bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Flow Nasal Cannula Versus Noninvasive Ventilation as Initial Treatment in Acute Hypoxia: A Propensity Score-Matched Study
Authors: Munroe Elizabeth S. , Prevalska Ina , Hyer Madison , Meurer William J. , Mosier Jarrod M. , Tidswell Mark A. , Prescott Hallie C. , Wei Lai , Wang Henry , Fung Christopher M.
Published: May 2024

IMPORTANCE:

Patients presenting to the emergency department (ED) with hypoxemia often have mixed or uncertain causes of respiratory failure. The optimal treatment for such patients is unclear. Both high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) are used.

OBJECTIVES:

We sought to compare the effectiveness of initial treatment with HFNC versus NIV for acute hypoxemic respiratory failure.

DESIGN, SETTING, AND PARTICIPANTS:

We conducted a retrospective cohort study of patients with acute hypoxemic respiratory failure treated with HFNC or NIV within 24 hours of arrival to the University of Michigan adult ED from January 2018 to December 2022. We matched patients 1:1 using a propensity score for odds of receiving NIV.

MAIN OUTCOMES AND MEASURES:

The primary outcome was major adverse pulmonary events (28-d mortality, ventilator-free days, noninvasive respiratory support hours) calculated using a win ratio.

RESULTS:

A total of 1154 patients were included. Seven hundred twenty-six (62.9%) received HFNC and 428 (37.1%) received NIV. We propensity score matched 668 of 1154 (57.9%) patients. Patients on NIV versus HFNC had lower 28-day mortality (16.5% vs. 23.4%, p = 0.033) and required noninvasive treatment for fewer hours (median 7.5 vs. 13.5, p < 0.001), but had no difference in ventilator-free days (median [interquartile range]: 28 [26, 28] vs. 28 [10.5, 28], p = 0.199). Win ratio for composite major adverse pulmonary events favored NIV (1.38; 95% CI, 1.15–1.65; p < 0.001).

CONCLUSIONS AND RELEVANCE:

In this observational study of patients with acute hypoxemic respiratory failure, initial treatment with NIV compared with HFNC was associated with lower mortality and fewer composite major pulmonary adverse events calculated using a win ratio. These findings underscore the need for randomized controlled trials to further understand the impact of noninvasive respiratory support strategies.
Prophylactic Antibiotics Delivered Via the Respiratory Tract to Reduce Ventilator-Associated Pneumonia: A Systematic Review, Network Meta-Analysis, and Trial Sequential Analysis of Randomized Controlled Trials
Authors: Li Jie , Lyu Shan , Luo Jian , Liu Ping , Albuainain Fai A. , Alamoudi Omar A. , Rochette Violaine , Ehrmann Stephan
Published: May 2024

OBJECTIVES:

To assess the effects of antibiotics delivered via the respiratory tract in preventing ventilator-associated pneumonia (VAP).

DATA SOURCES:

We searched PubMed, Scopus, the Cochrane Library, and ClinicalTrials.gov for studies published in English up to October 25, 2023.

STUDY SELECTION:

Adult patients with mechanical ventilation of over 48 h and receiving inhaled or instilled antibiotics (with control group) to prevent VAP were included.

DATA EXTRACTION:

Two independent groups screened studies, extracted the data, and assessed the risk of bias. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the certainty/quality of the evidence. Results of a random-effects model were reported for overall and predefined subgroup meta-analyses. The analysis was primarily conducted on randomized controlled trials, and observational studies were used for sensitivity analyses.

DATA SYNTHESIS:

Seven RCTs with 1445 patients were included, of which six involving 1283 patients used nebulizers to deliver antibiotics. No obvious risk of bias was found among the included RCTs for the primary outcome. Compared with control group, prophylactic antibiotics delivery via the respiratory tract significantly reduced the risk of VAP (risk ratio [RR], 0.69 [95% CI, 0.53–0.89]), particularly in subgroups where aminoglycosides (RR, 0.67 [0.47–0.97]) or nebulization (RR, 0.64 [0.49–0.83]) were used as opposed to other antibiotics (ceftazidime and colistin) or intratracheal instillation. No significant differences were observed in mortality, mechanical ventilation duration, ICU and hospital length of stay, duration of systemic antibiotics, need for tracheostomy, and adverse events between the two groups. Results were confirmed in sensitivity analyses.

CONCLUSIONS:

In adult patients with mechanical ventilation for over 48 h, prophylactic antibiotics delivered via the respiratory tract reduced the risk of VAP, particularly for those treated with nebulized aminoglycosides.
Improved Early Outcomes With Off-Pump Coronary Artery Bypass Grafting in Patients With Left Ventricular Dysfunction: A Systematic Review and Meta-Analysis
Authors: Abdul Qadeer Muhammad , Khalid Mariam , Abdul Muqeet Farid Anusha , Fatima Tehreem , Mariam Khalid Fariha , Ali Syed Ibrahim , Mujtaba Gonal , Elahi Naz , Kamal Siddiqi Ahmed , Said Sameh M.
Published: May 2024

The ongoing debate surrounding coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass persists, particularly in individuals with left ventricular dysfunction. The objective of this study was to evaluate the safety and efficacy of these 2 strategies through a comprehensive meta-analysis of existing studies. A systematic search of PubMed, EMBASE, Web of Science, and the Cochrane Central Registry was conducted from inception to July 2023. The primary focus was on studies comparing on-pump versus off-pump CABG as the primary treatment for multivessel coronary artery disease in patients with left ventricular dysfunction (ejection fraction ≤40%), with mortality as the primary outcome. The meta-analysis included 26 studies with a total of 35,863 patients. The results revealed a significant reduction in mortality risk [risk ratio (RR), 0.75; 95% confidence interval (CI), 0.60–0.93; P = 0.009] and other perioperative morbidities associated with off-pump CABG. These included stroke (RR, 0.67; 95% CI, 0.54–0.82; P = 0.0002), myocardial infarction (RR, 0.74; 95% CI, 0.56–0.97; P = 0.03), pulmonary complications (RR, 0.71; 95% CI, 0.55–0.92; P = 0.010), postoperative transfusion (RR, 0.70; 95% CI, 0.55–0.88; P = 0.002), neurological dysfunction (RR, 0.80; 95% CI, 0.64–1.00; P = 0.05), infection (RR, 0.74; 95% CI, 0.56–0.97; P = 0.03), renal failure (RR, 0.79; 95% CI, 0.67–0.95; P = 0.010), and reoperation for bleeding (RR, 0.66; 95% CI, 0.52–0.84; P = 0.0006). However, no significant difference was observed between the 2 groups regarding postoperative atrial fibrillation (RR, 0.97; 95% CI, 0.84–1.12; P = 0.69). In conclusion, off-pump CABG demonstrates a lower perioperative mortality risk and improved overall early outcomes compared with on-pump techniques in individuals with reduced left ventricular function.
Clinical Features of Cardiac Calcified Amorphous Tumor: A Narrative Review
Authors: Takahashi Yu , Inaba Yusuke , Tsuchiya Hiroshi , Minegishi Sachito , Niino Tetsuya , Endo Hidehito , Kubota Hiroshi
Published: May 2024

A cardiac calcified amorphous tumor (CAT) is a non-neoplastic cardiac mass composed of calcified nodules surrounded by amorphous fibrous tissue in a context of degeneration and chronic inflammation. Although CAT cases are increasingly reported, its clinical manifestation remains unclear. We aimed to conduct a narrative review of CAT and identify its clinical characteristics. We conducted a comprehensive literature search using PubMed, with the keyword “Cardiac Calcified Amorphous Tumor” to identify relevant articles. A total of 113 articles published between 1997 and 2022 were retrieved. The clinical features allowing for assess patient background, differences with and without end-stage renal disease (ESRD), symptom-related factors, risk factors for embolism caused by CAT, and features of CAT, such as shape, location, mobility, pathology, and treatment, were statistically analyzed in 106 criteria-matched cases. The mean patient age was 60.2 ± 18.6 years, with 45 men and 61 women. Of the data collected from 21 countries, 52 patients were from Japan. Mobile CAT was more common in the chronic renal failure group. Linear, club-shaped, and spindle-shaped CAT tended to be mobile and more common in the ESRD group as well as located in the mitral valve region. The shape, mobility, location, and underlying mechanism of CAT depended on the presence or absence of ESRD. The risk of embolism was considered high because mobile CAT was more common in the ESRD group, and CAT originated in the mitral valve region. Hence, early diagnosis based on periodic examination in patients with ESRD and aggressive surgical treatment are necessary.
Comparing the Use of 80% Trichloroacetic Acid and 50% Trichloroacetic Acid for the Treatment of Ice Pick Acne Scars
Authors: Dac Thuy Luong Nguyen , Thuy Trang Vu Thi , Tran Nguyen Ngoc , Phuong Thao Doan Thi
Published: May 2024

BACKGROUND

Chemical reconstruction of skin scars (CROSS) using high concentration trichloroacetic acid (TCA) is a safe, effective, and low-cost treatment for ice pick acne scars.

OBJECTIVE

To compare the efficacy and effectiveness of the CROSS technique using 50% TCA and 80% TCA for treating ice pick scars.

MATERIALS AND METHODS

A nonrandomized, single-blinded, and self-controlled clinical trial was undertaken. Four CROSS sessions were conducted using 50% TCA on the left hemiface and 80% TCA on the right hemiface. The E′ chelle d'Evaluation Clinique des Cicatrices d'Acne (ECCA) acne grading scale was used to assess the scars pretreatment and posttreatment. Complications were evaluated after each session.

RESULTS

Thirty-one patients participated in our study. Significant differences were found between pretreatment and posttreatment ECCA scores (p < .0001) on both hemifaces. Scores were significantly lower on the side treated with 80% TCA; however, there was no statistical significance in mean ECCA score differences (pretreatment minus posttreatment) between the 2 treatment sides. The adverse events were more serious on the sides treated with 80% TCA.

CONCLUSION

The CROSS method using TCA was well-tolerated and effective for treating ice pick acne scars. Less severe complications were associated with 50% TCA, whereas efficacy was the same as 80% TCA.
Grading the Whipple’s procedure: a strategy for structured skill advancement in surgical training
Authors: Limbu Yugal , Regmee Sujan , Adhikari Spandan D. , Mishra Aakash , Ghimire Roshan , Maharjan Dhiresh K. , Shrestha Suman , Thapa Prabin B.
Published: May 2024

Introduction:

The Whipple’s procedure or pancreatoduodenectomy (PD), is recognized for its technical intricacy in surgical practice. This study aims to categorize PD into four types based on procedural complexity and anticipated postoperative outcomes, intending to integrate this classification into the progressive training of surgical fellows.

Methods:

In this retrospective cohort study, 242 PDs, performed by a single unit across multiple centers from January 2016 to December 2022, were categorized into four types based on technical complexity and extent of surgical intervention. These types were: Type 1 (dilated duct, firm pancreas), Type 2 (as Type 1 + vascular reconstruction), Type 3 (nondilated duct, soft pancreas), and Type 4 (as Type 3 + vascular reconstruction). The study assessed patient characteristics, surgical parameters, and perioperative morbidity and mortality, comparing the outcomes of the four PD types.

Results:

Type 1 PD was predominant (65.2%), with the lowest 30-day mortality (2.53%). Conversely, Type 4 PD, though least performed (3.3%), exhibited the highest mortality (25%) and major complications (25%). Statistically significant differences were noted in the incidence of clinically relevant-postoperative pancreatic fistula, delayed gastric emptying, and wound complications among the PD types, with overall surgical morbidity being higher in Types 3 and 4.

Conclusion:

In conclusion, our data compellingly links morbidity, such as postoperative pancreatic fistula, with the technical challenges of the procedure, even though not all mortality can be attributed solely to surgical factors. The implementation of this system offers a structured approach to surgical training, paving the way for trainees to adeptly navigate and proficiently perform this complex surgical technique.
Advancing Equity: Understanding, Addressing, and Mitigating Bias in Assessment in Medical Education
Authors: Sheffield Virginia , Finta Mary , Erinc Abigail , Sonn Tammy L. , Lukela Jennifer Reilly
Published: May 2024

Despite the growing presence of women and historically underrepresented groups in academic medicine, significant disparities remain. This article examines a key aspect of these disparities: biases in assessment and learning environments. Reviewing current literature, including in OBGYN, reveals persistent gender and racial biases in subjective clinical narrative assessments. The paper then outlines a 2-pronged approach for change: first, enhancing the learning environment, and subsequently, providing targeted recommendations for individuals, academic leaders, and healthcare institutions to effectively address these biases.
Benign Lobular Inner Nuclear Layer Proliferation associated with Congenital Hypertrophy of the Retinal Pigment Epithelium
Authors: Boca Tarquin , Cohen Salomon Y. , Hermouet Elsabeth , Srour Mayer , Miere Alexandra
Published: May 2024

Purpose:

To report two cases of benign intraretinal tumors of the inner nuclear layer (INL) associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE).

Methods:

Multimodal imaging of two cases, including fundus color and autofluorescence photography, structural and en face spectral-domain optical coherence tomography (SD-OCT), OCT-angiography, fluorescein and indocyanine green angiography.

Results:

During a routine examination, intraretinal tumors of the INL associated with several CHRPE lesions were observed in one eye of two male patients, aged 27 and 32 years, respectively. Multimodal imaging showed white multifocal lobulated lesions with arching extensions, located in the INL, which allowed diagnosing benign lobular inner nuclear layer proliferation (BLIP).

Conclusion:

BLIP is a rare benign tumor located in the INL with a unique pattern and only 4 cases have been reported to date. The present two cases allowed confirming that BLIP is associated with CHRPE, suggesting a concomitant developmental anomaly of the RPE and the inner retina.
Ameloblastic Carcinoma With Orbital Invasion
Authors: Beecher Mark B. , Tong Jessica Y. , Gilhotra Amardeep , Selva Dinesh
Published: May 2024

Ameloblastic carcinomas are malignant tumors arising from the odontogenic epithelium and defined as having features of ameloblastic differentiation in addition to cytological features of malignancy. Orbital involvement is rare and generally involves invasion of the orbital floor, apex, or soft tissue. This report describes an advanced presentation of ameloblastic carcinoma with orbital invasion and provides a review of the literature. A 58-year-old male presented with a 2-year history of a mid-facial mass, causing intracranial invasion and distortion of most skull foramina, nasopharynx, nasal cavity, and both orbits. Notably, there was an en-plaque pattern of circumferential tracking of the tumor along both orbital walls without invasion beyond the extraconal space, causing compression of the orbital apex and proptosis. Histology demonstrated nests of ameloblastic carcinoma and the advanced tumor was deemed nonresectable, with treatment being palliative.
Benign Islet Cells Within Peripancreatic Lymph Nodes
Authors: Baraban Ezra , Thompson Elizabeth D. , Matoso Andres , Hruban Ralph H. , Argani Pedram
Published: May 2024

The presence of epithelial cells within lymph node parenchyma is typically indicative of a metastatic malignancy. However, there are rare instances in which non-neoplastic epithelial or epithelioid cells may be found within lymph nodes, either due to aberrant embryologic migration, mechanical displacement, or physiological trafficking. These can potentially lead to serious potential diagnostic pitfalls, as when such situations are encountered by surgical pathologists, there is substantial risk of overdiagnosing these as metastatic malignancy. Herein, we describe 2 cases of benign pancreatic islet cells within peripancreatic lymph nodes, and underscore the potential for misdiagnosis of this phenomenon as foci of metastatic well-differentiated neuroendocrine tumor. The benign nature of these intranodal islet cells was supported by: (1) the absence of a well-differentiated neuroendocrine tumor in the entirely submitted concomitant pancreatic resection specimen and (2) the presence of an admixture of insulin and glucagon expressing cells by immunohistochemistry in a distribution characteristic of non-neoplastic pancreatic islets. Both cases were incidental microscopic findings in pancreatic resections for intraductal papillary mucinous neoplasms that were previously biopsied and showed associated microscopic areas of fibrosis and chronic pancreatitis and thus this phenomenon may be related to mechanical displacement from prior injury and/or biopsy.
P Value Reporting and Reliability in Plastic and Reconstructive Surgery: A Primer for Readers and Investigators
Authors: Fahmy Joseph N. , Colwell Amy S. , Chung Kevin C.
Published: May 2024

The P value is ubiquitous in research. However, misuse and misinterpretation are common. This article aims to demystify the P value for researchers, students, physicians, and experienced investigators alike. To accomplish this aim, the origins of the P value, what it represents, and principles of application are described through use of examples from real data sets. Developing understanding of the true meaning of this statistical measure has the power to improve and inform clinical research.
Extended Reduction Malarplasty for Asians with Flat and Wide Faces: Comparison with L-Shaped Osteotomy
Authors: Hattori Yoshitsugu , Uda Hirokazu , Mashiko Takanobu , Fukuta Keizo , Sugawara Yasushi
Published: May 2024

Background:

Reduction malarplasty is effective in correcting prominent zygomatic body and arch in Asian populations, but periorbital zygomatic bony protrusion may not be sufficiently improved. In this study, the authors present the extended reduction malarplasty procedures to correct it simultaneously and compare the outcome with that of conventional L-shaped osteotomy.

Methods:

A retrospective review of consecutive patients who underwent reduction malarplasty between August of 2021 and September of 2023 at the authors’ hospital was conducted. Computed tomographic images obtained before and after surgery were assessed to evaluate the facial skeletal changes, and to compare between the extended and conventional L-shaped malarplasty results.

Results:

Twenty patients with extended reduction malarplasty and 23 patients with conventional reduction malarplasty were eligible for the study. Cephalometric analyses showed significant reduction in the zygomatic width in both groups, but the protrusion of the periorbital area was improved significantly more in the extended reduction malarplasty group. In terms of facial angulation, the extended reduction malarplasty also provided more horizontal convexity in the periorbital area, whereas the angular change in the caudal part of the zygoma was not significantly different.

Conclusions:

The extended reduction malarplasty enabled reduction of the protrusion of the periorbital area and the prominent zygomatic body and arch, and provided more 3-dimensionality and horizontal convexity with the midface contour. It is a viable option for harmonizing the facial profile for Asian patients with flat and wide faces.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Refocusing the Military Health System to support Role 4 definitive care in future large-scale combat operations
Authors: Remondelli Mason H. , McDonough Matthew M. , Remick Kyle N. , Elster Eric A. , Potter Benjamin K. , Holt Danielle B.
Published: May 2024

The last 20 years of sustained combat operations during the Global War on Terror generated significant advancements in combat casualty care. Improvements in point-of-injury care, en route care, and forward surgical care appropriately aligned with the survival, evacuation, and return to duty needs of the small-scale unconventional conflict. However, casualty numbers in large-scale combat operations have brought into focus the critical need for modernized casualty receiving and convalescence: Role 4 definitive care. Historically, World War II was the most recent conflict in which the United States fought in multiple operational theaters, with hundreds of thousands of combat casualties returned to the continental United States. These numbers necessitated the establishment of a “Zone of the Interior,” which integrated military and civilian health care networks for definitive treatment and rehabilitation of casualties. Current security threats demand refocusing and bolstering the Military Health System's definitive care capabilities to maximize its force regeneration capacity in a similar fashion. Medical force generation, medical force sustainment and readiness, and integrated casualty care capabilities are three pillars that must be developed for Military Health System readiness of Role 4 definitive care in future large-scale contingencies against near-peer/peer adversaries.
Early detection of phlebitis among hematology-oncology patients: a best practice implementation project
Authors: Toh Shao Wei , Tamarra Ramil Marty Alicabo , Goh Ying Xuan , Chang Ya Qi , Hollen Valerie Tantiana , Ng Iris Xin Qi , Ahmad Noor Melati , Tho Poh Chi , Lee Yee Mei
Published: May 2024

Introduction:

Peripherally-inserted venous catheters (PIVC) are essential for cancer patients to receive treatment. Phlebitis is a major complication of PIVC. Currently, nurses’ assessment of phlebitis mainly involves visual inspection. However, the latest literature suggests palpation for tenderness to promote the early detection of phlebitis.

Objectives:

This project evaluated the effectiveness of a bundle approach to increase nurses’ compliance with PIVC site assessment to promote early detection of phlebitis (grade 2 and above).

Methods:

The JBI Evidence Implementation Framework was used to conduct this project in a 28-bed hematology-oncology ward in a Singapore hospital. The bundle approach used in this project consisted of a training presentation, medical mannequin, and phlebitis scale card. The rate of nurses’ compliance with best practice for PIVC site assessment was measured at 1 month and 6 months post-implementation. The incidence of phlebitis was monitored up until 12 months post-implementation.

Results:

Baseline data indicated that only 18.75% (3 out of 16) nurses palpated for tenderness when assessing for phlebitis. Data at 1 month and 6 months post-implementation reported sustained high compliance rates of 85.71% (24 out of 28) and 89.29% (25 out of 28), respectively. Late detection of phlebitis was reduced by 66% (from three cases to one case) at 6 months post-implementation, and no patients required invasive interventions.

Conclusions:

The bundle approach used in this project facilitated early detection of phlebitis following the inclusion of palpation into nurses’ assessment for phlebitis.

Spanish abstract:

http://links.lww.com/IJEBH/A204
The potential use of daridorexant in eating disorders: beyond the treatment of insomnia?
Authors: Caldiroli Alice , Affaticati Letizia M. , Capuzzi Enrico , La Tegola Davide , Colmegna Fabrizia , Clerici Massimo , Dakanalis Antonios , Buoli Massimiliano
Published: May 2024

A strong interplay exists between sleep and dietary habits, and sleep disturbances have been repeatedly documented in individuals with eating disorders (EDs). The orexin system – implicated in sleep regulation, energy homeostasis, and food reward - may represent a mechanist link between sleep alterations and disordered eating behaviors. Daridorexant is a dual orexin receptor antagonist (DORA) recently approved for the treatment of insomnia, with demonstrated efficacy and tolerability. Owing to its action on orexin neurons, the compound represents an intriguing option for addressing both sleep-related and core symptoms of EDs. By inhibiting motor hyperactivity, daridorexant may reduce excessive physical exercise in individuals with anorexia nervosa (AN) restricting type. Additionally, the compound may exert anti-binge effects, suggesting broad applicability in binge ED, bulimia nervosa, and binge/purging AN. In this framework, daridorexant emerges as a promising therapeutic option, offering a multifaceted approach to improving circadian rhythms, energy balance, and overall quality of life in individuals with diverse ED subtypes.
Kaposi’s sarcoma herpesvirus viral FLICE inhibitory protein modulates A20 deubiquitinase activity
Authors: Herold Kevin , Ruffin Ayana , Chmura Jennifer C. , Dellomo Anna J. , Ehrlich Elana S.
Published: May 2024

KSHV viral FLICE inhibitory protein (vFLIP) is a potent activator of NF-κB signalling and an inhibitor of apoptosis and autophagy. Inhibition of vFLIP function and NF-κB signalling promotes lytic reactivation. Here we provide evidence for a novel function of vFLIP through inhibition of the deubiquitinating (DUB) activity of the negative regulator, A20. We demonstrate direct interaction of vFLIP with Itch and A20 and provide evidence for subsequent loss of A20 DUB activity. Our results provide further insight into the function of vFLIP in the regulation of NF-κB signalling.
Divergent landscapes of A-to-I editing in postmortem and living human brain
Authors: Rodriguez de los Santos Miguel , Kopell Brian H. , Buxbaum Grice Ariela , Ganesh Gauri , Yang Andy , Amini Pardis , Liharska Lora E. , Vornholt Eric , Fullard John F. , Dong Pengfei , Park Eric , Zipkowitz Sarah , Kaji Deepak A. , Thompson Ryan C. , Liu Donjing , Park You Jeong , Cheng Esther , Ziafat Kimia , Moya Emily , Fennessy Brian , Wilkins Lillian , Silk Hannah , Linares Lisa M. , Sullivan Brendan , Cohen Vanessa , Kota Prashant , Feng Claudia , Johnson Jessica S. , Rieder Marysia-Kolbe , Scarpa Joseph , Nadkarni Girish N. , Wang Minghui , Zhang Bin , Sklar Pamela , Beckmann Noam D. , Schadt Eric E. , Roussos Panos , Charney Alexander W. , Breen Michael S.
Published: May 2024

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higherADAR1andADARB1expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries illuminate the nuanced functions and intricate regulatory mechanisms of RNA editing within the human brain.
Growth regulation bringing modularity to morphogenesis of complex three-dimensional exoskeletons
Authors: Ito Hiroshi C. , Uchiumi Yu
Published: May 2024

Diverse three-dimensional morphologies of arthropods’ appendages, including beetle horns, are formed through the non-uniform growth of epidermis. Prior to moulting, epidermal tissue peels off from the old cuticle and grows non-uniformly to shape protruding appendages, which are often branching, curving, or twisting, from the planar epidermis. This non-uniform growth is possibly regulated by the distribution of morphogens on the epidermal cell sheet. Previous studies have identified molecules and signalling pathways related to such morphogenesis; however, how local regulation of cell sheet growth can transform planar epidermis globally into complex three-dimensional structures, such as beetle horns, remains unclear. To reveal the relationship between epidermal growth regulation and generated structures, this study theoretically examined how various shapes can be generated from planar epidermis under a deductive growth model that corresponds morphogen distributions to non-uniform growth on tissue. The results show that the heterochronic expression of multiple morphogens can flexibly fuse multiple simple shapes to generate various structures emulating complex appendages of beetles. These findings indicate that morphogenesis through such a mechanism may have developmental stability and modularity, providing insights into the evolution of the diverse morphology of arthropods.
Physical confinement selectively favours bacterial growth based on cell shape
Authors: Sreepadmanabh M , Ganesh Meenakshi , Sanjenbam Pratibha , Kurzthaler Christina , Agashe Deepa , Bhattacharjee Tapomoy
Published: May 2024

How are bacterial communities altered by changes in their microenvironment? Evidence from homogeneous liquid or flat plate cultures implicates biochemical cues — such as variation in nutrient composition1,2, response to chemoattractants and toxins3,4, and inter-species signalling5,6— as the primary modes of bacterial interaction with their microenvironment. However, these systems fail to capture the effect of physical confinement on bacteria in their natural habitats. Bacterial niches like the pores of soil, mucus, and infected tissues are disordered microenvironments with material properties defined by their internal pore sizes and shear moduli7–11. Here, using three-dimensional matrices that match the viscoelastic properties of gut mucus, we test how altering the physical properties of their microenvironment influences bacterial growth under confinement. We find that low aspect-ratio bacteria form compact, spherical colonies under confinement while high aspect-ratio bacteria push their progenies further outwards to create elongated colonies with a higher surface area, enabling increased access to nutrients. As a result, the population level growth of high aspect-ratio bacteria is more robust to increased physical confinement compared to that of low aspect-ratio bacteria. Thus, our results capture experimental evidence showing that physical constraints can play a selective role in bacterial growth based on cell shape.
Chronic ethanol exposure produces long-lasting, subregion-specific physiological adaptations in RMTg-projecting mPFC neurons
Authors: Przybysz Kathryn R , Shillinglaw Joel E , Wheeler Shannon R , Glover Elizabeth J
Published: May 2024

Chronic ethanol exposure produces neuroadaptations in the medial prefrontal cortex (mPFC) which facilitate the maladaptive behaviors interfering with recovery from alcohol use disorder. Despite evidence that different cortico-subcortical projections play distinct roles in behavior, few studies have examined the physiological effects of chronic ethanol at the circuit level. The rostromedial tegmental nucleus (RMTg) is a GABAergic midbrain region involved in aversive signaling and is functionally altered by chronic ethanol exposure. Our recent work identified a dense input from the mPFC to the RMTg, yet the effects of chronic ethanol exposure on this circuitry is unknown. In the current study, we examined physiological changes after chronic ethanol exposure in prelimbic (PL) and infralimbic (IL) mPFC neurons projecting to the RMTg. Adult male Long-Evans rats were injected with fluorescent retrobeads into the RMTg and rendered dependent using a 14-day chronic intermittent ethanol (CIE) vapor exposure paradigm. Whole-cell patch-clamp electrophysiological recordings were performed in fluorescently-labeled (RMTg-projecting) and -unlabeled (projection-undefined) layer 5 pyramidal neurons 7-10 days following ethanol exposure. CIE significantly increased intrinsic excitability as well as excitatory and inhibitory synaptic drive in RMTg-projecting IL neurons. In contrast, no lasting changes in excitability were observed in RMTg-projecting PL neurons, although a CIE-induced reduction in excitability was observed in projection-undefined PL neurons. CIE also increased excitatory synaptic drive in RMTg-projecting PL neurons. These data uncover novel subregion- and circuit-specific neuroadaptations in the mPFC following chronic ethanol exposure and reveal that the IL mPFC-RMTg projection is uniquely vulnerable to long-lasting effects of chronic ethanol.
Targeting SCD triggers lipotoxicity of cancer cells and enhances anti-tumor immunity in breast cancer brain metastasis mouse models
Authors: Sammarco Alessandro , Guerra Giorgia , Eyme Katharina M. , Kennewick Kelly , Qiao Yu , Hokayem Joelle El , Williams Kevin J. , Su Baolong , Zappulli Valentina , Bensinger Steven J. , Badr Christian E.
Published: May 2024

Breast cancer brain metastases (BCBM) are a significant cause of mortality and are incurable. Thus, identifying BCBM targets that reduce morbidity and mortality is critical. BCBM upregulate Stearoyl-CoA Desaturase (SCD), an enzyme that catalyzes the synthesis of monounsaturated fatty acids, suggesting a potential metabolic vulnerability of BCBM. In this study, we tested the effect of a brain-penetrant clinical-stage inhibitor of SCD (SCDi), on breast cancer cells and mouse models of BCBM. Lipidomics, qPCR, and western blot were used to study the in vitro effects of SCDi. Single-cell RNA sequencing was used to explore the effects of SCDi on cancer and immune cells in a BCBM mouse model. Pharmacological inhibition of SCD markedly reshaped the lipidome of breast cancer cells and resulted in endoplasmic reticulum stress, DNA damage, loss of DNA damage repair, and cytotoxicity. Importantly, SCDi alone or combined with a PARP inhibitor prolonged the survival of BCBM-bearing mice. When tested in a syngeneic mouse model of BCBM, scRNAseq revealed that pharmacological inhibition of SCD enhanced antigen presentation by dendritic cells, was associated with a higher interferon signaling, increased the infiltration of cytotoxic T cells, and decreased the proportion of exhausted T cells and regulatory T cells in the tumor microenvironment (TME). Additionally, pharmacological inhibition of SCD decreased engagement of immunosuppressive pathways, including the PD-1:PD-L1/PD-L2 and PVR/TIGIT axes. These findings suggest that SCD inhibition could be an effective strategy to intrinsically reduce tumor growth and reprogram anti-tumor immunity in the brain microenvironment to treat BCBM.
Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking
Authors: Sokol Kelly H. , Lee Cameron J. , Rogers Thomas J. , Waldhart Althea , Ellis Abigail E. , Madireddy Sahithi , Daniels Samuel R. , Ye Xinyu , Olesnavich Mary , Johnson Amy , Furness Benjamin R. , Sheldon Ryan D. , Lien Evan C.
Published: May 2024

Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic acid and adrenic acid. These PUFAs then accumulate in phospholipids, particularly ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools dictates their sensitivity to ferroptosis.
Establishing neuroanatomical correspondences across mouse and marmoset brain structures
Authors: Mezias Christopher , Huo Bingxing , Bota Mihail , Jayakumar Jaikishan , Mitra Partha Pratim
Published: May 2024

Interest in the common marmoset is growing due to evolutionarily proximity to humans compared to laboratory mice, necessitating a comparison of mouse and marmoset brain architectures, including connectivity and cell type distributions. Creating an actionable comparative platform is challenging since these brains have distinct spatial organizations and expert neuroanatomists disagree. We propose a general theoretical framework to relate named atlas compartments across taxa and use it to establish a detailed correspondence between marmoset and mice brains. Contrary to conventional wisdom that brain structures may be easier to relate at higher levels of the atlas hierarchy, we find that finer parcellations at the leaf levels offer greater reconcilability despite naming discrepancies. Utilizing existing atlases and associated literature, we created a list of leaf- level structures for both species and establish five types of correspondence between them. One-to-one relations were found between 43% of the structures in mouse and 47% in marmoset, whereas 25% of mouse and 10% of marmoset structures were not relatable. The remaining structures show a set of more complex mappings which we quantify. Implementing this correspondence with volumetric atlases of the two species, we make available a computational tool for querying and visualizing relationships between the corresponding brains. Our findings provide a foundation for computational comparative analyses of mesoscale connectivity and cell type distributions in the laboratory mouse and the common marmoset.
Temperature-dependent intracellular crystallization of firefly luciferase in mammalian cells is suppressed by D-luciferin and stabilizing inhibitors
Authors: Hasegawa Haruki
Published: May 2024

Firefly luciferase (Fluc) fromPhotinus pyralisis one of the most widely used reporter proteins in biomedical research. Despite its widespread use, Fluc’s protein phase transition behaviors and phase separation characteristics have not received much attention. Current research uncovers Fluc’s intrinsic property to phase separate in mammalian cells upon a simple cell culture temperature change. Specifically, Fluc spontaneously produced needle-shaped crystal-like inclusion bodies upon temperature shift to the hypothermic temperatures ranging from 25°C to 31°C. The crystal-like inclusion bodies were not associated with or surrounded by membranous organelles and were likely built from the cytosolic pool of Fluc. Furthermore, the crystal-like inclusion formation was suppressed when cells were cultured in the presence of D-luciferin and its synthetic analog, as well as the benzothiazole family of so-called stabilizing inhibitors. These two classes of compounds inhibited intracellular Fluc crystallization by different modes of action as they had contrasting effects on steady-state luciferase protein accumulation levels. This study suggests that, under substrate insufficient conditions, the excess Fluc phase separates into a crystal-like state that can modulate intracellular soluble enzyme availability and protein turnover rate.
Stigma among Ebola Disease Survivors in Mubende and Kassanda districts, Central Uganda, 2022
Authors: Zalwango Gorreti Marie , Paige Sarah , Migisha Richard , Nakafeero Simbwa Brenda , Nsubuga Edirisa Junior , Asio Alice , Kabami Zainah , Zalwango Jane Frances , Kawungezi Peter Chris , Wanyana Mercy Wendy , King Patrick , Naiga Hellen Nelly , Agaba Brian , Zavuga Robert , Earle-Richardson Giulia , Kwesiga Benon , Bulage Lilian , Kadobera Daniel , Ario Alex Riolexus , Harris Julie R.
Published: May 2024

Background

Ebola disease survivors often experience stigma in multiple forms, including felt (perceived) stigma, enacted (action-based) stigma, and structural (institutional) stigma. On September 20, 2022, Uganda declared a Sudan Virus Disease (SVD, caused bySudan ebolavirus) outbreak after a patient with confirmed Sudan virus (SUDV) infection was identified in Mubende District. The outbreak led to 142 confirmed and 22 probable cases over the next two months. We examined the types of stigma experienced by survivors and their household members and its effect on their well-being.

Methods

We conducted a qualitative study during January 2023 in Mubende and Kassanda Districts. We conducted in-depth and key informant interviews with ten SVD survivors, ten household members of SVD survivors, and ten key informants (district officials and health workers in the affected communities). Interviews were recorded, translated, transcribed, and analyzed thematically.

Results

Survivors reported experiencing isolation and rejection by community members and loss of work. They reported being denied purchases at shops or having their money collected in a basket and disinfected (enacted stigma), which led to self-isolation (felt stigma). Educational institutions denied admission to some students from affected homes, while parents of children in some affected families stopped sending children to school due to verbal abuse from students and teachers (structural stigma). Prolonged SVD symptoms and additional attention to survivors from responders (including home visits by health workers, public distribution of support items, and conspicuous transport from home to the survivor’s clinic) were perceived as aggravating both felt and enacted stigma. Even after the outbreak had been declared over, survivors felt that they were still considered a threat to the community.

Conclusion

Survivors experienced felt stigma, enacted stigma, and structural stigma. Strengthening community engagement to counteract stigma, rethinking response activities that aggravate stigma, management of long-term SVD symptoms for survivors, integrated response interventions by partners, private distribution of support items, and increasing awareness and sensitization through video messages could reduce stigma among persons affected in future similar outbreaks.
A 20-year experience with initial and repeated electro- and echocardiographic screening in youth, athletes, and adults revealing high number of abnormalities
Authors: Bates Sharon , Movahed Mohammad Reza
Published: May 2024

Background

To further analyze the impacts, findings, and modalities of multiple cardiac screenings to answer the question – are multiple screens necessary in youth?

Methods

Over 20 years, the Anthony Bates Foundation (ABF) has offered free and low-cost cardiac screenings to youth and their families nationwide. The volunteer force has provided blood pressure, and ultrasound tests to participants throughout the 20 years. After year 7, electrocardiograms were added to the screening.

Results

Over the 20 years, ABF abnormal findings held steady between 10 - 13%, with Potential Life-Threatening (PLT) findings at 2.5%. The participants that have experienced multiple screening tests on average would repeat within 2.5 years, have abnormal findings at 31.84%, PLT at 11.43%, and total echocardiography-related abnormal findings at 16.82%. The variance between male and female attendance by age is also noted during the review of ABF repeat screened data. Male attendance was at 59.65% and female 40.35%. The abnormality rate of males for the first visit was 10.9% followed by the second visit of 18.80%. The abnormality rate of females for the first visit was 12.22% followed by the second visit of 17.09%. A detailed analysis of abnormal findings is presented in this manuscript.

Conclusions

Cardiac screening involving multiple repeated screenings appears to be effective in detecting increasing numbers of abnormal findings that can be lifesaving.
Noninvasive time-lapse 3D subcellular analysis of embryo development for machine learning-enabled prediction of blastocyst formation
Authors: Lee Chungha , Kim Geon , Shin Taeseop , Lee Sangho , Kim Jae Young , Choi Kyoung Hee , Do Jieun , Park Jaehyeong , Do Jaephil , Kim Ji Hyang , Park YongKeun
Published: May 2024

In developmental biology and in vitro fertilization (IVF), image-based assessment of embryos is pivotal. Traditional methods in clinical IVF have been constrained to 2D morpho-kinetic profiling and manual selection, hindered by the absence of noninvasive techniques for quantitative 3D imaging over extended durations. Here, we overcome these limitations by employing low-coherence holotomography to monitor mouse preimplantation embryo development from the 2-cell stage to the expanded blastocyst. This approach enables the generation of 3D refractive index tomograms of unlabeled embryos, facilitating the observation of subcellular developmental dynamics. We investigated the 3D spatiotemporal profiles of embryo development, identifying key morpho-kinetic parameters that distinguish between embryos with differing developmental outcomes—specifically, Grade A embryos that successfully progressed to expanded blastocysts within 72 hours, and Grade C embryos that did not. Using machine learning, we demonstrate the 3D morpho-kinetic parameters can offer a noninvasive, quantitative framework for predicting embryos with high developmental potential.
Drosophilalarvae demonstrate associative learning and memory in response to thermal conditioning
Authors: Polizos Nikolaos T. , Dancausse Stephanie , Rios Consuelo , Klein Mason
Published: May 2024

Organisms have evolved the ability to detect, process, and respond to many different surrounding stimuli in order to successfully navigate their environments. Sensory experiences can also be stored and referenced in the form of memory. TheDrosophilalarva is a simple model organism that can store associative memories during classical conditioning, and is well-suited for studying learning and memory at a fundamental level. Much progress has been made in understanding larval learning behavior and the associated neural circuitry for olfactory conditioning, but other sensory systems are relatively unexplored. Here, we investigate memory formation in larvae treated with a temperature-based associative conditioning protocol, pairing normally neutral temperatures with appetitive (fructose, FRU) or aversive (salt, NaCl) stimuli. Associative memory is tested using thermal gradient geometries, and we quantify navigation strength towards or away from conditioned temperatures. We find that larvae demonstrate short-term associative learning. They navigate towards warmer or colder temperatures paired with FRU, and away from warmer temperatures paired with NaCl. These results, especially when combined with future investigations of thermal memory circuitry in larvae, should provide broader insight into how sensory stimuli are encoded and retrieved in insects and more complex systems.