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.

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.

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.

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.

Water-soluble microencapsulation using gum Arabic and skim milk enhances viability and efficacy of Pediococcus acidilactici probiotic strains for application in broiler chickens.

Objective: This study aimed to develop and evaluate the effectiveness of a water-soluble microencapsulation method for probiotic strains using gum Arabic (GA) and skim milk (SKM) over a three-month storage period following processing. Methods: Four strains of Pediococcus acidilactici (BYF26, BYF20, BF9, and BF14) that were typical lactic acid bacteria (LAB) isolated from the chicken gut were mixed with different ratios of gum Arabic (GA) and skim milk (SKM) as coating agents before spray drying at an inlet temperature 140°C. After processing, the survivability and probiotic qualities of the strains were assessed from two weeks to three months of storage at varied temperatures, and de-encapsulation was performed to confirm the soluble properties. Finally, the antibacterial activity of the probiotics was assessed under simulated gastrointestinal conditions. Results: As shown by scanning electron microscopy, spray-drying produced a spherical, white-yellow powder. The encapsulation efficacy (EE percent) was greatest for a coating containing a combination of 30% gum Arabic: 30% skim milk (w/v) (GA:SKM30) compared to lower concentrations of the two ingredients (p<0.05). Coating with GA:SKM30 (w/v) significantly enhanced (p<0.05) BYF26 survival under simulated gastrointestinal conditions (pH 2.5-3) and maintained higher survival rates compared to non-encapsulated cells under an artificial intestinal juices (AIJ) condition of pH 6. De-encapsulation tests indicated that the encapsulated powder dissolved in water while keeping viable cell counts within the effective range of 106 for 6 hours. In addition, following three months storage at 4°C, microencapsulation of BYF26 in GA:SKM30 maintained both the number of viable cells (p<0.05) and the preparation's antibacterial efficacy against pathogenic bacteria, specifically strains of Salmonella. Conclusion: Our prototype water-soluble probiotic microencapsulation GA:SKM30 effectively maintains LAB characteristics and survival rates, demonstrating its potential for use in preserving probiotic strains that can be used in chickens and potentially in other livestock.

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.

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.

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.

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.

Is Immunotherapy Beneficial in Patients with Oncogene-Addicted Non-Small Cell Lung Cancers? A Narrative Review.

Over the past 20 years, there has been a paradigm shift in the care of patients with non-small cell lung cancer (NSCLC), who now have a range of systemic treatment options including targeted therapy, chemotherapy, immunotherapy (ICI), and antibody-drug conjugates (ADCs). A proportion of these cancers have single identifiable alterations in oncogenes that drive their proliferation and cancer progression, known as "oncogene-addiction". These "driver alterations" are identified in approximately two thirds of patients with lung adenocarcinomas, via next generation sequencing or other orthogonal tests. It was noted in the early clinical development of ICIs that patients with oncogene-addicted NSCLC may have differential responses to ICI. The toxicity signal for patients with oncogene-addicted NSCLC when treated with ICIs also seemed to differ depending on the alteration present and the specific targeted agent used. Developing a greater understanding of the underlying reasons for these clinical observations has become an important area of research in NSCLC. In this review, we analyze the efficacy and safety of ICI according to specific mutations, and consider possible future directions to mitigate safety concerns and improve the outcomes for patients with oncogene-addicted NSCLC.

Real-World evidence revelations: The potential of patient support programmes to provide data on medication usage.

Patient Support Programmes (PSPs) are used by the pharmaceutical industry to provide education and support to consumers to overcome the challenges they face managing their condition and treatment. Whilst there is an increasing number of PSPs, limited information is available on whether these programmes contribute to safety signals. PSPs do not have a scientific hypothesis, nor are they governed by a protocol. However, by their nature, PSPs inevitably generate adverse event (AE) reports. The main goal of the research was to gather all Novartis-initiated PSPs for sacubitril/valsartan, followed by research in the company safety database to identify all AE reports emanating from these PSPs. Core data sheets (CDS) were reviewed to assess if these PSPs contributed to any new, regulatory-authority approved, validated signals. Overall, AEs entered into the safety database from PSPs confirmed no contribution to CDS updates. Detailed review of real-world data revealed tablet splitting or taking one higher dose tablet a day instead of twice daily. This research, and subsequent analyses, revealed that PSPs did not impact safety label changes for sacubitril/valsartan. It revealed an important finding concerning drug utilisation i.e. splitting of sacubitril/valsartan tablets to reduce cost. This finding suggests that PSPs may contribute important real-world data on patterns of medication usage. There remains a paucity of literature available on this topic, hence further research is required to assess if it would be worth designing PSPs for collecting data on drug utilisation and (lack of) efficacy. Such information from PSPs could be important for all stakeholders.

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.

Giant Response and Selectivity of Hansen Solubility Parameters-Based Graphene-SBS Co-Polymer Matrix Composite Room Temperature Sensor to Organic Vapours.

A styrene-butadiene-styrene co-polymer matrix nanocomposite filled with graphene nanoplatelets was studied to prepare chemiresistive volatile organic compounds (VOCs) room temperature sensors with considerable response and selectivity. Nanofiller concentration was estimated from the electrical conductivity percolation behaviour of the nanocomposite. Fabricated sensors provided selective relative responses to representative VOCs differing by orders of magnitude. Maximum observed average relative responses upon exposure to saturated vapours of the tested VOCs were ca. 23% for ethanol, 1600% for acetone, and the giant values were 9 × 106% for n-heptane and 10 × 106% for toluene. The insensitivity of the sensor to the direct saturated water vapour exposure was verified. Although high humidity decreases the sensor's response, it paradoxically enhances the resolution between hydrocarbons and polar organics. The non-trivial sensing mechanism is explained using the Hansen solubility parameters (HSP), enabling a rational design of new sensors; thus, the HSP-based class of sensors is outlined.

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.].

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.