bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term efficacy and safety of subcutaneous tocilizumab in clinical trials of polyarticular or systemic juvenile idiopathic arthritis
Authors: Brunner Hermine I , Ruperto Nicolino , Ramanan Athimalaipet V , Horneff Gerd , Minden Kirsten , Calvo Penades Inmaculada , Alexeeva Ekaterina , Cleary Gavin , Stern Sara M , Kone-Paut Isabelle , Maldonado Velázquez María del Rocío , Rabinovich C Egla , Remesal Agustin , Silva Clovis Artur , Nikishina Irina , Zucchetto Mauro , Brockwell Laura , Gordon Oliver , Nagel Sandra , De Benedetti Fabrizio ,   for the PRINTO and PRCSG Investigators, Cuttica Rubén , Rama Maria Elena , Akikusa Jonathan , Chaitow Jeffrey , Len Claudio , Silva Clovis Artur , Schmeling Heinrike , Schneider Rayfel , Kone-Paut Isabelle , Hufnagel Markus , Minden Kirsten , Horneff Gerd , de Benedetti Fabrizio , Velázquez María del Rocío Maldonado , Rubio Nadina , Alekseeva Ekaterina , Remesal Agustin , Boteanu Alina , Torrent Rosa Bou , Penades Inmaculada Calvo , Ramanan Athimalaipet V , Cleary Gavin , Brunner Hermine I , Janow Ginger , Weiss Jennifer , Lovell Daniel , Martin Alan , Nanda Kabita , Wagner-Weiner Linda , Stern Sara , Zeft Andrew , Dare Jason
Published: March 2024

Objective

To investigate the safety and efficacy of subcutaneous tocilizumab (SC-TCZ) treatment in a long-term extension (LTE) of clinical trials in polyarticular or systemic juvenile idiopathic arthritis (pJIA or sJIA).

Methods

Patients with pJIA or sJIA from two open-label, 52-week phase 1b core trials of SC-TCZ who had adequate response per investigator assessment entered the LTE and continued SC-TCZ treatment according to body weight–based dosing regimens until commercial availability or up to 5 years. Pharmacokinetics, pharmacodynamics, and efficacy were assessed for up to 3 years, and safety for up to 5 years in the LTE.

Results

Forty-four patients with pJIA and 38 patients with sJIA entered the LTE. Tocilizumab trough concentrations were maintained within the range expected to provide clinical benefit (mean values: pJIA, ∼10 μg/ml; sJIA, ∼75 μg/ml over 3 years). Pharmacodynamic parameters (interleukin-6, soluble interleukin-6 receptor, erythrocyte sedimentation rate, C-reactive protein) were maintained throughout the LTE at levels achieved in the core trials. Inactive disease per American College of Rheumatology provisional criteria was reported for 90% (17/19) and 53% (8/15) of patients with pJIA and 91% (10/11) and 92% (12/13) of patients with sJIA in the <30 and ≥30 kg body weight groups, respectively. Serious adverse events in the LTE were reported in six patients with pJIA (13.6%; five serious infections) and five patients with sJIA (13.2%; one serious infection).

Conclusion

Patients with pJIA or sJIA experienced long-term disease control with SC-TCZ treatment. Long-term safety was consistent with the known tocilizumab safety profile.

Clinical trial registration

clinicaltrials.gov, NCT02165345
SERPINA3, FGA, AGP1, ITIH3 and SAA1 as novel biomarkers for eosinophilic granulomatosis with polyangiitis diagnosis and activity assessment
Authors: Liu Yun , Kong Xiufang , Zhang Xiao , Chen Zhihong , Wang Jinghua , Chen Huiyong , Jiang Lindi
Published: March 2024

Objective

The objective of this study was to identify novel biomarkers for diagnosis and prediction of active eosinophilic granulomatosis with polyangiitis (EGPA) through data-independent acquisition (DIA) analysis.

Methods

Plasma samples from 11 EGPA patients and 10 healthy controls (HCs) were analysed through DIA to identify potential biomarkers. The results were validated in 32 EGPA patients, 24 disease controls (DCs), and 20 HCs using ELISA. The receiver operating characteristic (ROC) curve was used to assess the diagnostic value of candidate biomarkers.

Results

Thirty-five differentially expressed proteins (DEPs) (24 upregulated and 11 downregulated) were screened between the EGPA and HC groups. Five proteins, including serine proteinase inhibitor A3 (SERPINA3), alpha-fibrinogen (FGA), alpha-1 acid glycoprotein 1(AGP1), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), and serum amyloid A1 (SAA1), were significantly upregulated in EGPA compared with HCs. Apart from SAA1, all proteins were also higher in EGPA patients compared with DCs. Furthermore, a panel of SERPINA3 and SAA1 exhibited potential diagnostic value for EGPA, with an area under the curve (AUC) of 0.953, while a panel of SERPINA3, FGA, AGP1 and ITIH3 showed good discriminative power for differentiating EGPA from DCs, with an AUC of 0.926. Moreover, SERPINA3, FGA and AGP levels were significantly higher in active EGPA and correlated well with disease activity. A combination of SERPINA3 and AGP1 exhibited an excellent AUC of 0.918 for disease activity assessment.

Conclusion

SERPINA3, FGA, AGP1, ITIH3 and SAA1 were identified as potential biomarkers for EGPA diagnosis and disease activity assessment. Among them, as a single biomarker, SERPINA3 had the best diagnostic performance.
Investigating a clinically informed sleep disturbance threshold for physical and mental health among Gulf War Illness veterans
Authors: Allen Nathaniel , Crock Lucas , Chun Timothy , Reinhard Matthew J
Published: March 2024

Study Objectives

This study (1) assessed sleep quality and health in Gulf War veterans (GWV) meeting the Gulf War Illness (GWI) criteria and (2) compared health associations for both those meeting a “clinically disturbed sleep” threshold, and those below, as determined by the Pittsburgh Sleep Quality Index (PSQI) cutoff for military populations (≥10) on measures of physical, mental, and cognitive health.

Methods

Participant data consisted of questionnaires and assessments completed prior to group assignment in a clinical trial. The sample consisted of 147 GWV, where 81.0% were males, and the median age was 53.4 years.

Results

The mean (SD) PSQI global score was 12.34 (4.00) with 61% of the sample qualifying as clinically disturbed sleepers according to the cutoff (global PSQI ≥ 10). GWI veterans with PSQI scores ≥10 did not differ from others in age (p = 0.20), sex (p = 0.19), or years of education (p = 0.87), but showed worse GW-related symptomology on the Gulf War Kansas questionnaire (p < 0.01), and poorer mental health on the Veterans Rand-36 (p < 0.01).

Conclusions

Disturbed sleep was associated with measures of pain, fatigue, and cognitive health. Our results suggest that a previously determined clinical threshold for clinically disturbed sleep is useful when examining the health status of the study population. Given that GWI is associated with elevated PSQI scores and a high frequency of disturbed sleep, cutoffs determining sleep health should be sensitive to population exposures and health history to improve interpretability.
Equitable Artificial Intelligence in Obstetrics, Maternal–Fetal Medicine, and Neonatology
Authors: McAdams Ryan M. , Green Tiffany L.
Published: March 2024

Artificial intelligence (AI) offers potential benefits in the interconnected fields of obstetrics, maternal–fetal medicine, and neonatology to bridge disciplinary silos for a unified approach. Artificial intelligence has the capacity to improve diagnostic accuracy and clinical decision making for the birthing parent–neonate dyad. There is an inherent risk of ingrained biases in AI that perpetuate existing inequalities; thus, care must be taken to include diverse data sets with interdisciplinary collaboration that centers equitable AI implementation. As AI plays an increasingly important role in perinatal care, we advocate for its cautious, equity-focused application to benefit the perinatal dyad while avoiding the intensification of health care disparities and disciplinary silos.
Pleural mesothelioma in situ: a comprehensive review
Authors: Danuzzo Federica , Raveglia Federico , Spinelli Francesca , Sibilia Chiara Maria , Cassina Enrico , Libretti Lidia , Pirondini Emanuele , Tuoro Antonio , Bono Francesca , Paladino Maria Emilia , Cortinovis Diego , Petrella Francesco
Published: March 2024

Pleural mesothelioma is a rare and aggressive cancer that affects the pleura. In recent years, there has been increasing interest and attention in detecting and diagnosing early-stage or precancerous forms of mesothelioma because of its severe prognosis and short life expectancy at the time of diagnosis. Mesothelioma in situ represents a clear opportunity to improve and innovate the diagnostic approach and the multimodality treatment of mesothelioma: the diagnosis of pleural mesothelioma at the ‘in-situ phase’ means early disease detection and thus paves the way to new possible curable strategies. Since 2021, when mesothelioma in situ was finally identified and described as a new histological entity, its diagnosis and management became a challenge and the subject of ongoing research; several aspects remain open and still outstanding as regards diagnostic techniques, time and probability of progression, need for and methods of follow up, aggressive and early surgery. This narrative review aims to provide a comprehensive overview of mesothelioma in situ covering its definition, risk factors, diagnostic criteria, and tricky aspects of early detection. It also highlights its clinical significance, new perspectives, and potential future indications in the context of pleural mesothelioma multidisciplinary management.
What is the Long-term Wear of a 5-Mrad Highly Crosslinked Polyethylene Liner? A 14-year RSA Study
Authors: Callary Stuart A. , Sharma Deepti K. , D’Apollonio Taisha M. , Critchley Owain , Mercer Graham , Wilson Christopher , Campbell David G.
Published: March 2024

Background

Lower doses of irradiation (≤ 5 Mrad) during the manufacture of highly crosslinked polyethylene acetabular liners may result in less crosslinking and an increased wear rate. Radiostereometric analysis (RSA) studies have found that wear of more highly irradiated highly crosslinked polyethylene liners (7 to 10 Mrad) decreases at longer-term follow-up compared with earlier reports of the same cohorts. Although wear of 5-Mrad irradiated liners appears to increase at midterm follow-up, it is unclear whether that remains true at longer follow-up.

Questions/purposes

We asked: (1) In patients who underwent THA with a 5-Mrad highly crosslinked polyethylene liner, what is the wear rate evaluated with RSA during the first 14 years? (2) Does the wear rate decrease after 6 years in situ?

Methods

This is a brief follow-up of prior RSA studies performed at 2 and 6 years. We prospectively reviewed the longer-term wear rate in 13 patients who underwent primary THAs with the same design of a 5-MRad irradiated crosslinked acetabular liner and a 28-mm cobalt-chromium articulation. Of the initial 30 patients who were enrolled, 13 (43%) were available at the 14-year timepoint; nine patients had died, 1 patient had withdrawn, 1 had an intraoperative fracture, 3 patients were too infirm to have radiographs, 2 had no baseline RSA radiographs, and 1 had poor-quality RSA images. Tantalum markers were inserted during surgery, and all patients had RSA radiographic examinations at 1 week, 6 months, and 1, 2, 6, and 14 years postoperatively.

Results

The mean ± standard deviation proximal, 2D, and 3D wear rates calculated between 1 year and 14 years were 0.019 ± 0.013 mm, 0.022 ± 0.015 mm, and 0.025 ± 0.019 mm per year, respectively. No patient had proximal 2D or 3D wear rates exceeding 0.06 mm per year. An increasing wear rate over time was measured for proximal and 2D wear rates between 6 and 14 years (0.024 and 0.030 mm per year) compared with that between 1 and 6 years (0.008 and 0.010 mm per year; p = 0.03).

Conclusion

The proximal, 2D, and 3D wear of a highly crosslinked polyethylene liner produced using 5-Mrad radiation remains low in the longer-term. With the small numbers available in a long-term RSA study such as this, we confirmed that the wear rate did not decrease at longer-term follow-up, unlike previous RSA studies of more highly irradiated highly crosslinked polyethylene liners. Nevertheless, the wear rate remains very low and below the threshold typically associated with the development of osteolysis (0.1 mm/year of wear). This should provide assurance to orthopaedic surgeons monitoring patients with this 5-Mrad irradiated liner in situ, while providing useful information to manufacturers of future highly crosslinked polyethylene liners.

Level of Evidence

Level IV therapeutic study.
Effects of different neuraxial analgesia modalities on the need for physician interventions in labour
Authors: Wang Lizhong , Huang Jiayue , Chang Xiangyang , Xia Feng
Published: March 2024

BACKGROUND

Neuraxial labour analgesia can be initiated with epidural (EPL), combined spinal epidural (CSE) or dural puncture epidural (DPE) and maintained with continuous epidural infusion (CEI), patient-controlled epidural analgesia (PCEA) or programmed intermittent epidural bolus (PIEB), but the optimal analgesia modality is still controversial.

OBJECTIVE

To compare the effects of commonly used neuraxial analgesia modalities on the proportion of women needing physician interventions, as defined by the need for physician-administered epidural top-ups for inadequate analgesia in labour.

DESIGN

Bayesian network meta-analysis.

DATA SOURCES

PubMed, Embase, CENTRAL, Web of Science and Wanfang Data were searched from January 1988 to August 2023 without language restriction.

ELIGIBILITY CRITERIA

Randomised controlled trials comparing two or more modalities of the following six neuraxial analgesia modalities in healthy labouring women: EPL+CEI+PCEA, EPL+PIEB+PCEA, CSE+CEI+PCEA, CSE+PIEB+PCEA, DPE+CEI+PCEA and DPE+PIEB+PCEA.

RESULTS

Thirty studies with 8188 women were included. Compared with EPL+CEI+PCEA, EPL+PIEB+PCEA [odds ratio (OR) = 0.44; 95% credible interval (CrI), 0.22 to 0.86], CSE+PIEB+PCEA (OR = 0.29; 95% CrI, 0.12 to 0.71) and DPE+PIEB+PCEA (OR = 0.19; 95% CrI, 0.08 to 0.42) significantly reduced the proportion of women needing physician interventions. DPE+PIEB+PCEA had fewer women needing physician interventions than all other modalities, except for CSE+PIEB+PCEA (OR = 0.63; 95% CrI, 0.25 to 1.62). There were no significant differences in local anaesthetic consumption, maximum pain score, and the incidence of instrumental delivery between the different neuraxial modalities.

CONCLUSIONS

PIEB+PCEA is associated with a lower risk of physician interventions in labour than CEI+PCEA. DPE or CSE and PIEB+PCEA may be associated with a lower likelihood of physician interventions than other neuraxial modalities. Otherwise, the new neuraxial analgesia techniques do not appear to offer significant advantages over traditional techniques. However, these results should be interpreted with caution due to limited data and methodological limitations.

TRIAL REGISTRATION

PROSPERO (CRD42023402540).
Hypericin Alleviates Chronic Kidney Disease–induced Left Ventricular Hypertrophy by Regulation of FGF23-FGFR4 Signaling Pathway
Authors: Liu Min , Cheng Linting , Ye Qianru , Liu Huamin , Shu Cong , Gao Haocheng , Liu Xin , Zhang Xiuhua , Chen Gaozhi
Published: March 2024

Chronic kidney disease (CKD) is a significant global health threat that imposes a substantial burden on both individuals and societies. CKD frequently correlates with cardiovascular events, particularly left ventricular hypertrophy (LVH), which contributes to the high mortality rate associated with CKD. Fibroblast growth factor 23 (FGF23), a hormone primarily involved in regulating calcium and phosphorus metabolism, has been identified as a major risk factor for LVH in CKD patients. Elevated serum FGF23 levels are known to induce LVH and myocardial fibrosis by activating the fibroblast growth factor receptor 4 (FGFR4) signal pathway. Therefore, targeting FGFR4 and its downstream signaling pathways holds potential as a treatment strategy for cardiac dysfunction in CKD. In our current study, we have discovered that Hypericin, a key component derived from Hypericum perforatum, has the ability to alleviate CKD-related LVH by targeting the FGFR4/phospholipase C gamma 1 (PLCγ1) signaling pathway. Through in vitro experiments using rat cardiac myocyte H9c2 cells, we observed that Hypericin effectively inhibits FGF23-induced hypertrophy and fibrosis by suppressing the FGFR4/PLCγ1/calcineurin/nuclear factor of activated T-cell (NFAT3) signaling pathway. In addition, our in vivo studies using mice on a high-phosphate diet and rat models of 5/6 nephrectomy demonstrated that Hypericin has therapeutic effects against CKD-induced LVH by modulating the FGFR4/PLCγ1/calcineurin/NFAT3 signaling pathway. In conclusion, our research highlights the potential of Hypericin as a candidate for the treatment of CKD-induced cardiomyopathy. By suppressing the FGFR4/PLCγ1 signaling pathway, Hypericin shows promise in attenuating LVH and myocardial fibrosis associated with CKD.
Chronotropic Responses to GLP-1 Receptor Agonists and Sitagliptin in Atria From Diabetic Rats
Authors: Akcabag Esra , Aksoyalp Zinnet Sevval , Oner Feride , Bayram Zeliha , Ozbey Gul , Nacitarhan Cahit , Ozdem Sebahat , Tasatargil Arda , Ozdem Sadi S.
Published: March 2024

Type 2 diabetes mellitus increases the risk of cardiovascular diseases. Therefore, elucidation of the cardiovascular effects of antidiabetics is crucial. Incretin-based therapies are increasingly used for type 2 diabetes mellitus treatment as monotherapy and in combination. We aimed to study the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sitagliptin on beating rates in isolated atria from diabetic rats. The chronotropic responses to GLP-1 RAs and sitagliptin as monotherapy and in combinations with metformin, pioglitazone, and glimepiride in isolated atria from control and diabetic rats were determined. GLP-1 (7–36), GLP-1 (9–36), and exendin-4 (1–39) produced increases in beating rates in both control and diabetic rat atria. However, sitagliptin increased the beating frequency only in the diabetic group. Exendin (9–39), nitro-l-arginine methyl ester hydrochloride, and indomethacin blocked responses to GLP-1 RAs but not the response to sitagliptin. Glibenclamide, 4-aminopyridine, apamin, charybdotoxin, superoxide dismutase, and catalase incubations did not change responses to GLP-1 RAs and sitagliptin. GLP-1 RAs increase beating rates in isolated rat atrium through GLP-1 receptor, nitric oxide, and cyclooxygenase pathways but not potassium channels and reactive oxygen radicals.
Outcomes of ERCP in Patients With Cystic Fibrosis
Authors: Haider Salman , Ramai Daryl , Shah Saira , Riyat Nayna D. , Spadaccini Marco , Chandan Saurabh , Maida Marcello , Rahman Asad Ur , Barakat Monique T.
Published: March 2024

Background:

Cystic fibrosis (CF) is a multisystem disorder that leads to abnormal transport of chloride and sodium across secretory epithelia resulting in thickened, viscous secretions in the bronchi, biliary tract, pancreas, intestine, and the reproductive system. Defects in the biliary tract can predispose to stone formation requiring endoscopic retrograde cholangiopancreatography (ERCP). However, there is a paucity of data assessing ERCP outcomes in patients with CF.

Methods:

We identified patients from the Healthcare Cost and Utilization Project (HCUP)—National Inpatient Sample (NIS) between the years 2016 and 2020. Our study group included patients with CF of all ages who underwent an inpatient ERCP. We used ICD10 diagnostic and procedural codes to identify patients, procedures, and complications of the procedure.

Results:

From 2016 to 2020, a total of 860,679 inpatient ERCPs were identified. Of these procedures, 535 (0.06%) were performed in patients with CF. The mean age of patients with CF undergoing ERCP was 60.62 years, of which 48% were males and 52% were females. Patients in the CF group had a higher incidence of post-ERCP pneumothorax (0.93%) than the patients in the non-CF group (0.15%). The occurrence of other ERCP-related adverse events was similar in both groups (P>0.05). On multivariate regression analysis, patients with CF were 1.75 times more likely to develop post-ERCP infections [odds ratio (OR): 1.75; 95% CI: 1.03-2.94; P=0.035) and 7.64 times more likely to develop post-ERCP pneumothorax (OR: 7.64; 95% CI: 1.03-56.5; P=0.046) compared to patients without CF after adjusting for confounders. The groups had no significant difference in mortality, post-ERCP pancreatitis, bleeding, perforation, pneumoperitoneum, and gas embolism. There was also no significant difference in the length of stay between the study and control groups.

Conclusions:

ERCP is a safe procedure in patients with CF with a comparable risk of postprocedural complications and mortality to those who do not have cystic fibrosis. However, patients with CF may experience a higher risk of post-ERCP infections and post-ERCP pneumothorax. Further studies are needed to prospectively evaluate outcomes of ERCP in patients with CF and to determine methods of mitigating adverse events.
Impact of iodine supply in infancy and childhood
Authors: Turck Dominique
Published: March 2024

Purpose of review

To assess the most relevant articles on the impact of iodine supply in at-risk populations, namely infants and young children, pregnant and lactating women.

Recent findings

The 2022 Iodine Global Network Annual Report confirmed the dramatic decrease of severe iodine deficiency over the last 30 years, thanks to universal iodine iodization. However, mild to moderate deficiency is still present in many countries, where recent data showed a decrease of iodine intake and an impairment of iodine status. Unfortunately, there is yet no validated biomarker to classify the iodine status at the individual level. Available data show that there is no clear evidence to link mild-to-moderate iodine deficiency to adverse health outcomes in pregnant and lactating women as well as in infants and children. The description of a negative impact of maternal iodine excess on neurodevelopment of infants is of concern.

Optimization of salt iodization (e.g. careful increase in iodine concentration in salt, use by food industry in processed foods) combined with targeted, personalized supplementation under medical supervision if needed (e.g. low intake of iodine rich foods, vegan diet) seems currently preferable to blanket supplementation.
Paediatric voice disorder: who to refer and how to assess? A summary of recent literature
Authors: Cohen Wendy , Wynne David M.
Published: March 2024

Purpose of review

The purpose of this review is to update the reader with recent advances and current opinion on the assessment and management of paediatric voice disorders.

Recent findings

Access to advanced multidisciplinary paediatric voice clinics has increased over the last decade. Often the assessment is combined between speech therapy/pathology and ENT surgery. Vocal fold nodules remain the most prevalent diagnosis at a paediatric voice clinic, but significant diseases will also present, for example laryngeal papilloma. Recently, more consideration of the psychosocial aspect of voice disorders and evaluation of auditory processing disorders have shown how these can have a negative impact. There also appears to be a lack of parental and teacher awareness of paediatric voice disorders and their significance.

We would recommend multiparametric assessment and analysis of all children with a voice disorder. Most paediatric voice conditions will respond to skilled voice therapy. However, the exact techniques and dosage requires further evaluation and research. Paediatric voice conditions are common and should not be dismissed, as they may represent significant disease, for example papilloma, vagal palsy or have a significant psychosocial impact on the child.
Topical review: Task shifting and the recruitment and retention of eye health workers in underserved areas
Authors: Somerville Joel G. , Strang Niall C. , Jonuscheit Sven
Published: March 2024

SIGNIFICANCE

Many populations experience difficulty accessing eye care, especially in rural areas. Implementing workforce recruitment and retention strategies, as well as task shifting through widening scope of practice, can improve eye care accessibility. This article provides novel evidence on the compatibility of these strategies aimed at enhancing ophthalmic workforce recruitment, retention, and efficacy.

PURPOSE

The global burden of blindness is unequally distributed, affects rural areas more, and is frequently associated with limited access to eye care. The World Health Organization has specified both task shifting and increasing human resources for eye health as instruments to improve access to eye care in underserved areas. However, it is uncertain whether these two instruments are sufficiently compatible to provide positive synergic effects. To address this uncertainty, we conducted a structured literature review and synthesized relevant evidence relating to task shifting, workforce recruitment, retention, and eye care. Twenty-three studies from across the globe were analyzed and grouped into three categories: studies exploring recruitment and retention in human resources for eye health in general, studies discussing the relationship between task shifting and recruitment or retention of health workers in general, and studies specifically discussing task shifting and recruitment or retention in eye care workers.

FINDINGS

Our findings demonstrate that incentives are effective for initiating task shifting and improving recruitment and retention in rural areas with a stronger effect noted in midlevel eye care professionals and trainees. Incentives can take various forms, e.g., financial and nonfinancial. The consideration of context-specific motivational factors is essential when designing strategies to facilitate task shifting and to improve recruitment and retention.
Acute Burn Care
Authors: Davis Brittany N. , Xu Hope , Gottlieb Lawrence J. , Vrouwe Sebastian Q.
Published: March 2024

Learning Objectives:

After studying this article and viewing the videos, the participant should be able to: 1. Describe the current epidemiology of burn injuries. 2. Understand burn pathophysiology and perform a wound assessment. 3. Summarize the initial emergency management of a burn patient. 4. Calculate the anticipated fluid resuscitation requirements for a burn injury, and diagnose the complications of overresuscitation. 5. Describe the diagnosis and management of inhalation injury. 6. List the goals of wound care for superficial and deep burns, and describe the closed dressing technique. 7. Perform excision of a burn wound. 8. Compare various wound closure techniques using autografts and skin substitutes.

Plastic surgeons are essential members of the multidisciplinary burn team. Burn injuries remain common, and plastic surgeons have an opportunity to develop and innovate the field of acute burn care in light of workforce shortages. Burn pathophysiology is complex and dynamic, which informs the challenges encountered during the perioperative phase. Accurate burn wound assessment remains difficult, with implications for diagnosis and management. A systematic approach is required when stabilizing a major burn and/or inhalation injury with newly updated fluid resuscitation and triage guidelines. Wound care continues to evolve, with an emphasis on a closed dressing technique. For deeper burns, new surgical techniques are emerging for surgical débridement, along with improvements to traditional methods of tangential excision. Following excision, a number of established and novel techniques are available to close the wound with either autografts or skin substitutes.
Renovating the Commission on Cancer’s Quality Measure Portfolio
Authors: Boffa Daniel J. , Lum Sharon S. , Palis Bryan , McCabe Ryan , Park Ko Un , Siddiqui Minhaj M. , Facktor Matthew , Mullet Timothy , Nelson Heidi
Published: March 2024

Importance:

Nearly 75% of newly diagnosed cancer patients in the United States will receive care from a hospital that is accredited by the Commission on Cancer (CoC). To support hospitals in their quality assurance efforts, the CoC maintains a portfolio of quality measures to give hospitals compliance data with select best practices for cancer care. As the CoC quality measures have evolved over recent years, many clinicians may lack awareness of the intent and content of the measure portfolio, as well as the mechanism by which new measures originate.

Observations:

The CoC quality measures are based on data that hospitals submit to the National Cancer Database, allowing the CoC to track compliance with a subset of consensus best practices. Each year, new measures are designed by diverse teams of specialists in the different treatment modalities for the tumor types covered by the portfolio. These proposed measures are then subjected to a range of vetting, refinement, and prioritization steps before being voted into the portfolio by the Quality Assurance and Data Committee of the CoC. Over the past 4 years, the CoC has worked to renovate not only the portfolio but also the process used to create and launch new measures, revise existing measures, and retire obsolete measures.

Conclusion and Relevance:

In the following overview, we outline the current measure process, highlight important changes to the portfolio, and share opportunities to further increase the impact.
Comparing Plasma Donor–derived Cell-free DNA to Gene Expression in Endomyocardial Biopsies in the Trifecta-Heart Study
Authors: Halloran Philip F. , Reeve Jeff , Mackova Martina , Madill-Thomsen Katelynn S. , Demko Zachary , Olymbios Michael , Campbell Patrick , Melenovsky Vojtech , Gong Timothy , Hall Shelley , Stehlik Josef
Published: March 2024

Background.

Plasma donor–derived cell-free DNA (dd-cfDNA) is used to screen for rejection in heart transplants. We launched the Trifecta-Heart study (ClinicalTrials.gov No. NCT04707872), an investigator-initiated, prospective trial, to examine the correlations between genome-wide molecular changes in endomyocardial biopsies (EMBs) and plasma dd-cfDNA. The present report analyzes the correlation of plasma dd-cfDNA with gene expression in EMBs from 4 vanguard centers and compared these correlations with those in 604 kidney transplant biopsies in the Trifecta-Kidney study (ClinicalTrials.gov No. NCT04239703).

Methods.

We analyzed 137 consecutive dd-cfDNA-EMB pairs from 70 patients. Plasma %dd-cfDNA was measured by the Prospera test (Natera Inc), and gene expression in EMBs was assessed by Molecular Microscope Diagnostic System using machine-learning algorithms to interpret rejection and injury states.

Results.

Top transcripts correlating with dd-cfDNA were related to genes increased in rejection such as interferon gamma-inducible genes (eg, HLA-DMA) but also with genes induced by injury and expressed in macrophages (eg, SERPINA1 and HMOX1). In gene enrichment analysis, the top dd-cfDNA-correlated genes reflected inflammation and rejection pathways. Dd-cfDNA correlations with rejection genes in EMB were similar to those seen in kidney transplant biopsies, with somewhat stronger correlations for TCMR genes in hearts and ABMR genes in kidneys. However, the correlations with parenchymal injury-induced genes and macrophage genes were much stronger in hearts.

Conclusions.

In this first analysis of Trifecta-Heart study, dd-cfDNA correlates significantly with molecular rejection but also with injury and macrophage infiltration, reflecting the proinflammatory properties of injured cardiomyocytes. The relationship supports the utility of dd-cfDNA in clinical management of heart transplant recipients.
Rapid structural analysis of bacterial ribosomesin situ
Authors: Powell Barrett M. , Brant Tyler S. , Davis Joseph H. , Mosalaganti Shyamal
Published: March 2024

Rapid structural analysis of purified proteins and their complexes has become increasingly common thanks to key methodological advances in cryo-electron microscopy (cryo-EM) and associated data processing software packages. In contrast, analogous structural analysis in cells via cryo-electron tomography (cryo-ET) remains challenging due to critical technical bottlenecks, including low-throughput sample preparation and imaging, and laborious data processing methods. Here, we describe the development of a rapidin situcryo-ET sample preparation and data analysis workflow that results in the routine determination of sub-nm resolution ribosomal structures. We apply this workflow toE. coli, producing a 5.8 Å structure of the 70S ribosome from cells in less than 10 days, and we expect this workflow will be widely applicable to related bacterial samples.
Generative Models for Prediction of Non-B DNA Structures
Authors: Cherednichenko Oleksandr , Poptsova Maria
Published: March 2024

Motivation

Deep learning methods have been successfully applied to the tasks of predicting non-B DNA structures, however model performance depends on the availability of experimental data for training. Experimental technologies for non-B DNA structure detection are limited to the subsets that are active at the time of an experiment and cannot detect entire functional set of elements. Recently deep generative models demonstrated promising results in data augmentation approach improving classifier performance trained on augmented real and generated data. Here we aimed at testing performance of diffusion models in comparison to other generative models and explore the data augmentation approach for the task of non-B DNA structure prediction.

Results

We tested denoising diffusion probabilistic and implicit models (DDPM and DDIM), Wasserstein generative adversarial network (WGAN) and vector quantised variational autoencoder (VQ-VAE) for the task of improving detection of Z-DNA, G-quadruplexes and H-DNA. We showed that data augmentation increased the quality of classifiers with diffusion models being the best for Z-DNA and H-DNA while WGAN worked better for G4s. Diffusion models are the best in diversity for all types of non-B DNA structures, WGAN produced the best novelty for G-quadruplexes and H-DNA. Since diffusion models require substantial resources, we showed that distillation technique can significantly enhance sampling in training diffusion models. When considering three criteria -quality of generated samples, sampling speed, and diversity, we conclude that trade-off is possible between generative diffusion model and other architectures such as WGAN and VQ-VAE.

Availability

The code with conducted experiments is freely available athttps://github.com/powidla/nonB-DNA-structures-generation.

Contact

mpoptsova@hse.ru

Supplementary information

Supplementary data are available atJournal Nameonline.
Mutation ofGmDMPgenes triggers haploid induction in soybean
Authors: Zhong Yu , Yang Mingliang , Cheng Dehe , Liu Jinchu , Han Qi , Liu Chunyan , Qi Xiaolong , Yan Tongzheng , Teng Lei , Xv Chang , Hou Jingjing , Sun Lianjun , Liu Chenxu , Chen Qingshan , Chen Shaojiang
Published: March 2024

The development of homozygous lines is a key step in plant breeding and production. Generally, homozygous lines can be obtained through traditional time-consuming way of several generations selfing or through a way of doubled haploid (DH) technology, which has obvious advantages to accelerate breeding. However, no effective haploid production system so far has been established in soybean. Here we show that mutations of the soybeanGmDMP1andGmDMP2genes can be used to induce haploid with an average haploid induction rate of 0.61%. We also found that 22.9% of soybean haploids can produce seeds through spontaneous chromosome doubling. Those findings laid a solid foundation for establishing DH technology in soybean, which will accelerate soybean breeding.
Pure Nano Genesis: Pioneering Universal Aqueous Nanostrategies from Pure Molecules to Revolutionise Diverse Applications
Authors: Zhao Wenwen , Li Qiu , He Peng , Li Changqing , Aryal Muna , Fabiilli Mario L. , Xiao Haijun
Published: March 2024

In this paper, we propose a novel universal approach for the construction of stable and aqueous nanoparticles, Pure Nano systems, comprising solely small conjugated molecules without any excipients. Our experiments confirm that the generation of surface charges plays an essential role during the spontaneous aggregation of conjugated molecules in the process of Pure Nano system fabrication, as it governs growth and confers physiochemical stability to particles at the nano scale. This approach overcomes solubility challenges in highly hydrophobic conjugated molecules by obviating excipients and enabling up to 100% drug loading capacity. Confirmation of this capability stems from the successful preparation of approximately 100 Pure Nano systems, incorporating different combinations of 27 conjugated molecules distinguished by their diverse dissociation types and degrees. The proposed preparation method is robust, simple, fast, and reliable, making it well-suited for large-scale manufacturing due to its array of unique features. This strategy affords a singular, molecular-focused approach, showcasing the intrinsic bioactivity of its constituent molecules while enabling aqueous dispersion for diverse applications. Andin vivoexperiments confirm the exceptional efficacy of various Pure Nano systems in reinstating dextran sodium sulfate induced acute ulcerative colitis to a healthy state, restoring myocardial ischemia/reperfusion injury to normal levels, and effectively treating cancer in mice with significantly improved median survival rates. This innovative nano drug delivery system represents a groundbreaking advancement with the potential to revolutionise translational nanomedicine. Positioned at the forefront of therapeutic possibilities, it is anticipated to substantially improve the efficacy and safety of nano therapies. This advancement heralds a new era, offering a highly targeted and efficient approach in the treatment of diverse medical conditions.
Application of chimeric antigens to paper-based diagnostics for detection of West Nile virus infections ofCrocodylus porosus –a novel animal test case
Authors: Johnston Ryan A. , Habarugira Gervais , Harrison Jessica J. , Isberg Sally R. , Moran Jasmin , Morgan Mahali , Davis Steven S. , Melville Lorna , Howard Christopher B. , Henry Charles S. , Macdonald Joanne , Bielefeldt-Ohmann Helle , Hall Roy A. , Hobson-Peters Jody
Published: March 2024

Laboratory-based diagnostics like plaque reduction neutralization tests (PRNT) and ELISA are commonly used to detect seroconversion to flavivirus infections. However, faster, qualitative screening methods are needed for quicker diagnosis and better patient outcomes. Lateral flow assays (LFAs) can provide rapid results (5-15 mins) at the point-of-care, yet few commercial flavivirus antibody detection LFAs are available. We developed an LFA using novel chimeric viral antigens produced by genetically modifying the mosquito restricted Binjari virus (BinJV) to display the outer virion proteins of pathogenic viruses such as West Nile virus (WNV). The BinJV chimeric platform offers various advantages for diagnostic assay development, including rapid construction of new chimeras in response to emerging viral variants, safe, scalable antigen manufacturing, and structural indistinguishability to the wild-type pathogenic virion. As a demonstration of feasibility, we applied chimeric WNV (BinJV/WNV) antigen to LFA as the capture/test line reagent for detection of seroconversion of crocodilians to WNV – a virus affecting crocodilians on multiple continents. We verified the antigenic conservation of the chimera when applied to the LFA detection surface using monoclonal antibodies. Using well-characterised sera (n=60) from WNV seropositive or flavivirus naive Australian saltwater crocodiles (Crocodylus porosus), we illustrated 100% sensitivity and specificity, with results achieved in less than 15 minutes. The LFA further accurately detected seroconversion in animals experimentally infected with WNV. This qualitative screening method can be performed both inside and outside of a laboratory, and the assay design will guide the optimization of similar tests for vector borne virus infection detection in both humans and other animals.
Phosphorylation of Aly3 C-terminus impedes aberrant endocytosis ofS. pombehexose transporter Ght5
Authors: Toyoda Yusuke , Masuda Fumie , Saitoh Shigeaki
Published: March 2024

In fission yeast,Schizosaccharomyces pombe, transcriptional upregulation and cell-surface localization of the hexose transporter, Ght5, are required for cell proliferation in low glucose. As the target of rapamycin complex 2 (TORC2) signaling pathway inhibits α-arrestin Aly3-dependent endocytosis of Ght5, we hypothesized that this endocytosis was inhibited by phosphorylation. To identify phosphorylation sites required for cell proliferation in low glucose, serine and threonine residues of Aly3 and Ght5 reportedly phosphorylated were replaced with alanine. We found that C-terminal serine residues of Aly3, but not Ght5, are necessary for proliferation in low glucose. Expression of Aly3 protein unphosphorylated at the C-terminus led to increased ubiquitination and vacuolar accumulation of Ght5 in low glucose, but reversion of one of the alanine residues to serine reduced ubiquitination and vacuolar accumulation of Ght5. Also, Aly3 physically interacted with the HECT-type ubiquitin ligases Pub1 and Pub3, and these interactions were required for surface localization of Ght5 and proliferation in low glucose. This study reveals mechanisms by which Aly3 is regulated so that fission yeast can adapt to nutritional stress.
Parkinson’s disease patients display a DNA damage signature in blood that is predictive of disease progression
Authors: Sproviero Daisy , Payán-Gómez César , Milanese Chiara , Sun Shixiang , Gyenis Akos , Delia Domenico , Lashley Tammaryn , Vijg Jan , Hoeijmakers Jan H.J. , Mastroberardino Pier G.
Published: March 2024

Aging is the main risk factor for Parkinson’s disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of the Parkinson’s Progression Markers Initiative cohort to investigate the involvement of DNA damage in PD. Our findings revealed that PD patients exhibit disrupted DNA repair pathways and biased suppression of longer transcripts, indicating the presence of age-related, transcription-stalling DNA damage. Notably, this DNA damage signature was only detected in patients with more severe motor symptom progression over a three-year period, suggesting its potential as a predictor of disease severity. We further validated this signature in independent PD cohorts and confirmed increased signs of DNA damage in dopamine neurons of the substantia nigra pars compacta through histopathological analysis of PD brains. Our study sheds light on an aging-related mechanism in PD pathogenesis and identifies markers of disease progression providing a readily applicable diagnostic platform to prognosticate disease progression.

One Sentence Summary

Parkinson’s disease patients display a DNA damage signature in blood that is predictive of disease progression.
Evaluation of intracochlear pressure and distribution during fluid application in cochlea models and human petrous bone
Authors: Kim R. , Riemann C. , Kilgué A. , Schleyer S. , Pfeiffer CJ , Scholtz LU. , Schürmann M. , Todt I.
Published: March 2024

Introduction

The important factor during the application of substances for an inner ear therapy is the atraumatic execution as well as a homogeneous distribution over the cochlea in a reasonable time frame. Since faster delivery can be obtained with higher pressure but, higher pressure will lead to traumatic execution, there are certain constrains for the delivery process. Because of this, an optimized procedure for intracochlear delivery is needed, which enables reduction of intracochlear pressure during perfusion in reasonable time.

Hence, the aim of this study was to compare different techniques of substance application and their effects on intracochlear pressure in different models.

Material and Methods

Intracochlear pressure was measured by fiberoptic pressure sensors in artificial cochlea models and in a human temporal bone. The pressure sensor was introduced into the inner ear models via an additional channel or the lateral arcade of the temporal bone.

In all models the substance was applied by means of an inner ear catheter (MED-EL, Innsbruck, Austria) via the round window with methylene blue with or without second access to the cochlea (helicotrema/oval window).

Results

The application of substances showed significant differences in intracochlear pressure and substance distribution at the same velocity between the models with and without second access.

Conclusion

Using a second-hole technique leads to a faster homogeneous distribution, as well as a lower intracochlear pressure, which can be assumed to be an essential factor for hearing preservation during substance application.
Intron-loss in Kinetoplastea correlates with a non-functional EJC and loss of NMD factors
Authors: Gabiatti Bernardo Papini , Freire Eden Ribeiro , Odenwald Johanna , Holetz Fabiola , Carrington Mark , Kramer Susanne , Zoltner Martin
Published: March 2024

In metazoans, mRNA quality is tightly monitored from transcription to translation. A key role lies with the exon junction complex (EJC) that is placed upstream of the exon-exon junction after splicing. The EJC inner core is composed of Magoh, Y14, eIF4AIII and BTZ and the outer core of proteins involved in mRNA splicing (CWC22), export (Yra1), translation (PYM) and non-sense mediated decay (NMD, UPF1/2/3). The protozoan parasiteTrypanosoma bruceiencodes only two genes with introns, but all mRNAs are processed bytrans-splicing. The presence of the three core EJC proteins and a potential BTZ homologue (Rbp25) in trypanosomes has been suggested as an adaptation of the EJC function to marktrans-spliced mRNAs.

We analysed trypanosome EJC components and noticed major differences between eIF4AIII and Magoh/Y14: (i) whilst eIF4AIII is essential, knocking out both Magoh and Y14 elicits only a mild growth phenotype and does not affect processing, export or stability of the twocis-spliced mRNAs (ii) eIF4AIII localization is mostly nucleolar, with a minor proportion in the nucleoplasm and cytoplasm, while Magoh and Y14 are nucleolar and nucleoplasmic but excluded from the cytoplasm (iii) eIF4AIII associates with nucleolar proteins (including NOM1/Sgd1p) and the splicing factor CWC22, but not with Y14 or Magoh, while Magoh and Y14 associate with each other, but not with eIF4AIII, CWC22 or the nucleolar proteins. Our data argue against the presence of a functional EJC in trypanosomes, but rather indicate that eIF4AIII adopted non-EJC related, essential functions, while Magoh and Y14 became redundant.

Trypanosomes also possess homologues to the NMD proteins UPF1 and UPF2. We found that depletion of UPF1 causes only a minor reduction in growth and detailed phylogenetic analyses show several independent losses of UPF1 and UPF2, as well as total loss of UPF3 in the Kinetoplastida group. The data indicate that UPF1-dependent NMD is not essential in trypanosomes consistent with the observation that the cells tolerate the presence of mRNAs with allele-specific, endogenous PTCs (premature termination codons).

Altogether, our comprehensive analyses of conserved components provide no evidence for a canonical EJC or NMD pathway in (almost) intron-less trypanosomatids.