bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence, patient burden and physicians’ perception of pruritus in haemodialysis patients
Authors: Engler Franziska , Kerschbaum Julia , Keller Felix , Mayer Gert ,   the Austrian Dialysis and Transplant Registry collaborators, Antlanger Marlies , Edlinger Roland , Horn Sabine , Kathrein Hermann , Kirsch Bernhard , Leutgeb-Pohn Elisabeth , Luschnik Roland , Oberbauer Rainer , Post Matthias , Rosenkranz Alexander , Schmaldienst Sabine , Werzowa Johannes , Wöhrer Sebastian , Winter Gottfried , Sprenger-Mähr Hannelore , Zodl Herbert
Published: July 2023

Background

Chronic kidney disease–associated pruritus (CKD-aP) is an underrated symptom in patients with impaired kidney function. The present study assessed the prevalence, impact on quality of life (QoL) and risk factors for CKD-aP in a contemporary national cohort of patients on haemodialysis. In addition, we evaluated attending physicians’ awareness and approach to therapy.

Methods

Validated patient's and physician's questionnaires on pruritus severity and QoL were used in combination with information obtained by the Austrian Dialysis and Transplant Registry.

Results

The prevalence of mild, moderate and severe pruritus in 962 observed patients was 34.4%, 11.4% and 4.3%. Physicians’ estimated prevalence values were 25.0 (95% CI 16.8–33.2), 14.4 (11.3–17.6) and 6.3% (4.9–8.3), respectively. The estimated national prevalence estimate extrapolated from the observed patients was 45.0% (95% CI 39.5–51.2) for any, 13.9% (95% CI 10.6–17.2) for moderate and 4.2% (95% CI 2.1–6.2) for severe CKD-aP. CKD-aP severity was significantly associated with impaired QoL. Risk factors for moderate–severe pruritus were higher C-reactive protein [odds ratio (OR) 1.61 (95% CI 1.07–2.43)] and parathyroid hormone (PTH) values [OR 1.50 (95% CI 1.00–2.27)]. Therapy for CKD-aP included changes in the dialysis regimen, topical treatments, antihistamines, gabapentin and pregabalin and phototherapy in a majority of centres.

Conclusions

While the overall prevalence of CKD-aP in our study is similar to that in previously published literature, the prevalence of moderate–severe pruritus is lower. CKD-aP was associated with reduced QoL and elevated markers of inflammation and PTH. The high awareness of CKD-aP in Austrian nephrologists may explain the lower prevalence of more severe pruritus.
Associations of neutral pH, low-GDP peritoneal dialysis solutions with patient survival, transfer to haemodialysis and peritonitis
Authors: Chen Jenny H C , Johnson David W , Cho Yeoungjee , Cheetham Melissa , Sud Kamal , Hayat Ashik , Stallard Belinda , Clayton Philip , Davies Christopher E , Borlace Monique , Boudville Neil
Published: July 2023

Background

Peritoneal dialysis (PD) solutions containing low levels of glucose degradation products (GDPs) are associated with attenuation of peritoneal membrane injury and vascular complications. However, clinical benefits associated with neutral-pH, low-GDP (N-pH/L-GDP) solutions remain unclear.

Methods

Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the associations between N-pH/L-GDP solutions and all-cause mortality, cause-specific mortality, transfer to haemodialysis (HD) for ≥30 days and PD peritonitis in adult incident PD patients in Australia and New Zealand between 1 January 2005 and 31 December 2020 using adjusted Cox regression analyses.

Results

Of 12 814 incident PD patients, 2282 (18%) were on N-pH/L-GDP solutions. The proportion of patients on N-pH/L-GDP solutions each year increased from 11% in 2005 to 33% in 2017. During the study period, 5330 (42%) patients died, 4977 (39%) experienced transfer to HD and 5502 (43%) experienced PD peritonitis. Compared with the use of conventional solutions only, the use of any form of N-pH/L-GDP solution was associated with reduced risks of all-cause mortality {adjusted hazard ratio [aHR] 0.67 [95% confidence interval (CI) 0.61–0.74]}, cardiovascular mortality [aHR 0.65 (95% CI 0.56–0.77)], infection-related mortality [aHR 0.62 (95% CI 0.47–0.83)] and transfer to HD [aHR 0.79 (95% CI 0.72–0.86)] but an increased risk of PD peritonitis [aHR 1.16 (95% CI 1.07–1.26)].

Conclusions

Patients who received N-pH/L-GDP solutions had decreased risks of all-cause and cause-specific mortality despite an increased risk of PD peritonitis. Studies assessing the causal relationships are warranted to determine the clinical benefits of N-pH/L-GDP solutions.
A digital health trust framework guided by values from the science of yoga
Authors: Venkatasubramanian Akarsh
Published: July 2023

The ongoing digital age is reengineering a global health system supported and strengthened by digital technologies. However, a fundamental mistrust still exists among innovators, health care professionals, policy-makers and the public, with digital health technologies often considered untrustworthy. Values build trust, and the ‘values’ of digital health technologies are their ethical principles. This manuscript contributes two broad and unique additions to the ongoing conversation on digital health and trust. Firstly, it suggests four major ethics (privacy, agency, safety, security) as the pillars of a pass framework to trust digital health technologies. Secondly, it perceives these ethics as values that help build trust, through the lens of yoga. Observing these two conditions, it infers that the foundations of the science of yoga present values that help digital health technologies pass the trust test.
New Assays for Rapid Detection of Beet Leafhopper-Associated Plant Pathogens, ‘Candidatus Phytoplasma trifolii’, Beet Curly Top Virus, and Spiroplasma citri
Authors: Swisher Grimm Kylie D. , Gorman Christopher J. , Crosslin James M.
Published: July 2023

The beet leafhopper Circulifer tenellus is an important pest of agricultural crops in the United States, where it transmits beet curly top virus, beet leafhopper-transmitted virescence agent phytoplasma, and Spiroplasma citri to numerous crops, affecting yield and quality. Each of these pathogens have been linked to serious disease outbreaks within Washington State in the past century. To mitigate the risk of disease, growers target the beet leafhopper in their insect pest management programs. Knowledge of pathogen prevalence in beet leafhopper populations could help growers make better management decisions, but timely diagnostics is required. Four new assays were developed for the rapid detection of the beet leafhopper-associated pathogens. These include two assays that detect Beet leafhopper transmitted virescence agent (a PCR and a real-time PCR SYBR green assay), a duplex PCR assay that simultaneously detects beet curly top virus and Spiroplasma citri, and a multiplex real-time PCR assay for the simultaneous detection of all three pathogens. The screening of dilution series generated from plant total nucleic acid extracts with these new assays typically led to detection at levels 10- to 100-fold more sensitive than the conventional PCR assays currently used. These new tools will allow the rapid detection of beet leafhopper-associated pathogens in both plant and insect specimens and will have the potential to be used in diagnostic laboratories seeking to disseminate fast and accurate results to growers for implementation in their insect pest monitoring programs.
Blockade of MIF biological activity ameliorates house dust mite‐induced allergic airway inflammation in humanized MIF mice
Authors: Dunbar Hazel , Hawthorne Ian J. , Tunstead Courteney , Armstrong Michelle E. , Donnelly Seamas C. , English Karen
Published: July 2023

Macrophage migration inhibitory factor (MIF) expression is controlled by a functional promoter polymorphism, where the number of tetranucleotide repeats (CATTn) corresponds to the level of MIF expression. To examine the role of this polymorphism in a pre‐clinical model of allergic asthma, novel humanized MIF mice with increasing CATT repeats (CATT5 and CATT7) were used to generate a physiologically relevant scale of airway inflammation following house dust mite (HDM) challenge. CATT7 mice expressing high levels of human MIF developed an aggressive asthma phenotype following HDM challenge with significantly elevated levels of immune cell infiltration, production of inflammatory mediators, goblet cell hyperplasia, subepithelial collagen deposition, and airway resistance compared to wild‐type controls. Importantly the potent MIF inhibitor SCD‐19 significantly mitigated the pathophysiology observed in CATT7 mice after HDM challenge, demonstrating the fundamental role of endogenous human MIF expression in the severity of airway inflammation in vivo. Up to now, there are limited reproducible in vivo models of asthma airway remodeling. Current asthma medications are focused on reducing the acute inflammatory response but have limited effects on airway remodeling. Here, we present a reproducible pre‐clinical model that capitulates asthma airway remodeling and suggests that in addition to having pro‐inflammatory effects MIF may play a role in driving airway remodeling.
Takotsubo Syndrome: An Epidemiologic Evaluation
Authors: Lancaster Ian , Steinhoff Jeffrey , White Allison
Published: July 2023

Takotsubo syndrome is characterized by regional wall motion abnormalities that reflect impairment of myocardial contractility in the absence of culprit epicardial coronary artery disease. The pathophysiologic mechanisms responsible for Takotsubo syndrome remain unknown and predominately occur in postmenopausal females suffering either a psychological or physical stressor. This study used the Hospital Corporation of America (HCA) Healthcare database evaluating demographic distribution of patients with Takotsubo syndrome to identify what comorbid conditions were most prevalent in patients found to have Takotsubo syndrome in the United States population and compare them to the traditional patient population with the condition. The patient population in the HCA Healthcare United States database was similar to prior known demographic factors including postmenopausal females and Caucasian ethnicity. Interestingly, in both the previously diagnosed group and diagnosed at the time of presentation with the Takotsubo syndrome group, there was a mismatch between the number of patients diagnosed with an underlying mood disorder and on psychiatric medication. This may provide further evidence of Takotsubo syndrome being a dramatic presentation of a mood disorder.
NOAC Therapy According to CHA2DS2-VASc Without Atrial Fibrillation: A Systematic Review
Authors: Maddalena Riccardo
Published: July 2023

According to Quality-Adjusted Life Expectancy, novel oral anticoagulant therapy is preferred when the stroke risk is higher than 0.9% per year. CHA2DS2-VASc is a tool to select those patients at high risk for stroke due to atherosclerosis and atrial cardiopathy, who could benefit from anticoagulation even in sinus rhythm. Systematic electronic database searches were conducted using Pubmed and Scopus. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement 2020 was followed. Thirteen studies were included, comprising altogether 19,600,104 patients. Data show that the predictive accuracy for stroke of CHA2DS2-VASc among patients with and without atrial fibrillation (AF) is similar, but the benefit of anticoagulation, considering the 1-year risk of stroke for every CHA2DS2-VASc value, starts from higher cutoffs in patients without AF (around CHA2DS2-VASc 4). Atrial fibrillation should no longer be considered a sine qua non for the prevention of thromboembolism in patients at high risk of stroke due to atherosclerosis and atrial disease, but only an additional risk factor to be included in the predictive model used to select patients for novel oral anticoagulant therapy, regardless of the rhythm. CHA2DS2-VASc-AF may be an option. Additional randomized clinical trials are needed.
Construction and evaluation of a novel prognostic risk model of aging-related genes in bladder cancer
Authors: Wang Delin , Ning Hao , Wu Haihu , Song Yufeng , Chu Yaru , Liu Feifan , Zhao Zhenlin , Wu Fei , Lyu Jiaju
Published: July 2023

Background

Bladder cancer (BLCA) is the most common malignancy of the urinary system. Muscle-invasive bladder cancer (MIBC), which constitutes approximately 25% of all BLCA cases, is characterized by frequent recurrence and early onset of metastasis. Bladder cancer most commonly occurs in elderly patients and is significantly associated with aging. However, the prognostic value of age-related genes in BLCA, especially in MIBC, remains unclear.

Materials and methods

Training and testing sets were obtained from The Cancer Genome Atlas BLCA project. Differentially expressed genes between BLCA and normal samples intersected with human aging-related genes. Univariate Cox regression and least absolute shrinkage and selection operator regression analyses were used to identify prognostic aging-related signatures, followed by the construction of a risk score model and nomogram. Kaplan-Meier and receiver operating characteristic analyses were conducted to assess the predictive power. An independent BLCA cohort of 165 samples was included for external validation. The CIBERSORT algorithm was used to explore the characteristics of the immune microenvironment.

Results

Seven genes (IGF1, NGF, GCLM, PYCR1, EFEMP1, APOC3, and IFNB1) were identified by Cox and least absolute shrinkage and selection operator analyses. After combining the gene signature with the clinical parameters of patients with BLCA, a risk-prognosis model and nomogram were constructed and validated with the testing set. Bladder cancer cases with high 7-gene signature scores (high-risk group) and low scores (low-risk group) showed distinct prognoses. Furthermore, 7 types of immune cells were significantly altered between the low- and high-risk groups.

Conclusions

Collectively, our data provide a 7-gene signature that serves as a potential biomarker for BLCA, especially MIBC. Moreover, this 7-gene signature highlights the role of the tumor immune microenvironment in prognosis and thus might be related to the response to anti-programmed cell death protein 1–based immunotherapy.
Adherence and related cardiovascular outcomes to single pill vs. separate pill administration of antihypertensive triple-combination therapy
Authors: Rea Federico , Morabito Gabriella , Savaré Laura , Pathak Atul , Corrao Giovanni , Mancia Giuseppe
Published: July 2023

Objective:

To compare adherence to antihypertensive treatment between patients prescribed a three-drug single-pill combination (SPC) of perindopril/amlodipine/indapamide (P/A/I) vs. the combination of an angiotensin-converting enzyme inhibitor (ACEI), a calcium-channel blocker (CCB), and a diuretic (D) as a two-drug SPC plus a third drug given separately.

Methods:

Using the healthcare utilization database of the Lombardy Region (Italy), the 28 210 patients, aged at least 40 years, who were prescribed P/A/I SPC during 2015–2018 were identified and the date of the first prescription was defined as the index date. For each patient prescribed the SPC, a comparator who started ACEI/CCB/D treatment as a two-pill combination was considered. Adherence to the triple combination was assessed over the year after the index date as the proportion of the follow-up days covered by prescription (PDC). Patients who had a PDC >75% were defined as highly adherent to drug therapy. Log-binomial regression models were fitted to estimate the risk ratio of treatment adherence in relation to the drug treatment strategy.

Results:

About 59 and 25% of SPC and two-pill combination users showed high adherence, respectively. Compared with patients under a three-drug two-pill combination, those who were treated with the three-drug SPC had a higher propensity to be highly adherent to the triple combination (2.38, 95% confidence interval: 2.32–2.44). This was the case regardless of the sex, age, comorbidities, and number of co-treatments.

Conclusions:

In a real-life setting, patients under three-drug SPC exhibited more frequently a high adherence to antihypertensive treatment than those prescribed a three-drug two-pill combination.
Acupuncture for neuropathic pain: focusing on the sympathetic nerve system
Authors: Ma Xin , Chen Wen , Fu Yiming , Li Hongping , Liu Cunzhi
Published: July 2023

Following peripheral nerve injury, the sympathetic nervous system responds to noxious inputs that induce or exacerbate pain. Dorsal root ganglion (DRG) sympathetic sprouting after peripheral nerve injury may induce abnormal firing of neurons. Moreover, the areas of the brain that respond to nociceptive stimuli overlap with those areas activated by the sympathetic nervous system. Acupuncture is a widely used alternative therapy for neuropathic pain. It has been shown to have beneficial effects on the regulation of function in the autonomic nervous system function. Based on previous studies, there are several possibilities for the regulation of sympathetic nerves using by acupuncture to relieve neuropathic pain. Acupuncture may act on the brain areas of pain and the sympathetic nervous system, decrease sympathetic nerve activity during neuropathic pain, attenuate sympathetic sprouting, and reduce the abnormal firing of neurons. Further studies are required to confirm these hypotheses. This review will help to better understand the potential mechanisms of acupuncture in neuropathic pain.
Assessment of cardiovascular disease risk: a 2023 update
Authors: Goldsborough Earl , Tasdighi Erfan , Blaha Michael J
Published: July 2023

Purpose of review

The aim of this study was to highlight the current best practice for atherosclerotic cardiovascular disease (CVD) risk evaluation, including selective use of adjunctive tools for risk stratification [e.g. coronary artery calcium (CAC) scoring] and risk enhancement [e.g. lipoprotein(a) [Lp(a)], polygenic risk scoring (PRS)].

Recent findings

New studies have evaluated the efficacy of various risk assessment tools. These studies demonstrate the role of Lp(a) as a risk-enhancing factor ready for more widespread use. CAC is the gold standard method of assessing subclinical atherosclerosis, enabling true risk stratification of patients, and informing net benefit assessment for initiating or titrating lipid-lowering therapy (LLT).

Lp(a) concentration and CAC scoring, apart from the traditional risk factors, add the most value to the current CVD risk assessment approaches of all available tools, especially in terms of guiding LLT. In addition to new integrative tools such as the MESA CHD Risk Score and Coronary Age calculator, the future of risk assessment may include PRS and more advanced imaging techniques for atherosclerosis burden. Soon, polygenic risk scoring may be used to identify the age at which to begin CAC scoring, with CAC scores guiding preventive strategies.
Outcomes of People of Color in an Efficacy Trial of Cognitive-Behavioral Treatments for Anxiety, Depression, and Related Disorders
Authors: Cardona Nicole D. , Ametaj Amantia A. , Cassiello-Robbins Clair , Tirpak Julianne Wilner , Olesnycky Olenka , Sauer-Zavala Shannon , Farchione Todd J. , Barlow David H.
Published: July 2023

Although evidence-based psychological treatments such as cognitive behavioral therapy (CBT) have strong empirical support for reducing anxiety and depression symptoms, CBT outcome research often does not report race and ethnicity variables, or assess how well CBT works for people from historically excluded racial and ethnic groups. This study presents post hoc analyses comparing treatment retention and symptom outcomes for participants of color (n = 43) and White participants (n = 136) from a randomized controlled efficacy trial of CBT. χ2 tests and one-way ANCOVA showed no observable differences between the two samples on attrition or on clinician-rated measures of anxiety and depression at posttreatment and follow-up. Moderate to large within-group effect sizes on anxiety and depression were found for Black, Latinx, and Asian American participants at almost all time points. These preliminary findings suggest that CBT for anxiety and comorbid depression may be efficacious for Black, Asian American, and Latinx individuals.
Acute shortening and angulation for complex open fractures: an updated perspective
Authors: Pierrie Sarah N. , Beltran Michael J.
Published: July 2023

Reestablishing an intact, healthy soft tissue envelope is a critical step in managing lower extremity injuries, particularly high-grade open tibia fractures. Acute shortening and angulation can be used independently or together to address complex soft tissue injuries, particularly when bone loss is present. These techniques facilitate management of difficult wounds and can be combined with local soft tissue rearrangement or pedicled flaps as needed, avoiding the need for free tissue transfer. After angular deformity correction, adjacent bone loss can be addressed with bone grafting or distraction histogenesis. This article discusses the indications for, surgical technique for, and limitations of acute shortening and angulation for management of open lower extremity fractures.
Reducing Intraoperative Hypothermia in Infants from the Neonatal Intensive Care Unit
Authors: Studer Abbey , Fleming Barbara , Jones Roderick C. , Rosenblatt Audrey , Sohn Lisa , Ivey Megan , Reynolds Marleta , Falciglia Gustave H.
Published: July 2023

Introduction:

Infants from the neonatal intensive care unit (NICU) undergoing surgery in the operating room (OR) are at greater risk for hypothermia during surgery than afterward due to environmental heat loss, anesthesia, and inconsistent temperature monitoring. A multidisciplinary team aimed to reduce hypothermia (<36.1 °C) for infants at a level IV NICU at the beginning of the operation (first OR temperature) or at any time during the operation (lowest OR temperature) by 25%.

Methods:

The team followed preoperative, intraoperative (first, lowest, and last OR), and postoperative temperatures. It sought to reduce intraoperative hypothermia using the “Model for Improvement” by standardizing temperature monitoring, transport, and OR warming, including raising ambient OR temperatures to 74°F. Temperature monitoring was continuous, secure, and automated. The balancing metric was postoperative hyperthermia (>38 °C).

Results:

Over 4 years, there were 1235 operations: 455 in the baseline and 780 in the intervention period. The percentage of infants experiencing hypothermia upon OR arrival and at any point during the operation decreased from 48.7% to 6.4% and 67.5% to 37.4%, respectively. Upon return to the NICU, the percentage of infants experiencing postoperative hypothermia decreased from 5.8% to 2.1%, while postoperative hyperthermia increased from 0.8% to 2.6%.

Conclusions:

Intraoperative hypothermia is more prevalent than postoperative hypothermia. Standardizing temperature monitoring, transport, and OR warming reduces both; however, further reduction requires a better understanding of how and when risk factors contribute to hypothermia to avoid further increasing hyperthermia. Continuous, secure, and automated data collection improved temperature management by enhancing situational awareness and facilitating data analysis.
A Combined Exoscopic and Endoscopic Approach for Radical Temporal Bone Resection and Usefulness of the Endoscopic Approach to the Medial Aspect of the Temporal Bone
Authors: Iwami Kenichiro , Watanabe Tadashi , Osuka Koji , Maruo Takashi , Ogawa Tetsuya , Fujimoto Yasushi
Published: July 2023

Radical temporal bone resection (TBR) for lateral skull base malignancies is technically challenging because of the vital anatomical structures located at the medial part of the temporal bone and their limited exposure. A possible solution is to adopt an additional endoscopic approach for medial osteotomy to reduce blind spots. The authors aimed to describe a combined exoscopic and endoscopic approach (CEEA) for cranial dissection in radical TBR and to determine the usefulness of the endoscopic approach to the medial aspect of the temporal bone. Having utilized the CEEA in for cranial dissection in radical TBR since 2021, the authors included 5 consecutive patients who underwent the procedure between 2021 and 2022. All surgeries were successful and resulted in no significant complications. The additional use of an endoscope improved visualization of the middle ear in 4 patients and that of the inner ear and carotid canal in 1 patient, enabling precise and safe cranial dissection. Furthermore, surgeons experienced reduced intraoperative postural stress with CEEA than with a microscopic approach. The main advantage of CEEA in radical TBR was the extension of the viewing angles of the endoscope, which allowed observation of the medial aspect of the temporal bone and limited tumor exposure and injury to vital structures. Given the other benefits of exoscopes and endoscopes, including compact size, ergonomics, and surgical field accessibility, CEEA proved to be an efficient treatment option for cranial dissection in radical TBR.
Feeding Outcomes After Mandibular Distraction for Airway Obstruction in Infants
Authors: Yi Amber , Brand William T. , Black Jonathan S.
Published: July 2023

Robin sequence is a congenital issue resulting in airway obstruction, difficulty feeding, and failure to thrive. Mandibular Distraction Osteogenesis is used to improve airway obstruction in these patients, but little data exists characterizing feeding outcomes following surgery. This study aims to evaluate feeding outcomes and weight gain following mandibular distraction for airway correction in infants. A single-center retrospective chart review was conducted, and patients under 12 months old who underwent mandibular distraction between December 2015 and July 2021 were included in the study. The presence of cleft palate, distance of distraction, and polysomnography results were recorded. The primary outcomes were the length of distraction, need for nasogastric tube or G-tube at discharge, time lapsed to achieve full oral feeds, and weight gain (kilogram). Ten patients met the criteria. Of those 10 patients, 4 were syndromic, 7 had a cleft palate, and 4 had a congenital cardiac diagnosis. The average length of stay postsurgery was 28 days. Eight patients achieved full oral feeds in an average of 65.6 days. Five patients required nasogastric tube or G-tube at discharge, with 3 of these patients later transitioning to full oral feeds. All patients gained weight 3 months postsurgery with an average of 0.521 kg/mo. Patients who achieved full oral feeds gained an average of 0.549 kg/mo. Patients with supplementation gained an average of 0.454 kg/mo. All patients demonstrated improvement in airway obstruction with an average postoperative apnea hypopnea index of 1.64. Further investigation is necessary to identify challenges seen in feeding after mandibular distraction osteogenesis and improve care.
Unigems: plasmids and parts to facilitate teaching on assembly, gene expression control and logic in E. coli
Authors: Siddall Alex , Williams Abbie Ann , Sanders Jason , Denton Jai A , Madden Dean , Schollar John , Bryk Jarosław
Published: July 2023

Synthetic biology enables the creative combination of engineering and molecular biology for exploration of fundamental aspects of biological phenomena. However, there are limited resources available for such applications in the educational context, where straightforward setup, easily measurable phenotypes and extensibility are of particular importance. We developed Unigems, a set of 10 plasmids that enable classroom-based investigation of gene expression control and biological logic gates to facilitate teaching synthetic biology and genetic engineering. It is built on a high-copy plasmid backbone and is easily extensible thanks to a common primer set that facilitates Gibson Assembly of PCR-generated or synthesised DNA parts into the target vector. It includes two reporter genes with either two constitutive (high- or low-level) or two inducible (lactose- or arabinose-) promoters, as well as a single-plasmid implementation of an AND logic gate. The set can readily be employed in undergraduate teaching settings, during outreach events and for training of iGEM teams. All plasmids have been deposited in Addgene.
Radioimmunotherapy as a pathogen-agnostic treatment method for post-COVID-19 opportunistic fungal infections
Authors: Carvalho Jorge L.C. , Malo Mackenzie E. , Allen Kevin J.H. , Frank Connor , Xiao Zhiwen , Jiao Rubin , Dadachova Ekaterina
Published: July 2023

Invasive fungal infections (IFI) such as mucormycosis are causing devastating morbidity and mortality in immunocompromised patients as anti-fungal agents do not work in the setting of suppressed immune system. COVID-19 pandemic has created a novel landscape for IFI in post-pandemic patients, which results from severe immune suppression caused by COVID-19 infection, comorbidities (diabetes, obesity) and immunosuppressive treatments such as steroids. The antigen-antibody interaction has been employed in radioimmunotherapy (RIT) to deliver lethal doses of ionizing radiation emitted by radionuclides to targeted cells and has demonstrated efficacy in several cancers. One of the advantages of RIT is its independence of immune status of a host which is crucial for immunosuppressed post-COVID-19 patients. In present work we targeted with RIT fungal pan-antigens 1,3-beta-glucan and melanin pigment, which are present in the majority of pathogenic fungi, thus making such targeting pathogen-agnostic. We demonstrated in experimental murine mucormycosis that 177Lutetium-labeled antibodies to these two antigens effectively decreased the fungal burden in major organs including the brain. These results are encouraging because they show the effectiveness of pathogen-agnostic RIT in significantly decreasing fungal burden in vivo, while they can be also potentially applied to treat the broad range of invasive fungal infections which express pan-antigens 1,3-beta-glucan or melanin.
Quantifying Cell-State Densities in Single-Cell Phenotypic Landscapes using Mellon
Authors: Otto Dominik , Jordan Cailin , Dury Brennan , Dien Christine , Setty Manu
Published: July 2023

Cell-state density characterizes the distribution of cells along phenotypic landscapes and is crucial for unraveling the mechanisms that drive cellular differentiation, regeneration, and disease. Here, we present Mellon, a novel computational algorithm for high-resolution estimation of cell-state densities from single-cell data. We demonstrate Mellon’s efficacy by dissecting the density landscape of various differentiating systems, revealing a consistent pattern of high-density regions corresponding to major cell types intertwined with low-density, rare transitory states. Utilizing hematopoietic stem cell fate specification to B-cells as a case study, we present evidence implicating enhancer priming and the activation of master regulators in the emergence of these transitory states. Mellon offers the flexibility to perform temporal interpolation of time-series data, providing a detailed view of cell-state dynamics during the inherently continuous developmental processes. Scalable and adaptable, Mellon facilitates density estimation across various single-cell data modalities, scaling linearly with the number of cells. Our work underscores the importance of cell-state density in understanding the differentiation processes, and the potential of Mellon to provide new insights into the regulatory mechanisms guiding cellular fate decisions.
Diurnal variation of brain activity in the human suprachiasmatic nucleus
Authors: Oka Satoshi , Ogawa Akitoshi , Osada Takahiro , Tanaka Masaki , Nakajima Koji , Kamagata Koji , Aoki Shigeki , Oshima Yasushi , Tanaka Sakae , Kirino Eiji , Nakamura Takahiro J. , Konishi Seiki
Published: July 2023

The suprachiasmatic nucleus (SCN) is the central clock for circadian rhythms. Animal studies have revealed daily rhythms in the neuronal activity in the SCN. However, the circadian activity of the human SCN has remained elusive. In this study, to reveal the diurnal variation of the SCN activity in humans, the SCN was localized, and its activity was investigated using perfusion imaging. We scanned each participant four times a day, every six hours, and higher activity was observed at noon while lower activity was recorded in the early morning. The SCN activity was then measured every thirty minutes for six hours from midnight to dawn and showed a decreasing trend and was comparable with the rodent SCN activity after switching off the lights. These results suggest that the diurnal variation of the human SCN follows the zeitgeber cycles of mammals and is modulated by physical lights rather than the local time.
Signatures of Jamming in the Cellular Potts Model
Authors: Devanny Alexander J. , Lee Daniel J. , Kampman Lucas , Kaufman Laura J.
Published: July 2023

We explore the jamming transition in the Cellular Potts Model (CPM) as a function of confinement, cell adhesion, and cell shape. To accurately characterize jamming, we compare Potts simulations of unconfined single cells, cellular aggregates, and confluent monolayers as a function of cell adhesion energies and target cell shape. We consider metrics that may identify signatures of the jamming transition, including diffusion coefficients, anomalous diffusion exponents, cell shape, cell-cell rearrangements, and velocity correlations. We find that the onset of jamming coincides with an abrupt drop in cell mobility, rapid transition to sub-diffusive behavior, and cessation of rearrangements between neighboring cells that is unique to confluent monolayers. Velocity correlations reveal collective migration as a natural consequence of high energy barriers to neighbor rearrangements for certain cell types. Cell shapes across the jamming transition in the Potts model are found to be generally consistent with predictions of vertex-type simulations and trends from experiment. Finally, we demonstrate that changes in cell shape can fluidize cellular monolayers at cellular interaction energies where jamming otherwise occurs.
The Impact of AI-Based Modeling on the Accuracy of Protein Assembly Prediction: Insights from CASP15
Authors: Ozden Burcu , Kryshtafovych Andriy , Karaca Ezgi
Published: July 2023

In CASP15, 87 predictors submitted around 11,000 models on 41 assembly targets. The community demonstrated exceptional performance in overall fold and interface contact prediction, achieving an impressive success rate of 90% (compared to 31% in CASP14). This remarkable accomplishment is largely due to the incorporation of DeepMind’s AF2-Multimer approach into custom-built prediction pipelines. To evaluate the added value of participating methods, we compared the community models to the baseline AF2-Multimer predictor. In over 1/3 of cases the community models were superior to the baseline predictor. The main reasons for this improved performance were the use of custom-built multiple sequence alignments, optimized AF2-Multimer sampling, and the manual assembly of AF2-Multimer-built subcomplexes. The best three groups, in order, are Zheng, Venclovas and Wallner. Zheng and Venclovas reached a 73.2% success rate over all (41) cases, while Wallner attained 69.4% success rate over 36 cases. Nonetheless, challenges remain in predicting structures with weak evolutionary signals, such as nanobody-antigen, antibody-antigen, and viral complexes. Expectedly, modeling large complexes remains also challenging due to their high memory compute demands.

In addition to the assembly category, we assessed the accuracy of modeling interdomain interfaces in the tertiary structure prediction targets. Models on seven targets featuring 17 unique interfaces were analyzed. Best predictors achieved the 76.5% success rate, with the UM-TBM group being the leader. In the interdomain category, we observed that the predictors faced challenges, as in the case of the assembly category, when the evolutionary signal for a given domain pair was weak or the structure was large. Overall, CASP15 witnessed unprecedented improvement in interface modeling, reflecting the AI revolution seen in CASP14.
Pathogenic aggregates alter actin organization and cellular viscosity resulting in stalled clathrin mediated endocytosis
Authors: Singh Surya Bansi , Rajput Shatruhan Singh , Sharma Aditya , Ananthanarayanan Vaishnavi , Nandi Amitabha , Patil Shivprasad , Majumdar Amitabha , Subramanyam Deepa
Published: July 2023

Protein aggregation is a common underlying feature of neurodegenerative disorders. Cells expressing neurodegeneration–associated mutant proteins show altered uptake of ligands, suggestive of impaired endocytosis, in a manner as yet unknown. Using live cell imaging, we show that clathrin-mediated endocytosis (CME) is affected due to altered actin cytoskeletal organization in the presence of Huntingtin aggregates. Additionally, we find that cells containing Huntingtin aggregates are stiffer and less viscous than their wild-type counterparts due to altered actin conformation, and not merely due to the physical presence of aggregate(s). We further demonstrate that CME and cellular viscosity can be rescued by overexpressing Hip1, Arp2/3 or transient LatrunculinA treatment. Examination of other pathogenic aggregates revealed that only a subset of these display defective CME, along with altered actin organization and increased stiffness. Together, our results point to an intimate connection between functional CME, actin organization and cellular stiffness in the context of neurodegeneration.
Preclinical assessment of CAR-NK cell-mediated killing efficacy and pharmacokinetics in a rapid zebrafish xenograft model of metastatic breast cancer
Authors: Shankar Nivedha Murali , Montero Paola Ortiz , Kurzyukova Anastasia , Rackwitz Wiebke , Künzel Stephan R. , Wels Winfried S. , Tonn Torsten , Knopf Franziska , Eitler Jiri
Published: July 2023

Natural killer (NK) cells are attractive effectors for adoptive immunotherapy of cancer. Results from first-in-human studies using chimeric antigen receptor (CAR)-engineered primary NK cells and NK-92 cells are encouraging in terms of efficacy and safety. In order to further improve treatment strategies and to test the efficacy of CAR-NK cells in a personalized manner, preclinical screening assays using patient-derived tumor samples are needed. Zebrafish (Danio rerio) embryos and larvae represent an attractive xenograft model to study growth and dissemination of patient-derived tumor cells because of their superb live cell imaging properties. Injection into the organism’s circulation allows investigation of metastasis, cancer cell-to-immune cell-interactions and studies of the tumor cell response to anti-cancer drugs.

Here, we established a zebrafish larval xenograft model to test the efficacy of CAR-NK cells against metastatic breast cancerin vivoby injecting metastatic breast cancer cells followed by CAR-NK cell injection into the Duct of Cuvier (DoC). We validated the functionality of the system with two different CAR-NK cell lines specific for PD-L1 and ErbB2 (PD-L1.CAR NK-92 and ErbB2.CAR NK- 92 cells) against the PD-L1-expressing MDA-MB-231 and ErbB2-expressing MDA-MB-453 breast cancer cell lines.

Injected cancer cells were viable and populated peripheral regions of the larvae, including the caudal hematopoietic tissue (CHT), simulating homing of cancer cells to blood forming sites. CAR-NK cells injected 2.5 hours later migrated to the CHT and rapidly eliminated individual cancer cells throughout the organism. Confocal live-cell imaging demonstrated intravascular migration and real-time interaction of CAR-NK cells with MDA-MB-231 cells, explaining the rapid and effectivein vivocytotoxicity.

Thus, our data suggest that zebrafish larvae can be used for rapid and cost-effectivein vivoassessment of CAR-NK cell potency and to predict patient response to therapy.
Reshaping water-related urban places with collaborative participation: a critical examination of the Kabataş waterfront
Authors: Cihan Yavuzcan Meryem Melis , Gür Elmira Ayşe
Published: July 2023

Purpose

This study aims to draw a general framework for recreating water-related urban places. It discusses design criteria and processes that will strengthen people's and the city's relationship with the waterfront. It also explores the functional requirements of a participatory process to incorporate social and functional relations into place making.

Design/methodology/approach

The study is based on a comprehensive case study of the Kabataş project process. Data collection methods include archive searches, questionnaires, interviews and analysis. The study analyses the architectural decisions, the role and perspectives of the key actors and the current dynamics that shape the process. It points out shortcomings and needs of communication and collaboration with different stakeholders, especially with the users.

Findings

The results show that political and power dynamics play an important role in shaping the process. Non-transparent processes increase the gap between the aspects of community and decision makers in current practices. Establishing holistic, waterfront-specific and collaborative approaches is a necessity. The results also show that the success of participation depends on procedural dynamics such as scope, method, timing, representativeness of the community, institutionalisation level, transparency and deliberation.

Originality/value

Despite the intense interest in waterfront regeneration, few studies have focused on the potential of the participatory process. The study examines the intersections of waterfront design decisions and collaborative participation at various scales and emphasises the importance of local actors in the social production of space.
Towards a sustainable agri-food ecosystem: the case study of South Korean public food procurement
Authors: Baek Seungha , Radziwon Agnieszka
Published: July 2023

Purpose

Public food procurement (PFP) plays an important role in establishing agri-food systems. The study explores local food system stakeholders' response to PFP interventions by addressing the question of how PFP transforms agri-food systems and how this new agri-food ecosystem is governed.

Design/methodology/approach

This article presents and discusses a unique case study of Jeonbuk, a rural province in South Korea, which successfully transformed its agri-food system into an ecosystem through its sustainability-oriented innovations (SOIs) among born ecopreneur farmers. This case not only offers insights into a novel way to create value chains through legislative, executive and judicial governance but also extends the body of knowledge on agri-food systems by introducing the concept of an agri-food ecosystem.

Findings

The findings indicate the importance of the ecosystem governance and knowledge exchange among internal and external ecosystem stakeholders. In particular, PFP institutions play a crucial role in facilitating the operation of public meal centers and cooperation among actors.

Practical implications

Taking an ecosystem lens to agri-food systems may offer agricultural cooperatives a wider perspective and better understanding of the governance structures necessary to successfully execute public interventions. Lastly, the Korean case differs from other developing countries, but its role model qualities could help to implement successful school meal programs elsewhere.

Originality/value

This paper reviewed and applied a conceptual framework aimed at identifying the role of PFP institutions in the value chain governance by studying a case study of a South Korean local school meal program. The study further extends the agricultural cooperatives research and contributes to a better understanding of the role of a municipality and an agri-food intermediary in the governance process involving producers and kitchens.
Resolving friction in the tramadol economy in Nigeria
Authors: Dele-Adedeji Ini , Ireland Lala , Klantschnig Gernot
Published: July 2023

Purpose

This paper aims to examine the friction that has surfaced since the adoption of policy measures restricting access to tramadol, a synthetic opioid, in Nigeria in 2018. Our analysis reveals how non-licensed pharmaceutical actors, who have played an integral part in the supply chain, have been criminalised for activities that have previously been sanctioned by the state. This criminalisation has given rise to friction between what is perceived as illegal by the state and what is acceptable for other actors in the tramadol economy.

Design/methodology/approach

The paper is based on more than 20 in-depth interviews with illicit actors and regulators in the tramadol economy in Lagos, Nigeria’s commercial centre, and a review of key policy documents, media reports and popular cultural outputs on tramadol.

Findings

The paper highlights the effects of prohibitionist policies and the voices of criminalised actors to provide a contextual view of the Nigerian tramadol economy. Relying on the concepts of friction and quasilegality, we show how social relationships have become the main backbone of the illicit tramadol economy and how they enable participants to resolve the pervasive friction between illegality and social acceptability of tramadol.

Originality/value

This paper provides an inside understanding of the nuances of the rarely studied illicit trade in synthetic opioids and how restrictive policies that are seemingly not well thought through have created friction in the Nigerian context.
Colonization of urban futures in the Global South: lessons from the case of Isfahan 2040
Authors: Zackery Ali , Taheri Demneh Mohsen , Ebadi Nejad Maryam
Published: July 2023

Purpose

Due to the limitations of conventional urban planning, it is essential to develop novel techniques of urban futruing. This paper aimed to use the scenario technique to create four plausible narratives of the future of Isfahan. Also, the authors described the problems of city foresight in the Global South.

Design/methodology/approach

This paper chronicles the Schwartzian steps taken to build explorative scenarios of Isfahan City in Iran in 2040. After using a STEEPV (Social, Technological, Environmental, Economic, Political, Value) analysis, the authors prioritized the collected variables by combining influence diagrams, the iceberg metaphor and an expert-based survey. Once the key uncertainties were derived, four scenarios were developed and discussed.

Findings

Through thematic analysis of the official visions of Isfahan’s future and the juxtaposition of these narratives with insight yielded in the scenario-development process, the paper concludes that the Northernness of the prevailing urban imaginaries, uncritical mimetic benchmarking, depoliticization of urban futures and the decorative reductionistic visions colonize urban futures in Isfahan/Iran. Critical/deconstructive city foresight and application of discomfort/ignorance criteria in the generation of scenarios can improve the rigor and quality of city foresight in the Global South.

Originality/value

The application of city foresight in the Global South has been limited. The paper is a step toward bridging this gap and providing some recommendations on how city foresight in the Global South might differ from its counterparts in the Global North.