Logotyp: till Uppsala universitets webbplats

Background

Postpartum depression affects around 12% of mothers in developed countries, with consequences for the whole family. Many women with depressive symptoms remain undetected and untreated. The aim of this study was to investigate to what extent women with depressive symptoms at 6 weeks postpartum are identified by the healthcare system, the interventions they received, and remission rates at 6 months postpartum.

Methods

Postpartum women scoring 12–30 on the Edinburgh Postnatal Depression Scale (EPDS) at 6 weeks after delivery (n = 697) were identified from the longitudinal cohort study “Biology, Affect, Stress, Imaging and Cognition” (BASIC) in Uppsala, Sweden. A total of 593 women were included. Background and remission information at 6 months was collected from the BASIC dataset. Medical records were examined to identify interventions received.

Results

Most women (n = 349, 58.7%) were not identified by the healthcare system as having depressive symptoms and 89% lacked any record of interventions. Remission rates at 6 months postpartum were 69% in this group. Among women identified by the healthcare system, 90% received interventions and about 50% were in remission at 6 months postpartum. The EPDS reduction during the study period was largest in the group identified by the child health services (CHS, −5.15) compared to the non-identified (−4.24, p < 0.001).

Conclusions

Despite screening guidelines, many women with depressive symptoms had no documentation of screening or interventions by the healthcare system. Furthermore, a significant proportion did not achieve remission despite interventions. Being identified by CHS was associated with the largest reduction of symptoms. Research is needed to understand gaps in the healthcare processes, to better identify peripartum depression.

Background. Peripartum depression is a common complication with potential long-term adverse effects on the woman and her family. Approximately 30%-50% of newly delivered women experience prolonged depressive symptoms at 6-12 months postpartum. Early detection may facilitate preventive and treatment interventions. Aim. To investigate correlates for and create a tool for predicting long-term symptomatology in women experiencing depressive symptoms at 6 weeks postpartum.

Materials and Methods. Data from the Biology, Affect, Stress, Imaging, and Cognition study was used, to identify women who scored high (>= 12) on the Edinburgh Postnatal Depression Scale (EPDS) at 6 weeks postpartum (n = 697). Further, we collected data from medical records and included 40 variables based on earlier studies and clinical experience. A total of 654 women were included. Elastic net linear regression analysis was performed to identify predictors of continued symptoms at 6 months postpartum. An equation predicting the EPDS score at 6 months postpartum based on weighted variables was developed.

Results. High education level and sleep for more than 6 hr per night in pregnancy week 17 were protective factors. Parity, pregnancy complications, stressful events, attention deficit hyperactivity disorder/attention deficit disorder, history of depression, depressive symptoms, and anxiety during pregnancy were predictive factors of prolonged depressive symptoms. A prediction tool with area under curve 0.73 and positive predictive value of 79%-83% depending on chosen EPDS cutoff was developed for clinical use.

Conclusions. Our prediction tool offers a method to identify women at risk for persisting depressive symptoms postnatally, based on their significant depressive symptoms during the first weeks after delivery. Screening in order to identify these women can already start in the antenatal setting.

Background: Postpartum depression (PPD) is a common peripartum complication with approximately 13-17% of women being affected. About 30-50% continue to have symptoms 12 months postpartum. Earlier studies have examined women's experiences of treatments to evaluate their effectiveness in supporting women's recovery from PPD. Studies implementing a broader qualitative research focus-exploring factors associated with both personal circumstances and the health care system, and their perceived contribution to remission-are currently lacking.

Aim: To identify the factors women with short- and long-term PPD symptoms view as most important for faster remission.

Method: Participants from a Swedish cohort study (Mom2B) with depressive symptoms above the clinical cut-off of 11 on the Edinburg Postnatal Depression Scale early postpartum, were invited to participate in an interview study. Semi-structure interviews were performed online (n = 12) or via telephone (n = 6). The interviews were transcribed and analyzed using Systematic Text Condensation.

Results: Five themes describing factors of importance for recovery from PPD were identified; 1) Others take responsibility; 2) Practical support; 3) Emotional validation; 4) Thresholds and 5) Struggling to prioritize oneself.

Conclusion: Synthesized from the resulting themes, a five-stage recovery process was identified: realization of symptoms, acceptance, recognizing the need for help, knowledge, and receiving help. This study highlights the key factors in PPD recovery from the perspective of affected women, providing insights to inform and improve postpartum care. The results can help staff visualize the process, which makes them better equipped to support the women effectively.

Concerted electron-proton transfer (CEPT) reactions avoid charged intermediates and may be energetically favorable for redox and radical-transfer reactions in natural and synthetic systems. Tryptophan (W) often partakes in radical-transfer chains in nature but has been proposed to only undergo sequential electron transfer followed by proton transfer when water is the primary proton acceptor. Nevertheless, our group has shown that oxidation of freely solvated tyrosine and W often exhibit weakly pH-dependent proton-coupled electron transfer (PCET) rate constants with moderate kinetic isotope effects (KIE approximate to 2-5), which could be associated with a CEPT mechanism. These results and conclusions have been questioned. Here, we present PCET rate constants for W derivatives with oxidized Ru- and Zn-porphyrin photosensitizers, extracted from laser flash-quench studies. Alternative quenching/photo-oxidation methods were used to avoid complications of previous studies, and both the amine and carboxylic acid groups of W were protected to make the indole the only deprotonable group. With a suitably tuned oxidant strength, we found an ET-limited reaction at pH < 4 and weakly pH-dependent rates at pH > similar to 5 that are intrinsic to the PCET of the indole group with water (H2O) as the proton acceptor. The observed rate constants are up to more than 100 times higher than those measured for initial electron transfer, excluding the electron-first mechanism. Instead, the reaction can be attributed to CEPT. These conclusions are important for our view of CEPT in water and of PCET-mediated radical reactions with solvent-exposed tryptophan in natural systems.

Proton-Coupled Electron Transfer (PCET) reactions are widespread in nature, in particular as key steps in biological electron transport chains that involve redox active amino acids, such as tyrosine and tryptophan. Previous kinetic studies on PCET from tryptophan derivatives in water, where water was the main proton acceptor, have shown a change in mechanism when the electron transfer driving force was varied. At higher driving forces, using strong oxidants, pH-independent PCET rate constants were measured and assigned to a stepwise electron transfer followed by proton transfer mechanism, while at lower driving forces the rate constants became pH dependent and larger than the neat electron transfer rate constant with the same oxidant, and the mechanism was assigned as concerted electron-proton transfer (CEPT). The observed pH dependence is, however, not expected from a CEPT mechanism where water is the proton acceptor. Recently, a new theoretical model was developed that proposed a large association constant between OH- and the indolic NH group that would explain the unusual pH dependent rate constants. 

In this work, we first tested this new model by measuring fluorescence of different tryptophan derivatives at a range of pH-values, since OH- is a known quencher for indole emission. Our results indicate no binding with OH- up to at least pH 10. Instead, IR, 2DIR and Raman spectra showed important differences between indole and different tryptophan derivatives. Moreover, indole showed pH-independent PCET rate constants with a range of oxidant strengths, in contrast to the previous reports on tryptophane derivatives. This points to an involvement of the amino- and carboxylic acid groups, in particular the esterified carboxylic acid that was present in all tryptophan derivatives where pH dependence was previously observed. Our results indicate that the observed pH dependence is not intrinsic to PCET from the indole moiety, but rather originates from interactions with the amino- and carboxylic acid groups. These findings highlight the importance of considering potential interactions between redox active residues and the backbone-forming groups when studying PCET mechanisms in amino acids and proteins.

A new elementary reaction, denoted proton-coupled energy transfer (PCEnT), has been recently reported in a series of donor-acceptor molecules. In this reaction, excited state energy transfer is made possible by a simultaneous transfer of a proton on the energy acceptor. This type of elementary reaction could have, by analogy to proton-coupled electron transfer, an important role in photochemistry and energy transportation of biological systems. In the previously reported case, the reaction is shown to occur intramolecularly in a covalently linked system in a 77 K glass. In this work, we identify a suitable bimolecular system for PCEnT and provide direct evidence for PCEnT in a room temperature solution using fluorescence spectroscopy. Based on these results, we discuss some simple design principles for PCEnT, including some of the current obstacles in designing a successful system.

Triplet-triplet annihilation is a photophysical phenomenon where two low-energy triplets combine to generate a higher energy singlet. This way, low energy photons can be used to generate a high energy species that can be used to activate photochemical processes, of interest for photoredox catalysis and solar energy conversion, or decay by emitting a high energy photon in so-called p-type delayed fluorescence with potential applications in optoelectronics.

In this work, we demonstrate triplet-triplet annihilation from benzo[ghi]perylene in solution, both from direct excitation and from sensitization with tris(2,2′-bipyridine)ruthenium [Ru(bpy)3]2+. From transient absorption and emission results, we extract the intrinsic triplet lifetime τT and the annihilation rate constant kTTA. Our results indicate benzo[ghi]perylene as a suitable candidate for triplet-triplet annihilation applications. Furthermore, we observe the repopulation of [Ru(bpy)3]2+ excited state from benzo[ghi]perylene singlet, resulting in simultaneous long-lived emission from both species. This observation provides a strategy to extend the lifetime of a short-lived triplet (at the expense of quantum yield), and to tune the color of the resulting emission by changing the concentration of the individual components. These results are interesting for the design of optoelectronic systems.

Objective: Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and up to 5 years after transsphenoidal surgery with emphasis on the hypothalamic-pituitary-adrenal axis (HPA).

Design and methods: Data from the Swedish Pituitary Register was used to analyze anterior pituitary function in 838 patients with NFPA diagnosed between 1991 and 2014. Patients who were reoperated or had received radiotherapy were excluded.

Results: Preoperative ACTH, TSH, LH/FSH, and GH deficiencies were reported in 31% (236/755), 39% (300/769), 51% (378/742), and 28% (170/604) of the patients, respectively. Preoperative median tumor volume was 5.0 (2.4-9.0) cm(3). Among patients with preoperative, 1 year and 5 years postoperative data on the HPA axis (n = 428), 125 (29%) were ACTH-deficient preoperatively. One year postoperatively, 26% (32/125) of them had recovered ACTH function while 23% (70/303) patients had developed new ACTH deficiency. Thus, 1 year postoperatively, 163 (38%) patients were ACTH-deficient (P < .001 vs. preoperatively). No further increase was seen 5 years postoperatively (36%, P = .096). At 1 year postoperatively, recoveries in the TSH and LH/FSH axes were reported in 14% (33/241) and 15% (46/310), respectively, and new deficiencies in 22% (88/403) and 29% (83/288), respectively.

Conclusions: Adrenocorticotrophic hormone deficiency increased significantly at 1 year postoperatively. Even though not significant, some patients recovered from or developed new deficiency between 1 and 5 years postoperatively. This pattern was seen in all axes. Our study emphasizes that continuous individual evaluations are needed during longer follow-up of patients operated for NFPA.

INTRODUCTION: This study aims to describe whether the clinical behaviour of nonfunctioning pituitary neuroendocrine tumours/nonfunctioning pituitary adenomas (NF-PitNETs/NFPAs) is affected by pituitary cell lineage differentiation, focusing on patients with silent corticotroph tumours (SCTs) and silent gonadotroph tumours (SGTs).

METHODS: Patients (N = 101) who underwent primary surgery for NF-PitNETs/NFPAs from August 2014 to March 2020 at Uppsala University Hospital were included. Data on sex, age, MRI, pituitary function and immunohistochemical analysis of anterior pituitary hormone and transcription factor expression, were explored.

RESULTS: Seventy-three patients had SGTs, and 18 had SCTs. Binary logistic regression revealed that having SCT versus SGT (OR 6.41 (CI: 1.20-34.42), p = 0.03), being older at the time of surgery (OR 1.07 (CI: 1.02-1.12), p = 0.01), and having a larger preoperative tumour volume (OR 1.17 (CI: 1.04-1.32), p = 0.01) were associated with an increased likelihood of postoperative pituitary failure. Patients with preoperative pituitary failure were older at the time of surgery (p = 0.01) and more often had preoperative elevation of prolactin levels (p = 0.01) than patients without preoperative pituitary failure. SCT patients were younger at the time of surgery than SGT patients (p = 0.003), but no significant difference in preoperative tumour volume was detected.

CONCLUSION: The results indicate that cell lineage differentiation in NF-PitNETs/NFPAs influences clinical behaviour. Patients with SCTs were younger at the time of surgery, and harbouring a SCT was associated with an increased likelihood of having postoperative pituitary failure. These findings emphasise the importance of routine immunohistochemical analyses of anterior pituitary hormone and transcription factor expression to identify silent corticotroph tumours.

Purpose: Most studies regarding quality of life in patients with non-functioning pituitary adenoma are based on general questionnaires that might not capture disease-specific aspects, making further exploration of patients’ experiences with non-functioning pituitary adenoma necessary. This study aimed to describe how patients that have undergone surgery due to non-functioning pituitary adenoma experience the effects of the disease on their life.

Methods: Semi-structured interviews were held with eight participants who had undergone surgery due to non-functioning pituitary adenoma. Participants were recruited from an outpatient endocrinology clinic at a tertiary hospital in Sweden. Inductive qualitative content analysis was used.

Results: The analysis identified an overarching theme, Life has changed but not necessarily for the worse, and three subthemes: The knowledge about the tumour evoked existential concerns, Suffering became a part of life and Finding comfort in a new everyday life.

Conclusion: The findings show that the participants’ lives have changed due to non-functioning pituitary adenoma. While this change was not always for the worse, the quality of life was negatively impacted for some, despite optimal treatment. A changed view on life and general trust in the healthcare system could temper the impact of non-functioning pituitary adenoma. Moreover, communication between healthcare professionals and patients remains a central aspect of patients’ experiences.

In this paper, we present principles of constructing and resolving ambiguity in implicit discourse relations. Following these principles, we created a dataset in both English and Egyptian Arabic that controls for semantic disambiguation, enabling the investigation of prosodic features in future work. In these datasets, examples are two-part sentences with an implicit discourse relation that can be ambiguously read as either causal or concessive, paired with two different preceding context sentences forcing either the causal or the concessive reading. We also validated both datasets by humans and language models (LMs) to study whether context can help humans or LMs resolve ambiguities of implicit relations and identify the intended relation. As a result, this task posed no difficulty for humans, but proved challenging for BERT/CamelBERT and ELECTRA/AraELECTRA models.

We investigate whether prosody can help to disambiguate discourse relations. To address this question, we conducted a controlled experiment examining the impact of prosody in the absence of context, which is crucial for disambiguation. The aim was to determine whether specific prosodic features correlate with the disambiguation of implicit discourse relations. The dataset used in the experiment consisted of 22 pairs of examples, recorded by 21 native speakers of Egyptian Arabic. These examples are two-part sentences with an implicit discourse relation that can be ambiguously read as either causal or concessive, paired with two different preceding context sentences forcing either the causal or the concessive reading. We use linear mixed-effects models to analyze the impact of causal versus concessive discourse relations on prosodic features. We find that, relative to the causal relation, the concessive relation was produced with a longer pause duration between discourse segments, a wider f0 interquartile range for the second segment, and a lower last f0 max for the first segment. These differences are statistically significant, suggesting that speakers use prosody to distinguish between causal and concessive relations.

Most research on implicit discourse relation identification has focused on written language, however, it is also crucial to understand these relations in spoken discourse. We introduce a novel method for implicit discourse relation identification across both text and speech, that allows us to extract examples of semantically equivalent pairs of implicit and explicit discourse markers, based on aligning speech+transcripts with subtitles in another language variant. We apply our method to Egyptian Arabic, resulting in a novel high-quality dataset of spoken implicit discourse relations. We present a comprehensive approach to modeling implicit discourse relation classification using audio and text data with a range of different models. We find that text-based models outperform audio-based models, but combining text and audio features can lead to enhanced performance.

Implicit discourse relation classification is a challenging task, as it requires inferring meaning from context. While contextual cues can be distributed across modalities and vary across languages, they are not always captured by text alone. To address this, we introduce an automatic method for distantly related and unrelated language pairs to construct a multilingual and multimodal dataset for implicit discourse relations in English, French, and Spanish.  For classification, we propose a multimodal approach that integrates textual and acoustic information through Qwen2-Audio, allowing joint modeling of text and audio for implicit discourse relation classification across languages. We find that while text-based models outperform audio-based models, integrating both modalities can enhance performance, and cross-lingual transfer can provide substantial improvements for low-resource languages.

Research on discourse relation recognition has been mainly text-based. However, speech and gesture may carry relevant cues. While integrating these modalities can benefit implicit discourse relation recognition, simple concatenation cannot fully capture how they complement each other. To address this, we introduce a controlled multimodal fusion approach that integrates text, speech, and co-speech gestures. This approach adaptively balances their contributions during prediction. To enable this multimodal setting, we extend existing text–audio datasets by adding the corresponding video for each instance. We present comprehensive experiments on implicit discourse relation recognition across four languages. We find that controlled fusion outperforms both text-only and naive concatenation baselines, particularly in multilingual settings where it yields consistent gains across languages, with substantial improvements for low-resource languages.

Immune checkpoint blockade therapy aims to activate the immune system to eliminate cancer cells. However, clinical benefits are only recorded in a subset of patients. Here, we leverage genome-wide CRISPR/Cas9 screens in a Tumor-Immune co-Culture System focusing on triple-negative breast cancer (TNBC). We reveal that NEDD8 loss in cancer cells causes a vulnerability to nivolumab (anti-PD-1). Genetic deletion of NEDD8 only delays cell division initially but cell proliferation is unaffected after recovery. Since the NEDD8 gene is commonly essential, we validate this observation with additional CRISPR screens and uncover enhanced immunogenicity in NEDD8 deficient cells using proteomics. In female immunocompetent mice, PD-1 blockade lacks efficacy against established EO771 breast cancer tumors. In contrast, we observe tumor regression mediated by CD8+ T cells against Nedd8 deficient EO771 tumors after PD-1 blockade. In essence, we provide evidence that NEDD8 is conditionally essential in TNBC and presents as a synergistic drug target for PD-1/L1 blockade therapy. NEDD8 is a ubiquitin-like protein that governs protein neddylation, previously demonstrated to be essential for cell survival. Here the authors show that NEDD8 loss in breast cancer cells is associated with enhanced immunogenicity and increased sensitivity to PD-1 blockade in preclinical cancer models.

The lack of reliable atomic data can be a severe limitation in astrophysical modelling, in particular of events such as kilonovae that require information on all neutron-capture elements across a wide range of ionization stages. Notably, the presence of non-orthonormalities between electron orbitals representing configurations that are close in energy can introduce significant inaccuracies in computed energies and transition probabilities. Here, we propose an explicit targeted optimization (TO) method that can effectively circumvent this concern while retaining an orthonormal orbital basis set. We illustrate this method within the framework of small-scale atomic structure models of Au I, using the Grasp2018 multiconfigurational Dirac-Hartree-Fock atomic structure code. By comparing to conventional optimization schemes we show how a TO approach improves the energy level positioning and ordering. TO also leads to better agreement with experimental data for the strongest E1 transitions. This illustrates how small-scale models can be significantly improved with minor computational costs if orbital non-orthonormalities are considered carefully. These results should prove useful to multi-element atomic structure calculations in, for example, astrophysical opacity applications involving neutron-capture elements.

The Galactic evolution of copper remains poorly understood, partly due to the strong departures from local thermodynamic equilibrium (LTE) affecting Cu I lines. A key source of uncertainty in non-LTE modelling is the treatment of inelastic Cu + H collisions. We present new rate coefficients based on a combined asymptotic LCAO (linear combination of atomic orbitals) and free electron model approach, which show significant differences from previous calculations. Applying these updated rates to non-LTE stellar modelling, we find reduced line-to-line scatter and improved consistency between metal-poor dwarfs and giants. Our non-LTE analysis reveals a strong upturn in the [Cu/Fe] trend towards lower [Fe/H] < -1.7. We show that this may reflect the interplay between external enrichment of Cu-rich material of the Milky Way halo at low metallicities, and metallicity-dependent Cu yields from rapidly rotating massive stars. This highlights the unique diagnostic potential of accurate Cu abundances for understanding both stellar and Galactic evolution.

The use of advanced x-ray sources plays a key role in the study of dynamic processes in magnetically ordered materials. The progress in x-ray free-electron lasers enables the direct and simultaneous observation of the femtosecond evolution of electron and spin systems through transient x-ray absorption spectroscopy and x-ray magnetic circular dichroism, respectively. Such experiments allow us to resolve the response seen in the population of the spin-split valence states upon optical excitation. Here, we utilize circularly polarized ultrashort soft x-ray pulses from the new helical afterburner undulator at the free-electron laser FLASH in Hamburg to study the femtosecond dynamics of a laser-excited CoPt alloy at the Co L₃-edge absorption. Despite employing a weaker electronic excitation level, we find a comparable demagnetization for the Co 3d-states in CoPt compared to previous measurements on CoPd. This is attributed to the distinctly different spin–orbit coupling between 3d and 4d vs 3d and 5d elements in the corresponding alloys and multilayers.

Time-resolved absorption spectroscopy and magnetic circular dichroism with circularly polarized soft x-rays (XAS and XMCD) are powerful tools to probe electronic and magnetic dynamics in magnetic materials element- and site-selectively. By employing these methods, groundbreaking results have been obtained, for instance, for magnetic alloys, which helped to fundamentally advance the field of ultrafast magnetization dynamics. At the free-electron laser facility FLASH, key capabilities for ultrafast XAS and XMCD experiments have recently improved. In an upgrade, an APPLE-III helical afterburner undulator was installed at FLASH2 in September 2023. This installation allows for the generation of circularly polarized soft x-ray pulses with a duration of a few tens of femtoseconds covering the L-3,L-2-edges of the important 3d transition metal elements with pulse energies of several mu J. Here, we present first experimental results with such ultrashort x-ray pulses from the FL23 beamline employing XMCD at the L-3,L-2-edges of the 3d metals, Co, Fe, and Ni. We obtain significant dichroic difference signals indicating a degree of circular polarization close to 100%. With the pulse-length preserving monochromator at beamline FL23 and an improved pump-laser setup, FLASH can offer important and efficient experimental instrumentation for ultrafast demagnetization studies and other investigations of ultrafast spin dynamics in 3d transition metals, multilayers, and alloys.

Manipulating magnetism at the THz timescale in atomically thin ferromagnets by exploiting the interactions of spins with optical phonon modes presents an innovative idea for THz spintronics and magnonics. Utilizing the coupling of phonon modes to the magnetization could lead to new ways of generating and controlling spin wave excitations in future applications. We use femtosecond optical laser pulses to generate excitons, bound electron-hole pairs, in bulk-like ferromagnet CrI₃ flakes and probe the subsequent charge and spin dynamics with optical pump-probe spectroscopy. In CrI₃, exciton formation is known to drive coherent optical phonon modes with 2.4 and 3.9 THz frequencies corresponding to the bending and stretching of the Cr-I bonds. We show that both phonon modes also lead to magnetization oscillations. This establishes spin-phonon coupling for both modes, contrary to previous observations that only report the 3.9 THz phonon mode can influence the CrI₃ magnetization.

Objective. To examine the association between individual rheumatoid arthritis (RA) autoantibodies, sex and age at RA onset. Methods. Anti-CCP2, IgA-, IgG- and IgM-RF were analysed centrally in baseline sera from 1600 RA patients diagnosed within one year of RA symptom onset. Cut-offs for RF isotypes were determined at the 98th percentile based on RA-free controls, close to the 98.4% anti-CCP2 specificity. Results. Anti-CCP2 was found in 1020 patients (64%), IgA RF in 692 (43%), IgG RF in 529 (33%) and IgM RF in 916 (57%) of the patients. When assessed one by one, anti-CCP2 and IgM RF were both associated with lower age at RA diagnosis. When assessed in one joint model, the association to IgM RF weakened and a strong association between IgA RF and higher age at RA diagnosis appeared. IgA RF and IgG RF associated with male sex, and IgM RF with female sex, with no difference for anti-CCP2. When the model was adjusted for sex, the association between IgM RF and age disappeared, whereas the strong associations between IgA RF and high age and between anti-CCP2 and low age at diagnosis remained. Further adjustments for smoking, shared epitope and inclusion year did not change the outcome. Univariate analyses stratified on anti-CCP2 and IgA RF status confirmed the findings. Conclusion. Anti-CCP associate with low, and IgA RF with high age at RA onset. RFs and anti-CCP2 display opposing association with sex. These results underscore that studies on RA phenotypes in relation to autoantibodies should accommodate age and sex.

Objectives: To investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis.

Methods: IgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated peptide version 2 (anti-CCP2) and 16 individual antibodies against citrullinated protein (ACPA) reactivities were analysed centrally in baseline sera from 1600 patients with RA classified according to the 1987 American College of Rheumatology (ACR) criteria. These results were related to C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), number of swollen and tender joints (SJC and TJC), 28-joint disease activity scores (DAS28 and DAS28CRP), global disease activity evaluated by the patients and Health Assessment Questionnaire, all obtained at baseline.

Results: Individually, all autoantibodies except immunoglobulin G (IgG) RF associated with low SJC and TJC and with high ESR. In IgM RF-negative patients, ACPA associated strictly with low number of swollen and tender joints. This association persisted in multiple regression and stratified analyses where IgM and IgA RF instead associated with inflammation expressed as ESR. Among subjects without any ACPA peptide reactivity, there was no association between RF isotypes and ESR. The effect of RF on ESR increased with the number of ACPA reactivities, especially for IgM RF. In patients fulfilling the 1987 ACR criteria without taking RF into account, associations between IgM RF and high ESR, as well as between ACPA and low joint counts, remained.

Conclusion: Whereas ACPA associate with low counts of affected joints in early RA, RF associates with elevated measures of systemic inflammation in an ACPA-dependent manner. This latter finding corroborates in vitro models of ACPA and RF in immune complex-induced inflammation. These phenotypic associations are independent of classification criteria.

Background and Aims:

The diagnostic and prognostic properties of anti-integrin alpha v beta 6 immunoglobulin G (IgG) autoantibodies in ulcerative colitis (UC) are poorly understood. We aimed to assess the diagnostic performance of anti-integrin alpha v beta 6 autoantibodies and examine their association with disease outcomes.

Methods:

Serum samples from a Swedish inception cohort of patients with suspected inflammatory bowel disease (IBD, n = 473) were analyzed using an in-house fluorescence enzyme immunoassay based on EliA technology. Findings were validated in a Norwegian population-based inception cohort (n = 570). Diagnostic performance was assessed by calculating the area under the curve (AUC) with 95% confidence intervals and determining sensitivity and specificity. Reclassification was evaluated using the net reclassification index.

Results:

In the discovery cohort, patients with UC, IBD-unclassified, or colonic Crohn's disease exhibited higher median autoantibody levels compared to symptomatic and healthy controls. In the validation cohort, the autoantibody demonstrated 79% sensitivity and 94% specificity for UC vs symptomatic controls at a cut-off of 400 UA/l. Its diagnostic performance (AUC = 0.92, 95% CI, 0.89-0.95) was superior to hs-CRP (AUC = 0.65, 95% CI, 0.60-0.70, P < .001) and faecal calprotectin (fcalpro) (AUC = 0.88, 95% CI, 0.84-0.92, P = .09). Combining the autoantibody with fcalpro further improved diagnostic accuracy (AUC = 0.97, 95% CI, 0.95-0.98) and patient reclassification (P < .001). Autoantibody positivity was associated with a severe phenotype of UC, characterised by increased inflammatory activity and higher IL-17A and granzyme B levels. Higher autoantibody levels were linked to an aggressive disease course, remaining stable in aggressive UC but decreasing in indolent disease (P = .003).

Conclusions:

Anti-integrin alpha v beta 6 is a reliable diagnostic and prognostic marker for UC, with potential clinical implementation.

Antibiotic resistance is a growing global health threat that risks the lives of millions. Among the resistance mechanisms, that mediated by metallo-beta-lactamases is of particular concern as these bacterial enzymes dismantle most beta-lactam antibiotics, which are our widest applied and cheapest to produce antibiotic agents. So far, no clinically applicable metallo-beta-lactamase inhibitors are available. Aiming to adapt to structural variations, we introduce the inhibitor concept: dynamically chiral phosphonic acids. We demonstrate that they are straightforward to synthesize, penetrate bacterial membranes, inhibit the metallo-beta-lactamase enzymes NDM-1, VIM-2 and GIM-1, and are non-toxic to human cells. Mimicking the transition state of beta-lactam hydrolysis, they target the Zn ions of the metallo-beta-lactamase active site. As a unique feature, both of their stereoisomers bind metallo-beta-lactamases, which provides them unparalleled adaptability to the structural diversity of these enzymes, and may allow them to hamper bacteria's ability for resistance development.

Previous research and theory indicate an importance of the quality of the early caregiving environment in the development of self-regulation. However, it is unclear how attachment security and maternal sensitivity, two related but distinct aspects of the early caregiving environment, may differentially predict self-regulation at school start and whether a distinction between hot and cool executive function is informative in characterizing such predictions through mediation. In a 5-year longitudinal study (n = 108), we examined these associations using measures of maternal sensitivity and attachment security at 10–12 months, executive function at 4 years, and self-regulation at 6 years. Surprisingly, and despite methodological rigor, we found few significant bivariate associations between the study variables. We found no credible evidence of a longitudinal association between maternal sensitivity or attachment security in infancy and self-regulation at 6 years, or between executive function at 4 years and self-regulation at 6 years. The lack of bivariate longitudinal associations precluded us from building mediation models as intended. We discuss our null findings in terms of their potential theoretical implications, as well as how measurement type, reliability, and validity, may play a key role in determining longitudinal associations between early caregiving factors and later self-regulation and related abilities.

Background

Identifying predictors and mechanisms in the development of childhood internalizing (INT) and externalizing (EXT) problems is crucial for early intervention. Inhibitory control has been linked to INT and EXT, with emotion regulation (ER) potentially mediating these associations. However, specific pathways between early inhibitory control, ER, and later INT and EXT remain unclear. Additionally, regulation of distinct emotions (anger, fear, sadness, joy) may play a role.

Methods

The sample included 94 typically developing children from the EFFECT study, a longitudinal project on the development of self-regulation. At age 4, inhibitory control was measured using the Day/Night Stroop Task. At age 6, general ER, as well as regulation of specific emotions (anger, fear, sadness, and joy), were assessed using the Emotion Questionnaire (parent-report). INT and EXT at ages 9–10 were measured using the Strengths and Difficulties Questionnaire (parent-report). Correlational and path analyses were conducted.

Results

No longitudinal associations were found between inhibitory control at 4 years and either INT or EXT at ages 9–10, or with ER at age 6. Consequently, we found no evidence of mediation by ER. General ER at 6 years emerged as a predictor of both INT and EXT at 9–10 years. While not statistically significant, effect sizes linking regulation of some specific emotions (anger, fear) with subsequent INT and EXT problems warrant further research.

Conclusion

The results reflect the complexity of studying longitudinal effects of early inhibitory control. A modest sample size with attrition, and measurement constraints may have attenuated effects and limited generalizability. Meanwhile, our findings highlight ER as a target for intervention across both INT and EXT.

Background: Cognitive control develops progressively from childhood through early adulthood, supported by protracted maturation of the dorsal anterior cingulate cortex (dACC). While structural and functional development of this region is well-characterized, the neurochemical substrates underlying its maturation remain largely unexplored. Choline, a metabolite essential for membrane synthesis, myelination, and cholinergic neurotransmission, may play a critical role in dACC development.

Methods: We used proton magnetic resonance spectroscopy (.H-MRS) to measure choline concentration (tCho/tCr) in the dACC of 106 participants (23 children aged 6-9 years, 38 adolescents aged 13-17 years, 45 adults aged 30-40 years). Cognitive control performance was assessed using a composite measure derived from multiple cognitive control tasks. Bayesian linear regression models examined age-group differences in choline concentration and associations between choline and cognitive control performance.

Results: Adults showed higher dACC choline concentrations than both children and adolescents, while evidence for differences between children and adolescents was inconclusive. Critically, the relationship between choline and cognitive control performance showed a developmental shift; the association was negative in children, inconclusive in adolescents, and positive in adults, with strong evidence of a difference between children and adults.

Conclusions: These findings suggest a developmental change in the functional significance of dACC choline concentration, potentially reflecting a shift from supporting active circuit reorganization in childhood to maintaining established networks in adulthood. The cross-sectional design limits causal inference, and we emphasise the need for replication given the modest sample size. Meanwhile, this study provides the first characterization of dACC choline concentration across development, and indicates that a single biomarker may carry different functional significance at different developmental stages.

The reduced effectiveness of chemotherapy in many patients undergoing treatment highlights the need for novel drug combinations that target drug resistance mechanisms contributing to tumor survival. Dynamic conditions within the tumor microenvironment influence the response to anti-cancer drugs. Accordingly, identifying effective drug concentrations and interactions (additive, synergistic, or antagonistic) in relevant tumor tissue models will inform new treatment combinations. To address this need for combinatorial chemotherapeutic (CTx) screening assays, we have developed a new assay called CombiCTx, which uses a device with three reservoirs containing gels loaded with anti-cancer drugs. The drug-loaded device is inverted and placed in a standard culture dish above cancer cells, and both are then enclosed in gel. Drugs diffuse from the reservoirs and expose cancer cells to overlapping dynamic drug gradients. We imaged diffusion of the anti-cancer drug doxorubicin in the assay using time-lapse microscopy, and established an imaging protocol for quantifying MDA-MB-231 breast cancer cell survival responses along drug gradients. Finally, evaluating combination effects of navitoclax and gemcitabine with CombiCTx revealed localized effects of navitoclax, attributed to limited diffusion, while gemcitabine seemed to diffuse readily throughout the assay and revealed a mild synergy in navitoclax affected regions. These data demonstrate the capacity of CombiCTx to evaluate the cytotoxic effects of anti-cancer drug combinations while accounting for drug diffusion differences, which is relevant in the context of the 3D tumor environment and may thereby help inform clinical treatment strategies.

Bioprinting is increasingly used to create complex tissue constructs for an array of research applications, and there are also increasing efforts to print tissues for transplantation. Bioprinting may also prove valuable in the context of drug screening for personalized medicine for treatment of diseases such as cancer. However, the rapidly expanding bioprinting research field is currently limited by access to bioprinters. To increase the availability of bioprinting technologies we present here an open source extrusion bioprinter based on the E3D motion system and tool changer to enable high-resolution multimaterial bioprinting. As proof of concept, the bioprinter is used to create collagen constructs using freeform reversible embedding of suspended hydrogels (FRESH) methodology, as well as multimaterial constructs composed of distinct sections of laminin and collagen. Data is presented demonstrating that the bioprinted constructs support growth of cells either seeded onto printed constructs or included in the bioink prior to bioprinting. This open source bioprinter is easily adapted for different bioprinting applications, and additional tools can be incorporated to increase the capabilities of the system.

A new class of materials, bone adhesives, could revolutionise the treatment of highly fragmented fractures. We present the first biological safety investigation of a bio-inspired bone adhesive. The formulation was based upon a modified calcium phosphate cement that included the amino acid phosphoserine. This material has recently been described as substantially stronger than other bioresorbable calcium phosphate cements. Four adhesive groups with the active substance (phosphoserine) and two control groups without phosphoserine were selected for in vitro and in vivo biocompatibility testing. The test groups were subject for cell viability assay and subcutaneous implantation in rats that was followed by gene expression analysis and histology assessment after 6 and 12 weeks. All adhesive groups supported the same rate of cell proliferation compared to the alpha-TCP control and had viability between 45-64% when compared to cell control. There was no evidence of an increased immune response or ectopic bone formation in vivo. To conclude, this bio-inspired bone adhesive has been proven to be safe, in the present study, without any harmful effects on the surrounding soft tissue. 

Phosphoserine (pSER) is a phosphorylated amino acid commonly found in non-collagenous bone proteins and is implicated in the regulation of calcium phosphate (CaP) mineral formation and interfacial interactions in native bone. Here, we soaked 3D printed collagen scaffolds, with or without prior mineralisation, in pSER and investigated the early cellular response by assessing pre-osteoblast viability through ATP content measurements at day 3. The scaffolds were further evaluated in a rat uni-cortical femoral defect model and analysed by micro-computed tomography (µCT) and histology after 6 weeks. In parallel, standard 2D cultures of MC3T3-E1 cells and rat mesenchymal stromal cells (rMSCs) were exposed to pSER, nanohydroxyapatite (nHA), or a combination of both to assess dose-dependent effects in the absence of a scaffold environment. Using a dose-dependent screening approach, we identified 0.05% pSER on mineralised collagen scaffolds as the concentration that resulted in the highest cell viability, whereas higher concentrations were cytotoxic. This concentration was further evaluated in a time-dependent setup over 7 days and again showed increased cell viability compared to untreated collagen scaffolds. Similar trends were observed in vivo where CaP-containing groups demonstrated a higher bone volume fraction than CaP-free collagen groups, and pSER-associated effects were detectable but less pronounced. Overall, the results indicate that collagen scaffolds combining pSER and CaP lead to a dose-dependent enhanced pre-osteoblast viability in vitro. Future work will explore how these pSER-modified collagen bioinks influence bone cell differentiation and aim to elucidate the mechanisms through which pSER supports bone regeneration in vivo. 

Introduction: The presented study aimed to investigate whether a mechanical chest compression piston device with a suction cup assisting chest recoil could impact the hemodynamic status when compared to a bare piston during cardiopulmonary resuscitation.

Methods: 16 piglets were anesthetized and randomized into 2 groups. After 3 minutes of induced ventricular fibrillation, a LUCAS 3 device was used to perform chest compressions, in one group a suction cup was mounted on the device's piston, while in the other group, compressions were per -formed by the bare piston. The device was used in 30:2 mode and the animals were manually ventilated. Endpoints of the study were: end tidal carbon dioxide, coronary and cerebral perfusion pressures, and brain oxygenation (measured using near infrared spectroscopy). At the end of the protocol, the animals that got a return to spontaneous circulation were observed for 60 minutes, then euthanized.

Results: No difference was found in end tidal carbon dioxide or tidal volumes. Coronary perfusion pressure and cerebral oxygenation were higher in the Suction cup group over the entire experiment time, while cerebral perfusion pressure was higher only in the last 5 minutes of CPR. A passive tidal volume (air going in and out the airways during compressions) was detected and found correlated to end tidal carbon dioxide.

Conclusions: The use of a suction cup on a piston-based chest compression device did not increase end tidal carbon dioxide, but it was associated to a higher coronary perfusion pressure.

BACKGROUND: Ventilation during cardiopulmonary resuscitation (CPR) has long been a part of the standard treatment during cardiac arrests. Ventilation is usually given either during continuous chest compressions (CCC) or during a short pause after every 30 chest compressions (30:2). There is limited knowledge of how ventilation is delivered if it effects the hemodynamics and if it plays a role in the occurrence of lung injuries. The aim of this study was to compare ventilation parameters, hemodynamics, blood gases and lung injuries during experimental CPR given with CCC and 30:2 in a porcine model.

METHODS: Sixteen pigs weighing approximately 33 kg were randomized to either receive CPR with CCC or 30:2. Ventricular fibrillation was induced by passing an electrical current through the heart. CPR was started after 3 min and given for 20 min. Chest compressions were provided mechanically with a chest compression device and ventilations were delivered manually with a self-inflating bag and 12 l/min of oxygen. During the experiment, ventilation parameters and hemodynamics were sampled continuously, and arterial blood gases were taken every five minutes. After euthanasia and cessation of CPR, the lungs and heart were removed in block and visually examined followed by sampling of lung tissue which were examined using microscopy.

RESULTS: In the CCC group and the 30:2 group, peak inspiratory pressure (PIP) was 58.6 and 35.1 cmH₂O (p < 0.001), minute volume (MV) 2189.6 and 1267.1 ml (p < 0.001), peak expired carbon dioxide (PECO₂) 28.6 and 39.4 mmHg (p = 0.020), partial pressure of carbon dioxide (PaCO₂) 50.2 and 61.1 mmHg (p = 0.013) and pH 7.3 and 7.2 (p = 0.029), respectively. Central venous pressure (CVP) decreased more over time in the 30:2 group (p = 0.023). All lungs were injured, but there were no differences between the groups.

CONCLUSIONS: Ventilation during CCC resulted in a higher PIP, MV and pH and lower PECO₂ and PaCO₂, showing that ventilation mode during CPR can affect ventilation parameters and blood gases.

Background

A major barrier to the analysis of ventilation waveform data collected during CPR is the presence of artefacts caused by chest compressions. This study describes the development and evaluation of an algorithm to extract parameters regarding ventilation volume, pressure, and frequency from pneumotachography waveform data collected during ongoing simulated CPR.

Method

Ventilation waveform data was collected from a pneumotachograph connected to the respiratory circuit of a ventilator and a test lung. Both regular ventilation and ventilation during simulated CPR were used to develop the algorithm. A grid search was employed to optimize the algorithm parameters compared to the ventilator settings. The parameters were then manually tuned using clinical data from ventilation during CPR. The performance of the algorithm was described in terms of the median error vs. the known ventilator settings in the simulated data.

Results

Compared to the ventilator settings, the largest systematic errors of the algorithm was an overestimation of peak pressures during asynchronous CPR (median error of 3 (IQR 0.3–5.8) cmH₂O), and an underestimation of inspiratory volumes during synchronous CPR (median error 46 (IQR −76 to 10) ml).

Conclusion

In an experimental setting, the developed algorithm provides a novel solution to measure ventilation parameters during ongoing chest compressions. The algorithm is freely available under an open-source licence for use and further development. Further studies will be needed to validate the algorithm.

Background

Despite the critical role of ventilation in cardiopulmonary resuscitation, scientific understanding of manual ventilation parameters during cardiac arrest is limited, with current cardiopulmonary resuscitation guidelines largely based on expert opinion rather than robust clinical evidence. The aim of this study was to present an extensive description of ventilation during cardiopulmonary resuscitation and ventilation parameters such as volume, pressure and frequency and compare them across different ventilation modes and airway modalities.

Methods

The Cardiac Arrest ventilation study (CAvent) was a multicenter, observational cohort study conducted in both nurse- and physician-staffed advanced life support settings. Key ventilation parameters—such as pressure, volume, and frequency—were captured using a portable pneumotachograph and capnography device. 

Results

The analysis included 28120 ventilations across 311 separate ventilation periods in 241 individual patients, of which 134 received asynchronous ventilations, 86 synchronous and 21 a mix of both. Endotracheal tube was the most frequently used airway modality, used in 58% of the cases. In asynchronous and synchronous ventilation, inspiratory tidal volume, expiratory tidal volume, peak inspiratory pressure and ventilation frequency [DS1] [DS2] was 407 vs. 423 ml, 384 vs. 356 ml, 48.1 vs. 32. 4 and 11.2 vs 5.0 respectively. Bag-valve-mask had the lowest effective lung ventilation and endotracheal tube during asynchronous ventilation had the highest peak inspiratory pressure.

Conclusion

ALS-provided manual ventilation during CPR varies greatly across ventilation modes and airway modalities. The ventilation frequency was higher in asynchronous ventilation while inspiratory tidal volumes did not differ between ventilation modes or modalities. Asynchronous ventilation with an endotracheal tube resulted in the highest peak inspiratory pressure and Bag-valve-mask ventilations in the lowest effective lung ventilation. 

Glioblastoma (GBM) is the most common primary brain cancer. It causes death mainly by local invasion via several routes, including infiltration of white matter tracts and penetration of perivascular spaces. However, the pathways that mediate these invasion routes are only partly known. Here, we conduct an integrative study to identify cell states and central drivers of route-specific invasion in GBM. Combining single-cell profiling and spatial protein detection in patient-derived xenograft models and clinical tumor samples, we demonstrate a close association between the differentiation state of GBM cells and their choice of invasion route. Computational modeling identifies ANXA1 as a driver of perivascular involvement in GBM cells with mesenchymal differentiation and the transcription factors RFX4 and HOPX as orchestrators of growth and differentiation in diffusely invading GBM cells. Ablation of these targets in tumor cells alters their invasion route, redistributes the cell states, and extends survival in xenografted mice. Our results define a close association between GBM cell differentiation states and invasion routes, identify functional biomarkers of route-specific invasion, and point toward targeted modulation of specific invasive cell states as a therapeutic strategy in GBM.

The brain tumor glioblastoma is characterized by extensive tumor cell plasticity, a property increasingly recognized as a therapeutic vulnerability. However, our ability to monitor plastic changes in living cells remains limited, hindering efforts to identify the genetic dependencies that govern state changes. Here, we present CRISPR-tag, a method for endogenously tagging cell-state proteins, enabling real-time, single-cell monitoring of GB state dynamics in vitro and ex vivo. Guided by integrative transcriptomic analysis, we generated a panel of fluorescent reporters capturing the major axes of GB cellular variation. These reporters reveal diverse phenomena, including oscillatory expression, lineage-coupled state inheritance, and spatially dependent drug responses in explant assays. Leveraging CRISPR-tag with genome-wide perturbations, we identify regulators of cellular states. Together, CRISPR-tag establishes a scalable platform for resolving and causally perturbing cell state trajectories in glioblastoma, providing a basis for the mechanistic analysis of tumor plasticity and the development of state-targeted therapies.

Background: Patient-derived xenograft (PDX) models of glioblastoma (GBM) are a central tool for neuro-oncology research and drug development, enabling the detection of patient-specific differences in growth, and in vivo drug response. However, existing PDX models are not well suited for large-scale or automated studies. Thus, here, we investigate if a fast zebrafish-based PDX model, supported by longitudinal, AI-driven image analysis, can recapitulate key aspects of glioblastoma growth and enable case-comparative drug testing.

Methods: We engrafted 11 GFP-tagged patient-derived GBM IDH wild-type cell cultures (PDCs) into 1-day-old zebrafish embryos, and monitored fish with 96-well live microscopy and convolutional neural network analysis. Using light-sheet imaging of whole embryos, we analyzed further the invasive growth of tumor cells.

Results: Our pipeline enables automatic and robust longitudinal observation of tumor growth and survival of individual fish. The 11 PDCs expressed growth, invasion and survival heterogeneity, and tumor initiation correlated strongly with matched mouse PDX counterparts (Spearman R = 0.89, p < 0.001). Three PDCs showed a high degree of association between grafted tumor cells and host blood vessels, suggesting a perivascular invasion phenotype. In vivo evaluation of the drug marizomib, currently in clinical trials for GBM, showed an effect on fish survival corresponding to PDC in vitro and in vivo marizomib sensitivity.

Conclusions: Zebrafish xenografts of GBM, monitored by AI methods in an automated process, present a scalable alternative to mouse xenograft models for the study of glioblastoma tumor initiation, growth, and invasion, applicable to patient-specific drug evaluation.

Background & Aim

Various initiatives have been taken and recommended to improve foodservice and nutritional care to hospitals patients. However, a broad description and analysis of what has been done to reach a better foodservice is lacking. Consequently, the aim of this paper is to map aspects highlighted as important in scientific articles pertaining to the improvement of foodservice for hospital inpatients.

Methods

A scoping review was conducted, including literature searches in four databases (CINAHL, PubMed, Scopus, Web of Science) and an article selection process. Included studies were peer reviewed primary research written in English, published in 2000–2023, focusing on quality and improvement work in organisations and practice concerning provision of food and meals to hospital inpatients. Besides data charting of article characteristics, data were obtained for qualitative synthesis.

Results

Out of the 103 included articles, almost all (n=102) contained aspects associated with systems of different kinds. Foremost were systems for ordering, production, delivery and menus. Additionally, there were systems for structures, evaluation, and control. Other frequently occurring aspects concerned patients (n=84), e.g. considering their nutritional requirements, preferences, and cultural habits, as well as empowering patients with freedom of choice, information and guidance. Aspects concerning professional development, e.g. training, competence and teamwork were scarcer (n=46) and even fewer articles entailed aspects regarding leadership (n=21).

Conclusions

The broad spectrum of aspects that were identified may provide guidance to quality improvement of hospital foodservice. It also indicated research gaps in this field, foremost concerning relational competence and leadership.

Background: Recently, numerous initiatives have been taken to improve food and meals for hospital inpatients. Research providing in-depth knowledge on leading such improvement initiatives and implementing changes, specifically through facilitation within this multilevel context, is essential. This study aims to explore nutrition leaders' experiences in implementing changes to improve food and meal provision for hospital inpatients, focusing on facilitation activities.

Method: This is a qualitative interview study within the social constructivist paradigm. Participants were recruited through professional networks, advertisements, and snowballing. Eighteen semi-structured interviews were conducted individually with participants in leadership roles of food and meal improvement initiatives at Swedish hospitals. The interviews were transcribed verbatim and analysed thematically through an i-PARIHS lens.

Results: Three themes of facilitation activities were identified: 'Building Relationships', 'Placing Food and Meals on the Agenda', and 'Cultivating Skills'. Building relationships involved establishing connections between the service and clinical divisions. Creating common structures and multidisciplinary teamwork enabled collaboration across organisational boundaries. Placing food and meals on the agenda involved both initial and ongoing communication activities, as food and meal tasks were often considered low priority. Cultivating skills encompassed creating learning opportunities for implementing lasting changes, tailored to specific contexts and adopted within everyday practices.

Conclusions: Collaboration between foodservice and clinical professionals, along with the dissemination of knowledge, appears to be important for implementing changes. Active leadership supports successful implementations by providing structured approaches, including feedback systems, and by contributing to the recognition of improvement initiatives, according to experiences shared during interviews.

We give a simplified and direct proof of the Kato square root estimate for parabolic operators with elliptic part in divergence form and coefficients possibly depending on space and time in a merely measurable way. The argument relies on the nowadays classical reduction to a quadratic estimate and a Carleson-type inequality. The precise organization of the estimates is different from earlier works. In particular, we succeed in separating space and time variables almost completely despite the non-autonomous character of the operator. Hence, we can allow for degenerate ellipticity dictated by a spatial A2-weight, which has not been treated before in this context.

We solve the Kato square root problem for parabolic operators whose coefficients can be written as the sum of a complex part, which is elliptic, and a real anti-symmetric part which is in BMO. In particular, we allow for unbounded coefficients.

We consider second order degenerate parabolic equations with real, measurable, and time-dependent coefficients. We allow for degenerate ellipticity dictated by a spatial -weight. We prove the existence of a fundamental solution and derive Gaussian bounds. Our construction is based on the original work of Kato (Nagoya Math. J. 19, 93–125 1961).

We study the boundary behavior of solutions to fractional Laplacian. As the first result, the isolation of the first eigenvalue of the fractional Lane-Emden equation is proved in the bounded open sets with Wiener regular boundary. Then, a generalized Hopf's lemma and a global boundary Harnack inequality are proved for the fractional Laplacian. (c) 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

In this work, a generalized Hopf’s lemma and a global boundary Harnack inequality are proved for solutions to fractional p-Laplacian equations. Then the isolation of the first   (s,p)  -eigenvalue is shown in bounded open sets satisfying the Wiener criterion.