EOL) care, are valued by patients and the public but are systematically disadvantaged by the quality-adjusted life-year (QALY) framework, leading to an unfair and inefficient allocation of health care resources.Using a discrete choice experiment, we find some support for this argument. Only a small proportion of public respondents prioritized survival in EOL scenarios, and most prioritized nonhealth aspects such as dignity and family relations.Together, these results suggest that the QALY may be a poor measure of the value of EOL care, as it neglects nonhealth aspects of quality and well-being that appear to be important to people in hypothetical EOL scenarios.

Defining futile and potentially avoidable interhospital trauma transfers.

PURPOSE: Interhospital transfer of critically injured patients to a major trauma service reduces preventable death in major trauma. Yet some of those transferred die without intervention. These 'futile' interhospital trauma transfers (IHTs), and other potentially avoidable IHTs place enormous stress on families of trauma victims, can delay care, and incur great cost to public health resources. This study sought to characterise these IHTs using current state guidelines for interhospital transfer. METHODS: A retrospective cohort study was conducted using our institution's trauma registry from January 2016-December 2020. All adult patients transferred to our major trauma service were analysed. Futile IHTs were defined as death or transfer to hospice care without surgical, endoscopic, or radiological intervention, and without ICU admission, within 72 h of admission. Potentially avoidable IHTs were defined as all patients discharged alive without intervention or ICU care, and secondary over-triage patients are a subset of these patients who were discharged within 72 h of admission. Patient demographics, injuries, and treatments were categorised from electronic records and analysed. RESULTS: Of 2,837 IHTs, seven (0.2 %) met criteria for futility. The majority were female, median age of 80 (IQR 85-75) and had a median Injury Severity Score (ISS) of 16 (IQR 25.5-11.5). By contrast, 1391 patients (49 %) were classified as potentially avoidable and 513 (18 %) were considered secondary over-triage. The majority were male, median age of 43 (IQR 62-28), and had a median ISS of 9 (IQR 13-4). Of these potentially avoidable IHTs, 984 (70.7 %) were discharged directly home. CONCLUSION: Futile IHTs were infrequent, however over half of all trauma patients transferred from other hospitals were discharged without tertiary-level intervention. Trauma services should consider developing systems such as telehealth to support regional general and orthopaedic surgeons to co-manage lower risk trauma, particularly minor head and minor spinal trauma patients. This could be an integral part of safely reducing potentially avoidable IHTs and their associated costs while maintaining a low rate of preventable mortality in trauma.

Association between socioeconomic deprivation and bone health status in the UK biobank cohort participants.

The effect of deprivation on total bone health status has not been well defined. We examined the relationship between socioeconomic deprivation and poor bone health and falls and we found a significant association. The finding could be beneficial for current public health strategies to minimise disparities in bone health. PURPOSE: Socioeconomic deprivation is associated with many illnesses including increased fracture incidence in older people. However, the effect of deprivation on total bone health status has not been well defined. To examine the relationship between socioeconomic deprivation and poor bone health and falls, we conducted a cross-sectional study using baseline measures from the United Kingdom (UK) Biobank cohort comprising 502,682 participants aged 40-69 years at recruitment during 2006-2010. METHOD: We examined four outcomes: 1) low bone mineral density/osteopenia, 2) fall in last year, 3) fracture in the last five years, and 4) fracture from a simple fall in the last five years. To measure socioeconomic deprivation, we used the Townsend index of the participant's residential postcode. RESULTS: At baseline, 29% of participants had low bone density (T-score of heel < -1 standard deviation), 20% reported a fall in the previous year, and 10% reported a fracture in the previous five years. Among participants experiencing a fracture, 60% reported the cause as a simple fall. In the multivariable logistic regression model after controlling for other covariates, the odds of a fall, fracture in the last five years, fractures from simple fall, and osteopenia were respectively 1.46 times (95% confidence interval [CI] 1.42-1.49), 1.26 times (95% CI 1.22-1.30), 1.31 times (95% CI 1.26-1.36) and 1.16 times (95% CI 1.13-1.19) higher for the most deprived compared with the least deprived quantile. CONCLUSION: Socioeconomic deprivation was significantly associated with poor bone health and falls. This research could be beneficial to minimise social disparities in bone health.

A right to health-based approach to dental caries: towards a comprehensive control strategy.

BACKGROUND: Health is a matter of human rights and dental caries is the most common non-communicable disease (NCD) globally. Consequently, dental caries is a matter of human rights and its control, particularly prevention, must be a priority. Although largely preventable, this is too often neglected, both in the literature of human rights- and health law, and in dental research. The right to oral health has recently been acknowledged by the World Health Organization (WHO), but it is insufficiently clear what this right entails. SUMMARY: This article introduces a right to health-based narrative in the context of dental caries. The right to health is stipulated in human rights treaties, including the International Covenant on Economic, Social and Cultural Rights (ICESCR) and the Convention on the Rights of the Child (CRC). States that are Parties to these treaties, which are virtually all States globally, are mandated to ensure the enjoyment of individuals' right to the highest attainable standard of health, including oral health. KEY MESSAGES: Dental caries is a matter of human rights. States have binding obligations to address dental caries: they require the regulation of the healthcare system, i.e. the traditional focus on operative care, but also put the regulation of other risk factors on an equal footing, such as the regulation of the living environment and access to fluoride. A right to health-based approach to dental caries thus offers a comprehensive approach to dental caries control, particularly prevention.

Improving usual care outcomes in major depression in youth by targeting memory specificity: A randomized controlled trial of adjunct computerized memory specificity training (c-MeST).

OBJECTIVE: Extending on previous findings that computerized Memory Specificity Training (c-MeST) improves memory specificity and depressive symptoms in Major Depressive Disorder (MDD) in adults, this study aimed to assess the effects of c-MeST in youth with MDD on memory specificity and depression in addition to other treatment. METHODS: Participants aged 15-25 (N = 359, 76 % female; M age = 19.2, SD = 3.1), receiving predominantly psychological therapy or counseling (85 %) and/or antidepressants (52 %) were randomized to usual care and c-MeST or usual care. Cognitive and clinical outcomes were assessed at baseline and at one, three, and six-month follow-ups. RESULTS: The usual care and c-MeST group reported higher memory specificity at one-month (d = 0.42, p = .022), but not at three or six months (d's < 0.15, p's > 0.05). The rate of MDE was numerically lower in the c-MeST group at each follow-up time-point, but group was not a statistically significant predictor at one month (64 % usual care and c-MeST vs. 68 % usual care, OR = 0.81, p = .606), three months (67 % usual care and c-MeST vs. 72 % usual care, OR = 0.64, p = .327) or six months (55 % usual care and c-MeST vs. 68 % usual care, OR = 0.56, p = .266). The usual care and c-MeST group did report lower depressive symptoms at one month (d = 0.42, p = .023) and six-months (d = 0.84, p = .001), but not three-months (d = 0.13, p > .05). CONCLUSIONS: c-MeST may reduce symptoms in youth with MDD when provided alongside other treatments. However, there are significant limitations to this inference, including high attrition in the study and a need for more data on the acceptability of the intervention.

Morphological and electrophysiological characterization of a novel displaced astrocyte in the mouse retina.

Astrocytes throughout the central nervous system are heterogeneous in both structure and function. This diversity leads to tissue-specific specialization where morphology is adapted to the surrounding neuronal circuitry, as seen in Bergman glia of the cerebellum and Müller glia of the retina. Because morphology can be a differentiating factor for cellular classification, we recently developed a mouse where glial-fibrillary acidic protein (GFAP)-expressing cells stochastically label for full membranous morphology. Here we utilize this tool to investigate whether morphological and electrophysiological features separate types of mouse retinal astrocytes. In this work, we report on a novel glial population found in the inner plexiform layer and ganglion cell layer which expresses the canonical astrocyte markers GFAP, S100ß, connexin-43, Sox2 and Sox9. Apart from their retinal layer localization, these cells are unique in their radial distribution. They are notably absent from the mid-retina but are heavily concentrated near the optic nerve head, and to a lesser degree the peripheral retina. Additionally, their morphology is distinct from both nerve fiber layer astrocytes and Müller glia, appearing more similar to amacrine cells. Despite this structural similarity, these cells lack protein expression of common neuronal markers. Additionally, they do not exhibit action potentials, but rather resemble astrocytes and Müller glia in their small amplitude, graded depolarization to both light onset and offset. Their structure, protein expression, physiology, and intercellular connections suggest that these cells are astrocytic, displaced from their counterparts in the nerve fiber layer. As such, we refer to these cells as displaced retinal astrocytes.

Reducing the harms of alcohol: nutritional interventions and functional alcohol alternatives.

The health risks and harm associated with regular alcohol consumption are well documented. In a recent WHO statement published in The Lancet Public Health alcohol consumption has been estimated to contribute worldwide to 3 million deaths in 2016 while also being responsible for 5·1% of the global burden of disease and injury. The total elimination of alcohol consumption, which has been long imbedded in human culture and society, is not practical and prohibition policies have proved historically ineffective. However, valuable strategies to reduce alcohol harms are already available and improved alternative approaches are currently being developed. Here, we will review and discuss recent advances on two main types of approaches, that is nutritional interventions and functional alcohol alternatives.

Sensitivity analysis of paediatric knee kinematics to the graft surgical parameters during anterior cruciate ligament reconstruction: A sequentially linked neuromusculoskeletal-finite element analysis.

BACKGROUND AND OBJECTIVE: Incidence of paediatric anterior cruciate ligament (ACL) rupture has increased substantially over recent decades. Following ACL rupture, ACL reconstruction (ACLR) surgery is typically performed to restore passive knee stability. This surgery involves replacing the failed ACL with a graft, however, surgeons must select from range of surgical parameters (e.g., type, size, insertion, and pre-tension) with no robust evidence guiding these decisions. This study presents a systemmatic computational approach to study effects of surgical parameter variation on kinematics of paediatric knees. METHODS: This study used sequentially-linked neuromusculoskeletal (NMSK) finite element (FE) models of three paediatric knees to estimate the: (i) sensitivity of post-operative knee kinematics to four surgical parameters (type, size, insertion, and pre-tension) through multi-input multi-output sensitivity analysis; (ii) influence of motion and loading conditions throughout stance phase of walking gait on sensitivity indices; and (iii) influence of subject-specific anatomy (i.e., knee size) on sensitivivty indices. A previously validated FE model of the intact knee for each subject served as a reference against which ACLR knee kinematics were compared. RESULTS: Sensitivity analyses revealed significant influences of surgical parameters on ACLR knee kinematics, albeit without discernible trend favouring any one parameter. Graft size and pre-tension were primary drivers of variation in knee translations and rotations, however, their effects fluctuated across stance indicating motion and loading conditions affect system sensitivity to surgical parameters. Importantly, the sensitivity of knee kinematics to surgical parameter varied across subjects, indicating geometry (i.e., knee size) influenced system sensitivity. Notably, alterations in graft parameters yielded substantial effects on kinematics (normalized root-mean-square-error > 10 %) compared to intact knee models, indicating surgical parameters vary post-operative knee kinematics. CONCLUSIONS: Overall, this initial study highlights the importance of surgical parameter selection on post-operative kinematics in the paediatric ACLR knee, and provides evidence of the need for personalized surgical planning to ultimately enhance patient outcomes.

Technical and clinical considerations of a physical liver phantom for CT radiomics analysis.

OBJECTIVE: This study identifies key characteristics to help build a physical liver computed tomography (CT) phantom for radiomics harmonization; particularly, the higher-order texture metrics. MATERIALS AND METHODS: CT scans of a radiomics phantom comprising of 18 novel 3D printed inserts with varying size, shape, and material combinations were acquired on a 64-slice CT scanner (Brilliance 64, Philips Healthcare). The images were acquired at 120 kV, 250 mAs, CTDIvol of 16.36 mGy, 2 mm slice thickness, and iterative noise-reduction reconstruction (iDose, Philips Healthcare, Andover, MA). Radiomics analysis was performed using the Cancer Imaging Phenomics Toolkit (CaPTk), following automated segmentation of 3D regions of interest (ROI) of the 18 inserts. The findings were compared to three additional ROI obtained of an anthropomorphic liver phantom, a patient liver CT scan, and a water phantom, at comparable imaging settings. Percentage difference in radiomic metrics values between phantom and tissue was used to assess the biological equivalency and <10% was used to claim equivalent. RESULTS: The HU for all 18 ROI from the phantom ranged from -30 to 120 which is within clinically observed HU range of the liver, showing that our phantom material (T3-6B) is representative of biological CT tissue densities (liver) with >50% radiomic features having <10% difference from liver tissue. Based on the assessment of the Neighborhood Gray Tone Difference Matrix (NGTDM) metrics it is evident that the water phantom ROI show extreme values compared to the ROIs from the phantom. This result may further reinforce the difference between a structureless quantity such as water HU values and tissue HU values found in liver. CONCLUSION: The 3-D printed patterns of the constructed radiomics phantom cover a wide span of liver tissue textures seen in CT images. Using our results, texture metrics can be selectively harmonized to establish clinically relevant and reliable radiomics panels.

Identification of allergens from Aspergillus fumigatus-Potential association with lung damage in asthma.

BACKGROUND: Component-resolved diagnosis allows detection of IgE sensitization having the advantage of reproducibility and standardization compared to crude extracts. The main disadvantage of the traditional allergen identification methods, 1- or 2-dimensional western blotting and screening of expression cDNA libraries with patients' IgEs, is that the native structure of the protein is not necessarily maintained. METHODS: We used a novel immunoprecipitation technique in combination with mass spectrometry to identify new allergens of Aspergillus fumigatus. Magnetic Dynabeads coupled with anti-human IgE antibodies were used to purify human serum IgE and subsequently allergens from A. fumigatus protein extract. RESULTS: Of the 184 proteins detected by subsequent mass peptide fingerprinting, a subset of 13 were recombinantly expressed and purified. In a panel of 52 A. fumigatus-sensitized people with asthma, 23 non-fungal-sensitized asthmatics and 18 healthy individuals, only the former showed an IgE reaction by immunoblotting and/or ELISA. We discovered 11 proteins not yet described as A. fumigatus allergens, with fructose-bisphosphate aldolase class II (FBA2) (33%), NAD-dependent malate dehydrogenase (31%) and Cu/Zn superoxide dismutase (27%) being the most prevalent. With respect to these three allergens, native versus denatured protein assays indicated a better recognition of the native proteins. Seven of 11 allergens fulfilled the WHO/IUIS criteria and were accepted as new A. fumigatus allergens. CONCLUSION: In conclusion, we introduce a straightforward method of allergen identification from complex allergenic sources such as A. fumigatus by immunoprecipitation combined with mass spectrometry, which has the advantage over traditional methods of identifying allergens by maintaining the structure of the proteins.

Corrigendum: Study protocol for a randomized controlled trial of the RASPERA project: recalling and anticipating specific positive events to boost resilience in adolescents.

[This corrects the article DOI: 10.3389/fpubh.2023.1216988.].

Corrigendum: Study protocol for a randomized controlled trial of the RASPERA project: recalling and anticipating specific positive events to boost resilience in adolescents.

[This corrects the article DOI: 10.3389/fpubh.2023.1216988.].

Clinical consequences of infliximab immunogenicity and the effect of proactive therapeutic drug monitoring: exploratory analyses of the randomised, controlled NOR-DRUM trials.

BACKGROUND: Antidrug antibodies to TNF inhibitors might affect clinical outcomes. Proactive therapeutic drug monitoring allows for early detection of antidrug antibodies and might reduce negative clinical consequences. We aimed to explore how antidrug antibodies to the TNF inhibitor infliximab influence treatment outcomes, and to assess the effect of proactive therapeutic drug monitoring. METHODS: This was a predefined exploratory analysis of data from the randomised, controlled NOR-DRUM trials. The trials were conducted in rheumatology, gastroenterology, and dermatology departments at 21 Norwegian hospitals. Adult patients (aged 18-75 years) with immune-mediated inflammatory diseases were randomly assigned to proactive therapeutic drug monitoring or standard infliximab dosing in the NOR-DRUM A trial (30-week follow-up) and the NOR-DRUM B trial (52-week follow-up). Antidrug antibodies were assessed with a drug-sensitive assay before each infusion. The outcomes of remission (at week 30), disease worsening (during 52 weeks), infusion reactions, and infliximab discontinuation were assessed according to the presence of antidrug antibodies and use of therapeutic drug monitoring. FINDINGS: Between March 1, 2017, and Dec 12, 2019, 616 patients were included in the NOR-DRUM trials, of whom 615 had at least one serum infliximab and antidrug antibody assessment and were included in the present analyses. Mean age was 45 years (IQR 32-56), 305 (50%) patients were women, and 310 (50%) patients were men. Antidrug antibodies were detected in 147 (24%) patients. Remission at week 30 occurred in 25 (35%) of 72 patients with antidrug antibodies and 180 (54%) of 335 without antidrug antibodies (risk ratio 0·62 [95% CI 0·45-0·86]; p=0·0037). In patients with antidrug antibodies compared with patients without antidrug antibodies, higher rates were found for: disease worsening over 52 weeks (0·76 per person-year vs 0· 35 per person-year, hazard ratio [HR] 2·02 [95% CI 1·33-3·07]; p=0·0009), infusion reactions (0·16 per person-year vs 0·03 per person-year, HR 17·02 [6·98-41·47]; p<0·0001), and infliximab discontinuation (1·00 per person-year vs 0·20 per person-year, HR 6·64 [4·84-9·11]; p<0·0001). These associations were more pronounced in patients with high concentrations of antidrug antibodies than in those with low concentrations of antidrug antibodies. Independent of antibody status, therapeutic drug monitoring was associated with a lower risk of disease worsening (HR 0·41 [0·29-0·59]; p=0·0001) or an infusion reaction (HR 0·30 [0·12-0·73]; p=0·0076), and was associated with an increase in the rate of infliximab discontinuation (HR 1·37 [1·02-1·83]; p=0·037). INTERPRETATION: In patients where antidrug antibodies were detected, remission was less likely to be reached and sustained, and infusion reaction or discontinuation of infliximab was more likely. Timely detection of antidrug antibodies by proactive therapeutic drug monitoring facilitated treatment decisions that reduced the negative consequences, both regarding infliximab effectiveness and safety. This highlights the role of proactive therapeutic drug monitoring in optimising infliximab therapy. FUNDING: Inter-regional KLINBEFORSK grants and South-Eastern Norway Regional Health Authority grants.

Sagittal plane knee kinematics can be measured during activities of daily living following total knee arthroplasty with two IMU.

Knee function is rarely measured objectively during functional tasks following total knee arthroplasty. Inertial measurement units (IMU) can measure knee kinematics and range of motion (ROM) during dynamic activities and offer an easy-to-use system for knee function assessment post total knee arthroplasty. However, IMU must be validated against gold standard three-dimensional optical motion capture systems (OMC) across a range of tasks if they are to see widespread uptake. We computed knee rotations and ROM from commercial IMU sensor measurements during walking, squatting, sit-to-stand, stair ascent, and stair descent in 21 patients one-year post total knee arthroplasty using two methods: direct computation using segment orientations (r_IMU), and an IMU-driven iCloud-based interactive lower limb model (m_IMU). This cross-sectional study compared computed knee angles and ROM to a gold-standard OMC and inverse kinematics method using Pearson's correlation coefficient (R) and root-mean-square-differences (RMSD). The r_IMU and m_IMU methods estimated sagittal plane knee angles with excellent correlation (>0.95) compared to OMC for walking, squatting, sit-to-stand, and stair-ascent, and very good correlation (>0.90) for stair descent. For squatting, sit-to-stand, and walking, the mean RMSD for r_IMU and m_IMU compared to OMC were <4 degrees, < 5 degrees, and <6 degrees, respectively but higher for stair ascent and descent (~12 degrees). Frontal and transverse plane knee kinematics estimated using r_IMU and m_IMU showed poor to moderate correlation compared to OMC. There were no differences in ROM measurements during squatting, sit-to-stand, and walking across the two methods. Thus, IMUs can measure sagittal plane knee angles and ROM with high accuracy for a variety of tasks and may be a useful in-clinic tool for objective assessment of knee function following total knee arthroplasty.