bluuebunny/crossref_metadata_2025 huggingface dataset:
Finding Home: The Experience of Home on Journeys Away from Intimate Partner Violence
Authors: Henze-Pedersen Sofie , Poulsen Juliane Birkedal
Published: June 2023

Violence in the intimate sphere can send women and children out of their homes and onto journeys over vast geographical distances and into various forms of temporary accommodation. When women and children are displaced like this, they have to settle and re-settle on their complex journeys away from intimate partner violence. This article shows that not all these places will be or become home and that the absence of home can entail different forms of distress, such as fear, alienation and despondency. The concept of home is (re)emerging in social work. By employing a threefold understanding of home as a physical place, a feeling and a practice, this article offers new insights into the role of home in the recovery process of women and children subjected to violence. Home is an essential place for adults and children. Therefore, this article argues that home is an important concept for social workers working with families subjected to violence, as finding home can be a central part of the recovery process. This article is based on data from two studies on families experiencing intimate partner violence, drawing on fieldwork at a women’s shelter and on semi-structured interviews with women and children.
Residential Social Care Experiences of LGBTQ+ Young People in England: A Qualitative Interview Study
Authors: Schaub Jason , Stander Willem J , Montgomery Paul
Published: June 2023

Lesbian, gay, bisexual, transgender and queer or questioning (LGBTQ+) young people are overrepresented in out-of-home social care and face significant physical health, mental health and well-being inequalities compared with their non-LGBTQ+ peers. Their residential care experiences have been missing from the knowledge base, with no prior in-depth published research in the UK. Theoretically informed by an intersectional minority stress framework and combining qualitative and co-production methodologies, this study produced a nuanced understanding of the residential care experiences of LGBTQ+ young people. We interviewed twenty young people (sixteen–twenty-four years old) in England with a broad range of LGBTQ+ and multiple intersecting minority identities. We analysed data using reflexive thematic analysis, producing four themes: widespread discrimination and marginalisation; unmet mental and sexual health needs; importance of affirming professional relationships and resilience and self-relying strategies. Findings suggest that multiple minority identities magnified young people’s challenges. Combining the findings with our systematic scoping review developed an explanatory model which provides a dynamic understanding of (un)supportive or (dis)affirming residential care environments. Implications for policy, practice and research include LGBTQ+ inclusive policies and services, mandatory competency-based training combined with ongoing reflexive supervisory practice and incorporating the voices of LGBTQ+ young people in service delivery.
The importance of the dorsal branch of the arcuate fasciculus in phonological working memory
Authors: Barbeau Elise B , Kousaie Shanna , Brass Kanontienentha , Descoteaux Maxime , Petrides Michael , Klein Denise
Published: June 2023

Phonological working memory (PWM) is important for language learning and processing. The most studied language brain regions are the classical Broca’s area on the inferior frontal gyrus and Wernicke’s area on the posterior temporal region and their anatomical connection via the classic arcuate fasciculus (AF) referred to here as the ventral AF (AFv). However, areas on the middle frontal gyrus (MFG) are essential for PWM processes. There is also a dorsal branch of the AF (AFd) that specifically links the posterior temporal region with the MFG. Furthermore, there is the temporo-frontal extreme capsule fasciculus (TFexcF) that courses ventrally and links intermediate temporal areas with the lateral prefrontal cortex. The AFv, AFd and TFexcF were dissected virtually in the same participants who performed a PWM task in a functional magnetic resonance imaging study. The results showed that good performance on the PWM task was exclusively related to the properties of the left AFd, which specifically links area 8A (known to be involved in attentional aspects of executive control) with the posterior temporal region. The TFexcF, consistent with its known anatomical connection, was related to brain activation in area 9/46v of the MFG that is critical for monitoring the information in memory.
Highly branched and complementary distributions of layer 5 and layer 6 auditory corticofugal axons in mouse
Authors: Issa Lina K , Sekaran Nathiya V C , Llano Daniel A
Published: June 2023

The auditory cortex exerts a powerful, yet heterogeneous, effect on subcortical targets. Auditory corticofugal projections emanate from layers 5 and 6 and have complementary physiological properties. While several studies suggested that layer 5 corticofugal projections branch widely, others suggested that multiple independent projections exist. Less is known about layer 6; no studies have examined whether the various layer 6 corticofugal projections are independent. Therefore, we examined branching patterns of layers 5 and 6 auditory corticofugal neurons, using the corticocollicular system as an index, using traditional and novel approaches. We confirmed that dual retrograde injections into the mouse inferior colliculus and auditory thalamus co-labeled subpopulations of layers 5 and 6 auditory cortex neurons. We then used an intersectional approach to relabel layer 5 or 6 corticocollicular somata and found that both layers sent extensive branches to multiple subcortical structures. Using a novel approach to separately label layers 5 and 6 axons in individual mice, we found that layers 5 and 6 terminal distributions partially spatially overlapped and that giant terminals were only found in layer 5-derived axons. Overall, the high degree of branching and complementarity in layers 5 and 6 axonal distributions suggest that corticofugal projections should be considered as 2 widespread systems, rather than collections of individual projections.
Restrictive Versus Permissive Use of Broad-spectrum Antibiotics in Patients Receiving Allogeneic Stem Cell Transplantation and With Early Fever Due to Cytokine Release Syndrome: Evidence for Beneficial Microbiota Protection Without Increase in Infectious Complications
Authors: Weber Daniela , Hiergeist Andreas , Weber Markus , Ghimire Sakhila , Salzberger Bernd , Wolff Daniel , Poeck Hendrik , Gessner André , Edinger Matthias , Herr Wolfgang , Meedt Elisabeth , Holler Ernst
Published: June 2023

Background

Intestinal microbiome contributes to the pathophysiology of acute gastrointestinal (GI) graft-versus-host disease (GvHD) and loss of microbiome diversity influences the outcome of patients after allogeneic stem cell transplantation (SCT). Systemic broad-spectrum antibiotics have been identified as a major cause of early intestinal dysbiosis.

Methods

In 2017, our transplant unit at the university hospital in Regensburg changed the antibiotic strategy from a permissive way with initiation of antibiotics in all patients with neutropenic fever independent of the underlying cause and risk to a restrictive use in cases with high likelihood of cytokine release syndrome (eg, after anti-thymocyte globulin [ATG] therapy). We analyzed clinical data and microbiome parameters obtained 7 days after allogeneic SCT from 188 patients with ATG therapy transplanted in 2015/2016 (permissive cohort, n = 101) and 2918/2019 (restrictive cohort, n = 87).

Results

Restrictive antibiotic treatment postponed the beginning of antibiotic administration from 1.4 ± 7.6 days prior to 1.7 ± 5.5 days after SCT (P = .01) and significantly reduced the duration of antibiotic administration by 5.8 days (P < .001) without increase in infectious complications. Furthermore, we observed beneficial effects of the restrictive strategy compared with the permissive way on microbiome diversity (urinary 3-indoxylsulfate, P = .01; Shannon and Simpson indices, P < .001) and species abundance 7 days post-transplant as well as a positive trend toward a reduced incidence of severe GI GvHD (P = .1).

Conclusions

Our data indicate that microbiota protection can be achieved by a more careful selection of neutropenic patients qualifying for antibiotic treatment during allogeneic SCT without increased risk of infectious complications.
Spontaneous coronary artery dissection in women with acute myocardial infarction: is there a new role for autoimmunity?
Authors: Civieri Giovanni , Vadori Marta , Masiero Giulia , Iop Laura , Tansella Donatella , Pergola Valeria , Cozzi Emanuele , Iliceto Sabino , Tona Francesco
Published: June 2023

Aims

Spontaneous coronary artery dissection (SCAD) is an uncommon cause of acute myocardial infarction in women and has an unclear pathophysiology. Autoantibodies (AAs) targeting angiotensin-II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) have known detrimental effects on endothelial function. We investigated the prevalence of these AAs in SCAD-affected female patients.

Methods and results

Female patients diagnosed at coronary angiography with myocardial infarction and SCAD were consecutively enrolled. Autoantibodies targeting angiotensin-II receptor type 1 and ETAR-AA titres and seropositivity prevalence were compared between SCAD patients, ST-elevation myocardial infarction (STEMI) patients, and healthy women. Ten women with SCAD and 20 age-matched controls (10 women with STEMI and 10 healthy women) were included. Six out of 10 (60%) women with myocardial infarction and SCAD were seropositive for AT1R-AAs and ETAR-AAs. In contrast, only one (10%) healthy woman and one (10%) STEMI patient were seropositive for AT1R-AAs (P = 0.03 and P = 0.03, respectively). One STEMI patient was seropositive for ETAR-AAs, while none of the healthy women was found to be seropositive (P = 0.03 and P = 0.01, respectively). The median AA titre was significantly higher in SCAD patients than in healthy women (P = 0.01 for AT1R-AAs; P = 0.02 for ETAR-AAs) and STEMI patients (P < 0.001 for AT1R-AAs; P = 0.002 for ETAR-AAs).

Conclusion

Autoantibodies targeting angiotensin-II receptor type 1 and ETAR-AA seropositivity is significantly higher in SCAD women with myocardial infarction than in healthy women or female patients with STEMI. Our findings, corroborated by previous data in the literature and biological plausibility, suggest a possible role for AT1R-AAs and ETAR-AAs in the pathophysiology of SCAD in women with acute myocardial infarction and should warrant further studies with larger sample sizes.
Circulating Biomarkers, Fraction of Exhaled Nitric Oxide, and Lung Function in Patients With Human Immunodeficiency Virus and Tuberculosis
Authors: Maenetje Pholo , Baik Yeonsoo , Schramm Diana B , Vangu Mboyo Di-Tamba Willy , Wallis Robert S , Mlotshwa Mandla , Tiemessen Caroline T , Li Yun , Kornfeld Hardy , Churchyard Gavin , Auld Sara C , Bisson Gregory P
Published: June 2023

Background

Identification of proinflammatory factors responding to Mycobacterium tuberculosis is important to reduce long-term sequelae of pulmonary tuberculosis (TB).

Methods

We examined the association between plasma biomarkers, the fraction of exhaled nitric oxide (FeNO), and lung function among a prospective cohort of 105 adults newly diagnosed with TB/human immunodeficiency virus (HIV) in South Africa. Participants were followed for 48 weeks from antiretroviral therapy (ART) initiation with serial assessments of plasma biomarkers, FeNO, lung function, and respiratory symptoms. Linear regression and generalized estimating equations were used to examine the associations at baseline and over the course of TB treatment, respectively.

Results

At baseline, higher FeNO levels were associated with preserved lung function, whereas greater respiratory symptoms and higher interleukin (IL)-6 plasma levels were associated with worse lung function. After ART and TB treatment initiation, improvements in lung function were associated with increases in FeNO (rate ratio [RR] = 86 mL, 95% confidence interval [CI] = 34–139) and decreases in IL-6 (RR = −118 mL, 95% CI = −193 to −43) and vascular endothelial growth factor ([VEGF] RR = −178 mL, 95% CI = −314 to −43).

Conclusions

Circulating IL-6, VEGF, and FeNO are associated with lung function in adults being treated for TB/HIV. These biomarkers may help identify individuals at higher risk for post-TB lung disease and elucidate targetable pathways to modify the risk of chronic lung impairment among TB survivors.
Development of antisense peptide-peptide nucleic acids against fluoroquinolone-resistant Escherichia coli
Authors: Kim Se Kye , Lee Jun Bong , Lee Hyung Tae , Han Dalmuri , Yoon Jang Won
Published: June 2023

Background

Fluoroquinolones (FQs) are potent and broad-spectrum antibiotics commonly used to treat MDR bacterial infections, but bacterial resistance to FQs has emerged and spread rapidly around the world. The mechanisms for FQ resistance have been revealed, including one or more mutations in FQ target genes such as DNA gyrase (gyrA) and topoisomerase IV (parC). Because therapeutic treatments for FQ-resistant bacterial infections are limited, it is necessary to develop novel antibiotic alternatives to minimize or inhibit FQ-resistant bacteria.

Objectives

To examine the bactericidal effect of antisense peptide-peptide nucleic acids (P-PNAs) that can block the expression of DNA gyrase or topoisomerase IV in FQ-resistant Escherichia coli (FRE).

Methods

A set of antisense P-PNA conjugates with a bacterial penetration peptide were designed to inhibit the expression of gyrA and parC and were evaluated for their antibacterial activities.

Results

Antisense P-PNAs, ASP-gyrA1 and ASP-parC1, targeting the translational initiation sites of their respective target genes significantly inhibited the growth of the FRE isolates. In addition, ASP-gyrA3 and ASP-parC2, which bind to the FRE-specific coding sequence within the gyrA and parC structural genes, respectively, showed selective bactericidal effects against FRE isolates.

Conclusions

Our results demonstrate the potential of targeted antisense P-PNAs as antibiotic alternatives against FQ-resistance bacteria.
Analysis of thermostability for seven Phe to Ala and six Pro to Gly mutants in the Fab constant region of adalimumab
Authors: Yoshikawa Moeka , Nakamura Hitomi , Oda-Ueda Naoko , Ohkuri Takatoshi
Published: June 2023

To identify amino acids that play important roles in the structural stability of Fab, seven phenylalanine residues in the Fab constant region of the therapeutic antibody adalimumab were subjected to alanine mutagenesis. Six Fab mutants, H:F130A, H:F154A, H:F174A, L:F118A, L:F139A and L:F209A, showed decreased thermostability compared with wild-type Fab. In contrast, the Tm for the L:F116A mutant was 1.7°C higher than that of wild-type Fab, indicating that the F116 residue was unfavorable for Fab thermostability. Six proline mutants, H:P131G, H:P155G, H:P175G, L:P119G, L:P120G and L:P141G, were also prepared to investigate the effect of proline residues adjacent to mutated phenylalanine residues. The thermostability of the H:P155G and L:P141G mutants in particular was significantly reduced, with decreases in Tm of 5.0 and 3.0°C, respectively, compared with wild-type Fab. The H:P155 and L:P141 residues have a cis conformation, whereas the other mutated proline residues have a trans conformation. H:P155 and L:P141 had stacking interactions with the H:F154 and L:Y140, respectively, at the interface between the variable and constant regions. It is suggested that the interactions of the aromatic ring with a cis-form proline at the interface between the variable and constant regions is important for stability of Fab.
Evaluating relapse-free survival as an endpoint for overall survival in adjuvant immunotherapy trials
Authors: Li Yuanfang , Yuan Shuqiang , Chen Yingbo , Nie Man , Li Jibin , Chen Guoming , Chen Xiaojiang , Zhang Ruopeng , Zheng Ziqi , Wei Chengzhi , Zhou Zhiwei , Nie Runcong , Wang Yun
Published: June 2023

Background

Relapse-free survival (RFS) has been considered a primary endpoint to assess the effects of immunotherapy in the adjuvant setting among patients with early-stage disease. However, it is not clear whether RFS is a valid surrogate endpoint for overall survival (OS) in this clinical context.

Methods

Phase II or III clinical trials of adjuvant immunotherapy that reported hazard ratios on OS and RFS were identified. We used a weighted regression analysis at the arm and trial levels to assess the efficacy of RFS as a surrogate for OS, quantified by the weighted coefficient of determination (R2). Strong correlations (R2 ≥ 0.7) at the arm and trial levels indicated valid surrogacy. The surrogate threshold effect was also evaluated.

Results

Fifteen high-quality randomized clinical trials involving 13 715 patients were included. At the arm level, moderate and strong associations were observed between RFS2-year and OS3-year (R2 = 0.58, 95% confidence interval [CI] = 0.25 to 0.92) and RFS3-year and OS5-year (R2 = 0.72, 95% CI = 0.38 to 1.00), respectively. At the trial level, a moderate association was observed between effect of treatment on RFS and OS (R2 = 0.63, 95% CI = 0.33 to 0.94). The surrogate threshold effect for RFS was 0.86. Consistent results were confirmed in several sensitivity analyses based on different trial phases, experimental arms, cancer types, and treatment strategies.

Conclusions

Our meta-analysis failed to find a clinically strong association between RFS and OS in randomized clinical trials of adjuvant immunotherapy. Our findings challenge the use of RFS as the primary efficacy endpoint and suggest the use of OS in this clinical context.
The programmed death ligand 1 interactome demonstrates bidirectional signaling coordinating immune suppression and cancer progression in head and neck squamous cell carcinoma
Authors: Nieto Cera , Miller Bettina , Alzofon Nathaniel , Chimed Tugy , Himes Jack , Joshi Molishree , Gomez Karina , Chowdhury Farshad N , Le Phuong N , Weaver Alice , Somerset Hilary , Morton J Jason , Wang Jing H , Wang Xiao-Jing , Gao Dexiang , Hansen Kirk , Keysar Stephen B , Jimeno Antonio
Published: June 2023

Background

The programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are validated cancer targets; however, emerging mechanisms and impact of PD-L1 intracellular signaling on cancer behavior are poorly understood.

Methods

We investigated the cancer cell intrinsic role of PD-L1 in multiple patient-derived models in vitro and in vivo. PD-L1 overexpression, knockdown, and PD-L1 intracellular domain (PD-L1–ICD) deletion (Δ260-290PD-L1) models were assessed for key cancer properties: clonogenicity, motility, invasion, and immune evasion. To determine how PD-L1 transduces signals intracellularly, we used the BioID2 platform to identify the PD-L1 intracellular interactome. Both human papillomavirus-positive and negative patient-derived xenografts were implanted in NOD-scid-gamma and humanized mouse models to investigate the effects of recombinant PD-1, anti–PD-L1, and anti–signal transducer and activator of transcription 3 (STAT3) in vivo.

Results

PD-L1 intracellular signaling increased clonogenicity, motility, and invasiveness in multiple head and neck squamous cell carcinoma (HNSCC) models, and PD-1 binding enhanced these effects. Protein proximity labeling revealed the PD-L1 interactome, distinct for unbound and bound PD-1, which initiated cancer cell–intrinsic signaling. PD-L1 binding partners interleukin enhancer binding factors 2 and 3 (ILF2-ILF3) transduced their effect through STAT3. Δ260-290PD-L1 disrupted signaling and reversed pro-growth properties. In humanized HNSCC in vivo models bearing T-cells, PD-1 binding triggered PD-L1 signaling, and dual PD-L1 and STAT3 inhibition were required to achieve tumor control.

Conclusions

Upon PD-1 binding, the PD-L1 extracellular and intracellular domains exert a synchronized effect to promote immune evasion by inhibiting T-cell function while simultaneously enhancing cancer cell–invasive properties.
Exosome-like nanoparticles derived from Allium tuberosum prevent neuroinflammation in microglia-like cells
Authors: Ishida Tomoaki , Kawada Kei , Jobu Kohei , Morisawa Shumpei , Kawazoe Tetsushi , Nishimura Satomi , Akagaki Keita , Yoshioka Saburo , Miyamura Mitsuhiko
Published: June 2023

Objective

Exosome-like nanoparticles (ELNs), which are plant-derived extracellular membrane vesicles, can regulate mammalian gene expression. ELNs can cross the blood-brain barrier, making them potential therapeutic agents or drug-delivery carriers for neuroinflammation-related diseases. Here, we investigated the anti-neuroinflammatory potential of ELNs extracted from Allium tuberosum (A-ELNs).

Methods

A-ELNs were extracted, and their miRNA profile was characterized. A-ELNs were also applied to BV-2 microglial and MG-6 cells derived from C57/BL6 mice stimulated with lipopolysaccharide (LPS), followed by an examination of levels of inflammatory-related factors. To test their drug-carrying potential, A-ELNs were mixed with dexamethasone, an anti-inflammatory drug, to prepare dexamethasone-incorporated A-ELNs (Dex-A-ELNs).

Key findings

A-ELNs showed a particle size of 145 ± 2 nm and characteristic miRNAs. A-ELNs significantly decreased the LPS-induced nitric oxide (NO) and inflammatory cytokines levels in BV-2 and MG-6 cells. The mRNA expression of heme oxygenase-1 was significantly increased, and that of inducible NO synthase and inflammatory cytokines was significantly decreased by A-ELNs in BV-2 cells. Dex-A-ELNs inhibited NO production in BV-2 cells more potently than either A-ELNs or dexamethasone alone.

Conclusion

A-ELNs can alleviate microglial inflammation. Their effects can be potentiated by incorporating anti-inflammatory drugs, such as dexamethasone, making them potential therapeutic agents or drug-delivery carriers for neuroinflammation.
Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study)
Authors: Stumpf Julian , Thomusch Oliver , Opgenoorth Mirian , Wiesener Michael , Pascher Andreas , Woitas Rainer Peter , Suwelack Barbara , Rentsch Markus , Witzke Oliver , Rath Thomas , Banas Bernhard , Benck Urs , Sommerer Claudia , Kurschat Christine , Lopau Kai , Weinmann-Menke Julia , Jaenigen Bernd , Trips Evelyn , Hugo Christian
Published: June 2023

Background

We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year “Harmony” trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids.

Methods

The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards.

Results

Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314–0.976; P = .041).

The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period.

Conclusions

With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients.

Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT 00724022, FU study DRKS00005786)
The mediating effect of social functioning on the relationship between catastrophizing and pain among patients with chronic low back pain
Authors: Papianou Lauren N , Wilson Jenna M , Edwards Robert R , Sieberg Christine B , Meints Samantha M
Published: June 2023

Objective

Pain catastrophizing can be characterized as an interpersonal form of coping used to elicit support or empathy from others. Despite intentions of increasing support, catastrophizing can impair social functioning. While considerable work has addressed the relationship between catastrophizing and pain, limited empirical work has examined this relationship within a social context. First, we examined the role of catastrophizing as a potential contributor to group differences (chronic low back pain [cLBP] vs pain-free controls) in social functioning. Then we conducted a follow-up, exploratory analysis to examine the relationships between catastrophizing, social functioning, and pain within the subgroup of participants with cLBP.

Methods

In this observational study, participants with cLBP (N = 62) and pain-free controls (N = 79) completed validated measures of pain, social functioning, and pain catastrophizing. A mediation analysis was conducted to examine whether catastrophizing mediated group differences (cLBP vs controls) in social functioning. A follow-up, exploratory mediation analysis then tested whether social functioning mediated the association between catastrophizing and pain within the subgroup of cLBP participants.

Results

Participants with cLBP reported higher levels of pain, impaired social functioning, and higher catastrophizing compared to pain-free controls. Catastrophizing partially mediated the group difference in impaired social functioning. Additionally, social functioning mediated the association between higher catastrophizing and greater pain within the subgroup of cLBP participants.

Conclusions

We showed that impaired social functioning was driving the relationship between higher pain catastrophizing and worse pain among participants with cLBP. Interventions, such as cognitive behavioral therapy, should address catastrophizing in individuals with cLBP, while simultaneously improving social functioning.
Cytokine storm associated with severe COVID‐19 infections: The potential mitigating role of omega‐3 fatty acid triglycerides in the ICU
Authors: Driscoll David F. , Bistrian Bruce R.
Published: June 2023

Cytokine storm during severe COVID‐19 infection increases the risk of mortality in critically ill patients in the intensive care unit. Multiple therapeutic proposals include, for example, anti‐inflammatory and immunosuppressive agents, selective inhibitors of key pro‐inflammatory receptors, and key enzymes necessary for viral replication. Unfortunately, safe and effective therapy remains an elusive goal. An alternative anti‐inflammatory approach vis á vis omega‐3 fatty acids, which yields less pro‐inflammatory mediators by altering eicosanoid metabolism, has been proposed. Although theoretically promising, enteral tube delivery or oral capsules containing specific doses of omega‐3 fatty acids take precious time (7 days to 6 weeks) to be incorporated in plasma cell membranes to be most effective, making this route of administration in the acute care setting an unfeasible therapeutic approach. Parenteral administration of precise doses of omega‐3 fatty acid triglycerides in an injectable emulsion can greatly accelerate the incorporation and potential therapeutic effects (within hours), but at present, there is no commercially available product designed for this purpose. We describe a potential formulation that may address this deficiency, while recognizing that the high incidence of hyperlipidemia that occurs during severe COVID‐19 infection must be recognized as a complicating factor, and, therefore, caution is advised.
Pediatric Lateral Humeral Condyle Fractures: Reliability of a Modified Jakob Classification System and its Impact on Treatment Planning With or Without Arthrography
Authors: Miller Joseph S. , Weishuhn Luke , Goodrich Eric , Patel Jay , McCarthy James J. , Mehlman Charles T.
Published: June 2023

Background:

Various lateral humeral condyle fracture (LHCF) classification systems have been in use since the 1950s, but limited research exists on their reliability. The most widely utilized, yet un-validated system is that of Jakob and colleagues. The purpose of the current study was to analyze the reliability of a modified Jakob classification system and its value in guiding treatment either with or without arthrography.

Methods:

Interrater and intrarater reliability studies were performed using radiographs and arthrograms from 32 LHCFs. Radiographs were presented to 3 pediatric orthopaedic surgeons and 6 pediatric orthopaedic surgery residents who were asked to classify the fractures according to a modified Jakob classification system, enunciate their treatment plan, and whether they would utilize arthrography. Classification was repeated within 2 weeks to assess intrarater reliability. The treatment plan using radiographs only and radiographs with arthrography were compared at both rating points.

Results:

The modified Jakob system had excellent interrater reliability using only radiographs with a kappa value of 0.82 and an overall agreement of 86%. The average kappa for intrarater reliability using only radiographs was 0.88 with a range of 0.79 to 1.00 and an average overall agreement of 91% with a range of 84% to 100%. Interrater and intrarater reliability was poorer using both radiographs and arthrography. On average, arthrography changed the treatment plan in 8% of cases.

Conclusions:

The modified Jakob classification system proved to be a reliable classification system for LHCFs, independent of arthrography, given the excellent free-marginal multirater kappa values.

Level of Evidence:

Level III—diagnostic.
Cast or Nail? Using a Preference-Based Tool for Shared Decision-Making in Pediatric Femoral Shaft Fracture Treatment
Authors: Catanzano Anthony A. , Hutyra Carolyn , Risoli Thomas J. , Green Cynthia L. , Mather R. Chad , Alman Benjamin
Published: June 2023

Background:

Femoral shaft fractures are common injuries in children 2 to 7 years of age, with treatments ranging from casting to flexible intramedullary nails (FIN). Each treatment has unique attributes and outcomes are overall similar. Given equivalent outcomes, we hypothesized that a shared decision-making process, using adaptive conjoint analysis (ACA), can be used to assess individual family situations to determine ultimate treatment choice.

Methods:

An interactive survey incorporating an ACA exercise to elicit the preferences of individuals was created. Amazon Mechanical Turk was used to recruit survey respondents simulating the at-risk population. Basic demographic information and family characteristics were collected. Sawtooth Software was utilized to generate relative importance values of five treatment attributes and determine subjects’ ultimate treatment choice. Student’s t-test or Wilcoxon rank sum test was used to compare relative importance between groups.

Results:

The final analysis included 186 subjects with 147 (79%) choosing casting as their ultimate treatment choice, while 39 (21%) chose FIN. Need for second surgery had the highest overall average relative importance (42.0), followed by a chance of serious complications (24.6), time away from school (12.9), effort required by caregivers (11.0), and return to activities (9.6). Most respondents (85%) indicated the generated relative importance of attributes aligned “very well or well” with their preferences. For those who chose casting instead of FIN, the need for secondary surgery (43.9 vs. 34.8, P<0.001) and the chance of serious complications (25.9 vs. 19.6, P<0.001) were the most important factors. In addition, returning to activities, the burden to caregivers, and time away from school were all significantly more important to those choosing surgery versus casting (12.6 vs. 8.7 P<0.001, 12.6 vs. 9.8 P=0.014, 16.6 vs. 11.7 P<0.001, respectively).

Conclusions:

Our decision-making tool accurately identified subjects’ treatment preferences and appropriately aligned them with a treatment decision. Given the increased emphasis on shared decision-making in health care, this tool may have the potential to improve shared decision-making and family understanding, leading to improved satisfaction rates and overall outcomes.

Level of Evidence:

Level—III.
Assessing Factors Influencing Commitment to a Disparities Reduction Intervention: Social Justice Attitudes and Organizational Mission
Authors: Marsteller Jill A. , Hsu Yea-Jen , Weeks Kristina , Oduwole Modupe , Boonyasai Romsai T. , Avornu Gideon D. , Dietz Katherine B. , Zhou Zehui , Brown Deven , Hines Anika , Chung Suna , Lubomski Lisa , Carson Kathryn A. , Ibe Chidinma , Cooper Lisa A. ,   for the RICH LIFE Project Investigators
Published: June 2023

This mixed-methods study aims to understand what the perceptions of leaders and healthcare professionals are regarding causes of disparities, cultural competence, and motivation before launching a disparity reduction project in hypertension care, contrasting perceptions in Federally Qualified Health Centers (FQHCs), and in a non-FQHC system. We interviewed leaders of six participating primary care systems and surveyed providers and staff. FQHC respondents reported more positive cultural competence attitudes and behavior, higher motivation to implement the project, and less concern about barriers to caring for disadvantaged patients than those in the non-FQHC practices; however, egalitarian beliefs were similar among all. Qualitative analysis suggested that the organizational missions of the FQHCs reflect their critical role in serving vulnerable populations. All system leaders were aware of the challenges of provider care to underserved groups, but comprehensive initiatives to address social determinants of health and improve cultural competence were still needed in both system types. The study provides insights into the perceptions and motivations of primary care organizational leaders and providers who are interested in improving chronic care. It also offers an example for care disparity programs to understand commitment and values of the participants for tailoring interventions and setting baseline for progress.
Can the Buffalo Concussion Treadmill Test Be Used as a Prognostic Indicator for Patients With Sport-Related Mild Traumatic Brain Injury?
Authors: Kumar Amitesh , Kara Stephen , van der Werf Bert , Fulcher Mark
Published: June 2023

Objective:

To establish whether time to exercise cessation using the Buffalo Concussion Treadmill Test (BCTT) protocol can be used as a prognostic indicator of recovery after sport-related mild traumatic brain injury (SR-mTBI).

Design:

Retrospective analysis of prospectively collected data.

Setting:

Specialist Concussion Clinic.

Participants:

Three hundred and twenty one patients presenting between 2017 and 2019 who underwent BCTT for SR-mTBI.

Interventions:

Participants who remained symptomatic at a 2-week follow-up appointment after SR-mTBI underwent BCTT to develop a progressive subsymptom threshold exercise program with fortnightly follow-up until clinical recovery.

Main Outcome Measures:

Clinical recovery was the primary outcome measure.

Results:

A total of 321 participants were eligible to participate in this study (mean age 22.94% and 46% female). The BCTT test duration was divided into 4-minute intervals and those who completed full 20 minutes. There was higher probability of clinical recovery in those who finished the entire 20-minute BCTT protocol compared with those who managed 17–<20 minutes (Hazard Ratio, HR 0.57), 13 to 16 minutes (HR 0.53), 9 to 12 minutes (HR 0.6), 5 to 8 minutes (HR 0.4), and 1 to 4 minutes (HR 0.7), respectively. Those seen earlier after injury (P = 0.009), male patients (P = 0.116), younger patients (P = 0.0003), and those with physiological or cervical dominant (P = 0.416) symptom clusters were more likely to achieve clinical recovery. Fifty percent of those who completed the full BCTT protocol achieved clinical recovery at day 19 post‐injury.

Conclusions:

The group completing full 20 minutes of BCTT achieved clinical recovery more quickly than those who did not complete full BCTT.
Dynamics of Serum CA19-9 in Patients Undergoing Pancreatic Cancer Resection
Authors: van Oosten A.F. , Groot V.P. , Dorland G. , Burkhart Richard A. , Wolfgang C.L. , van Santvoort H.C. , He J. , Molenaar I.Q , Daamen L.A.
Published: June 2023

Background:

Carbohydrate antigen (CA) 19-9 is an established perioperative prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). However, it is unclear how CA19-9 monitoring should be used during postoperative surveillance to detect recurrence and to guide the initiation of recurrence-focused therapy.

Objective:

This study aimed to elucidate the value of CA19-9 as a diagnostic biomarker for disease recurrence in patients who underwent PDAC resection.

Methods:

Serum CA19-9 levels at diagnosis, after surgery, and during postoperative follow-up were analyzed in patients who underwent PDAC resection. All patients with at least two postoperative follow-up CA19-9 measurements prior to recurrence were included. Patients deemed to be non-secretors of CA19-9 were excluded. The relative increase in postoperative CA19-9 was calculated for each patient by dividing the maximum postoperative CA19-9 value by the first postoperative value. Receiver operating characteristic (ROC) analysis was performed to identify the optimal threshold for the relative increase in CA19-9 levels to identify recurrence in the training set using Youden’s index. The performance of this cutoff was validated in a test set by calculating the area under the curve (AUC) and was compared to the performance of the optimal cutoff for postoperative CA19-9 measurements as a continuous value. In addition, sensitivity, specificity, and predictive values were assessed.

Results:

In total, 271 patients were included, of whom 208 (77%) developed recurrence. ROC analysis demonstrated that a relative increase in postoperative serum CA19-9 of 2.6x was predictive of recurrence, with 58% sensitivity, 83% specificity, 95% positive predictive value, and 28% negative predictive value. The AUC for a 2.6x relative increase in CA19-9 level was 0.719 in the training set and 0.663 in the test set. The AUC of postoperative CA19-9 as a continuous value (optimal threshold, 52) was 0.671 in the training set. In the training set, the detection of a 2.6-fold increase in CA19-9 preceded the detection of recurrence by a mean difference of 7 months (P<0.001) and in the test set by 10 months (P<0.001).

Conclusion:

A relative increase in postoperative serum CA19-9 level of 2.6-fold is a stronger predictive marker for recurrence than a continuous CA19-9 cutoff. A relative CA19-9 increase can precede the detection of recurrence on imaging for up to 7–10 months. Therefore, CA19-9 dynamics can be used as a biomarker to guide the initiation of recurrence-focused treatment.
Predicting Outcomes Following Endovascular Abdominal Aortic Aneurysm Repair Using Machine Learning
Authors: Li Ben , Verma Raj , Beaton Derek , Tamim Hani , Hussain Mohamad A , Hoballah Jamal J , Lee Douglas S , Wijeysundera Duminda N , de Mestral Charles , Mamdani Muhammad , Al-Omran Mohammed
Published: June 2023

Objective:

To develop machine learning (ML) models that predict outcomes following endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA).

Summary Background Data:

EVAR carries non-negligible peri-operative risks; however, there are no widely used outcome prediction tools.

Methods:

The National Surgical Quality Improvement Program targeted database was used to identify patients who underwent EVAR for infrarenal AAA between 2011-2021. Input features included 36 pre-operative variables. The primary outcome was 30-day major adverse cardiovascular event (MACE; composite of myocardial infarction, stroke, or death). Data were split into training (70%) and test (30%) sets. Using 10-fold cross-validation, 6 ML models were trained using pre-operative features. The primary model evaluation metric was area under the receiver operating characteristic curve (AUROC). Model robustness was evaluated with calibration plot and Brier score. Subgroup analysis was performed to assess model performance based on age, sex, race, ethnicity, and prior AAA repair.

Results:

Overall, 16,282 patients were included. The primary outcome of 30-day MACE occurred in 390 (2.4%) patients. Our best performing prediction model was XGBoost, achieving an AUROC (95% CI) of 0.95 (0.94-0.96) compared to logistic regression [0.72 (0.70 – 0.74)]. The calibration plot showed good agreement between predicted and observed event probabilities with a Brier score of 0.06. Model performance remained robust on all subgroup analyses.

Conclusions:

Our newer ML models accurately predict 30-day outcomes following EVAR using pre-operative data and perform better than logistic regression. Our automated algorithms can guide risk mitigation strategies for patients being considered for EVAR.
Novel neutralizing mouse-human chimeric monoclonal antibodies against the SARS-CoV-2 receptor binding domain
Authors: Ghorbani Ahmad , Maghsood Faezeh , Yadegari Hamidreza , Bahadori Tannaz , Zarnani Amir-Hassan , Razavi Seyed Alireza , Jeddi-Tehrani Mahmood , Amiri Mohammad Mehdi , Shokri Fazel
Published: June 2023

Introduction. Neutralizing antibodies have been widely used for the prophylaxis and treatment of COVID-19.

Hypothesis. The major target for these neutralizing antibodies is the receptor-binding domain (RBD) of the viral spike protein.

Aim. In the present study, we developed and characterized three neutralizing chimeric mouse-human mAbs for potential therapeutic purposes.

Methodology. Light and heavy chain variable region genes of three mouse mAbs (m4E8, m3B6, and m1D1) were amplified and ligated to human Cγ1 and Cκ constant region genes by PCR. After cloning into a dual promoter mammalian expression vector, the final constructs were transiently expressed in DG-44 cells and the purified chimeric antibodies were characterized by ELISA and Western blotting. The neutralizing potency of the chimeric mAbs was determined by three different virus neutralization tests including sVNT, pVNT, and cVNT.

Results. All three recombinant chimeric mAbs display human constant regions and are able to specifically bind to the RBD of SARS-CoV-2 with affinities comparable to the parental mAbs. Western blot analysis showed similar epitope specificity profiles for both the chimeric and the parental mouse mAbs. The results of virus neutralization tests (sVNT, pVNT, and cVNT) indicate that c4E8 had the most potent neutralizing activity with IC50 values of 1.772, 0.009, and 0.01 µg ml−1, respectively. All chimeric and mouse mAbs displayed a similar pattern of reactivity with the spike protein of the SARS-CoV-2 variants of concern (VOC) tested, including alpha, delta, and wild-type.

Conclusion. The chimeric mAbs displayed neutralizing potency similar to the parental mouse mAbs and are potentially valuable tools for disease control.
Diagnosing Left Bundle Branch Block in 12-lead Electrocardiogram using Self-Attention Convolutional Neural Networks
Authors: Sadeghi Alireza , Rezaee Alireza , Hajati Farshid
Published: June 2023

The left bundle branch block is a cardiac conduction disorder that affects the heart’s electrical system. It causes the left ventricle of the heart to contract later than the right ventricle, leading to an irregular heartbeat. The diagnosis of left bundle branch block is crucial in determining the most effective treatment for heart irregularities, including cardiac resynchronization therapy. Cardiac resynchronization therapy uses a pacemaker-like device to resynchronize the heart’s contractions and improve its function. However, diagnosing left bundle branch block accurately can be challenging using traditional diagnostic methods that rely on electrocardiograms. This study introduces Self-Attention Convolutional Neural Networks for the detection of left bundle branch block from 12-lead electrocardiograms data using SE-Residual blocks and a self-attention mechanism to highlight important input data features for more accurate diagnosis of left bundle branch block. The model is trained and validated on a database of 10,344 12-lead electrocardiogram samples using a 10-fold cross-validation approach. The results demonstrate an accuracy of 98.91% ± 0.1%, specificity of 99.28% ± 0.15%, precision of 73.09% ± 3.5%, recall or sensitivity of 82.83% ± 4.34%, F1 score of 77.5% ± 1.59%, and area under the receiver operating characteristics curve of 0.91 ± 0.02. The experimental results demonstrate that the proposed deep learning model achieves high accuracy, specificity, and F1 score. These findings suggest that the proposed model can serve as an effective diagnostic tool for identifying left bundle branch block with a high level of efficiency, improving the diagnostic process, and promoting early treatment in medical settings.
Identification of cross-reacting IgG hotspots to prevent immune evasion of SARS-CoV-2 variants
Authors: Harhala Marek , Gembara Katarzyna , Baniecki Krzysztof , Pikies Aleksandra , Nahorecki Artur , Jędruchniewicz Natalia , Kaźmierczak Zuzanna , Rybicka Izabela , Klimek Tomasz , Witkiewicz Wojciech , Barczyk Kamil , Kłak Marlena , Dąbrowska Krystyna
Published: June 2023

The major factor that shapes the global perspective for increase or diminution of successive pandemic waves of COVID-19 is the immunological protection. The SARS-CoV-2 virus constantly develops new variants, and capability of immune evasion is among the major factors that promote variant spreading in the human population. After two years of the pandemic and virus evolution, it is almost impossible to explain effects of all possible combinations different viral strains, a few types of vaccinations or new variants infecting an individual patient. Instead of variant-to-variant comparisons, identification of key protein regions linked to immune evasion could be efficient.

Here we report an approach for experimental identification of SARS-CoV-2 protein regions that (i) have characteristics of cross-reacting IgG hot-spots, and (ii) are highly immunogenic. Cross-reacting IgG hot spots are regions of protein frequently recognized in many variants by cross-reacting antibodies. Immunogenic regions efficiently induce specific IgG production in SARS-CoV-2 infected patients. We determined four regions that demonstrate both significant immunogenicity and the activity of a cross-reacting IgG hot-spot in protein S, and two such regions in protein N. Their distribution within the proteins suggests that they may be useful in vaccine design and in serological diagnostics of COVID-19.