bluuebunny/crossref_metadata_2025 huggingface dataset:
Using provocative design to foster electronic informed consent innovation
Authors: De Sutter Evelien , Verreydt Stef , Yskout Koen , Geerts David , Borry Pascal , Outtier An , Ferrante Marc , Vandermeulen Corinne , Vanmechelen Nele , Van der Schueren Bart , Huys Isabelle
Published: November 2022

Background

The development of technological applications in clinical research, such as electronic informed consent (eIC), is on the rise. The involvement of end users throughout the design process of eIC is of utmost importance to improve the current informed consent process.

Methods

Using a provocative design, we conducted interviews with 30 clinical research participants. Provotypes were used as a starting base to discuss various aspects relevant to eIC. By providing a medium to encourage divergent thinking, participants’ views and concerns were solicited. Thematic analysis was undertaken using NVivo.

Results

The majority of participants placed trust in the principal investigator or the hospital to perform the role of eIC hosting party. Differing opinions were reported on the amount of information required related to stakeholders’ access to an eIC system, and thus, to participants’ personal data, to enable trust in an eIC system. Nevertheless, this study indicates a general willingness of participants to share personal data with physicians and pharmaceutical companies on an international level, and to receive requests for new research studies via an eIC system. Participants suggested to tailor an eIC system based upon their preferences, for example, regarding whom they want to share their personal data with. Moreover, they expressed a desire to choose how they can contact the research team, and to indicate which study-related information they would like to receive electronically. In addition, positive opinions were voiced on the integration of a test to assess participants’ understanding before providing their eIC.

Conclusions

Following a research through design approach, insights have been generated which inform the design of eIC. Provotypes were designed to help participants think beyond what is familiar to them. Study findings revealed that not all situations were perceived as provocative, because of participants’ motivation to advance scientific research and the trust they place in the research team. Nevertheless, the use of provocative design resulted in additional insights, generated by clinical research participants, which could be considered in the further design of eIC.
Equality and social determinants of spatial accessibility, availability, and affordability to primary health care in Hong Kong, a descriptive study from the perspective of spatial analysis
Authors: Xiong Xuechen , Li Victor Jing , Huang Bo , Huo Zhaohua
Published: November 2022

Objective

Primary health care (PHC) is widely perceived to be the backbone of health care systems. Since the outbreak of COVID-19, PHC has not only provided primary medical services, but also served as a grassroots network for public health. Our research explored the accessibility, availability, and affordability of primary health care from a spatial perspective, to understand the social determinants affecting access to it in Hong Kong.

Method

This constitutes a descriptive study from the perspective of spatial analysis. The nearest neighbor method was used to measure the geographic accessibility of PHC based on the road network. The 2SFCA method was used to measure spatial availability and affordability to primary health care, while the SARAR model, Spatial Error model, and Spatial Lag model were then constructed to explain potential factors influencing accessibility and availability of PHC.

Results

In terms of accessibility, 95% of residents in Hong Kong can reach a PHC institution within 15 minutes; in terms of availability, 83% of residents can receive PHC service within a month; while in terms of affordability, only 32% of residents can afford PHC services with the support of medical insurance and medical voucher. In Hong Kong, education status and household income show a significant impact on accessibility and availability of PHC. Regions with higher concentrations of residents with post-secondary education receive more PHC resources, while regions with higher concentrations of high-income households show poorer accessibility and poorer availability to PHC.

Conclusion

The good accessibility and availability of primary health care reflects that the network layout of existing PHC systems in Hong Kong is reasonable and can meet the needs of most residents. No serious gap between social groups further shows equality in resource allocation of PHC in Hong Kong. However, affordability of PHC is not ideal. Indeed, narrowing the gap between availability and affordability is key to fully utilizing the capacity of the PHC system in Hong Kong. The private sector plays an important role in this, but the low coverage of medical insurance in outpatient services exacerbates the crowding of public PHC and underutilization of private PHC. We suggest diverting patients from public to private institutions through medical insurance, medical vouchers, or other ways, to relieve the pressure on the public health system and make full use of existing primary health care in Hong Kong.
The use of intercultural interpreter services at a pediatric emergency department in Switzerland
Authors: Buser Sina , Gessler Noemi , Gmuender Myriam , Feuz Ursula , Jachmann Anne , Fayyaz Jabeen , Keitel Kristina , Brandenberger Julia
Published: November 2022

The aim of our study was to analyze the use of interpreter services and improve communication during health encounters with families with limited language proficiency (LLP) at the pediatric emergency department (ED) of the University Hospital of Bern.

This study is a pre- and post-intervention study analyzing the use of interpreter services for LLP families. All families originating from a country with a native language other than German, English or French presenting to the ED were eligible to participate in the study. If they agreed to participate, the language proficiency of the caregiver present during the health encounter was systematically assessed during a phone interview within a few days after the consultation, using a standardized screening tool. If screened positive (relevant LLP), a second phone interview with an interpreter was conducted. Further variables were extracted including nationality, age, gender and date of visit using administrative health records. To increase the use of interpreter services, a package of interventions was implemented at the department during 3 months. It consisted of: i) in person and online transcultural teaching ii) awareness raising through the regular information channels and iii) the introduction of a pathway to systematically identify and manage LLP families.

The proportion of LLP families who received an interpreter was 11.0% (14/127) in the pre-intervention period compared to 14.8% (20/135) in the post-intervention period. The interpreter use was therefore increased by 3.8% (95% CI − 0.43 to 0.21; p = 0.36).

The assessed level of language proficiency of caregivers differed from the self-reported level of language proficiency. Of the study participants in the interview whose language proficiency was screened as limited, 77.1% estimated their language proficiency level as intermediate. More than half of the LLP families who did not receive an interpreter and participated in the interview reported, that they would have liked an interpreter during the consultation.

Conclusions: Interpreter services are largely underused during health encounters with LLP families. Relying on caregivers´ self-assessed language proficiency and their active request for an interpreter is not sufficient to ensure safe communication during health encounters. Systematic screening of language proficiency and standardized management of LLP families is feasible and needed at health care facilities to ensure equitable care. Further studies are needed to analyze personal and institutional barriers to interpreter use and find interventions to sustainably increase the use of interpreter services for LLP families.
A bacteria-regulated gut peptide determines host dependence on specific bacteria to support host juvenile development and survival
Authors: Lee Jaegeun , Yun Hyun Myoung , Han Gangsik , Lee Gang Jun , Jeon Che Ok , Hyun Seogang
Published: November 2022

Background

Commensal microorganisms have a significant impact on the physiology of host animals, including Drosophila. Lactobacillus and Acetobacter, the two most common commensal bacteria in Drosophila, stimulate fly development and growth, but the mechanisms underlying their functional interactions remain elusive.

Results

We found that imaginal morphogenesis protein-Late 2 (Imp-L2), a Drosophila homolog of insulin-like growth factor binding protein 7, is expressed in gut enterocytes in a bacteria-dependent manner, determining host dependence on specific bacteria for host development. Imp-L2 mutation abolished the stimulatory effects of Lactobacillus, but not of Acetobacter, on fly larval development. The lethality of the Imp-L2 mutant markedly increased under axenic conditions, which was reversed by Acetobacter, but not Lactobacillus, re-association. The host dependence on specific bacteria was determined by Imp-L2 expressed in enterocytes, which was repressed by Acetobacter, but not Lactobacillus. Mechanistically, Lactobacillus and Acetobacter differentially affected steroid hormone-mediated Imp-L2 expression and Imp-L2-specific FOXO regulation.

Conclusions

Our finding may provide a way how host switches dependence between different bacterial species when benefiting from varying microbiota.
Isolation and evaluation of the efficacy of bacteriophages against multidrug-resistant (MDR), methicillin-resistant (MRSA) and biofilm-producing strains of Staphylococcus aureus recovered from bovine mastitis
Authors: Mohammadian Fatemeh , Rahmani Hamideh Kalateh , Bidarian Behnam , Khoramian Babak
Published: November 2022

Background

Staphylococcus aureus (S. aureus) is one of the major causes of bovine mastitis with significant economic losses around the worldwide. The emergence of multidrug-resistant (MDR), methicillin-resistant (MRSA) and biofilm-producing strains of S. aureus challenges the treatment strategies based on the antibiotic application. Today, alternative or combinational treatment options such as bacteriophage application has received much attention. The goal of the present study was to focus on isolation and evaluation of the efficacy of bacteriophages with specific lytic activity against S. aureus strains with low cure rates (MDR, MRSA and biofilm-producing strains).

Results

In the present study, two phages belonging to the Podoviridae family with specific lytic activity against S. aureus were isolated from the sewage of dairy farms and designated as Staphylococcus phage M8 and Staphylococcus phage B4. Latent period and burst size for Staphylococcus phage M8 (70 min, 72 PFU/cell) and Staphylococcus phage B4 (30 min, 447 PFU/cell) were also defined. Our results revealed the susceptibility of MDR (4/20; 20%), MRSA (4/13; 30.8%) and biofilm-producing (1/10; 10%) strains to Staphylococcus phage M8. Moreover, one biofilm-producing strain (1/10; 10%) was susceptible to Staphylococcus phage B4. Furthermore, both phages kept their lytic activity in milk. They reduced the S. aureus population by about 3 logs in cultured milk after 8 h of incubation.

Conclusion

In conclusion, it seems that both phages had the potential to serve as biological control agents alone or in combination with other agents such as antibiotics against infections induced by S. aureus. However, further studies are needed to investigate the efficacy of these phages in vivo.
Formation of intracellular vesicles within the Gram+ Lactococcus lactis induced by the overexpression of Caveolin-1β
Authors: Flourieusse A. , Bourgeois P. , Schenckbecher E. , Palvair J. , Legrand D. , Labbé C. , Bescond T. , Avoscan L. , Orlowski S. , Rouleau A. , Frelet-Barrand A.
Published: November 2022

Background

Caveolae are invaginated plasma membrane domains of 50–100 nm in diameter involved in many important physiological functions in eukaryotic cells. They are composed of different proteins, including the membrane-embedded caveolins and the peripheric cavins. Caveolin-1 has already been expressed in various expression systems (E. coli, insect cells, Toxoplasma gondii, cell-free system), generating intracellular caveolin-enriched vesicles in E. coli, insect cells and T. gondii. These systems helped to understand the protein insertion within the membrane and its oligomerization. There is still need for fundamental insights into the formation of specific domains on membrane, the deformation of a biological membrane driven by caveolin-1, the organization of a caveolar coat, and the requirement of specific lipids and proteins during the process. The aim of this study was to test whether the heterologously expressed caveolin-1β was able to induce the formation of intracellular vesicles within a Gram+ bacterium, Lactococcus lactis, since it displays a specific lipid composition different from E. coli and appears to emerge as a good alternative to E. coli for efficient overexpression of various membrane proteins.

Results

Recombinant bacteria transformed with the plasmid pNZ-HTC coding for the canine isoform of caveolin-1β were shown to produce caveolin-1β, in its functional oligomeric form, at a high expression level unexpected for an eukaryotic membrane protein. Electron microscopy revealed several intracellular vesicles from 30 to 60 nm, a size comparable to E. coli h-caveolae, beneath the plasma membrane of the overexpressing bacteria, showing that caveolin-1β is sufficient to induce membrane vesiculation. Immunolabelling studies showed antibodies on such neo-formed intracellular vesicles, but none on plasma membrane. Density gradient fractionation allowed the correlation between detection of oligomers on Western blot and appearance of vesicles measurable by DLS, showing the requirement of caveolin-1β oligomerization for vesicle formation.

Conclusions

Lactococcus lactis cells can heterologously overexpress caveolin-1β, generating caveolin-1β enriched intracellular neo-formed vesicles. These vesicles might be useful for potential co-expression of membrane proteins of pharmaceutical interest for their simplified functional characterization.
Removal of dental implants displaced into the maxillary sinus: a retrospective single-center study
Authors: Bennardo Francesco , Barone Selene , Buffone Caterina , Colangeli Walter , Antonelli Alessandro , Giudice Amerigo
Published: November 2022

Background

The use of dental implants in the prosthetic rehabilitation of the posterior atrophic maxilla might be a challenge procedure because of low bone quantity and quality. This study aimed to report cases of implant displacement or migration into the maxillary sinus treated from 2008 to 2021.

Materials and methods

All patients with unintentional insertion and/or displacement of dental implants into the maxillary sinus cavity that underwent surgical removal were included. Variables assessed included the patients’ characteristics, past medical history, clinical and radiological findings at presentation, surgical approach (transoral, transnasal, combined), and outcome.

Results

A total of forty patients (23 male, 17 female) underwent surgical removal of dental implant displaced in the maxillary sinus. The mean age was 52,3 + 11,3 years. Seven patients presented with oro-antral fistula (OAF). In 15 cases, an ostium obstruction was diagnosed. Twenty-five patients underwent transoral surgery under local anesthesia. Eleven patients were treated solely via transnasal endoscopic approach, and four patients who had an associated OAF underwent surgery through a combined transnasal and transoral approach. All patients healed uneventfully without complications.

Conclusion

These results and recent literature validate that transoral and transnasal approach, or a combination of these procedures, can be used safely to treat complications following displacement/migration of dental implants in the maxillary sinus. Early surgical removal minimizes sinus inflammation and prevents more invasive procedures. Each procedure presents specific indications that must be carefully evaluated prior to treatment choice to optimize intervention outcomes.
Chemoradiation for elderly patients (≥ 65 years) with esophageal cancer: a retrospective single-center analysis
Authors: Linde Philipp , Mallmann Markus , Adams Anne , Wegen Simone , Rosenbrock Johannes , Trommer Maike , Marnitz Simone , Baues Christian , Celik Eren
Published: November 2022

Background

Present studies on the efficacy and safety of curative chemoradiation therapy (CRT) with esophageal cancer reflect heterogenous results especially in elderly patients. The aim of this study was to evaluate the toxicity and efficacy of CRT in patients ≥ 65 years. In a cohort, the focus centered around treatment-related toxicity (CTCAE Grade > 3), overall survival as well as progression free survival, comparing these rates in-between patients older than 70 years to those younger than 70 years.

Methods

A total of 67 patients older than 65 years (34 (50.7%) were older than 70 years) met the inclusion criteria for retrospective analysis (period from January 2013 to October 2017). Treatment consisted of radiotherapy and chemotherapy with carboplatin/paclitaxel or fluorouracil (5-FU)/cisplatin with the intention of neoadjuvant or definite chemoradiation. A sum of 67 patients received CRT (44 (65.6%) patients in neoadjuvant, 23 (34.4%) in definite intent). Of these, 22 and 12 patients were older than 70 years (50% and 52.2% in both treatment groups, respectively). Median age was 71 years and patients had a good physical performance status (ECOG 0: 57.6%, ECOG 1: 27.3%). Median follow-up was 24 months. Most patients had advanced tumour stages (T3 stage: n = 51, 79.7%) and nodal metastasis (N1 stage: n = 54, 88.5%). A subgroup comparison was conducted between patients aged ≤ 70 years and > 70 years.

Results

In severe (CTCAE Grade 3–5) toxicities (acute and late), no significant differences were observed between both patient groups (< 70 years vs. > 70 years). 21% had acute grade 3 events, 4 patients (4%) had grade 4 events, and two patients (3%) had one grade 5 event. Late toxicity after CRT was grade 1 in 13 patients (22%), grade 2 in two (3%), grade 3 in two (3%), grade 4 in four (7%), and grade 5 in one (2%). Median overall survival (OS) of all patients was 30 months and median progression-free survival (PFS) was 16 months. No significant differences were seen for OS (32 months vs. 25 months; p = 0.632) and PFS (16 months vs. 12 months; p = 0.696) between older patients treated with curative intent and younger ones. Trimodal therapy significantly prolonged both OS and PFS (p = 0.005; p = 0.018), regardless of age.

Conclusion

CRT in elderly patients (≥ 65 years) with esophageal cancer is feasible and effective. Numbers for acute and late toxicities can be compared to cohorts of younger patients (< 65 years) with EC who received the same therapies. Age at treatment initiation alone should not be the determining factor. Instead, functional status, risk of treatment-related morbidities, life expectancy and patient´s preferences should factor into the choice of therapy.
Examining how and why polygenic dopamine composite levels moderate adolescents’ vulnerability to peer victimization
Authors: Gao Yemiao , Xiong Yuke , Liu Xia , Liu Jinmeng , Li Jinwen , Wang Hui
Published: November 2022

Extensive literature documents that dopaminergic genes play an important role in the link between adverse environments and adolescents’ problem behavior. However, little is known about the potential mechanism underlying adolescents’ vulnerability to peer victimization. The current study examined the effect of the interplay between a polygenic dopamine composite (i.e., COMT Val158Met and DRD2-141C Ins/Del polymorphisms) and peer victimization on adolescents’ externalizing problems as well as the mediating role of emotion dysregulation in the interactive effects in a sample of 393 Chinese adolescents (Mean age = 14.71 years; 50.1% girls). A significant moderation of dopaminergic genetic composite was observed in girls but not in boys. In addition, emotion dysregulation partially explained the moderating effect of dopaminergic genes. Specifically, girls with genic composite indexing low dopamine activity reported a higher level of emotion dysregulation when faced with more peer victimization. More difficulties with emotion regulation, in turn, predicted more pronounced externalizing problems in girls. This study underscores polygenic underpinnings of adolescent vulnerability to negative peer experiences and suggests the importance of considering sex differences when investigating genic influence on the relationship between adverse environments and externalizing problems.
Electrophysiological and computational analysis of Cav3.2 channel variants associated with familial trigeminal neuralgia
Authors: Mustafá Emilio R. , Gambeta Eder , Stringer Robin N. , Souza Ivana A. , Zamponi Gerald W. , Weiss Norbert
Published: November 2022

Trigeminal neuralgia (TN) is a rare form of chronic neuropathic pain characterized by spontaneous or elicited paroxysms of electric shock-like or stabbing pain in a region of the face. While most cases occur in a sporadic manner and are accompanied by intracranial vascular compression of the trigeminal nerve root, alteration of ion channels has emerged as a potential exacerbating factor. Recently, whole exome sequencing analysis of familial TN patients identified 19 rare variants in the gene CACNA1H encoding for Cav3.2T-type calcium channels. An initial analysis of 4 of these variants pointed to a pathogenic role. In this study, we assessed the electrophysiological properties of 13 additional TN-associated Cav3.2 variants expressed in tsA-201 cells. Our data indicate that 6 out of the 13 variants analyzed display alteration of their gating properties as evidenced by a hyperpolarizing shift of their voltage dependence of activation and/or inactivation resulting in an enhanced window current supported by Cav3.2 channels. An additional variant enhanced the recovery from inactivation. Simulation of neuronal electrical membrane potential using a computational model of reticular thalamic neuron suggests that TN-associated Cav3.2 variants could enhance neuronal excitability. Altogether, the present study adds to the notion that ion channel polymorphisms could contribute to the etiology of some cases of TN and further support a role for Cav3.2 channels.
Combined mitoxantrone and anti-TGFβ treatment with PD-1 blockade enhances antitumor immunity by remodelling the tumor immune landscape in neuroblastoma
Authors: Lucarini Valeria , Melaiu Ombretta , D’Amico Silvia , Pastorino Fabio , Tempora Patrizia , Scarsella Marco , Pezzullo Marco , De Ninno Adele , D’Oria Valentina , Cilli Michele , Emionite Laura , Infante Paola , Di Marcotullio Lucia , De Ioris Maria Antonietta , Barillari Giovanni , Alaggio Rita , Businaro Luca , Ponzoni Mirco , Locatelli Franco , Fruci Doriana
Published: November 2022

Background

Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we identified a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitize poorly T-cell-infiltrated neuroblastoma (NB) to the host antitumor immune response.

Methods

975A2 and 9464D NB cell lines derived from spontaneous tumors of TH-MYCN transgenic mice were employed to study drug combinations able of enhancing the antitumor immune response using in vivo and ex vivo approaches. Migration of immune cells towards drug-treated murine-derived organotypic tumor spheroids (MDOTS) were assessed by microfluidic devices. Activation status of immune cells co-cultured with drug-treated MDOTS was evaluated by flow cytometry analysis. The effect of drug treatment on the immune content of subcutaneous or orthotopic tumors was comprehensively analyzed by flow-cytometry, immunohistochemistry and multiplex immunofluorescence. The chemokine array assay was used to detect soluble factors released into the tumor microenvironment. Patient-derived organotypic tumor spheroids (PDOTS) were generated from human NB specimens. Migration and activation status of autologous immune cells to drug-treated PDOTS were performed.

Results

We found that treatment with low-doses of mitoxantrone (MTX) recalled immune cells and promoted CD8+ T and NK cell activation in MDOTS when combined with TGFβ and PD-1 blockade. This combined immunotherapy strategy curbed NB growth resulting in the enrichment of a variety of both lymphoid and myeloid immune cells, especially intratumoral dendritic cells (DC) and IFNγ- and granzyme B-expressing CD8+ T cells and NK cells. A concomitant production of inflammatory chemokines involved in remodelling the tumor immune landscape was also detected. Interestingly, this treatment induced immune cell recruitment against PDOTS and activation of CD8+ T cells and NK cells.

Conclusions

Combined treatment with low-dose of MTX and anti-TGFβ treatment with PD-1 blockade improves antitumor immunity by remodelling the tumor immune landscape and overcoming the immunosuppressive microenvironment of aggressive NB.
The role of social, demographic and territorial factors in the late detection of hip dysplasia in children in the Republic of Kazakhstan
Authors: Tastanbekova Zhanna , Karabekova Roza , Lozovoy Vassiliy , Angelov Aleksandr , Suleimenov Zhomart , Khuzhakhmedova Rimma
Published: November 2022

Background

The aim of this research is to identify and study the role of social, demographic and territorial factors in the late detection of children with hip dysplasia.

Methods

We conducted a retrospective cohort study of epidemiological data of patients treated in a hospital in the department of orthopedics of the unitary enterprise based on the right of "Multidisciplinary children's municipal hospital No.2" Nur-Sultan (Kazakhstan) in the period from September 2019 to February 2021. The analysis of archival case histories of 309 patients was carried out. There were 214 early and 95 late detections of this disease. Late detection of hip dysplasia was significantly more likely at birth in cranial presentation (81%, p <0.004).

Results

Two-dimensional analysis also showed that late detection was more likely in patients from rural areas (228 children, 73.8%, p < 0.001), and that (26 children, 11.4%, p = 0.005) these were children from regions with lower income (42500 tenge per month, p<0.001). There were also significant differences (p = 0.015) in the early (214 children, 69.26%) and late (95 children, 30.7%) diagnosis of hip dysplasia among children whose parents used a national cradle with tight swaddling (95% CI: 1.16 – 4.49).

Conclusions

In our study, we found that children from rural regions of the Republic of Kazakhstan, indigenous Kazakh nationality, using the national cradle in their everyday life, as well as from regions with low average incomes, were significantly more likely to be exposed to late detection of hip dysplasia.
Effect of an enteral amino acid blend on muscle and gut functionality in critically ill patients: a proof-of-concept randomized controlled trial
Authors: Heming Nicholas , Carlier Robert , Prigent Helene , Mekki Ahmed , Jousset Camille , Lofaso Frederic , Ambrosi Xavier , Bounab Rania , Maxime Virginie , Mansart Arnaud , Crenn Pascal , Moine Pierre , Foltzer Fabien , Cuenoud Bernard , Konz Tobias , Corthesy John , Beaumont Maurice , Hartweg Mickaël , Roessle Claudia , Preiser Jean-Charles , Breuillé Denis , Annane Djillali
Published: November 2022

Background

A defining feature of prolonged critical illness is muscle wasting, leading to impaired recovery. Supplementation with a tailored blend of amino acids may bolster the innate gut defence, promote intestinal mucosa repair and limit muscle loss.

Methods

This was a monocentric, randomized, double-blind, placebo-controlled study that included patients with sepsis or acute respiratory distress syndrome. Patients received a specific combination of five amino acids or placebo mixed with enteral feeding for 21 days. Markers of renal function, gut barrier structure and functionality were collected at baseline and 1, 2, 3 and 8 weeks after randomization. Muscle structure and function were assessed through MRI measurements of the anterior quadriceps volume and by twitch airway pressure. Data were compared between groups relative to the baseline.

Results

Thirty-five critically ill patients were randomized. The amino acid blend did not impair urine output, blood creatinine levels or creatinine clearance. Plasma citrulline levels increased significantly along the treatment period in the amino acid group (difference in means [95% CI] 5.86 [1.72; 10.00] nmol/mL P = 0.007). Alanine aminotransferase and alkaline phosphatase concentrations were lower in the amino acid group than in the placebo group at one week (ratio of means 0.5 [0.29; 0.86] (P = 0.015) and 0.73 [0.57; 0.94] (P = 0.015), respectively). Twitch airway pressure and volume of the anterior quadriceps were greater in the amino acid group than in the placebo group 3 weeks after randomization (difference in means 10.6 [0.99; 20.20] cmH20 (P = 0.035) and 3.12 [0.5; 5.73] cm3/kg (P = 0.022), respectively).

Conclusions

Amino acid supplementation increased plasma citrulline levels, reduced alanine aminotransferase and alkaline phosphatase levels, and improved twitch airway pressure and anterior quadriceps volume.

Trial registration ClinicalTrials.gov, NCT02968836. Registered November 21, 2016.
N6-methyladenosine-mediated SH3BP5-AS1 upregulation promotes GEM chemoresistance in pancreatic cancer by activating the Wnt signaling pathway
Authors: Lin Chengjie , Wang Yan , Dong Yihong , Lai Shihui , Wang Liang , Weng Shangeng , Zhang Xiang
Published: November 2022

Background

Pancreatic cancer (PC) is highly malignant. Chemotherapy is the main treatment strategy, especially for patients with advanced PC. However, chemoresistance has always been a frequently encountered bottleneck. Hence, there is an urgent need to enhance the sensitivity of PC to gemcitabine (GEM).

Results

We demonstrated that SH3BP5-AS1 was significantly upregulated in GEM-resistant PC and predicted a poorer prognosis. SH3BP5-AS1 stability was regulated by ALKBH5/IGF2BP1-mediated m6A modification. Loss of SH3BP5-AS1 reduced PC cell migration and invasion and enhanced the sensitivity of PC to GEM, as confirmed by gain- and loss-of-function assays in vitro and in vivo. Bioinformatics analysis revealed that SH3BP5-AS1 acted as a ceRNA against miR-139-5p and directly targeted CTBP1, affecting the biological behavior of PC cells. The mechanistic studies revealed that the upregulation of SH3BP5-AS1 increased CTBP1 expression by directly activating the Wnt signaling pathway, promoting GEM resistance.

Conclusions

This study revealed that SH3BP5-AS1 activated Wnt signaling pathway by sponging miR-139-5p, upregulating CTBP1 expression, and contributing to the sensitivity of PC cells to GEM. SH3BP5-AS1 might be a potential target for PC therapy.
Effect of personalized perioperative blood pressure management on postoperative complications and mortality in high-risk patients having major abdominal surgery: protocol for a multicenter randomized trial (IMPROVE-multi)
Authors: Bergholz Alina , Meidert Agnes S. , Flick Moritz , Krause Linda , Vettorazzi Eik , Zapf Antonia , Brunkhorst Frank M. , Meybohm Patrick , Zacharowski Kai , Zarbock Alexander , Sessler Daniel I. , Kouz Karim , Saugel Bernd
Published: November 2022

Background

Intraoperative hypotension is common in patients having non-cardiac surgery and is associated with serious complications and death. However, optimal intraoperative blood pressures for individual patients remain unknown. We therefore aim to test the hypothesis that personalized perioperative blood pressure management—based on preoperative automated blood pressure monitoring—reduces the incidence of a composite outcome of acute kidney injury, acute myocardial injury, non-fatal cardiac arrest, and death within 7 days after surgery compared to routine blood pressure management in high-risk patients having major abdominal surgery.

Methods

IMPROVE-multi is a multicenter randomized trial in 1272 high-risk patients having elective major abdominal surgery that we plan to conduct at 16 German university medical centers. Preoperative automated blood pressure monitoring using upper arm cuff oscillometry will be performed in all patients for one night to obtain the mean of the nighttime mean arterial pressures. Patients will then be randomized either to personalized blood pressure management or to routine blood pressure management. In patients assigned to personalized management, intraoperative mean arterial pressure will be maintained at least at the mean of the nighttime mean arterial pressures. In patients assigned to routine management, intraoperative blood pressure will be managed per routine. The primary outcome will be a composite of acute kidney injury, acute myocardial injury, non-fatal cardiac arrest, and death within 7 days after surgery.

Discussion

Our trial will determine whether personalized perioperative blood pressure management reduces the incidence of major postoperative complications and death within 7 days after surgery compared to routine blood pressure management in high-risk patients having major abdominal surgery.

Trial registration

ClinicalTrials.gov NCT05416944. Registered on June 14, 2022.
Effect of comprehensive geriatric assessment for frail elderly patients operated for colorectal cancer—the colorectal cancer frailty study: study protocol for a randomized, controlled, multicentre trial
Authors: Normann Maria , Ekerstad Niklas , Angenete Eva , Prytz Mattias
Published: November 2022

Background

Colorectal cancer (CRC) is the third most common cancer worldwide, with a median age of 72–75 years at diagnosis. Curative treatment usually involves surgery; if left untreated, symptoms may require emergency surgery. Therefore, most patients will be accepted for surgery, despite of high age or comorbidity. It is known that elderly patients suffer higher risks after surgery than younger patients, in terms of complications and mortality. Assessing frailty and offering frail elderly patients individualized treatment according to the comprehensive geriatric assessment (CGA) and care concept has been shown to improve the outcome for frail elderly patients in other clinical contexts.

Methods

This randomized controlled multicentre trial aims to investigate if CGA and care prior to curatively intended surgery for CRC in frail elderly patients will improve postoperative outcome. All patients ≥ 70 years with surgically curable CRC will be screened for frailty using the Clinical Frailty Scale (CFS-9). Frail patients will be offered inclusion. Randomization is stratified for colon or rectal cancer. Patients in the intervention group are, in addition to standard protocol, treated according to CGA and care. This consists of individualized assessments and interventions, established by a multiprofessional team. Patients in the control group are treated according to best known practice as stipulated by Swedish colorectal cancer treatment guidelines, within an enhanced recovery after surgery (ERAS) setting. The primary outcome is 90-day mortality. Secondary outcomes are the length of hospital stay and total number of hospital days within 3 months, discharge destination, 30-day readmission, ADL, safe medication assessment, CFS-9 score, complications, Health-Related Quality of Life (HRQoL) at 2-month follow-up in comparison to baseline measurements, health economical calculations including cost-effectiveness analysis based on costs of hospital care and primary care, mortality and HRQoL at baseline, 2- and 12-month follow-up and all-cause 1-year mortality.

Discussion

The trial is the first of its size and extent to investigate intervention with CGA and care prior to surgery for CRC in frail elderly patients. If this addition proves to be favourable, it could have implications on future care of frail elderly patients with CRC.

Trial registration

ClinicalTrials.govNCT04358328. Registered on 4 February 2020
Modulation of the porcine intestinal microbiota in the course of Ascaris suum infection
Authors: Springer Andrea , Wagner Liane , Koehler Sarina , Klinger Stefanie , Breves Gerhard , Brüggemann Dagmar A. , Strube Christina
Published: November 2022

Background

The porcine roundworm Ascaris suum impairs feed conversion and weight gain, but its effects on intestinal microbiota remain largely unexplored.

Methods

Modulation of the intestinal microbiota was assessed in pigs that were infected once with 10,000 A. suum eggs and pigs that received a trickle infection (1000 eggs/day over 10 days), compared with a non-infected control group. Six pigs each were sacrificed per group at days 21, 35 and 49 post-infection (p.i.). Faecal samples taken weekly until slaughter and ingesta samples from different intestinal compartments were subjected to next-generation sequencing of the bacterial 16S rRNA gene.

Results

The results revealed marked differences between the single- and the trickle-infected group. Single infection caused a remarkable but transient decrease in microbial diversity in the caecum, which was not observed in the trickle-infected group. However, an increase in short-chain fatty acid-producing genera in the caecum on day 21 p.i., which shifted to a decrease on day 35 p.i., was common to both groups, possibly related to changes in excretory–secretory products following the parasite’s final moult. Faecal microbial interaction networks were more similar between the single-infected and control group than the trickle-infected group. In addition, a lower degree of similarity over time indicated that A. suum trickle infection prevented microbiota stabilization.

Conclusions

These different patterns may have important implications regarding the comparability of experimental infections with natural scenarios characterized by continuous exposure, and should be confirmed by further studies.

Graphical Abstract
Aerococcus urinae, a rare cause of aortic root abscess: a case report
Authors: Tiong Chong Wei , Bartolo Caroline , Walton Aaron , Athan Eugene
Published: November 2022

Background

Aerococcus urinae is a bacterium of emerging clinical interest that most commonly causes urinary tract infections (UTI) but can also result in invasive infections. It is a catalase-negative, alpha-haemolytic gram-positive coccus that grows in clusters or tetrads and usually causes urinary tract infections. While rare, infective endocarditis must be considered when A. urinae is isolated in blood culture. The mortality rate of A. urinae infective endocarditis is similar to overall endocarditis mortality. We report a rare case of aortic root abscess caused by A. urinae.

Case presentation

An 82-year-old Caucasian man presented to hospital with behavioural change and severe malnutrition and was managed for psychotic depression. On day 34 of his inpatient stay, a febrile episode prompted blood cultures, which grew Aerococcus. urinae. Investigations revealed a bicuspid aortic valve, aortic valve endocarditis and aortic root abscess. He also had prostatomegaly. He underwent aortic valve replacement, received 6 weeks of intravenous ceftriaxone and recovered.

Conclusion

Infective endocarditis should be considered in patients with persistent Aerococcus urinae bacteraemia. Accurate identification with mass spectrometry is recommended to avoid misidentification as staphylococcus, streptococcus or enterococcus, which is a possibility with conventional laboratory methods.
Acute respiratory distress syndrome following administration of gadolinium contrast agent: a case report
Authors: Osawa Eduardo Atsushi , Kleiman Juliana Fernandez Fernandes , Maciel Alexandre Toledo
Published: November 2022

Background

Gadolinium-based contrast agents are used extensively in magnetic resonance imaging to assist diagnosis of medical conditions. Despite their documented safety profile, severe adverse events do occur, and their documentation may serve to raise the awareness of the medical community.

Case presentation

We report the case of a 15-year-old white Latin American female patient admitted to the intensive care unit for acute respiratory distress syndrome following administration of gadolinium. She did not have rash or tongue swelling but developed hypotension responsive to fluid administration and severe hypoxemia. Chest computed tomography revealed bilateral pulmonary compromise with multiple confluent consolidations. She received methylprednisolone and noninvasive ventilatory support including bilevel positive airway pressure ventilation and high-flow nasal cannula, and underwent a rapid recovery.

Conclusion

Gadolinium-based contrast agent-induced acute respiratory distress syndrome, albeit rare, should be included in the differential diagnosis of respiratory failure shortly after magnetic resonance imaging, which is nowadays a frequent diagnostic procedure, potentially increasing the awareness of this serious complication.
A novel fault location method for distribution networks with distributed generations based on the time matrix of traveling-waves
Authors: Cheng Liang , Wang Tao , Wang Yi
Published: November 2022

To improve location speed, accuracy and reliability, this paper proposes a fault location method for distribution networks based on the time matrix of fault traveling waves. First, an inherent time matrix is established according to the normalized topology of the target distribution network, and a post-fault time matrix is obtained by extracting the head data of initial waves from traveling wave detection devices. A time determination matrix is then obtained using the difference operation between the two matrices. The features of the time determination matrix are used for fault section identification and fault distance calculation, to accurately locate faults. The method is modified by considering economic benefits, through the optimal configuration of detection devices of traveling waves when calculating fault distances. Simulation results show that the proposed method has good adaptation with higher fault location accuracy than two other typical ones. It can deal with faults on invalid branches, and the error rate is under 0.5% even with connected DGs.
Distance to Multidisciplinary Team Clinic in Gaborone, Botswana, and Stage at Cervical Cancer Presentation for Women Living With and Without HIV
Authors: Friebel-Klingner Tara M. , Bazzett-Matabele Lisa , Ramogola-Masire Doreen , Monare Barati , Ralefala Tlotlo B. , Seiphetlheng Alexander , Ramontshonyana Gaobakwe , Vuylsteke Peter , Mitra Nandita , Wiebe Douglas J. , Rebbeck Timothy R. , McCarthy Anne Marie , Grover Surbhi
Published: November 2022

PURPOSE

Cervical cancer is the leading cause of cancer death for women in Botswana. Barriers in access to cancer care can lead to later stages at diagnosis and increased mortality. This study evaluated access, defined as travel time from a patient's residential village to a multidisciplinary team clinic in Gaborone, with stage of cervical cancer at presentation. In addition, because of the high HIV prevalence in Botswana, we explored the association between travel time and HIV status.

METHODS

Eligible patients with cervical cancer presenting to the multidisciplinary team between 2015 and 2020 were included. Data were abstracted from questionnaires and hospital records. Google Maps was used to calculate travel time. Multinomial regression was used to examine travel time and cancer stage, and multivariable logistic regression was used to investigate travel time and HIV status.

RESULTS

We identified 959 patients with cervical cancer of which 70.1% were women living with HIV. The median travel time was approximately 2 hours. Using a reference group of stage I disease and a travel time of < 1 hour, the odds of presenting with stage II increased for patients traveling 3-5 hours (adjusted odds ratio [OR], 2.00; 95% CI, 1.14 to 3.52) and > 5 hours (OR, 2.19; 95% CI, 1.15 to 4.19). There were no significant associations for stage III. For stage IV disease, the odds were increased for patients traveling 3-5 hours (OR, 2.93; 95% CI, 1.26 to 6.79) and > 5 hours (adjusted OR, 4.05; 95% CI, 1.62 to 10.10). In addition, the odds of patients presenting living with HIV increased with increasing travel time (trend test = 0.004).

CONCLUSION

This study identified two potential factors, travel time and HIV status, that influence access to comprehensive cervical cancer care in Botswana.
Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial
Authors: Hillmen Peter , Eichhorst Barbara , Brown Jennifer R. , Lamanna Nicole , O'Brien Susan M. , Tam Constantine S. , Qiu Lugui , Kazmierczak Maciej , Zhou Keshu , Šimkovič Martin , Mayer Jiří , Gillespie-Twardy Amanda , Shadman Mazyar , Ferrajoli Alessandra , Ganly Peter S. , Weinkove Robert , Grosicki Sebastian , Mital Andrzej , Robak Tadeusz , Österborg Anders , Yimer Habte A. , Salmi Tommi , Ji Meng , Yecies Jessica , Idoine Adam , Wu Kenneth , Huang Jane , Jurczak Wojciech
Published: November 2022

PURPOSE

Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities.

PATIENTS AND METHODS

ALPINE (ClinicalTrials.gov identifier: NCT03734016 ) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled.

RESULTS

Between November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/ TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib.

CONCLUSION

Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.