bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined Use of HArmonyCa and Hyaluronic Acid Fillers: A Holistic Approach to Facial Rejuvenation
Authors: Kus Sadiye , Sarigul Guduk Sukran
Published: December 2024

Background:

The multifactorial nature of aging necessitates a comprehensive assessment addressing contour, volume, and facial laxity, and a holistic treatment plan. We evaluated combined use of HArmonyCa with HA fillers to improve laxity and overall aesthetic outcomes. A detailed guide is also presented regarding facial shapes, special areas, and volume needs.

Methods:

This retrospective case series evaluates 10 patients’ facial laxities with Facial Laxity Rating Scale using 2-dimensional before and after photographs (posttreatment and 6-month mark). Overall improvement was assessed by the investigator and patients by comparing to baseline. Patient satisfaction was measured with a questionnaire.

Results:

The Facial Laxity Rating Scale scores (jowl and neck) were highest at baseline and lowest at 6-month mark. Facial laxity significantly improved over time for jowl (P < 0.001) and neck (P = 0.007). At the sixth month, facial laxity significantly improved compared with baseline both in jowl (P = 0.001) and neck (P = 0.011). Global Aesthetic Improvement Score evaluations improved significantly during the 6-month period (P < 0.001). Global Aesthetic Improvement Score was significantly higher at 6-month posttreatment compared with immediate posttreatment evaluation (P < 0.001). Patients were satisfied immediately after treatment and 6 months after. The satisfaction significantly improved at the sixth month compared with immediately after treatment (P = 0.033).

Conclusions:

A combined use of HArmonyCa and HA fillers improves laxity in the lower face and neck and enhances aesthetic outcomes with high patient satisfaction. Overall improvement and patient satisfaction are higher at the sixth month, which is attributable to biostimulation.
Ophthalmic Manifestations of Angiolymphoid Hyperplasia with Eosinophilia: A Systematic Review and Pooled Analysis of 86 Cases
Authors: Ahmed H. Shafeeq , Thrishulamurthy Chinmayee J. , Venkatesh Shwetha , Eshwaran Vidhya , James Thara Mary , Siddegowda Ramya Boregowda , Biligi Dayananda S
Published: December 2024

Purpose:

This systematic review aims to consolidate evidence on ophthalmological manifestations of angiolymphoid hyperplasia with eosinophilia, focusing on its presentation, diagnosis, and management.

Methods:

Preferred reporting items for systematic reviews and meta-analyses-adherent systematic review was conducted across 3 databases from inception until September 2024. Case reports and series detailing angiolymphoid hyperplasia with eosinophilia in ocular structures were included. Data on demographics, clinical presentation, diagnostic methods, and treatment outcomes were extracted and analyzed.

Results:

A total of 86 patients from 52 case reports/series were included. The median age was 41 years (IQR: 22–54), with a slight male predominance (51.16%, n = 44/86). The majority of patients (94.18%, n = 81/86) presented with unilateral eye involvement. The orbit was the most frequently involved location (45.35%, n = 39/86), followed by the upper eyelid (27.91%, n = 24/86). Clinical symptoms included proptosis (36.04%, n = 31/86), ptosis (26.74%, n = 23/86), and diplopia (11.67%, n = 10/86). Surgical excision was performed in 54.65% (n = 47/86) of cases, with biopsy done for diagnostic purposes in all patients. Recurrence occurred in 13.95% (n = 12/86), with risk factors including incomplete excision and prior angiolymphoid hyperplasia with eosinophilia in the same or opposite eye. Steroid therapy was used in 18.6% (n = 16/86) but showed limited success. Newer treatment strategies with propranolol showed efficacy in recurrent cases, with no recurrence reported in patients receiving this therapy.

Conclusion:

Angiolymphoid hyperplasia with eosinophilia in ocular structures presents diagnostic and therapeutic challenges. Surgical excision remains the mainstay of treatment, though recurrence is common. Therapeutic strategies with propranolol may offer alternative management options in recurrent cases.
Long-Term Outcomes of Neoadjuvant IntraArterial Chemotherapy for Locally Invasive Lacrimal Gland Carcinoma ex Pleomorphic Adenoma
Authors: Juratli Lena , Kim Jane , Juntipwong Sarinee , Elner Victor M. , McLean Scott , Chaudhary Neeraj , Worden Francis Paul , Demirci Hakan
Published: December 2024

Purpose:

There is no current standard treatment regimen for carcinoma ex pleomorphic adenoma (CXPA) of the lacrimal gland. Neoadjuvant intraarterial cytoreductive chemotherapy (IACC) followed by multimodal therapy has achieved good locoregional control in adenoid cystic carcinoma of the lacrimal gland. We reviewed our experience with neoadjuvant IACC followed by multimodal therapy for CXPA of the lacrimal gland.

Methods:

Three patients with CXPA of the lacrimal gland treated with neoadjuvant ICAA therapy followed by multimodal therapy at the University of Michigan were retrospectively reviewed.

Results:

Three patients had stage T4cN0M0 CXPA of the lacrimal gland (American Joint Committee on Cancer 8th ed). The first patient underwent 2 cycles of neoadjuvant IACC followed by multimodal therapy (exenteration, chemoradiotherapy, and adjuvant systemic chemotherapy). At 10 years of follow-up, there was no local recurrence or systemic metastasis. The second patient underwent 1 cycle of neoadjuvant IACC with multimodal therapy (systemic chemotherapy, globe-sparing orbital surgery, and chemoradiotherapy). After 5-year follow-up, there was no local recurrence or systemic metastasis. The third patient underwent 2 cycles of neoadjuvant IACC followed by multimodal therapy (globe-sparing orbital surgery, chemoradiotherapy, and adjuvant systemic chemotherapy). After 2 years, he developed parotid and retromandibular metastasis and underwent total parotidectomy with total neck dissection followed by chemoradiation and systemic anti-androgen therapy. After 7 years, he did not have any local recurrence or systemic metastasis.

Conclusions:

Neoadjuvant IACC with multimodal therapies can achieve favorable outcomes with locoregional control and improve disease-specific survival in patients with locally invasive advanced-stage CXPA of the lacrimal gland.
Thyroid Eye Disease and Artificial Intelligence: A Comparative Study of ChatGPT-3.5, ChatGPT-4o, and Gemini in Patient Information Delivery
Authors: Bahir Daniel , Hartstein Morris , Zloto Ofira , Burkat Cat , Uddin Jimmy , Hamed Azzam Shirin
Published: December 2024

Purpose:

This study aimed to compare the effectiveness of 3 artificial intelligence language models—GPT-3.5, GPT-4o, and Gemini, in delivering patient-centered information about thyroid eye disease (TED). We evaluated their performance based on the accuracy and comprehensiveness of their responses to common patient inquiries regarding TED. The study did not assess the repeatability of artificial intelligence responses, focusing on single-session evaluations per model.

Methods:

Five experienced oculoplastic surgeons assessed the responses generated by the artificial intelligence models to 12 key questions frequently asked by TED patients. These questions addressed TED pathophysiology, risk factors, clinical presentation, diagnostic testing, and treatment options. Each response was rated for correctness and reliability on a 7-point Likert scale, where 1 indicated incorrect or unreliable information and 7 indicated highly accurate and reliable information. Correctness referred to factual accuracy, while reliability assessed trustworthiness for patient use. The evaluations were anonymized, and the final scores were averaged across the surgeons to facilitate model comparisons.

Results:

GPT-3.5 emerged as the top performer, achieving an average correctness score of 5.75 and a reliability score of 5.68, excelling in delivering detailed information on complex topics such as TED treatment and surgical interventions. GPT-4o followed with scores of 5.32 for correctness and 5.25 for reliability, generally providing accurate but less detailed information. Gemini trailed with scores of 5.10 for correctness and 4.70 for reliability, often providing sufficient responses for simpler questions but lacking detail in complex areas like second-line immunosuppressive treatments. Statistical analysis using the Friedman test showed significant differences between models (p < 0.05) for key topics, with GPT-3.5 consistently leading.

Conclusions:

GPT-3.5 was the most effective model for delivering reliable and comprehensive patient information, particularly for complex treatment and surgical topics. GPT-4o provided reliable general information but lacked the necessary depth for specialized topics, while Gemini was suitable for addressing basic patient inquiries but insufficient for detailed medical information. This study highlights the role of artificial intelligence in patient education, suggesting that models like GPT-3.5 can be valuable tools for clinicians in enhancing patient understanding of TED.
“Don't Tell Nobody Nothing”: A Phenomenological Study on Fear of HIV Disclosure Among Older African Americans During Incarceration Living in Kentucky, USA
Authors: Tinman Jennifer S. , Nzama Nqobile , Patterson Jenifer , Harris Lesley M. , Kerr Jelani C.
Published: December 2024

The intersections of HIV with aging, incarceration, and racial disparities have been well studied, but little is known about the lived incarceration experiences of older African American persons living with HIV. This phenomenological study examined the fear of HIV disclosure among older African Americans living in Kentucky who have experienced incarceration. Based on the interviews analyzed, five main themes were identified: experiences with fear, experiences pertaining to confidentiality, experiences with disclosure, experiences with stigma, and the desire to be accepted. These themes demonstrate HIV disclosure fear within incarceration settings and the desire for support and services. Findings suggest that there should be more efforts to increase HIV knowledge and awareness within incarceration settings. Participants shared that having a support network alleviates isolation. We recommend that correctional settings implement policies to protect confidentiality violations and facilitate groups to help foster a more supportive environment for individuals living with HIV.
Examining Changes in Ulnar Collateral Ligament Reconstruction Surgery Patterns Among Professional Baseball Players
Authors: Almonroeder Thomas , Jones Margaret T. , Fields Jennifer B. , Erickson Jacob L. , Taylor Wayne A. , Bittner Michael H. , Jagim Andrew R.
Published: December 2024

Objective:

To retrospectively analyze publicly available elbow ulnar collateral ligament reconstruction (UCLR) injury data for professional baseball players.

Design:

Descriptive epidemiology study.

Setting:

A retrospective analysis using an open-source database was performed. The database contained all known UCLR surgeries among Major League Baseball (MLB) and Minor League Baseball (MiLB) players.

Participants:

In total, 1801 professional male professional baseball pitchers (age: 24.5 ± 3.9 years) who have undergone UCLR between 1974 and 2024.

Main Outcome Measures:

The number of UCLR procedures each year.

Independent Variables:

Change-point analysis was used to identify changes in the number of UCLR surgeries over time among MLB and MiLB players. For MLB players, number of UCLR surgeries from 1974 to 2023 was analyzed, while for MiLB players, data starting from 1981 to 2024 were analyzed.

Results:

For MLB players, 3 change points were identified, occurring around 1989 (95% confidence interval [CI], 1988–1990), 2000 (95% CI, 2000–2000), and 2012 (95% CI, 2011–2017). For MiLB players, 3 change points were identified occurring around 2001 (95% CI, 2001–2001), 2009 (95% CI, 2008–2010), and 2013 (95% CI, 2013–2015).

Conclusions:

Overall, there has been a rise in the number of UCLR surgeries per year for the past 50 years in professional baseball, with distinct time points identified, representing increases in the number of UCLR surgeries each year. A higher number of UCLR surgeries are performed per year in the MiLB than in the MLB.
The MPCETT: Assessing the Safety and Utility of Exercise Tolerance Testing in Children With Concussion Ages 6 to 12
Authors: Heitzman Michael , Krystofiak Jason , Toto Diana , Norton Jennifer , Naematullah Mustafa , Asselstine Sydney , Rybak Katelan , Joshi Puja
Published: December 2024

Objective:

Treadmill test protocols for concussion assessment have been validated for patients aged 13 years and older; however, no evidence-based guidelines exist for younger children. We designed and assessed the safety and utility of the Morahan Pediatric Concussion Exercise Tolerance Test (MPCETT) for assessing exercise tolerance in symptomatic children (SC) and recovered, asymptomatic children (AC) from 6 to 12 years of age.

Design:

Retrospective case series.

Setting:

Secondary care center.

Participants:

Children were diagnosed with concussion using consensus guidelines. At assessment, SC [n = 17; median (range) 10 (6–12) years; 18% female; 28 (13–50) days since injury] had persistent concussive symptoms, while AC [n = 24; 9 (7–12) years; 21% female; 21 (8–37) days since injury] required assessment for return to activity.

Interventions:

The MPCETT is a modified Buffalo Concussion Treadmill Test for pediatric populations. The test was administered to establish exercise tolerance and was terminated for increased symptoms or self-reported exhaustion.

Main outcome measures:

Presence of adverse events and exercise intolerance.

Results:

The number of adverse events was 0 in both groups. Exercise intolerance occurred in 64.7% (95% CI, 38.3%–85.8%) of children within the SC group versus 12.5% (95% CI, 2.7%–32.4%) within the AC group (P < 0.001).

Conclusions:

Pediatric exercise tolerance testing is safe and effective for assessing exercise intolerance in concussed children.
Carotid Artery Medialization in Velocardiofacial Syndrome: Importance of Nasoendoscopy
Authors: Moore Mark H. , Chaisrisawadisuk Sarut , Richards Chistina
Published: December 2024

Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome or DiGeorge syndrome, is a complex genetic disorder associated with a spectrum of phenotypic features, including craniofacial anomalies, congenital heart defects, and neurodevelopmental challenges. Among the more concerning, though under-recognized, presentation in VCFS is carotid artery medialization—a finding that places patients at substantial risk for vascular injury during pharyngeal surgeries. This report presents a case of VCFS in which carotid artery medialization was dramatically demonstrated during nasoendoscopic evaluation for velopharyngeal incompetence. The findings underscore the importance of comprehensive preoperative imaging in patients with VCFS to minimize surgical risk and optimize outcomes.
Musculoskeletal Disorders Among Surgeons and Attitudes Towards Wearable Devices for Ergonomic Optimization
Authors: LaMonica Lauren C. , Farha Mark W. , Mullen Connor R. , Hughes Tasha M. , Kozlow Jeffrey H. , Chrouser Kristin L.
Published: December 2024

Objective:

To assess the burden of ergonomic strain and to examine factors influencing intention to use wearable technology that may improve ergonomics during surgery.

Background:

Surgical ergonomic strain leads to high rates of work-related musculoskeletal disorders (MSDs) and pain, contributing to early surgeon retirement and an epidemic of burnout.

Methods:

A cross-sectional survey of surgeons at a single institution was conducted using two validated instruments, the Nordic Musculoskeletal Questionnaire and Unified Theory of Acceptance and Use of Technology (UTAUT2), assessing musculoskeletal strain and facilitators of wearable sensor use, respectively. Additional survey items examined preferred ergonomic device features. Partial least squares structural equation modeling tested model validity.

Results:

161 participants completed the entire survey. Most respondents were male (63.4%) and were more likely to be from General Surgery (26.1%) than from other subspecialties. The majority of surgeons had never received prior ergonomic training (n=107, 72.3%). Twenty surgeons (14.1%) required hospitalization and 31 (21.8%) surgeons changed operating responsibilities due to musculoskeletal injury with 77 (59.1%) reporting an impact of ergonomic pain on their ability to work as a surgeon. Perceived efficacy (β=0.190, P=0.005), social influence (β=0.135, P=0.039), hedonic motivation (β=0.274, P<0.001), and innovativeness (β=0.243, P<0.001) were significantly associated with behavioral intention to use a wearable ergonomic device. The waist (n=36, 24.3%), followed by the neck/upper back (n=29, 19.6%), were the most preferred sensor locations.

Conclusions:

Surgeons report a high burden of MSDs impacting their ability to work. Wearable sensors that provide feedback on ergonomic strain represent an opportunity to reduce MSDs among surgeons.
Acceptability, Feasibility, and Effectiveness of Concurrent High-Definition Transcranial Direct Current Stimulation and Cue Exposure in Cannabis Use Disorder
Authors: Chauhan Devika , Ghosh Abhishek , Naik Shalini S. , Rana Devender K. , Singh Shubh Mohan
Published: December 2024

Objectives

We studied the acceptability, feasibility, tolerability, and preliminary effectiveness of combined cue exposure and anodal high-definition transcranial direct current stimulation (HD-tDCS) on the right dorsolateral prefrontal cortex (DLPFC) on cannabis craving in cannabis use disorder (CUD).

Methods

We randomly assigned 48 participants equally in 4 groups: A, tDCS and cannabis cue exposure; B, tDCS and neutral image; C, sham tDCS and cue exposure; and D, sham tDCS and neutral image. The images were validated by Delphi consensus. All participants received 6 sessions. We explored the acceptance, protocol completion, and follow-up rates. We assessed cannabis cravings twice, at the end of sessions and 4 weeks after intervention; change in frequency and amount of cannabis and other substance use were assessed at 4 weeks after intervention; working memory and executive functions were tested at the end of sessions. We performed an intention-to-treat analysis.

Results

We observed low acceptance (19.6%) but high completion (91.7%) and follow-up rates. There were motivational and logistical reasons for low acceptance; monetary compensation improved treatment acceptance. Participants in all groups showed significant reductions in cannabis cravings at the end of sessions, except for group C, the reduction in cravings sustained at the follow-up. Frequency and amount of cannabis use reduced, and cognitive outcomes improved in all 4 groups; however, there was no between-group difference, and changes were higher in groups B and D. Adverse effects and attrition were not different between HD-tDCS and sham treatment.

Conclusions

Anodal right DLPFC HD-tDCS is a safe and promising treatment for CUD. Cue exposure does not add to its effect.
Limitations in quantum metrology approaches to imaging resolution
Authors: Iqbal S. , Xu Y. , Boyd R. W.
Published: December 2024

Can a quantum advantage for imaging resolution be realized with the help of quantum estimation theory? We expect so, but we show that, presently, theoretical tools are insufficiently developed to answer this question for extended objects. Still, there is much to be learned from the current state of the art. In this review, we re-examine prominent results in the literature and probe the limits of quantum metrology in addressing imaging resolution. In particular, we show that under restrictive but well-defined conditions, any quantum advantage in one-dimensional phase imaging appears to diminish for increasingly detailed objects. We also show that a previous attempt at tackling this question, while incomplete, does predict an advantage for single-molecule localization microscopy, although this method may not be feasible in the near term. As for experimental claims of Heisenberg-limited imaging resolution, we briefly address the many inherent difficulties in demonstrating that such a thing has indeed been achieved.

This article is part of the theme issue ‘The quantum theory of light’.
Unified space–time description of pulsed twin beams
Authors: Gatti Alessandra , Brambilla Enrico , Jedrkiewicz Ottavia
Published: December 2024

This work provides a mathematical derivation of a quasi-stationary (QS) model for multimode parametric down-conversion (PDC), which was presented in Gatti
et al
. (Gatti
et al
.,
Sci. Rep
.
13
, 16786) with heuristic arguments. Here, the model is derived from the 3D + 1 propagation equation of the quantum fields in a nonlinear crystal, and its approximations are discussed thoroughly. Thanks to its relative simplicity, and to the fact that it is valid in any gain regime, both at a quantum and classical level, it allows a unified description of disparate experimental observations conducted over the last 20 years, often described in the past by means of limited ad hoc models.

This article is part of the theme issue ‘The quantum theory of light’.
An operational distinction between quantum entanglement and classical non-separability
Authors: Korolkova Natalia , Sánchez-Soto Luis , Leuchs Gerd
Published: December 2024

Quantum entanglement describes superposition states in multi-dimensional systems—at least two partite—which cannot be factorized and are thus non-separable. Non-separable states also exist in classical theories involving vector spaces. In both cases, it is possible to violate a Bell-like inequality. This has led to controversial discussions, which we resolve by identifying an operational distinction between the classical and quantum cases.

This article is part of the theme issue ‘The quantum theory of light’.
Neural networks with quantum states of light
Authors: Labay-Mora Adrià , García-Beni Jorge , Giorgi Gian Luca , Soriano Miguel C. , Zambrini Roberta
Published: December 2024

Quantum optical networks are instrumental in addressing the fundamental questions and enable applications ranging from communication to computation and, more recently, machine learning (ML). In particular, photonic artificial neural networks (ANNs) offer the opportunity to exploit the advantages of both classical and quantum optics. Photonic neuro-inspired computation and ML have been successfully demonstrated in classical settings, while quantum optical networks have triggered breakthrough applications such as teleportation, quantum key distribution and quantum computing. We present a perspective on the state of the art in quantum optical ML and the potential advantages of ANNs in circuit designs and beyond, in more general, analogue settings characterized by recurrent and coherent complex interactions. We consider two analogue neuro-inspired applications, namely quantum reservoir computing and quantum associative memories, and discuss the enhanced capabilities offered by quantum substrates, highlighting the specific role of light squeezing in this context.

This article is part of the theme issue ‘The quantum theory of light’.
The formin FMNL2 plays a role in the response of melanoma cells to substrate stiffness
Authors: Clugston Joshua D. , Fox Sarah , Harden James L. , Copeland John W.
Published: December 2024

Background

Cells are constantly sensing and responding to changes in their local environment to adapt their behaviour and morphology. These external stimuli include chemical and mechanical signals, and much recent work has revealed the complexity of the cellular response to changes in substrate stiffness. We investigated the effects of substrate stiffness on the morphology and motility of A2058 human melanoma cells. FMNL2, a formin protein associated with actin cytoskeleton dynamics, regulates cell morphology and motility but its role in stiffness sensing remains unclear. This study examines how A2058 cells respond to substrates of varying stiffness and evaluates the impact of FMNL2 depletion on these responses.

Results

We found that with increasing substrate stiffness the cells transitioned from a rounded cell morphology to progressively more elongated morphologies with a concomitant increase in actin stress fiber alignment. Depletion of FMNL2 expression amplified these morphological changes, with knockdown cells showing consistently greater elongation and more pronounced stress fiber alignment compared to controls. Notably, the orientational order parameter (S) revealed higher alignment of actin filaments along the cell’s long axis in knockdown cells.

Substrate stiffness also affected cell motility, indicated by an apparent optimal stiffness that maximized motility followed by a notable decrease in distance travelled during cell migration on progressively stiffer substrates. This decrease was largely attributable to a decrease in the time the cells spent in motion as the substrate stiffness increased. FMNL2 depletion significantly exacerbated this effect, with knockdown cells traveling shorter net distances and spending less time moving across all substrates.

Conclusions

This study demonstrates that substrate stiffness profoundly influences A2058 melanoma cell morphology and motility, with FMNL2 playing a pivotal regulatory role. Our observations suggest that FMNL2 is critical for maintaining motility and morphological adaptability under increased stiffness. Loss of FMNL2 enhanced stress fiber alignment and cell elongation while impairing motility, particularly on stiff substrates, revealing FMNL2 as a mechanosensitive effector. However, further biochemical work should be performed to determine the exact mechanisms by which FMNL2 participates in regulation of melanoma cell response to substrate stiffness.
Atomistic Mechanism of Cation Permeation and Pore Voltage Sensitivity in Cyclic Nucleotide-Gated CNGA1 Ion Channel
Authors: Liu Haoran , Biedermann Johann , Sun Han
Published: December 2024

Mammalian cyclic nucleotide-gated (CNG) ion channels play a fundamental role in signal transduction within the visual and olfactory sensory cells, converting external stimuli into electrical signals. Here, using large-scale atomistic molecular dynamics (MD) simulations under transmembrane voltages, we uncover the atomistic mechanism of monovalent cation permeation in the homotetrameric CNGA1 channel, involving hydrated cations in the selectivity filter. We propose that hydration fluctuations in the central gate region, driven by pore flexibility, are the underlying mechanism for excess single-channel conductance noise and characteristic single-channel flickering. Furthermore, we suggest an atomistic mechanism for intrinsic voltage sensitivity in the channel pore, mediated by allosteric coupling between the selectivity filter and the central cavity gate. Our study provides atomistic insights into non-selective cation permeation and voltage sensitivity of the CNGA1 channel pore that could not be resolved by static structural analysis alone.
Oxygen saturation and acute mountain sickness during repeated altitude exposures simulating high-altitude working schedules
Authors: Waldner N. , Hartmann S. E. , Muralt L. , Lichtblau M. , Bader P. R. , Rawling J. M. , Lopez I. , Ulrich S. , Poulin M. J. , Bloch K.E. , Furian M.
Published: December 2024

Objective

To quantify the effect of two consecutive prolonged, intermittent exposures to high and very high altitudes on oxygen saturation (SpO2) and acute mountain sickness (AMS).

Methods

Healthy lowlanders (N=21), aged 18-30y, underwent two 7-day sojourns at the ALMA observatory, Chile (6hrs/day at 5050m, 18hrs/day at 2900m), separated by 1-week at 520m. SpO2(pulse oximetry) and AMS severity (AMSc, Environmental Symptom Questionnaire cerebral score) diagnosing AMS (AMSc≥0.7) were assessed daily at both altitudes.www.ClinicalTrials.gov:NCT02730143.

Results

SpO2at 2900m and 5050m on arrival day was mean±SD 93.6±0.5% and 79.9±1.0% (P<0.05 between altitudes), whereas the AMSc scores were 0.43±0.08 and 0.97±0.11 (P<0.05 between altitudes), respectively. At 2900m during a 7-day intermittent hypoxic exposure, SpO2increased by a mean(95%CI) 0.3%/day(0.1;0.4) and by 0.9%/day(0.4;1.3) at 5050m. Similarly, AMSc decreased by 0.05points/day(0.01;0.08) at 2900m and by 0.16points/day(0.11;0.21) at 5050m. During the second sojourn (vs. 1 sojourn), day1, SpO2at 2900m was unchanged but higher at 5050m by 2.9%(0.6;5.3). AMSc was lower at 2900m and 5050m by 0.37(0.16;0.59) and 0.37(0.11;0.63) (P<0.05 both comparisons vs 1 sojourn), respectively. Acclimatization with the 2 sojourn resulted in an increase in SpO2at 2900m by 0.3%/day(0.1;0.4) and at 5050m: 0.5%/day(0.1;0.8). AMSc remained unchanged with acclimatization at 2900m but decreased at 5050m by 0.08points/day(0.04;0.11).

Conclusions

In healthy lowlanders, a 7-day intermittent hypobaric hypoxic exposure of varying severity at high and very high altitude improved SpO2and AMS severity at 2900m, with larger improvements at 5050m. During a second identical sojourn, initial AMS severity was reduced despite comparable SpO2at 2900m compared to the 1 sojourn. No further acclimatization effects were observed in SpO2but in AMS symptoms at 2900m. In contrast, re-exposure to 5050m showed higher initial SpO2and lower AMSc values with further improvement with intermittent re-exposures. These findings highlight altitude-dependent acclimatization patterns and confirm the effectiveness of pre-conditioning to prevent AMS when planning sojourns to high altitudes.
Proteomic Profiling of Early-Stage Heart Failure Identifies Candidate Biomarkers and Molecular Pathways of Cardiac Inflammation in the Project Baseline Health Study
Authors: Kottilil Kalyani , Nguyen Maggie , Ramaker Megan , Cauwenberghs Nicholas , Kwee Lydia Coulter , Short Sarah , Plowman R. Scooter , Mentz Robert J. , Douglas Pamela S. , Holman Rury , Hernandez Adrian F. , Mahaffey Kenneth W. , Haddad Francois , Shah Svati H.
Published: December 2024

Background

Asymptomatic structural heart disease, or stage B heart failure (HF), is clinically relevant for early HF diagnosis and prevention; circulating biomarkers could have prognostic significance for this. Thus, we performed proteomics discovery in a well-phenotyped cohort, the Project Baseline Health Study (PBHS).

Methods

PBHS recruited participants with and without cardiovascular risk, collecting enrollment plasma biospecimens and cardiac imaging. Proteomic profiling (N=289) was performed using mass spectrometry on 503 individuals (185 stage B HF cases, 318 stage A HF controls). Logistic regression identified stage B-associated proteins, which were then eligible for inclusion in a joint protein score derived via elastic net. Scores were assessed for incident HF prediction in the UK Biobank (UKB) and the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), examined for exenatide interactions in EXSCEL, and tested for imaging trait associations in PBHS and UKB. Mechanistic analyses of multivariate significant proteins included incident HF prediction in UKB and EXSCEL, Mendelian randomization (MR), and targeted methylation loci associations with stage B HF in PBHS.

Results

Sixty-five proteins were associated with cases, of which 32 (49%) were retained via elastic net modeling; the resulting protein score showed good discrimination for cases versus controls (AUC 0.71, 95% CI [0.60, 0.82]). The protein score was significantly associated with incident HF in UKB and EXSCEL and left ventricular mass index (LVMI) in PBHS, as well as beneficially modified by exenatide in EXSCEL. Multivariate analysis prioritized 11 proteins associated with cases for mechanistic study, of which 4 (B2M, EFEMP1, CST3, HBB) showed significant incident HF associations in UKB and EXSCEL; CST3 and HBB were significant in MR. Methylation of cg08099136 inPSMB8was significantly associated with cases in PBHS.

Conclusions

Our findings highlight inflammatory biomarkers and mechanisms underpinning stage B HF. CpG hypomethylation atPSMB8may be implicated in inflammation, resulting in increased LVMI (a known HF risk factor), with circulating B2M a byproduct of this process.

ClinicalTrials.gov Identifier

NCT03154346
YAP engages RIF1 to dampen replication stress in squamous cell carcinoma.
Authors: Bojko Jodie , Flynn Benjamin , Aschenbrenner Bertram , Howard Alexander , Lay Emily , Krajic Natalia , Bailey Emma , Catalan Sandra , Gallacher Kelli , Sins Elodie , Wang Jun Alex , Jungwirth Ute , Lichtenberger Beate Maria , Walko Gernot
Published: December 2024

Squamous cancers are the most frequently diagnosed solid tumours world-wide. The closely related transcriptional co-regulators YAP and TAZ (WWTR1) have emerged as important drivers of tumour initiation and progression in various types of squamous cell carcinoma. How YAP and TAZ execute their oncogenic functions in squamous cancers is still not fully understood. Here, we report that in addition to controlling transcriptional programmes that determine the balance between proliferation and terminal differentiation, YAP also engages with RIF1, a key regulator of DNA replication timing and protector of stalled replication forks under replication stress. YAP modulates gene expression of RIF1 via TEAD transcription factors, and also stabilizes RIF1 protein on the chromatin. YAP-RIF1 complex formation increases in response to exogenous replication stress, and treatment with hydroxyurea to induce replication fork stalling acts synergistically with YAP depletion to impair cell proliferation. Our results thus demonstrate that YAP's oncogenic functions in squamous cell carcinoma involve both transcriptional and non-transcriptional mechanisms, and that RIF1 is key for squamous cell carcinoma cells to survive with their high levels of endogenous replication stress.
Antagonistic mechanisms of probioticAliivibriosp. strain Vl2 againstMoritella viscosa: Evidence from co-cultivation and transcriptomic analysis
Authors: Dobloug Marius Steen , Iakhno Stanislav , Nørstebø Simen Foyn , Sørum Henning
Published: December 2024

Winter ulcers are a significant challenge to the Norwegian aquaculture industry and the primary causative agent isMoritella viscosa. Control measures are limited due to the lack of effective vaccines and limited use of antibiotics, reflecting the global effort to combat antibiotic resistance. It was recently demonstrated that probioticAliivibriospp. colonize the skin and ulcers of Atlantic salmon and their association with a reduced prevalence of winter ulcers. These observations suggest thatM. viscosaandAliivibriospp. may interact within ulcersin vivo. In this study, we have investigated how the probioticAliivibriosp. strain Vl2 modulatesM. viscosa in vitro, using both co-cultures and CHSE cell cultures. We found that the probiotic strain exhibits antagonistic effects againstM. viscosa, reducing its growth and pathogenicity toward salmonid cells. Transcriptome analysis ofAliivibrioVl2 revealed potential mechanisms impeding the growth of the competing pathogen. Together, our findings demonstrate how the probiotic bacterium can inhibitM. viscosa in vitroand suggests potential mechanisms that may explain the reduced prevalence of winter ulcers observed in the field.
Cisplatin resistance reversal with treatment of Citric acid in cisplatin-resistant cell lines
Authors: Chaturvedi Siddhant , Venka Krishna
Published: December 2024

Gastric cancer (GC) is a prevalent and aggressive malignancy with significant morbidity and mortality rates, posing a major threat to human health globally. While surgery remains the preferred clinical treatment, chemotherapy continues to be the cornerstone for perioperative care, adjuvant therapy, and palliative treatment for patients with advanced stages of GC. Among the chemotherapeutic agents, cisplatin (DDP) has been widely used for decades as a first-line treatment for various solid tumors. However, its therapeutic efficacy is frequently undermined by the development of resistance, which is attributed to the complex interplay of multiple proteins and signaling pathways involved in the resistance mechanisms.

In this study, the issue of cisplatin resistance is addressed by employing citric acid as a treatment in cell lines. The findings demonstrate that citric acid effectively reverses cisplatin resistance, suggesting the potential involvement of a novel DNA damage repair mechanism. These results pave the way for further investigation into innovative therapeutic approaches to enhance the efficacy of cisplatin in treating gastric cancer.
“People will not even bring out their children to be immunised, because of the corona vaccine”: fake news, misinformation, vaccine hesitancy and the role of community engagement in COVID-19 vaccine acceptance in Southern Ghana
Authors: Kuatewo Mawulom , Ebelin Wisdom , Doegah Phidelia Theresa , Kpodo Lebene , Kpordorlor Atsu Godsway , Lissah Samuel , Djokoto Senanu , Aberese-Ako Matilda , Ansah Evelyn
Published: December 2024

Introduction

The novel coronavirus (COVID-19) is characterised by loads of fake news and misinformation, which can influence vaccine acceptance. According to the World Health Organisation, implementing a harmonized public health strategy during an outbreak necessitates effective community engagement and communication, which facilitates public trust and decision-making. This study explored the role of community engagement in the acceptance of COVID-19 vaccine in the midst of fake news and misinformation in two municipalities in Ghana.

Method

A qualitative case study was employed using in-depth interviews with government officials from the Ghana Health Service, Municipal Assembly, Information Services Department and the National Commission on Civic Education and community gatekeepers. Additionally, focus group discussions were conducted with a cross-section of community members to understand the role of community engagement in vaccine acceptance. Qualitative analysis software Nvivo 12 was used to support thematic coding and analysis. All ethical procedures and COVID-19 preventive protocols were observed.

Results

Study participants reported the sources of fake news and misinformation about the COVID-19 vaccines from interpersonal communication, the radio, and a popular anti-vaccine song. Some of the factors contributing to vaccine hesitancy were community members believed in the fake news and misinformation, low trust in the government and public institutions, and the lack of extensive education on COVID-19 vaccines. The Ghana Health Service was the most successful in engaging communities to promote vaccine acceptance in the midst of fake news and misinformation. It leveraged on its existing community-based health planning and services (CHPS) programme, which engaged the communities frequently through routine programmes such as durbars, antenatal clinics, child welfare clinics, and other community programmes to carry out engagement.

Conclusion

For Ghana to promote uptake of health interventions, it is important that communities are effectively engaged. This can be done through the provision of resources to responsible government institutions for community engagement. The gains made by government institutions during the pandemic can be sustained through continued community engagement, which will empower them to contribute towards population health.
Red-shifted GRAB acetylcholine sensors for multiplex imagingin vivo
Authors: Xie Shu , Miao Xiaolei , Li Guochuan , Zheng Yu , Li Mengyao , Ji En , Wang Jinxu , Li Shaochuang , Cai Ruyi , Geng Lan , Feng Jiesi , Wei Changwei , Li Yulong
Published: December 2024

The neurotransmitter acetylcholine (ACh) is essential in both the central and peripheral nervous systems. Recent studies highlight the significance of interactions between ACh and various neuromodulators in regulating complex behaviors. The ability to simultaneously image ACh and other neuromodulators can provide valuable information regarding the mechanisms underlying these behaviors. Here, we developed a series of red fluorescent G protein-coupled receptor activation-based (GRAB) ACh sensors, with a wide detection range and expanded spectral profile. The high-affinity sensor, rACh1h, reliably detects ACh release in various brain regions, including the nucleus accumbens, amygdala, hippocampus, and cortex. Moreover, rACh1h can be co-expressed with green fluorescent sensors in order to record ACh release together with other neurochemicals in various behavioral contexts using fiber photometry and two-photon imaging, with high spatiotemporal resolution. These new ACh sensors can therefore provide valuable new insights regarding the functional role of the cholinergic system under both physiological and pathological conditions.
Transcriptomics Unveil Canonical and Non-Canonical Heat Shock-Induced Pathways in Human Cell Lines
Authors: Reinschmidt Andrew , Solano Luis , Chavez Yonny , Hulsy William Drew , Nikolaidis Nikolas
Published: December 2024

The cellular stress response (CSR) is a conserved mechanism that protects cells from environmental and physiological stressors. The heat shock response (HSR), a critical component of the CSR, utilizes molecular chaperones to mitigate proteotoxic stress caused by elevated temperatures. We hypothesized that while the canonical HSR pathways are conserved across cell types, specific cell lines may exhibit unique transcriptional responses to heat shock. To test this, we compared the transcriptomic responses of HEK293, HepG2, and HeLa cells under control conditions immediately following heat shock and after an 8-hour recovery period. RNA sequencing revealed conserved activation of canonical HSR pathways, including the unfolded protein response, alongside enrichment of the non-canonical “Receptor Ligand Activity” pathway across all cell lines. Cell line-specific variations were also observed, with HepG2 cells displaying more uniquely expressed genes and elevated expression levels (fold changes) of shared genes under stress conditions. Validation by qPCR confirmed the activation of key genes within the “Receptor Ligand Activity” pathway across time points. These findings provide insights into conserved and context-specific aspects of the HSR, contributing to a more comprehensive understanding of stress response mechanisms across mammalian cells.
Cytoplasmic expression of the cell cycle regulator cyclin D1 in radial glial progenitor cells modulates brain cortex development
Authors: Pedraza Neus , Rocandio Daniel , Monserrat Maria Ventura , Zammou Bahira , Ortiz-Brugués Ariadna , Marfull-Oromí Pau , Chauhan Disha , Encinas Mario , Dolcet Xavier , Espinet Carme , Ferrezuelo Francisco , Garí Eloi , Egea Joaquim
Published: December 2024

During nervous system development, the interplay between cell cycle regulation and neurogenesis is fundamental to achieve the correct timing for neuronal differentiation. However, the molecular players regulating this transition are poorly understood. Among these, the cell-cycle regulatory cyclins and their cyclin-dependent kinases (Cdks) play a pivotal role. In the present work we uncover an unknown function of cyclin D1 (Ccnd1) during cortex development which is independent of cell cycle regulation and that relies on its cytoplasmic localization and membrane association. We show that Ccnd1 is localized in the cytoplasm of the radial glial process (RGP) of neuron progenitors in different regions of the developing brain, including the cortex. Cytoplasmic Ccnd1 is enriched at the distal tip of the RGP, adjacent to the meningeal basement membrane, and overlaps with β1-integrin at the plasma membrane.CCND1knock-out animals show an abnormal cortical layering in which the distribution of Tbr2+ and Ctip2+ cells are affected without displaying proliferation defects. This is consistent with a cytoplasmic function of Ccnd1 as overexpression by in utero electroporation of a dominant negative Ccnd1, unable to activate Cdks, and targeted to the cytoplasmic membranes, reproduces some of these Tbr2 and Ctip2 defects. Finally, we provide evidence that cytoplasmic Ccnd1 affects neuron morphology and that it is required for the proper detachment of the RGP from the meningeal basement membrane by a mechanism involving the phosphorylation of the integrin effector protein paxillin. Hence, we propose that Ccnd1 has an important cytoplasmic function for cortical development independently of cell cycle regulation.

Significant Statement

A key developmental step during nervous system formation is the transition from proliferating progenitors to postmitotic neurons. However, the molecular mechanisms regulating this process are not fully understood. Cyclin D1 (Ccnd1) is a canonical regulator of cell cycle in the cell nucleus. Surprisingly, we show that Ccnd1 is also located in the radial glial process of neuron progenitors and associated to the plasma membrane in different regions of the developing mouse brain. We uncover a novel function for this cytoplasmic Ccnd1 and show that it is required for proper cortical layering, independent of cell cycle regulation. Mechanistically, we provide evidence that this function is mediated by the integrin effector paxillin. We propose therefore that cytoplasmic Ccnd1 is important for cortex development independent of cell cycle regulation.
Gene network architecture, mutation and selection collectively drive developmental pattern evolvability and predictability
Authors: Booth Harry , Hadjivasiliou Z.
Published: December 2024

Much of the striking diversity of life on earth arises from mutations in conserved regulatory elements that govern reduced modules of Gene Regulatory Networks (GRNs). Although the mechanistic basis by which GRNs orchestrate cellular responses and tissue patterning during development is well understood, their evolutionary dynamics remain less clear. In this study, we probe how key evolutionary forces such as mutation, selection and historical contingency interact with GRN architecture to drive the diversification of developmental mechanisms and patterns. We introduce a novel high-throughput theoretical framework for GRN-driven pattern evolution to produce a comprehensive dataset of evolutionary trajectories. Utilizing computational and machine learning methods, we interpret this data within an evolutionary context. Our results elucidate the interplay between mutational and ecological influences and network architecture, revealing how historical contingencies affect the evolvability of GRNs and the predictability of their evolutionary outcomes. This work echoes recent synthetic and laboratory evolution experiments as well as comparative studies, providing a mechanistic basis for their interpretation. Our framework offers a powerful and adaptable platform for the investigation of GRN-drive pattern evolution, that links physical constraints that emerge from genetic architecture to evolutionary change and diversification.