bluuebunny/crossref_metadata_2025 huggingface dataset:
A toolbox to engineer the highly productive cyanobacterium Synechococcus sp. PCC 11901
Authors: Victoria Angelo J , Selão Tiago Toscano , Moreno-Cabezuelo José Ángel , Mills Lauren A , Gale Grant A R , Lea-Smith David J , McCormick Alistair J
Published: May 2024

Synechococcus sp. PCC 11901 (PCC 11901) is a fast-growing marine cyanobacterial strain that has a capacity for sustained biomass accumulation to very high cell densities, comparable to that achieved by commercially relevant heterotrophic organisms. However, genetic tools to engineer PCC 11901 for biotechnology applications are limited. Here we describe a suite of tools based on the CyanoGate MoClo system to unlock the engineering potential of PCC 11901. First, we characterized neutral sites suitable for stable genomic integration that do not affect growth even at high cell densities. Second, we tested a suite of constitutive promoters, terminators, and inducible promoters including a 2,4-diacetylphloroglucinol (DAPG)-inducible PhlF repressor system, which has not previously been demonstrated in cyanobacteria and showed tight regulation and a 228-fold dynamic range of induction. Lastly, we developed a DAPG-inducible dCas9-based CRISPR interference (CRISPRi) system and a modular method to generate markerless mutants using CRISPR-Cas12a. Based on our findings, PCC 11901 is highly responsive to CRISPRi-based repression and showed high efficiencies for single insertion (31% to 81%) and multiplex double insertion (25%) genome editing with Cas12a. We envision that these tools will lay the foundations for the adoption of PCC 11901 as a robust model strain for engineering biology and green biotechnology.
Wildfire risk management in the era of climate change
Authors: Synolakis Costas Emmanuel , Karagiannis Georgios Marios
Published: May 2024

The August 8, 2023 Lahaina fire refocused attention on wildfires, public alerts, and emergency management. Wildfire risk is on the rise, precipitated through a combination of climate change, increased development in the wildland–urban interface (WUI), decades of unmitigated biomass accumulation in forests, and a long history of emphasis on fire suppression over hazard mitigation. Stemming the tide of wildfire death and destruction will involve bringing together diverse scientific disciplines into policy. Renewed emphasis is needed on emergency alerts and community evacuations. Land management strategies need to account for the impact of climate change and hazard mitigation on forest ecosystems. Here, we propose a long-term strategy consisting of integrating wildfire risk management in wider-scope forest land management policies and strategies, and we discuss new technologies and possible scientific breakthroughs.
How framing strategies foster robust policy ideas
Authors: Béland Daniel , Cox Robert Henry
Published: May 2024

In this contribution, we identify how the framing strategies employed by policy and political actors make policy ideas robust. We examine the policy ideas of solidarity and sustainability to show how framing strategies that took advantages of the valence and polysemy of both ideas shaped them into robust policy ideas. Both ideas began as wide-ranging concepts designed to build coalitions in debates over a particular large-scale policy problem. Robustness is a quality that emerged over time as these ideas grew to become highly attractive framing devices to justify policy proposals. Moreover, they have proven to be resilient despite changing circumstances or even efforts of their opponents to reframe them in a negative way.
Regulation of mitochondrial network architecture and function in mesenchymal stem cells by micropatterned surfaces
Authors: Dong Zixuan , Han Weiju , Jiang Panyu , Hao Lijing , Fu Xiaoling
Published: May 2024

Mitochondrial network architecture, which is closely related to mitochondrial function, is mechanically sensitive and regulated by multiple stimuli. However, the effects of microtopographic cues on mitochondria remain poorly defined. Herein, polycaprolactone (PCL) surfaces were used as models to investigate how micropatterns regulate mitochondrial network architecture and function in rat adipose-derived stem cells (rASCs). It was found that large pit (LP)-induced rASCs to form larger and more complex mitochondrial networks. Consistently, the expression of key genes related to mitochondrial dynamics revealed that mitochondrial fusion (MFN1 and MFN2) and midzone fission (DRP1 and MFF) were increased in rASCs on LP. In contrast, the middle pit (MP)-enhanced mitochondrial biogenesis, as evidenced by the larger mitochondrial area and higher expression of PGC-1. Both LP and MP promoted ATP production in rASCs. It is likely that LP increased ATP levels through modulating mitochondrial network architecture while MP stimulated mitochondria biogenesis to do so. Our study clarified the regulation of micropatterned surfaces on mitochondria, highlighting the potential of LP and MP as a simple platform to stimulate mitochondria and the subsequent cellular function of MSCs.
A survey of the radiation safety practices of veterinary practitioners during portable equine radiography in Ireland
Authors: Daly Shauna , Skelly Cliona , Lewis Mandy , Toomey Rachel
Published: May 2024

Veterinary practitioners and other personnel involved in the examination are exposed to ionizing radiation while performing portable radiographs on horses. An online survey was distributed to all Veterinary Council of Ireland-registered practices where the self-reported practice profile is at least 20% equine work. The survey contained questions relating to radiation safety training, protocols, personal dosimetry and lead protection usage, repeat exposures, sedation, and personnel roles during the examination. The aim of the survey was to document the current radiation safety practices of equine veterinary practitioners during portable radiography. The results showed that although adherence to guidance set out by the Environmental Protection Agency (EPA) is reasonably good, compliance rates can be improved. Personal dosemeter usage and repeat rate reduction could particularly benefit from further improvement. This is of the utmost importance in ensuring that occupational radiation exposure to veterinary practitioners is kept to an absolute minimum during their daily practice.
Age-Related Changes in Sleep and Its Implications for Cognitive Decline in Aging Persons With Schizophrenia: A Critical Review
Authors: Baran Bengi , Lee Ellen E
Published: May 2024

Background and Hypothesis

Cognitive impairment is a core feature of schizophrenia that worsens with aging and interferes with quality of life. Recent work identifies sleep as an actionable target to alleviate cognitive deficits. Cardinal non-rapid eye movement (NREM) sleep oscillations such as sleep spindles and slow oscillations are critical for cognition. People living with schizophrenia (PLWS) and their first-degree relatives have a specific reduction in sleep spindles and an abnormality in their temporal coordination with slow oscillations that predict impaired memory consolidation. While NREM oscillatory activity is reduced in typical aging, it is not known how further disruption in these oscillations contributes to cognitive decline in older PLWS. Another understudied risk factor for cognitive deficits among older PLWS is obstructive sleep apnea (OSA) which may contribute to cognitive decline.

Study Design

We conducted a narrative review to examine the published literature on aging, OSA, and NREM sleep oscillations in PLWS.

Study Results

Spindles are propagated via thalamocortical feedback loops, and this circuitry shows abnormal hyperconnectivity in schizophrenia as revealed by structural and functional MRI studies. While the risk and severity of OSA increase with age, older PLWS are particularly vulnerable to OSA-related cognitive deficits because OSA is often underdiagnosed and undertreated, and OSA adds further damage to the circuitry that generates NREM sleep oscillations.

Conclusions

We highlight the critical need to study NREM sleep in older PWLS and propose that identifying and treating OSA in older PLWS will provide an avenue to potentially mitigate and prevent cognitive decline.
Clozapine Efficacy and Adverse Drug Reactions Among a Nationwide Study of 1021 Australians Prescribed Clozapine: The ClozaGene Study
Authors: Lind Penelope A , Parker Richard K , Northwood Korinne , Siskind Dan J , Medland Sarah E
Published: May 2024

Background and Hypothesis

The ClozaGene Study is a nationwide cohort of adults who have been treated with clozapine. While clozapine is indicated in the management of treatment-resistant schizophrenia, it is associated with a considerable adverse drug reaction (ADR) burden, and not all patients achieve adequate symptomatic response. The current study focuses on self-reported experiences of clozapine use and response, clozapine-associated ADRs, and mental health comorbidity.

Study Design

A total of 1021 participants (41.0% female; aged 46.2 ± 10.6 years [range 18–66]) were recruited via a mail-out based on prescriptions for clozapine. Participants completed a self-report questionnaire.

Study Results

Most participants (90.1%, n = 912) were living with schizophrenia while 41.5% reported a lifetime diagnosis of depression, 15.6% bipolar disorder, and 8.1% schizoaffective disorder. Clozapine was currently prescribed to 944 (92.5%) participants and 37.8% of these participants self-reported currently taking additional antipsychotic medication. Nearly 3 quarters of participants living with schizophrenia reported that clozapine helped control their schizophrenia symptoms moderately to very well. The most commonly reported ADRs were sialorrhea (80.3%), weight gain (71.0%), constipation (56.9%), and sedation (52.8%). The prevalence of clozapine cessation due to clozapine-induced myocarditis and neutropenia was 1% and 0.4%, respectively.

Conclusions

Our findings highlight the high rate of psychotic and metabolic symptoms and ADRs among adults prescribed clozapine in the general Australian population. Future genomic analyses will focus on identifying genetic variants influencing clozapine treatment response and side effects.
The dose disrupts the pathway: application of Paracelsus principle to mechanistic toxicology
Authors: Suvorov Alexander
Published: May 2024

Arguably the most famous principle of toxicology is “The dose makes the poison” formulated by Paracelsus in the 16th century. Application of the Paracelsus’s principle to mechanistic toxicology may be challenging as one compound may affect many molecular pathways at different doses with different and often nonlinear dose-response relationships. As a result, many mechanistic studies of environmental and occupational compounds use high doses of xenobiotics motivated by the need to see a clear signal indicating disruption of a particular molecular pathway. This approach ignores the possibility that the same xenobiotic may affect different molecular mechanism(s) at much lower doses relevant to human exposures. To amend mechanistic toxicology with a simple and concise guiding principle, I suggest recontextualization of Paracelsus’s following its letter and spirit: “The dose disrupts the pathway”. Justification of this statement includes observations that many environmental and occupational xenobiotics affect a broad range of molecular cascades, that most molecular pathways are sensitive to chemical exposures, and that different molecular pathways are sensitive to different doses of a chemical compound. I suggest that this statement may become a useful guidance and educational tool in a range of toxicological applications, including experimental design, comparative analysis of mechanistic hypotheses, evaluation of the quality of toxicological studies, and risk assessment.
Racial Disparities Exist in 90-day Unplanned Return to the Emergency Department Following Orthopaedic Trauma Surgery
Authors: Pean Christian , Chari Tristan , Valan Bruno , Peairs Emily , Poehlein Emily , Green Cynthia L. , Taylor Erica , Toth Alison , Olson Steven , DeBaun Malcolm
Published: May 2024

OBJECTIVES:

Introduction: Racial disparities in healthcare outcomes exist, including in orthopaedic trauma care. This study aimed to determine the impact of race, social deprivation, and payor status on 90-day emergency department (ED) revisits among orthopaedic trauma surgery patients at a Level 1 trauma academic medical center.

METHODS:

Design: Retrospective Chart Review Analysis

Setting:

Level 1 Academic Trauma Center in Durham, North Carolina

Patient Selection Criteria:

Adult Patients undergoing orthopaedic trauma surgery between 2017 and 2021

Outcome Measures and Comparisons: The primary outcome of this retrospective cohort study was 90-day return to the ED. Logistic regression analysis was performed for variables of interest [race, social deprivation (measured by Area Deprivation Index), and payor status] separately and combined, with each model adjusting for distance to the hospital. Results were interpreted as odds ratios (ORs) of 90-day ED revisits comparing levels of the respective variables. Statistical significance was assessed at α=0.05.

RESULTS:

A total of 3,120 adult patients who underwent orthopaedic trauma surgery between 2017 and 2021 were included in the analysis. Black race (OR=1.47; 95% CI: 1.17-1.84, p<0.001) and Medicaid coverage (OR=1.63, 95% CI: 1.20-2.21, p=0.002) were significantly associated with higher odds of return to ED compared to non-Black or non-Medicaid-covered patients. While ethnic minority (Hispanic/Latino or non-White) was statistically significant while adjusting only for distance to the hospital (OR=1.23, 95% CI: 1.00-1.50, p=0.047), it was no longer significant after adjusting for the other sociodemographic variables (OR=1.13, 95% CI: 0.91-1.39, p=0.27). Weighted Area Deprivation Index (ADI) was not associated with a difference in odds of return to ED in any adjusted models.

CONCLUSIONS:

The results highlight the presence of racial and socioeconomic disparities in ED utilization, with Black race and Medicaid coverage significantly associated with higher odds of return to the ED. Future research should delve deeper into comprehending the root causes contributing to these racial and socioeconomic utilization disparities and evaluate the effectiveness of targeted interventions to reduce them.

Level of Evidence:

Economic Level III. See Instructions for Authors for a complete description of levels of evidence.
Circulating tumor DNA- and cancer tissue-based next-generation sequencing reveals comparable consistency in targeted gene mutations for advanced or metastatic non-small cell lung cancer
Authors: Huang Weijia , Xu Kai , Liu Zhenkun , Wang Yifeng , Chen Zijia , Gao Yanyun , Peng Renwang , Zhou Qinghua
Published: May 2024

Background:

Molecular subtyping is an essential complementarity after pathological analyses for targeted therapy. This study aimed to investigate the consistency of next-generation sequencing (NGS) results between circulating tumor DNA (ctDNA)-based and tissue-based in non-small cell lung cancer (NSCLC) and identify the patient characteristics that favor ctDNA testing.

Methods:

Patients who diagnosed with NSCLC and received both ctDNA- and cancer tissue-based NGS before surgery or systemic treatment in Lung Cancer Center, Sichuan University West China Hospital between December 2017 and August 2022 were enrolled. A 425-cancer panel with a HiSeq 4000 NGS platform was used for NGS. The unweighted Cohen’s kappa coefficient was employed to discriminate the high-concordance group from the low-concordance group with a cutoff value of 0.6. Six machine learning models were used to identify patient characteristics that relate to high concordance between ctDNA-based and tissue-based NGS.

Results:

A total of 85 patients were enrolled, of which 22.4% (19/85) had stage III disease and 56.5% had stage IV disease. Forty-four patients (51.8%) showed consistent gene mutation types between ctDNA-based and tissue-based NGS, while one patient (1.2%) tested negative in both approaches. Advanced diseases and metastases to other organs would be fit for the ctDNA-based NGS, and the generalized linear model showed that T stage, M stage, and tumor mutation burden were the critical discriminators to predict the consistency of results between ctDNA-based and tissue-based NGS.

Conclusion:

ctDNA-based NGS showed comparable detection performance in the targeted gene mutations compared with tissue-based NGS, and it could be considered in advanced or metastatic NSCLC.
Enhanced external counterpulsation in cardiac rehabilitation in patients with coronary heart disease: a literature review
Authors: He Xifei , Lu Lijuan , Cheng Jie , Wang Zhaozhao , Yang Weimei , Fan Xuemei , Cui Yishuang
Published: May 2024

Enhanced external counterpulsation (EECP) is a non-invasive, outpatient, pulsatile-assisted circulation technique that has been used in many diseases, such as diabetes, stroke, and coronary heart disease (CHD). EECP can improve blood flow dynamics, vascular endothelial function, atherosclerosis outcomes, and other cardiovascular attributes through synchronous cardiac systolic and diastolic movements, thus playing a therapeutic role. EECP has been widely used in the treatment of refractory angina pectoris and plays a significant role in the treatment and rehabilitation of patients with CHD. As a passive aerobic exercise, it enables new ways for patients with cardiovascular disease who cannot carry out exercise rehabilitation to perform aerobic exercise. EECP will become increasingly important as the incidence of chronic disease increases and the rehabilitation discipline develops. With increasing attention being focused on EECP, the literature has grown rapidly. To help researchers gain a comprehensive understanding of this area, this review focuses on the progress made in applying EECP to CHD cardiac rehabilitation globally, including a brief history of EECP, the working principle of EECP, etc. This review will help researchers grasp the research outline and gaps in the literature regarding EECP and will provide a reference for them in future studies.
Comparison of Cardiovascular Health Between Parents and Non-Parents in NHANES 2011-2018
Authors: Gregory Emily F. , Maddox Adya I. , Tindall Alyssa , Ibarra Jose L. , Virudachalam Senbagam
Published: May 2024

Background and Objectives:

We compared cardiovascular health for parents and non-parents using the American Heart Association’s Life’s Essential 8 (LE8).

Methods:

This cross-sectional cohort analyzed 2011-2018 NHANES participants aged 20 to 54. The exposure was parenting, defined as living with a child. Logistic regression assessed whether parenting was associated with odds of ideal LE8 total or sub-scores. Regression adjusted for age, sex, race and ethnicity, educational attainment, marital status, and income. Subgroups included female sex, male sex, income <150% federal poverty levels, and parents of younger children.

Results:

6847 participants represented a weighted population of 79 120 285 (57% parents). Parenting was not associated with adjusted odds of ideal total LE8 (OR 0.91, 95% CI 0.76–1.09). Parenting was associated with decreased odds of ideal body mass index (BMI) (OR 0.81, 95% CI 0.72–0.91) and increased odds of smoking avoidance (OR 1.22, 95% CI 1.09–1.38). Associations varied by subgroup. Only the subgroup with lower incomes demonstrated reduced odds of ideal total LE8 for parents (OR 0.58, 95% CI 0.41–0.82).

Conclusions:

Parents and non-parents differed in smoking and BMI, though not in LE8 total. Families with low incomes may particularly benefit from dual generation cardiovascular risk reduction.
Risk factors and nomogram of clinically relevant pancreatic fistula after pancreaticoduodenectomy for periampullary cancer: A prospective multicenter cohort study
Authors: Vo Truong Quoc , Phan Minh Tri , Tran Cong Duy Long , Doan Tien My
Published: May 2024

Background

Clinically relevant postoperative pancreatic fistula (CRPF) is considered the most dangerous morbidity associated with pancreaticoduodenectomy (PD). The purpose of this study was to evaluate the risk factors and to construct a predicted model for CRPF after PD.

Materials and Methods

Consecutive patients who underwent pancreaticoduodenectomy between August 2021 and October 2023 at Cho Ray Hospital and University Medical Center were included in a multicenter cohort research. Multivariate logistic regression analyses were used to identify the risk factors of CRPF, and a nomogram was built based on these factors. The value of the nomogram in predicting CRPF was evaluated using the area under the receiver operating characteristic (ROC) curve.

Results

There were 183 eligible patients in this study (mean age: 57.5 ± 12.6 years; 101 males), and the prevalence of CRPF was 13.7% overall. Multivariate analyses showed that 4 risk factors related to CRPF, including preoperative serum albumin <3.5 g/dL, body mass index (BMI) ≥25 kg/m2, soft texture of the pancreas and estimated blood loss ≥400 mL were prognostic factors for CRPF (P < 0.05). We built a nomogram based on 4 variables to predict CRPF, and the area under the ROC curve for this nomogram was 0.855 (95% CI: 0.768–0.933).

Conclusions

Nomogram developed from 4 risk factors shows good performance to predict CRPF after PD. The clinical findings of this study will help surgeons identify perioperative risk factors for high-risk patients with pancreatic fistula who should be managed differently from other patients.

Clinical Trial Registry

ClinicalTrials.gov NCT05017207.

Statement of Significance

We successfully developed a nomogram to predict the risk of pancreatic fistula using 4 perioperative factors. By incorporating these risk factors into clinical practice, surgeons can develop appropriate treatment plans and interventions for high-risk patient populations, potentially reducing the morbidity associated with CRPF.
Empiric Antibiotic Therapy in 1402 Children With Parapneumonic Effusion/Pleural Empyema in Germany: A Long-term Surveillance Study
Authors: Forster Johannes , Piazza Giuseppina , Goettler David , Tanzberger Eva-Lotta , Kenntner Simone , Schoen Christoph , Streng Andrea , Liese Johannes G.
Published: May 2024

Objective:

This study investigated empiric antibiotic treatment (EAT), guideline adherence, antibiotic streamlining and clinical outcomes in 1402 hospitalized children with pediatric parapneumonic effusion/pleural empyema (PPE/PE).

Methods:

A nationwide surveillance study collected data on EAT, clinical course/outcome, pathogens, susceptibility testing and antibiotic streamlining of children with PPE/PE in Germany between 2010 and 2018. Subgroups were compared using χ
2 test/Fisher exact test, Mann–Whitney U test and linear regression analysis adjusting for patient age where appropriate.

Results:

Complete data on EAT were available for 1402 children. In children with monotherapy (n = 567) and in children with combination therapy of 2 antibiotics (n = 589), the most commonly used antibiotics were aminopenicillin/beta-lactamase inhibitor [138/567 (24.3%) and 102/589 (17.3%)] and cefuroxime [291/567 (51.3%) and 294/589 (49.9%)]. The most common combinations with these beta-lactams were macrolides, aminoglycosides and clindamycin. We observed no difference in clinical severity/outcome between EAT with aminopenicillin/beta-lactamase inhibitor and cefuroxime, neither when used in monotherapy nor when used in combination therapy of 2 antibiotics. Species diagnosis of Streptococcus pneumoniae (n = 192), Streptococcus pyogenes (n = 111) or Staphylococcus aureus (n = 38) in polymerase chain reaction or culture from pleural fluid or blood resulted in a switch to an appropriate narrow-spectrum beta-lactam therapy in 9.4%, 18.9 % and 5.2% of children. In a subset of children with reported bacterial susceptibility testing, penicillin resistance was reported in 3/63 (4.8%) of S. pneumoniae and methicillin resistance in S. aureus was reported in 10/32 (31.3%) of children.

Conclusion:

This study points to antibiotic overtreatment in children with PPE/PE, particularly the frequent use of combinations of antibiotics. Children receiving combinations of antibiotics did not show differences in clinical outcomes. The low rate of children with streamlined antibiotic therapy even upon pathogen detection indicates a necessity for antibiotic stewardship measures in PPE/PE and the need of investigating other potential therapeutic strategies as anti-inflammatory therapy.
Evaluation of Pediatric HIV Postexposure Prophylaxis Guideline Following Child Sexual Assault in Western Australia
Authors: Combs Momoko , Johnson Alice , Abbotsford Joanne , Bowen Asha C. , McLeod Charlie , Foley David A.
Published: May 2024

Background:

HIV postexposure prophylaxis (PEP) following child sexual assault (CSA) is recommended in select cases. High rates of poor adherence to PEP are reported. We evaluated adherence to the recommended management of children following CSA at the tertiary pediatric facility in Western Australia and compared our approach with international guidelines.

Methods:

Medical records were reviewed for all children <16 years old assessed at Perth Children’s Hospital between October 1, 2016 and November 30, 2020 following alleged CSA. Data, including exposure type, PEP adherence and follow-up, were collected. A review of contemporary national and international PEP guidelines was undertaken in parallel.

Results:

There were 511 alleged CSA events over the study period; 62/511 (12%) were appropriately risk-assessed as requiring PEP by the treating clinician. PEP was not prescribed in 8/62 (13%) events, with a reason documented for 6/8 (75%). Overall, less than half of children who were eligible for PEP were adherent to the 28-day regimen (23/54, 43%). Gastrointestinal upset contributed to early cessation in 5/54 (9%). Final 3-month blood-borne virus serology results were available in less than one in 3 children. A review of international clinical practice revealed significant heterogeneity of criteria for the provision of PEP and a paucity of pediatric-specific data.

Conclusions:

We identified several areas of our PEP management that required strengthening, with limited direction available in current international guidelines. We have adopted a broader use of fixed drug combinations and implemented a multifaceted follow-up program. It will be essential to review the impact of these changes.
Prospective randomized clinical trial evaluating efficacy and safety of a new ophthalmic viscosurgical device in patients undergoing cataract surgery
Authors: De Rosa Luigi , Furiosi Luca , Pellegrini Marco , Yu Angeli Christy , Scorcia Vincenzo , Busin Massimo
Published: May 2024

Purpose:

To evaluate the efficacy and safety of Bio-Hyalur LVD compared with Viscoat ophthalmic viscosurgical device (OVD) in patients undergoing routine cataract surgery.

Setting:

2 tertiary eyecare hospitals in Italy.

Design:

Prospective randomized clinical trial.

Methods:

This study compared the outcomes of Bio-Hyalur LVD vs Viscoat OVD in patients undergoing standard cataract surgery with phacoemulsification and intraocular lens implantation from January 2021 to April 2022. The primary outcome was mean change in IOP at 6 hours. Secondary outcomes included 1-day, 7-day, 30-day, and 90-day mean intraocular pressure (IOP); 7-day, 30-day, and 90-day corrected distance visual acuity; endothelial cell density (ECD); change in central corneal thickness (CCT); and complications including intraocular inflammation.

Results:

84 eyes of 84 patients (n = 41 in the Bio-Hyalur LVD group and n = 43 in the Viscoat group) were screened, enrolled, randomized, and included in the analysis. Mean change in IOP was significantly higher in the Viscoat group than in the Bio-Hyalur LVD group 6 hours (P = .034), 7 days (P < .001), 30 days (P < .001), and 90 days (P = .003) postoperatively. Mean change in uncorrected distance visual acuity and corrected distance visual acuity was significantly higher in the Bio-Hyalur LVD group 30 and 90 days postoperatively. No significant differences in ECD, CCT, and complication rates were observed between groups at any timepoint.

Conclusions:

Bio-Hyalur LVD OVD was safe and effective in patients undergoing routine cataract surgery. Bio-Hyalur LVD OVD did not confer a higher risk of postoperative increase in IOP.
Comparison of corneal endothelial cell loss in FLACS: impact on endothelial cells in different regions
Authors: Altansukh Altantsetseg , Ma Kathleen Sheng-Chuan , Doyodmaa Adiyabazar , Hung Ning , Kang Eugene Yu-Chuan , Quan Wuyong , Ma David Hui-Kang
Published: May 2024

Purpose:

To compare changes in corneal endothelial parameters after femtosecond laser–assisted cataract surgery (FLACS) and conventional phacoemulsification surgery (CPS) in different corneal regions.

Setting:

Chang Gung Memorial Hospital, Linkou, Taiwan.

Design:

Single-center, retrospective.

Methods:

Before and 1, 3, and 6 months postoperatively, specular microscopy was performed to measure endothelial cell density (ECD), corneal thickness, hexagonal cell rate (Hex), and coefficient of variation (CoV). Position 1 referred to the central cornea, position 2 was nearest to the main wound, and position 3 was at the peripheral zone diagonal to the main wound.

Results:

This study analyzed 96 eyes in the FLACS group and 110 eyes in the CPS group. Preoperatively, position 1 had lower ECD and CoV and higher Hex compared with the peripheral regions. FLACS patients had a significantly less phacoemulsification time and cumulative dissipated energy. At 1 month, FLACS patients showed a significantly smaller increase in corneal thickness at positions 1 and 2. At 3 months, FLACS patients had lower endothelial cell loss (ECL) at positions 1 and 3. ECL remained lower in FLACS patients at 6 months. The highest ECL was observed at position 2 in both groups and was progressive up to 6 months.

Conclusions:

After phacoemulsification, ECL varied in different corneal regions. At 3 months, the FLACS group exhibited significantly less ECL at the central cornea; however, the continued ECL at 6 months near the main wound suggested ongoing endothelial remodeling in the region.
Pain reflects the informational value of nociceptive inputs
Authors: Coll Michel-Pierre , Walden Zoey , Bourgoin Pierre-Alexandre , Taylor Veronique , Rainville Pierre , Robert Manon , Nguyen Dang Khoa , Jolicoeur Pierre , Roy Mathieu
Published: May 2024

Pain perception and its modulation are fundamental to human learning and adaptive behavior. This study investigated the hypothesis that pain perception is tied to pain's learning function. Thirty-one participants performed a threat conditioning task where certain cues were associated with a possibility of receiving a painful electric shock. The cues that signaled potential pain or safety were regularly changed, requiring participants to continually establish new associations. Using computational models, we quantified participants' pain expectations and prediction errors throughout the task and assessed their relationship with pain perception and electrophysiological responses. Our findings suggest that subjective pain perception increases with prediction error, that is, when pain was unexpected. Prediction errors were also related to physiological nociceptive responses, including the amplitude of nociceptive flexion reflex and electroencephalography markers of cortical nociceptive processing (N1-P2–evoked potential and gamma-band power). In addition, higher pain expectations were related to increased late event-related potential responses and alpha/beta decreases in amplitude during cue presentation. These results further strengthen the idea of a crucial link between pain and learning and suggest that understanding the influence of learning mechanisms in pain modulation could help us understand when and why pain perception is modulated in health and disease.
Improving Barriers to Timely Colonoscopies: A New Approach to Overcoming Gaps in Medical Care
Authors: Borgen Alex , Regan Hannah , Strelow Brittany
Published: May 2024

This study investigates delays in transitioning from positive noninvasive multitarget stool DNA test results to scheduled diagnostic colonoscopies and identifies strategies aimed at improving patient care. A retrospective review revealed a 53% reduction in the average time from positive multitarget stool DNA test results to ordering colonoscopies postintervention. The findings demonstrate the significance of implementing a new communication system to expedite transitions in health care processes, showcasing its potential to significantly improve efficiency in patient care and health care provider workflows across various clinical testing scenarios. The findings emphasize the transformative impact of this communication system, shedding light on its ability to streamline processes and enhance patient care and staff experience.
Cancer drugs and acute kidney injury: new therapies and new challenges
Authors: Gork Ittamar , Xiong Fei , Kitchlu Abhijat
Published: May 2024

Purpose of review

Cancer therapies continue to evolve at a rapid pace and although novel treatments, including immunotherapies and targeted therapies have allowed for substantial improvements in cancer survival, they carry associated risks of acute kidney injury (AKI). We aim to summarize the existing literature on AKI associated with the spectrum of systemic cancer treatments, including conventional chemotherapies, newer immunotherapies, and the growing number of targeted cancer therapies, which may be associated with both AKI and ‘pseudo-AKI’.

Recent findings

Conventional cytotoxic chemotherapies (e.g. cisplatin and other platinum-based agents, methotrexate, pemetrexed, ifosfamide, etc.) with well recognized nephrotoxicities (predominantly tubulointerstitial injury) remain in widespread use. Immunotherapies (e.g., immune checkpoint inhibitors and CAR-T therapies) may be associated with kidney immune-related adverse events, most often acute interstitial nephritis, and rarely, glomerular disease. Recently, multiple targeted cancer therapies have been associated with reduced renal tubular secretion of creatinine, causing elevations in serum creatinine and apparent ‘pseudo-AKI’. To complicate matters further, these agents have had biopsy-proven, ‘true’ kidney injury attributed to them in numerous case reports.

Clinicians in nephrology and oncology must be aware of the various potential kidney risks with these agents and recognize those with clinically meaningful impact on both cancer and kidney outcomes.
Double Chromogen-based Immunohistochemical Staining: An Efficient Approach for Utilizing Long-term Formalin-fixed Tissue in Biobanks
Authors: Maskey Dhiraj , Stevens Julia , Smith Caine C. , Novelli Mario , Sutherland Greg T.
Published: May 2024

The New South Wales Brain Tissue Resource Centre is a human brain bank that provides top-quality brain tissue for cutting-edge neuroscience research spanning various conditions from alcohol use disorder to neurodegenerative diseases. However, the conventional practice of preserving brain tissue in formalin poses challenges for immunofluorescent staining primarily due to the formalin’s tendency, over time, to create cross-links between antigens, which can obscure epitopes of interest. In addition, researchers can encounter issues such as spectral bleeding, limitations in using multiple colors, autofluorescence, and cross-reactivity when working with long-term formalin-fixed brain tissue. The purpose of the study was to test chromogen-based double immunolabeling to negate the issues with immunofluorescent staining. Colocalization of antigens was explored using chromogens 3-amino-9-ethylcarbazole (AEC) and 3,3,-diaminobenzidine in a sequential staining procedure where the AEC signal was eliminated by alcohol treatment. Combinations of 2 or 3 primary antibodies from the same or different species were trialed successfully with this protocol. The colocalization of antigens was also demonstrated with pseudocoloring that mimicked immunofluorescence staining. This staining technique increases the utility of archival formalin-fixed tissue samples.
Digital Pathology is a Fast and Effective Platform for Providing Head and Neck Pathology Consultations
Authors: Liu Bella L. , Haghighi Mehrvash , Westra William H.
Published: May 2024

Surgical pathology of the head and neck is one of the more challenging areas in all of diagnostic pathology. Its unparalleled diversity and complexity renders it highly vulnerable to diagnostic error compelling unconstrained access to specialized diagnostic expertise. Digital pathology (DP) is a state-of-the-art tool that could facilitate access to specialized expertise, but it is relatively untested in the context of pathology consultations. In a collaboration between Labcorp Dianon and a large academic hospital with subspecialized surgical pathology, DP was implemented to provide the pathology community access to head and neck pathology expertise. From this collaborative experience, glass slides from consecutive consult cases that had been previously diagnosed using DP were reviewed by an expert consultant in a blinded manner following an extended wash-out period. The intraobserver discrepancy rate was recorded. Major discrepancies were defined as those resulting in significant impact on clinical management and/or prognosis, whereas minor discrepancies were those with no impact on care or prognosis. Slides from 57 cases were available for review. The average wash-out period was 19 months. Five discrepancies were recorded (intraobserver concordance rate of 91%). All discrepancies were minor (major discrepancy rate, 0%; minor discrepancy rate, 9%). On appraisal of the discrepant cases, discordant diagnoses were attributed to subjective differences in interpretation rather than objective differences related to the inferiority of DP. DP decreased the median turnaround time by 97% (from 70 h 26 min to 2 h 25 min). DP provides efficient and fast access to expert consultants. The speed of case delivery does not compromise diagnostic precision. Discrepancies are uncommon, minor, and reflect subjective interpretative differences inherent to difficult and ambiguous head and neck cases, and not the inferiority of DP as a diagnostic platform. High concordance can be achieved even for those difficult and complex cases that are concentrated in the consultation practice. This observation carries profound implications regarding universal health care access to specialized diagnostic expertise.
Primitive Embryonic-Type Neuroectodermal/Glandular Complexes in Testicular Germ Cell Tumors
Authors: Whaley Rumeal D. , Ulbright Thomas M.
Published: May 2024

Embryonic-type neuroectodermal elements are often intimately mixed with primitive endodermal-type glands, like those of yolk sac tumors, in germ cell neoplasia in situ (GCNIS)-derived germ cell tumors of the testis. Because the primitive glands mimic tubules or rosettes of embryonic-type neuroectodermal elements, these embryonic-type neuroectodermal/glandular complexes may be misinterpreted as pure lesions of embryonic-type neuroectodermal elements, which, if of sufficient size, may lead to a diagnosis of embryonic-type neuroectodermal tumor, despite that the criteria of the World Health Organization for a “somatic-type malignancy” are not met. A diagnosis of embryonic-type neuroectodermal tumor in the testis may lead to retroperitoneal lymphadenectomy even in clinical stage I patients, and in postchemotherapy resections indicates a poor prognosis. The distinction of the neuroectodermal and glandular elements is not always straightforward based on morphology alone. We, therefore, studied 34 testis-derived germ cell tumors with embryonic-type neuroectodermal/glandular complexes and 2 purely glandular yolk sac tumors to characterize the immunophenotypes and determine an efficient immunohistochemical panel to aid in this differential. We found that GFAP, synaptophysin, and paired-like homeobox 2B (PHOX2B) expression was specific to embryonic-type neuroectodermal elements, although PHOX2B had poor sensitivity. In contrast, positive reactions with antibodies directed against AFP, villin, and CDX2 were specific for the glandular elements, although CDX2 had poor sensitivity. Other markers, including AE1/AE3 cytokeratin, SALL4, glypican 3, SOX2, SOX11, CD56, INSM1, and neurofilament, proved less helpful because of their nonspecificity and/or poor sensitivity. We conclude that the optimal immunohistochemical panel for distinguishing the components of embryonic-type neuroectodermal/glandular complexes includes stains for synaptophysin, GFAP, villin, and AFP.
Bivalirudin Monitoring in Pediatric Ventricular Assist Device and Extracorporeal Membrane Oxygenation: Analysis of Single-Center Retrospective Cohort Data 2018–2022
Authors: Engel Elissa R. , Perry Tanya , Block Mary , Palumbo Joseph S. , Lorts Angela , Luchtman-Jones Lori
Published: May 2024

OBJECTIVES:

The activated partial thromboplastin time (aPTT) is the most frequently used monitoring assay for bivalirudin in children and young adults on mechanical circulatory support including ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO). However, intrinsic variability of the aPTT complicates management and risks bleeding or thrombotic complications. We evaluated the utility and reliability of a bivalirudin-calibrated dilute thrombin time (Bival dTT) assay for bivalirudin monitoring in this population.

DESIGN:

Retrospective analysis of clinical data (including aPTT, dilute thrombin time [dTT]) and results of residual plasma samples from VAD patients were assessed in two drug-calibrated experimental assays. One assay (Bival dTT) was validated for clinical use in VAD patients, and subsequently used by clinicians in ECMO patients. Pearson correlation and simple linear regression were used to determine R
2 correlation coefficients between the different laboratory parameters using Statistical Package for Social Sciences (Armonk, NY).

SETTING:

ICUs at Cincinnati Children’s Hospital Medical Center.

SUBJECTS:

Children on VAD or ECMO support anticoagulated with bivalirudin.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

One hundred fifteen plasma samples from 11 VAD patients were analyzed. Both drug-calibrated experimental assays (anti-IIa and Bival dTT) showed excellent correlation with each other (R
2 = 0.94) and with the dTT (R
2 = 0.87), but poor correlation with aPTT (R
2 = 0.1). Bival dTT was selected for validation in VAD patients. Subsequently, clinically ordered results (105) from 11 ECMO patients demonstrated excellent correlation between the Bival dTT and the standard dTT (R
2 = 0.86) but very poor correlation with aPTT (R
2 = 0.004).

CONCLUSIONS:

APTT is unreliable and correlates poorly with bivalirudin’s anticoagulant effect in ECMO and VAD patients. A drug-calibrated Bival dTT offers superior reliability and opportunity to standardize results across institutions. Additional studies are needed to determine an appropriate therapeutic range and correlation with clinical outcomes.
Ultrasound in Cardiopulmonary Arrest and Resuscitation
Authors: Loscalzo Steven M. , White Lauren J. , Rosenblatt Samuel , Woods-Hill Charlotte Z. , Teran Felipe , Wolfe Heather , Himebauch Adam S. , Glau Christie , Nishisaki Akira , Conlon Thomas W.
Published: May 2024

Objectives

Information obtained from point-of-care ultrasound during cardiopulmonary arrest and resuscitation (POCUS-CA) can be used to identify underlying pathophysiology and provide life-sustaining interventions. However, integration of POCUS-CA into resuscitation care is inconsistent. We used expert consensus building methodology to help identify discrete barriers to clinical integration. We subsequently applied implementation science frameworks to generate generalizable strategies to overcome these barriers.

Measures and Main Results

Two multidisciplinary expert working groups used KJ Reverse-Merlin consensus building method to identify and characterize barriers contributing to failed POCUS-CA utilization in a hypothetical future state. Identified barriers were organized into affinity groups. The Center for Implementation Research (CFIR) framework and Expert Recommendations for Implementing Change (CFIR-ERIC) tool were used to identify strategies to guide POCUS-US implementation.

Results

Sixteen multidisciplinary resuscitation content experts participated in the working groups and identified individual barriers, consolidated into 19 unique affinity groups that mapped 12 separate CFIR constructs, representing all 5 CFIR domains. The CFIR-ERIC tool identified the following strategies as most impactful to address barriers described in the affinity groups: identify and prepare champions, conduct local needs assessment, conduct local consensus discussions, and conduct educational meetings.

Conclusions

KJ Reverse-Merlin consensus building identified multiple barriers to implementing POCUS-CA. Implementation science methodologies identified and prioritized strategies to overcome barriers and guide POCUS-CA implementation across diverse clinical settings.
MELATONIN ATTENUATES RENAL ISCHEMIA-REPERFUSION INJURY BY REGULATING MITOCHONDRIAL DYNAMICS AND AUTOPHAGY THROUGH AMPK/DRP1
Authors: Wang Huabin , Li Yi , Cao Xichao , Niu Heping , Li Xiaoran , Wang Jirong , Yang Jianwei , Xu Changhong , Wang Hailong , Wan Shun , Li Kunpeng , Fu Shengjun , Yang Li
Published: May 2024

Ischemia-reperfusion injury (IRI) often stems from an imbalance between mitochondrial dynamics and autophagy. Melatonin mitigates IRI by regulating mitochondrial dynamics. However, the precise molecular mechanism underlying the role of melatonin in reducing IRI through modulating mitochondrial dynamics remains elusive. The objective of this study was to investigate whether pretreatment with melatonin before IRI confers protective effects by modulating mitochondrial dynamics and mitophagy. Melatonin pretreatment was administered to HK-2 cells and live rats before subjecting them to hypoxia-reoxygenation or IRI, respectively. Cells and rat kidney models were evaluated for markers of oxidative stress, autophagy, mitochondrial dynamics, and the expression of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and phospho-AMPKα (P-AMPK). After renal IRI, increased mitochondrial fission and autophagy were observed, accompanied by exacerbated cellular oxidative stress injury and aggravated mitochondrial dysfunction. Nevertheless, melatonin pretreatment inhibited mitochondrial fission, promoted mitochondrial fusion, and attenuated autophagy levels. This intervention was correlated with a notable reduction in oxidative stress injury and remarkable restoration of mitochondrial functionality. Ischemia-reperfusion injury led to a decline in P-AMPK levels, whereas melatonin pretreatment increased the level of P-AMPK levels. Silencing AMPK with small interfering RNA exacerbated mitochondrial damage, and in this context, melatonin pretreatment did not alleviate mitochondrial fission or autophagy levels but resulted in sustained oxidative stress damage. Collectively, these findings indicate that melatonin pretreatment shields the kidneys from IRI by mitigating excessive mitochondrial fission, moderating autophagy levels, and preserving appropriate mitochondrial fission, all in an AMPK-dependent manner.