bluuebunny/crossref_metadata_2025 huggingface dataset:
Weight change and all-cause and cause-specific mortality: A 25-year follow-up study
Authors: Yang Huan , Wang Jianbing , Wang Xiaokun , Sun Wanyi , Tong Chenyunhao , Fan Jinhu , Qiao Youlin , Abnet Christian C.
Published: January 2024

Background:

Whether the dynamic weight change is an independent risk factor for mortality remains controversial. This study aimed to examine the association between weight change and risk of all-cause and cause-specific mortality based on the Linxian Nutrition Intervention Trial (NIT) cohort.

Methods:

Body weight of 21,028 healthy residents of Linxian, Henan province, aged 40–69 years was measured two times from 1986 to 1991. Outcome events were prospectively collected up to 2016. Weight maintenance group (weight change <2 kg) or stable normal weight group was treated as the reference. Cox proportional hazard model was performed to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the risk of mortality.

Results:

A total of 21,028 subjects were included in the final analysis. Compared with the weight maintenance group, subjects with weight loss ≥2 kg had an increased risk of death from all-cause (HRAll-cause = 1.14, 95% CI: 1.09–1.19, P <0.001), cancer (HRCancer = 1.12, 95% CI: 1.03–1.21, P = 0.009), and heart disease (HRHeart diseases = 1.21, 95% CI: 1.11–1.31, P <0.001), whereas subjects with weight gain ≥5 kg had 11% (HRCancer = 0.89, 95% CI: 0.79–0.99, P = 0.033) lower risk of cancer mortality and 23% higher risk of stroke mortality (HRStroke = 1.23,95% CI: 1.12–1.34, P <0.001). For the change of weight status, both going from overweight to normal weight and becoming underweight within 5 years could increase the risk of total death (HROverweight to normal = 1.18, 95% CI: 1.09–1.27; HRBecoming underweight = 1.35, 95% CI: 1.25–1.46) and cancer death (HROverweight to normal = 1.20, 95% CI: 1.04–1.39; HRBecoming underweight = 1.44, 95% CI: 1.24–1.67), while stable overweight could increase the risk of total death (HRStable overweight = 1.11, 95% CI: 1.05–1.17) and death from stroke (HRStable overweight = 1.44, 95% CI: 1.33–1.56). Interaction effects were observed between age and weight change on cancer mortality, as well as between baseline BMI and weight change on all-cause, heart disease, and stroke mortality (all P
interaction <0.01).

Conclusions:

Weight loss was associated with an increased risk of all-cause, cancer, and heart disease mortality, whereas excessive weight gain and stable overweight were associated with a higher risk of stroke mortality. Efforts of weight management should be taken to improve health status.

Trial registration:

https://classic.clinicaltrials.gov/, NCT00342654.
Normal Ileal Mucus is Inadequate for Epithelial Protection in Ileal Pouch Mucosa
Authors: Knowles Jonathan , Church James
Published: January 2024

BACKGROUND:

Clinical, nonspecific pouchitis is common after restorative proctocolectomy for ulcerative colitis, but its cause is unknown. A possible lack of protection for the ileal mucosa in its role as a reservoir for colonic-type bacteria may be the missing piece in defining the causes of pouchitis.

OBJECTIVE:

Review the causes of pouchitis and introduce the hypothesis that inadequate mucus protection in the pouch combined with a predisposition to abnormal inflammation is the most common cause of nonspecific pouchitis.

DATA SOURCES:

Review of PubMed and Medline for articles discussing pouchitis and intestinal mucus.

STUDY SELECTION:

Studies published from 1960 to 2023. The main search terms were “pouchitis,”,and “intestinal mucus,” while Boolean operators were used with multiple other terms to refine the search. Duplicates and case reports were excluded.

MAIN OUTCOME MEASURES:

Current theories about the etiology of pouchitis, descriptions of the role of mucus in the physiology of intestinal protection, and evidence of the effects of lack of mucus on mucosal inflammation.

RESULTS:

The cross-reference of “intestinal mucus” with “pouchitis” produced 9 references, none of which discussed the role of mucus in the development of pouchitis. Crossing “intestinal mucus” with “pouch” resulted in 32 papers, combining “pouchitis“ with “barrier function” yielded 37 papers and “pouchitis” with “permeability” only 8. No paper discussed the mucus coat as a barrier to bacterial invasion of the epithelium or mentioned inadequate mucus as a factor in pouchitis. However, an ileal pouch produces a colonic environment in the small bowel, and the ileum lacks the mucus protection needed for this sort of environment. This predisposes pouch mucosa to bacterial invasion and chronic microscopic inflammation that may promote clinical pouchitis in patients prone to an autoimmune response.

LIMITATIONS:

No prior studies address inadequate mucus protection and the origin of proctitis. There is no objective way of measuring the autoimmune tendency in patients with ulcerative colitis.

CONCLUSIONS:

Studies of intestinal mucus in the ileal pouch and its association with pouchitis are warranted.
Remnant cholesterol as a new lipid-lowering target to reduce cardiovascular events
Authors: Raggi Paolo , Becciu Maria Laura , Navarese Eliano P.
Published: January 2024

Purpose of review

Remnant cholesterol has become increasingly recognized as a direct contributor to the development of atherosclerosis and as an additional marker of cardiovascular risk. This review aims to summarize the pathophysiological mechanisms, and the current evidence base from epidemiological investigations and genetic studies that support a causal link between remnant cholesterol and atherosclerotic cardiovascular disease. Current and novel therapeutic approaches to target remnant cholesterol are discussed.

Recent findings

A recent Mendelian randomization study of over 12 000 000 single-nucleotide polymorphisms associated with high levels of remnant cholesterol, demonstrated a genetic association between remnant cholesterol and adverse cardiovascular events among 958 434 participants.

In this light, the emerging role of remnant cholesterol as an independent lipid risk marker warrants a reevaluation of lipid management guidelines and underscores the potential for novel therapeutic targets in cardiovascular disease prevention.
Malignancies and Lymphoproliferations in Children With Primary Immune Deficiency—A Single-center Experience
Authors: Aydogmus Cigdem , Turkyilmaz Ucar Ozge , Kaplan Sarikavak Sibel , Cipe Funda , Ulas Selami , Turan Isilay , Naiboglu Sezin , Yildirim Ilke , Kalay Gulsah , Kapci Nermin , Al Serdar , Gokmirza Ozdemir Pinar , Celiksoy Mehmet Halil
Published: January 2024

Primary immune deficiencies (PIDs) are rare genetic disorders characterized by impaired immune function, leading to frequent infections and immune dysregulation. Studies have shown that individuals with PID are at an increased risk of developing malignancies and lymphoproliferative disorders compared with the general population. In this single-center study, we aimed to analyze the occurrence of malignancies and lymphoproliferations in children diagnosed with PID. We retrospectively analyzed the medical records of 550 pediatric patients diagnosed with PIDs at our center. Among them, 17 (3,0%) patients were identified with malignancy and/or benign lymphoproliferation. Eight of the 17 patients (47.0%) had immune dysregulatory diseases, whereas ataxia-telangiectasia was the second most common PID associated with malignancy and/or benign lymphoproliferation (n = 5, 29.4%). Lymphoma was the predominant malignancy (n = 11, 64.7%), and Epstein-Barr virus was identified as the most common viral agent associated with malignancy and/or benign lymphoproliferation in patients with PID (n = 8, 47.0%). Our study highlights the association between PID and malignancies/lymphoproliferations, with immune dysregulation syndromes being the most common subclass associated with malignancies/lymphoproliferations. Early diagnosis, multidisciplinary management, and regular surveillance are crucial in improving patient outcomes and saving lives.
Intracranial Germinoma in Two Caucasian American Siblings With Autism Spectrum Disorder
Authors: Toll Stephanie A. , Flore Leigh Anne , Gorsi Hamza S. , Marupudi Neena I. , Mody Swati , Kupsky William , Wang Zhihong Joanne
Published: January 2024

Intracranial germ cell tumors (IGCTs) comprise 3% to 5% of all pediatric brain tumors in the West, with a significantly higher prevalence in Asia. Although these tumors are histologically diverse, repeated somatic variants have been demonstrated. Chromosomal aneuploidies, such as Klinefelter and Down syndromes, are associated with IGCTs, but no familial germline tumor syndromes are currently known. Here, we report the novel case of 2 American siblings with underlying autism spectrum disorder who developed intracranial germinoma within months of each other, in the absence of external risk factors. Extensive genetic testing was performed, including karyotyping, chromosomal microarray, and whole exome and whole genome sequencing, and did not identify any variants accounting for the phenotypes. Despite the absence of overlapping variants, a recent retrospective review demonstrated a threefold greater prevalence of autism spectrum disorder in patients with intracranial germinoma compared with national prevalence. This report highlights the complexity of tumor development, as well as the need for further research regarding IGCTs in a neurodivergent population.
Marker-controlled watershed algorithm and fuzzy C-means clustering machine learning: automated segmentation of glioblastoma from MRI images in a case series
Authors: Ghaderi Sadegh , Mohammadi Sana , Ghaderi Kayvan , Kiasat Fereshteh , Mohammadi Mahdi
Published: January 2024

Introduction and importance:

Automated segmentation of glioblastoma multiforme (GBM) from MRI images is crucial for accurate diagnosis and treatment planning. This paper presents a new and innovative approach for automating the segmentation of GBM from MRI images using the marker-controlled watershed segmentation (MCWS) algorithm.

Case presentation and methods:

The technique involves several image processing techniques, including adaptive thresholding, morphological filtering, gradient magnitude calculation, and regional maxima identification. The MCWS algorithm efficiently segments images based on local intensity structures using the watershed transform, and fuzzy c-means (FCM) clustering improves segmentation accuracy. The presented approach achieved improved segmentation accuracy in detecting and segmenting GBM tumours from axial T2-weighted (T2-w) MRI images, as demonstrated by the mean characteristics performance metrics for GBM segmentation (sensitivity: 0.9905, specificity: 0.9483, accuracy: 0.9508, precision: 0.5481, F_measure: 0.7052, and jaccard: 0.9340).

Clinical discussion:

The results of this study underline the importance of reliable and accurate image segmentation for effective diagnosis and treatment planning of GBM tumours.

Conclusion:

The MCWS technique provides an effective and efficient approach for the segmentation of challenging medical images.
Remaining Relevant in a Changing Healthcare Organization
Authors: Craven Kay , Gay Drillious , Foltz Jason , Kolasa Kathryn M.
Published: January 2024

Registered dietitian nutritionists working in ambulatory clinics should not be waiting for an administrator to invite them to the planning group for the transition from fee for service to value-based care payment models. Registered dietitian nutritionists should be identifying and promoting the services they can provide to ensure quality healthcare for patients. In this article, we describe value-based care as it is presented in dietetics literature. We also describe how registered dietitian nutritionists in our family medicine practice demonstrate their value as a member of the expanded interprofessional ambulatory care team providing quality care, reducing costs, and providing an exceptional experience for the patient. We call on educators of dietetics students, interns, and professionals to teach the necessary interprofessional skills to be successful in value-based care models of care.
Emerging treatment options for skin and soft tissue infections tailoring drug selection to individual patients
Authors: Castaldo Nadia , Vena Antonio , Limongelli Alessandro , Giacobbe Daniele Roberto , Bassetti Matteo
Published: January 2024

Purpose of review

To provide a brief overview of drugs in Phase II and III of development for the treatment of acute bacterial skin and skin structure infections (ABSSSI), offering insights into potential customized treatment options.

Recent findings

Several drugs are currently in advanced stages of evaluation for the treatment of ABSSSI, and numerous molecules are entering in the early development phases. Notably, many of these drugs exhibit unique mechanisms of action and interesting antimicrobial spectrum.

Tailoring antibiotic therapy based on patient characteristics, likely pathogens, type, site and severity of ABSSSI is crucial. Given the inherent limitations of available treatments, the development of novel agents is a pivotal avenue. Such advancements hold promise for enhancing treatment efficacy and simplifying drug selection for ABSSSI in everyday clinical practice.
Priapism in a Young Adult With Sickle Cell Disease
Authors: Frank Catherine , Toole Kimberly P.
Published: January 2024

This article presents a case study focusing on priapism in a patient with sickle cell disease, with repeated emergency department (ED) visits and hospitalizations. The patient was successfully identified and treated by the ED nurse practitioner (NP) with aspiration of the corpus cavernosum. Priapism is a persistent penile erection that continues for an extended time. There is some argument about what that length of time is, but generally, the consensus is more than 4 hr beyond sexual stimulation or unrelated to sexual stimulation or sexual interest (Bivalacqua et al., 2022). Priapism is a fairly common but underrecognized complication of sickle cell disease. It represents a urological emergency in which timely diagnosis and appropriate treatment are vital to preserving penile tissue and sexual function. The diagnosis is made clinically with a comprehensive history, physical examination, and appropriate laboratory test values. Initial management can be conservative with hydration and analgesics or, if necessary, more invasive with needle aspiration to promote detumescence. Permanent tissue damage or erectile dysfunction can result if priapism is unrecognized, untreated, or not treated immediately. The NP plays an integral role in treating and preventing permanent damage. Patient education should focus on instructions for preventing priapism and managing episodes at home.
Acute Hyperkalemia Management in the Emergency Department
Authors: Weant Kyle A. , Gregory Haili
Published: January 2024

Acute hyperkalemia is characterized by high concentrations of potassium in the blood that can potentially lead to life-threatening arrhythmias that require emergent treatment. Therapy involves the utilization of a constellation of different agents, all targeting different goals of care. The first, and most important step in the treatment of severe hyperkalemia with electrocardiographic (ECG) changes, is to stabilize the myocardium with calcium in order to resolve or mitigate the development of arrythmias. Next, it is vital to target the underlying etiology of any ECG changes by redistributing potassium from the extracellular space with the use of intravenous regular insulin and inhaled beta-2 agonists. Finally, the focus should shift to the elimination of excess potassium from the body through the use of intravenous furosemide, oral potassium-binding agents, or renal replacement therapy. Multiple nuances and controversies exist with these therapies, and it is important to have a robust understanding of the underlying support and recommendations for each of these agents to ensure optimal efficacy and minimize the potential for adverse effects and medication errors.
Optical Coherence Tomography Parameters and Optimal Cut-off Values for Predicting Visual Prognosis in Ethambutol-Induced Optic Neuropathy
Authors: Kang Min Chae , Eun Hyung Woo , Park Kyung-Ah , Oh Sei Yeul
Published: January 2024

Background:

The objective of this study was to evaluate the prognostic value of optical coherence tomography (OCT) parameters in patients with ethambutol-induced optic neuropathy (EON) and establish their optimal cut-off values for predicting visual acuity outcomes.

Methods:

A retrospective cross-sectional study was conducted on 64 eyes of 32 patients with EON who underwent OCT. Peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell-inner plexiform layer (mGCIPL) thickness were measured using Cirrus high-definition OCT (HD-OCT) within 3 months after EON diagnosis. Visual acuity of patients was recorded and analyzed at the first visit, the 1-year visit, and the latest visit. Prognostic capacities of OCT parameters for visual prognosis were evaluated and their optimal cut-off values for predicting final visual acuity were established.

Results:

Increased pRNFL thickness was significantly associated with better visual acuity at 1 year postdiagnosis and the latest visit. A significant association was established between increased pRNFL thickness and a higher rate of recovery to visual acuity >20/25 at 1 year postdiagnosis. Receiver-operating characteristic curves identified ideal cut-off values for OCT parameters as follows: pRNFL thickness of 83 μm (sensitivity 100%, specificity 48.3%) and mGCIPL thickness of 74 μm (sensitivity 100%, specificity 83.3%) for visual acuity >20/25 at 1 year, mGCIPL thickness of 61 μm (sensitivity 85.7%, specificity 71.4%) for visual acuity >20/40 at 1 year, with corresponding AUCs exceeding 0.7.

Conclusions:

Both pRNFL and mGCIPL thickness possess potential values for predicting visual outcomes in patients with EON. Future research should continue to explore the utility of OCT parameters in EON prognosis.
Safety and tolerability of cariprazine for the adjunctive treatment of major depressive disorder: a pooled analysis of phase 2b/phase 3 clinical trials
Authors: Thase Michael E. , Yeung Paul P. , Rekeda Ludmyla , Liu Meng , Varughese Shane
Published: January 2024

To characterize the safety and tolerability of adjunctive cariprazine in patients with major depressive disorder (MDD) and inadequate response to monotherapy antidepressant treatment (ADT). Post hoc analyses evaluated pooled data from 2 fixed-dose phase 3 cariprazine studies (1.5 and 3 mg/d [approved doses for MDD]). In a separate safety analysis, cariprazine 0.1–4.5 mg/d was evaluated using data from the 2 fixed-dose trials plus 3 flexible-dose studies grouped by modal-daily dose. In the pooled phase 3 studies (placebo = 503, 1.5 mg/d = 502, 3 mg/d = 503), overall cariprazine-treated patients had high rates of study completion (90%). Patients had mostly mild/moderate treatment-emergent adverse events that caused premature discontinuation of 4.3%. Only akathisia, nausea, and insomnia occurred in ≥5% of cariprazine patients (any group) and at twice the rate of placebo; potential dose-dependent responses were observed for akathisia and insomnia. Cariprazine had a neutral metabolic profile, with mean weight increase of <1 kg. Modal-dose results were similar, and both analyses were consistent with the known safety profile of cariprazine across its approved indications. Adjunctive cariprazine therapy was safe and generally well tolerated in patients with MDD who had not obtained an adequate response to ADT monotherapy; no new safety signals were identified.
T-Cell-Mediated Killing in Glioblastoma Organoids induced by Adenoviral Delivery of the CIITA Transgene
Authors: Salvato Ilaria , Klein Eliane , Poli Aurélie , Rezaeipour Mahsa , Ermini Luca , Nosirov Bakhtiyor , Lipsa Anuja , Oudin Anais , Baus Virginie , Dore Gian Mario , Cosma Antonio , Golebiewska Anna , Marchini Antonio , Niclou Simone P.
Published: January 2024

The immunosuppressive nature of the tumor microenvironment poses a significant challenge to effective immunotherapies against glioblastoma (GB). Boosting the immune response is critical for a successful therapy. Here, we adopted a cancer gene therapy approach to induce T-cell mediated killing of the tumor through increased activation of the immune system. Patient-based 3D GB models were infected with a replication-deficient adenovirus (AdV) armed with the Class II Major Histocompatibility Complex (MHC-II) TransactivatorCIITAgene (Ad-CIITA). Successful induction of surface MHC-II was achieved in infected GB cell lines and primary human GB organoids. Infection with an AdV carrying a mutant form ofCIITAwith a single amino acid substitution resulted in cytoplasmic accumulation of CIITA without subsequent MHC-II expression. Co-culture of infected tumor cells with either PBMCs or isolated T-cells led to dramatic breakdown of GB organoids. Intriguingly, both wild-type and mutant Ad-CIITA but not unarmed AdV, triggered immune-mediated tumor cell death in the co-culture system, suggesting an at least partially MHC-II-independent process. We further show that the observed cancer cell killing requires the presence of either CD8+or CD4+T-cells and the direct contact between GB and immune cells. We did not however detect evidence of activation of canonical T-cell mediated cell death pathways. While the precise mechanism remains to be determined, these findings highlight the potential of AdV-mediatedCIITAdelivery to enhance T-cell-mediated immunity against GB.
Self-amplifying ROS-sensitive SN38 Dimeric Prodrug nanoparticles for Combined Chemotherapy and Ferroptosis in Cancer Treatment
Authors: Qin Yu , Wang Fenghui , Gao Zeping , Tian Chutong , Kamei Ken-ichiro
Published: January 2024

Chemotherapy drugs are often limited by their own clinical shortcomings and serious adverse consequences. To solve these problems, we developed a self-amplifying reactive oxygen species (ROS)-sensitive dimeric prodrug nanoparticles, namely SN38-CA@FC NPs for tumor treatment. A ROS-sensitive 7-ethyl-10-hydroxycamptothecin (SN38) prodrug (SN38-CA) was synthesized by a thioacetal linker between SN38 and the ROS generator cinnamaldehyde (CA). The subsequent release of SN38 inflicts DNA damage, exerting chemotherapeutic effects, while the liberated CA intensifies ferroptosis through Fenton reaction-mediated disruption of the redox balance. This dual-action strategy not only leverages chemotherapy but also induces ferroptosis, establishing a synergistic therapeutic paradigm. The system is uniquely characterized by a positive feedback loop where ROS instigates the release of SN38/CA, which in turn promotes further ROS production. In experimental evaluations, this combination therapy exhibited potent antitumor activity against both A549 and LLC cancer cell lines, as well as in xenograft LLC-bearing C57BL/6 mouse models. Collectively, our findings introduce a transformative Nano-Drug Delivery System (NDDS) that holds significant promise for advancing cancer chemotherapy and ferroptosis-based therapies.
The effects of intermittent or continuous exercise on renal haemodynamics during moderate-intensity exercise
Authors: Kawakami Shotaro , Yasuno Tetsuhiko , Kawakami Saki , Ito Ai , Fujimi Kanta , Matsuda Takuro , Nakashima Shihoko , Masutani Kosuke , Uehara Yoshinari , Higaki Yasuki , Michishita Ryoma
Published: January 2024

Purpose

Moderate-intensity exercise has beneficial effects for individuals with CKD. However, it is unclear whether intermittent exercise (IE) has a different effect on renal haemodynamics compared to continuous exercise (CE). This study aimed to compare the effects of intermittent or continuous exercise on renal haemodynamics and renal injury during moderate-intensity exercise.

Methods

Ten males underwent IE or CE to consider the effect of exercise on renal haemodynamics during moderate-intensity exercise. Renal haemodynamic assessment and blood-sampling were conducted before exercise (pre) and immediately (post 0), 30-min (post 30), and 60-min (post 60) after exercise. Urine-sampling was conducted in pre, post 0 and post 60.

Results

There was no condition-by-time interaction (p = 0.073), condition (p = 0.696), or time (p = 0.433) effects regarding renal blood flow. There was a condition-by-time interaction effect regarding noradrenaline concentrations (p = 0.037). Moreover, both conditions significantly increased noradrenaline concentration at post 0 (IE: p = 0.003, CE: p < 0.001) and remained significantly higher in post 30 (p < 0.001) and post 60 (p < 0.001). Significant difference was found in noradrenaline concentrations at post 0 when comparing IE and CE (399 ± 119 vs. 552 ± 224 pg/ml, p = 0.037). Urinary neutrophil gelatinase-associated lipocalin concentrations increased at post 60 (p = 0.009), but none of them exceeded the cutoff values for the definition of renal damage. Other renal injury biomarkers showed a similar pattern.

Conclusion

These findings suggest that IE has a similar effect on renal haemodynamics and function, and AKI biomarkers compared to CE.
MAARU: Multichannel Acoustic Autonomous Recording Unit for spatial ecosystem monitoring
Authors: Heath Becky E , Le Penru Neel P , Skinner James , Orme C. David L. , Sethi Sarab S , Ewers Robert M , Picinali Lorenzo
Published: January 2024

1.

1 – Acoustic localisation, which relies on simultaneous multi-microphone recording, adds spatial information to recorded audio and has been used in ecosystem monitoring to count individuals to improve abundance estimates, locate illegal activities such as logging/poaching, and monitor behaviour such as habitat use or species interactions. Studies have shown many advantages of acoustic localisation, but uptake remains limited as the equipment is often expensive, inaccessible, or only suitable for short-term deployments.

2 –Here, we present a low-cost, open-source, 6-channel recorder built entirely from commercially available components which can be integrated into a solar-powered, networked system. The MAARU (Multichannel Acoustic Autonomous Recording Unit) works in long-term autonomous, passive, and ad-hoc deployments. We introduce MAARU’s hardware and software and present the results of lab and field tests investigating the device’s durability, localisation accuracy, and other applications.

3 –MAARU provides multichannel data with similar costs and power demands to equivalent omnidirectional recorders. MAARU devices have been deployed in the UK and Brazil, where we have shown MAARUs can accurately localise pure tones up to 6kHz and 65dB bird calls as far as 8m away (±10° range, 100% and >60% of signals respectively), louder calls may have even further detection radii. We also show how beamforming can be used on MAARU devices to improve species ID confidence scores by 20%+ and recall by 10%+ when using the BirdNET automated bird identification algorithms.

4 –MAARU is an accessible, low-cost option for those looking to explore spatial soundscape ecology accurately and easily. Ultimately, the added directional element of the multichannel recording provided by MAARU allows for a new type of exploration into sonic environments.

Abstract Figure
Opposing effects of acellular and whole cell pertussis vaccines onBordetella pertussisbiofilm formation, Siglec-F+ neutrophil recruitment and bacterial clearance in mouse nasal tissues
Authors: Hall Jesse M. , Gutiérrez-Ferman Jessica L. , Shamseldin Mohamed M. , Guo Myra , Gupta Yash A. , Deora Rajendar , Dubey Purnima
Published: January 2024

Despite global vaccination, pertussis caused byBordetella pertussis(Bp) is resurging. Pertussis resurgence is correlated with the switch from whole cell vaccines (wPV) that elicit TH1/TH17 polarized immune responses to acellular pertussis vaccines (aPV) that elicit primarily TH2 polarized immune responses. One explanation for the increased incidence in aPV-immunized individuals is the lack of bacterial clearance from the nose. To understand the host and bacterial mechanisms that contribute toBppersistence, we evaluated bacterial localization and the immune response in the nasal associated tissues (NT) of naïve and immunized mice followingBpchallenge.Bpresided in the NT of unimmunized and aPV-immunized mice as biofilms. In contrast,Bpbiofilms were not observed in wPV-immunized mice. Following infection, Siglec-F+ neutrophils, critical for eliminatingBpfrom the nose, were recruited to the nose at higher levels in wPV immunized mice compared to aPV immunized mice. Consistent with this observation, the neutrophil chemokine CXCL1 was only detected in the NT of wPV immunized mice. Importantly, the bacteria and immune cells were primarily localized within the NT and were not recovered by nasal lavage (NL). Together, our data suggest that the TH2 polarized immune response generated by aPV vaccination facilitates persistence in the NT by impeding the infiltration of immune effectors and the eradication of biofilms In contrast, the TH1/TH17 immune phenotype generated by wPV, recruits Siglec-F+ neutrophils that rapidly eliminate the bacterial burden and prevent biofilm establishment. Thus, our work shows that aPV and wPV have opposing effects onBpbiofilm formation in the respiratory tract and provides a mechanistic explanation for the inability of aPV vaccination to control bacterial numbers in the nose and prevent transmission.

Author Summary

Acellular pertussis vaccine (aPV) immunized individuals maintain a nasal reservoir ofBordetella pertussis(Bp) and thus have the potential to transmit the infection to vulnerable individuals. Here we provide a mechanistic explanation for the inability of aPV to eliminateBpfrom the nasal cavity. We show that following bacterial challenge of aPV immunized mice, Siglec-F+ neutrophils and other immune effectors are not recruited to the nose. Consequently,Bpremain in the nose and form biofilms. In contrast, whole cell pertussis (wPV) immunized mice produce immune effectors following bacterial challenge that recruit Siglec-F+ neutrophils to the nose.Bpburden is cleared from the nasal tissues, thereby preventing bacterial persistence and the formation of biofilms.
Implications of noncoding regulatory functions in the development of insulinomas
Authors: Ramos-Rodríguez Mireia , Subirana-Granés Marc , Norris Richard , Sordi Valeria , Fernández Ruiz Ángel , Fuentes-Páez Georgina , Pérez-González Beatriz , Berenguer Balaguer Clara , Raurell-Vila Helena , Chowdhury Murad , Corripio Raquel , Partelli Stefano , López-Bigas Núria , Pellegrini Silvia , Montanya Eduard , Nacher Montserrat , Falconi Massimo , Layer Ryan , Rovira Meritxell , Gonzalez-Perez Abel , Piemonti Lorenzo , Pasquali Lorenzo
Published: January 2024

Insulinomas are rare neuroendocrine tumours arising from the pancreatic β-cells. While retaining the ability to produce insulin, insulinomas feature aberrant proliferation and altered hormone secretion resulting in failure to maintain glucose homeostasis.

With the aim of uncovering the role of noncoding regulatory regions and their aberrations to the development of these tumors, we coupled epigenetic and gene expression profiling with whole-genome sequencing. As a result, we mapped H3K27ac sites in the tumoral tissue and unraveled overlapping somatic mutations associated with changes in regulatory functions. Critically, these regions impact insulin secretion, tumor development and epigenetic modifying genes, including key components of the polycomb complex. Chromatin remodeling is apparent as insulinoma-selective regions are mostly clustered in regulatory domains, shared across patients and containing a specific set of regulatory sequences dominated by the binding motif of the transcription factor SOX17. Moreover, a large fraction of these regions are H3K27me3-repressed in unaffected β-cells, suggesting that tumoral transition is coupled with derepression of β-cell polycomb-targeted domains.

Our work provides a compendium of aberrantcis-regulatory elements and transcription factors that alter β-cell function and fate in their progression to pancreatic neuroendocrine tumors and a framework to identify coding and noncoding driver mutations.
Minimal-invasive 3D laser printing of microimplantsin organismo
Authors: Afting Cassian , Mainik Philipp , Vazquez-Martel Clara , Abele Tobias , Kaul Verena , Göpfrich Kerstin , Lemke Steffen , Blasco Eva , Wittbrodt Joachim
Published: January 2024

Multi-photon 3D laser printing has gathered much attention in recent years as a means of manufacturing biocompatible scaffolds that can modify and guide cellular behaviorin vitro. However,in vivotissue engineering efforts have been limited so far to the implantation of beforehand 3D printed biocompatible scaffolds andin vivobioprinting of tissue constructs from bioinks containing cells, biomolecules, and printable hydrogel formulations. Thus, a comprehensive 3D laser printing platform forin vivoandin situmanufacturing of microimplants raised from synthetic polymer-based inks is currently missing.

Here we present a platform for minimal-invasive manufacturing of microimplants directly in the organism by one-photon photopolymerization and multi-photon 3D laser printing. Employing a commercially available elastomeric ink giving rise to biocompatible synthetic polymer-based microimplants, we demonstrate first applicational examples of biological responses toin situprinted microimplants in the teleost fishOryzias latipesand in embryos of the fruit flyDrosophila melanogaster. This provides a framework for future studies addressing the suitability of inks forin vivo3D manufacturing. Our platform bears great potential for the direct engineering of the intricate microarchitectures in a variety of tissues in model organisms and beyond.
First-in-classTransactivator-Free, Doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B-cell lymphomas
Authors: Justicia-Lirio Pedro , Tristán-Manzano María , Maldonado-Pérez Noelia , Barbero-Jiménez Carmen , Cortijo-Gutiérrez Marina , Pavlovic Kristina , Molina-Estevez Francisco J , Muñoz Pilar , Hinckley-Boned Ana , Griñán-Lison Carmen , Navarro-Marchal Saúl A , Muñoz-Ballester Julia , González-Sierra Pedro A , Herrera Concha , Marchal Juan A , Martín Francisco
Published: January 2024

Background

Despite their success treating type B cancers, Chimeric Antigen Receptor (CAR) T cells still showed limited efficacy in certain lymphomas and solid tumors. Reinforcing conventional CAR-T cells to release cytokines can improve their efficacy but also increase safety concerns. Several strategies have been developed to regulate their secretion using minimal promoters that are controlled by chimeric proteins harboring transactivators. However, these chimeric proteins can disrupt the normal physiology of target cells.

Methods

Co-transduction with CAR19 and Lent-On-Plus-IL-18 LVs allowed for generating constitutive CAR/Dox-inducible IL-18 CAR-T cells that respond to ultra-low doses of doxycycline (iTRUCK19.18). iTRUCK19.18 were evaluated against an aggressive Burkitt lymphoma modelin vitroandin vivo, against primary B-cell tumors and against a CD19-engineered pancreatic tumor model. Patient-derived iTRUCK19.18 cells were also generated.

Results

iTRUCK19.18 controlled IL-18 release through a dual mechanism dependent on doxycycline and T cell activation, thereby enhancing the safety profile. IL-18 release increased the activation state/proinflammatory profile of T cells in a doxycycline-dependent manner without altering cellular fitness, which was translated into an increased CAR-T cell antitumor activity against aggressive hematologic and solid tumor models. In a clinically relevant context, we generated patient-derived iTRUCK19.18 cells able to significantly increase elimination of primary B cells tumors under doxycycline. Furthermore, IL-18-releasing iTRUCK19.18 polarized pro-tumoral M2 macrophages towards an antitumoral phenotype (M1), suggesting the ability to modulate the tumor microenvironment.

Conclusion

We have generated the first transactivator-free inducible TRUCKs from healthy donors and B-cell neoplasms patients. iTRUCK19-18 exhibit dual safety control mechanisms for IL-18 secretion and improved antitumoral activity against type-B neoplasms. Inducible IL-18 secretion not only enhanced T cell potency but could also change the tumor microenvironment to a more antitumoral state.
Microalgal biofilm induces larval settlement in the model marine wormPlatynereis dumerilii
Authors: Hird Cameron , Jékely Gáspár , Williams Elizabeth A.
Published: January 2024

A free-swimming larval stage features in many marine invertebrate life cycles. To transition to a seafloor-dwelling juvenile stage, larvae need to settle out of the plankton, guided by specific environmental cues that lead them to an ideal habitat for their future life on the seafloor. Although the marine annelidPlatynereis dumeriliihas been cultured in research labs since the 1950s and has a free-swimming larval stage, specific environmental cues that induce settlement in this nereid worm are yet to be identified. Here we demonstrate that microalgal biofilm is a key settlement cue forP. dumeriliilarvae, inducing earlier onset of settlement, and enhancing subsequent juvenile growth as a primary food source. We tested the settlement response ofP. dumeriliito 40 different strains of microalgae, predominantly diatom species, finding thatP. dumeriliihave species-specific preferences in their choice of settlement substrate. The most effective diatom species for inducingP. dumeriliilarval settlement were benthic pennate species includingGrammatophora marina,Achnanthes brevipes, andNitzschia ovalis. The identification of specific environmental cues forP. dumeriliisettlement enables a link between its ecology and the sensory and nervous system signalling that regulate larval behaviour and development. Incorporation of diatoms intoP. dumeriliiculture practices will improve the husbandry of this marine invertebrate model.
Large-Scale COI Gene Data Analysis for the Development of a Gel-Based Multiplex PCR Test Capable of Identifying Biting Midge Vector Species and Haplotypes (Diptera: Ceratopogonidae) of theCulicoidessubgenusAvaritiaFox, 1955
Authors: Dähn Oliver , Werner Doreen , Mathieu Bruno , Kampen Helge
Published: January 2024

The emergence of culicoid-transmitted bluetongue and Schmallenberg viruses in several European countries demonstrated the ability of indigenous biting midge species to transmit pathogens. Entomologic research programmes identified members of the Obsoletus Group (CulicoidessubgenusAvaritia) as keyplayers in disease epidemiology in Europe. However, morphological identification of potential vectors to species level is challenging due to the existence of isomorphic species. PCR tests developed to facilitate genetic species determination have been dismantled by the discovery of new genetic variants (haplotypes) ofC. obsoletussensu stricto (s.s.), forming distinct clades. In this study, 4,422 GenBank entries of the mitochondrial cytochrome c oxidase subunit I (COI) gene of subgenusAvaritiamembers of the genusCulicoideswere analyzed to develop a conventional multiplex PCR, capable of detecting all vector species and recently described clades of the western Palaearctic in this subgenus. Numerous GenBank entries incorrectly assigned to a species were identified, analyzed and reassigned. The results suggest that the three clades ofC. obsoletusrepresent independent species, whereasC. montanusshould rather be regarded as a genetic variant ofC. obsoletuss.s.. Based on these findings, specific primers were designed and validated with DNA material from field-caught biting midges which achieved very high diagnostic sensitivity (100%) when compared to an established reference PCR (82.6%). Hence, the newly developed multiplex PCR represents the first molecular tool which enables both the identification of accepted species and of the three clades ofC. obsoletuss.s. and could provide new insights into the ecology of the latter.
Selective Regulation of a Defined Subset of Inflammatory and Immunoregulatory Genes by an NF-κB p50-IκBζ Pathway
Authors: Daly Allison E. , Yeh George , Soltero Sofia , Smale Stephen T.
Published: January 2024

The five NF-κB family members and three nuclear IκB proteins play important biological roles, but the mechanisms by which distinct NF-κB and IκB proteins contribute to selective gene transcription remain poorly understood, especially at a genome-scale level. Using nascent transcript RNA-seq, we observed considerable overlap between p50-dependent and IκBζ-dependent genes in Toll-like receptor 4 (TLR4)-activated macrophages. Key immunoregulatory genes, includingIl6,Il1b,Nos2,Lcn2,andBatf,are among the p50-IκBζ co-dependent genes. IκBζ bound genomic sites occupied by NF-κB dimers at earlier time points. However, p50-IκBζ co-dependence does not coincide with preferential binding of either p50 or IκBζ, as both proteins and RelA co-occupy thousands of genomic sites. A common feature of p50-IκBζ co-dependent genes is a nearby p50/RelA/IκBζ co-bound site exhibiting p50-dependent binding of both RelA and IκBζ. This result and others suggest that IκBζ may act in concert with RelA:p50 heterodimers. Notably, the IκBζ-dependent and p50-IκBζ-co-dependent genes comprise a high percentage of genes that exhibit the greatest differential expression between TLR4-stimulated and tumor necrosis factor receptor (TNFR)-stimulated macrophages. Thus, our genome-centric analysis reveals a defined p50-IκBζ pathway that selectively activates a set of key immunoregulatory genes and serves as an important contributor to the differential TNFR and TLR4 responses.
3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression
Authors: Mortenson Katelyn L. , Dawes Courtney , Wilson Emily R. , Patchen Nathan E. , Johnson Hailey E. , Gertz Jason , Bailey Swneke D. , Liu Yang , Varley Katherine E. , Zhang Xiaoyang
Published: January 2024

Cancer genomes are composed of many complex structural alterations on chromosomes and extrachromosomal DNA (ecDNA), making it difficult to identify non-coding enhancer regions that are hijacked to activate oncogene expression. Here, we describe a 3D genomics-based analysis called HAPI (Highly Active Promoter Interactions) to characterize enhancer hijacking. HAPI analysis of HiChIP data from 34 cancer cell lines identified enhancer hijacking events that activate both known and potentially novel oncogenes such asMYC, CCND1,ETV1,CRKL, andID4. Furthermore, we found enhancer hijacking among multiple oncogenes from different chromosomes, often includingMYC, on the same complex amplicons such as ecDNA. We characterized aMYC-ERBB2chimeric ecDNA, in whichERBB2heavily hijacksMYC’s enhancers. Notably, CRISPRi of theMYCpromoter led to increased interaction ofERBB2withMYCenhancers and elevatedERBB2expression. Our HAPI analysis tool provides a robust strategy to detect enhancer hijacking and reveals novel insights into oncogene activation.
Efficacy of Transposition of Plicated Medial Rectus Muscles in the Treatment of A- or V- Pattern Exotropia (An Egyptian Comparative Study)
Authors: El-aidy Lamiaa A. , Ibrahim Yasser M. , Elmarakby Mohamed A. , Ghali Manar A.
Published: January 2024

Objective

To report effectiveness of bimedial plication and vertical transposition for correction of exotropia associated with A- or V-pattern and compare it with bimedial resection and vertical transposition.

Methods and analysis

We retrospectively reviewed the results of surgery of patients who underwent bimedial plication (group I) versus bimedial resection (group II) with vertical offset to correct both exotropia and pattern deviation not secondary to oblique overaction in the period between January 2021 and January 2023. Results of both groups were compared. Success was considered when pattern deviation was ≤ 8 prism diopters PD and horizontal deviation was within 10 PD of orthophoria at 6 months postoperatively.

Results

The mean preoperative angle of exotropia in PD was 40.6 ± 7.2 in group I and 41.1 ± 7.5 in group II (p=.8). At 6 months postoperatively, they achieved angle of 4.6 ± 4.1 and 2.5 ± 4.5 PD respectively (no significant difference between both groups; p=.19). The mean preoperative pattern deviation was 21.3 ± 3.7 PD in group I and 21.6 ± 4.4 in group II. Postoperative pattern collapse was 16.7 ± 5.6 and 16.6 ± 4.1 respectively. The percentage of success in pattern collapse was 90.6% in group I and 84.4% in group II (no significant difference between both groups; p=.71).

Conclusion

Vertical transposition with plication of medial recti is a safe, effective, and rapid technique for correction of cases of A- or V- pattern exotropia not associated with oblique overaction. Results were not significantly different from resection/vertical transposition.

What is already known in this topic?

A- or V-pattern exotropia without significant inferior oblique overaction can be treated by vertical transposition of the horizontal recti after ordinary recession or resection.

Some studies reported muscle plication and transposition as an alternative technique to resection and transposition. Plication allow preservation of ciliary circulation and lowering the incidence of muscle loss.

What this study adds?

In this retrospective study, we concluded that medial rectus plication and transposition is an effective alternative technique to medial rectus resection and transposition in treatment of A- or V- pattern exotropia without significant inferior oblique overaction (No significant difference between both techniques).

What this study might affect research, practice or policy?

Vertical Transposition of plicated medial recti is a new promising technique which should be considered in managing cases of A- or V-pattern exotropia without significant inferior oblique overaction.
Development, validation and clinical utility of Short-term AdVerse-effects of Electroconvulsive therapy (SAVE) Checklist
Authors: Uppinkudru Chithra , Pathak Harsh , Raj Kumar K , Bridgit S , Bagali Kiran , Pantoji Makarand , Ezhumalai Nathiya , Parlikar Rujuta , Shah Vyoma , Balachander Srinivas , Sreeraj Vanteemar S , Mehta Urvakhsh Meherwan , Sinha Preeti , Arumugham Shyam Sundar , Venkatasubramanian Ganesan , Thirthalli Jagadisha
Published: January 2024

Electroconvulsive therapy (ECT) is one of the most effective treatments in psychiatry. However, it has many cognitive and non-cognitive adverse effects (AEs). There are lacunae in the systematic literature on non-cognitive AEs that need a standard, comprehensive and specific clinical tool to evaluate this. Hence, a checklist of short-term AEs of ECT (SAVE) with a 2-phase assessment was developed. Content validation was done using 15 experts’ ratings and predefined content validity ratio and index (CVR and CVI) in a two-stage modified Delphi method. The checklist had a good CVR and CVI with a final tool of 39 items. The tool was sensitive and identified the non-cognitive AEs after ECT. Cardiovascular and musculoskeletal systems displayed the highest incidence. Many participants exhibited delayed recovery in orientation, gait, and stance, highlighting a necessity for meticulous monitoring. SAVE is the first standardised tool to assess short-term ECT-related AEs systematically. This checklist identified a clinically significant incidence of AEs that would otherwise remain unnoticed. Its regular use may enhance the safety of ECT and patient comfort by supporting early identification and intervention for AEs. However, given the transient nature of AEs, further studies are needed to determine their predictive validity for long-term consequences.