bluuebunny/crossref_metadata_2025 huggingface dataset:
Topography-guided excimer laser ablation
Authors: Onishi Alex C. , Lee-Choi Calisa , Marvasti Amir H.
Published: April 2023

Purpose of review

Currently, the most commonly performed corneal refractive surgery is laser-assisted in-situ keratomileusis (LASIK). Customized forms of LASIK have been developed, which have allowed for improved outcomes and the enhanced correction of higher order aberrations (HOAs). This review discusses one form of custom LASIK, topography-guided LASIK, including factors involved in preoperative planning, and advantages and disadvantages compared with other forms of keratorefractive surgery.

Recent findings

Various treatment-planning approaches addressing discrepancies between the refractive and topographic astigmatic magnitude and axis have been used successfully, although there is debate regarding a superior method in the literature.

There are many forms of custom LASIK, which provide excellent outcomes. Topography-guided LASIK may be of particular use in highly aberrated corneas and may also provide outstanding outcomes in healthy eyes given its emphasis on treating the primary refractive surface of the eye.
Cold Snare Polypectomy in Small (<10 mm) Pedunculated Colorectal Polyps
Authors: Canakis Andrew , Chandan Saurabh , Bapaye Jay , Canakis Justin , Twery Benjamin , Mohan Babu P. , Ramai Daryl , Facciorusso Antonio , Bilal Mohammad , Adler Douglas G.
Published: April 2023

Introduction:

Endoscopic removal techniques for colorectal polyps include cold snare polypectomy (CSP) and hot snare polypectomy (HSP). Although HSP is recommended for pedunculated polyps (PPs) larger than 10 mm, data regarding use of CSP for PPs <10 mm continues to emerge. We aimed to investigate outcomes of these techniques in small (<10 mm) pedunculated colorectal polyps.

Methods:

Multiple databases were searched till June 2022 to identify studies involving the removal of small PPs with CSP and HSP. Random effects model was used to calculate outcomes and 95% CI. Primary outcome was the pooled rate of successful en-bloc resection. Secondary outcomes were immediate and delayed bleeding with CSP and HSP as well as prophylactic and post resection clip placement.

Results:

Six studies including 1025 patients (1111 polyps with a mean size 4 to 8.5 mm) were analyzed. 116 and 995 polyps were removed with HSP and CSP, respectively. The overall pooled rate of successful en-bloc resection with CSP was 99.7% (CI 99.1-99.9; I2 0%). Pooled immediate and delayed bleeding after CSP was 49.8% (CI 46.8-52.91; I2 98%) and 0% (CI 0.00-0.00; I2 0%), respectively. Delayed bleeding was higher with HSP, relative risk 0.05 (CI 0.01-0.43; I2 0%), P=0.006, whereas immediate bleeding was higher with CSP, relative risk 7.89 (CI 4.36-14.29; I2 0%), P<0.00001. Pooled rates of prophylactic clip placement and post-procedure clip placement (to control immediate bleeding) were 55.3% and 47.2%, respectively. Finally, right colon polyp location significantly correlated with frequency of immediate bleeding.

Conclusion:

Our analysis shows that CSP is safe and effective for resection of small PPs.
Unraveling the natural history of presymptomatic cystinuria
Authors: Tokhmafshan Fatima , Goodyer Paul R.
Published: April 2023

Purpose of review

Servais et al. recently published clinical practice recommendations for the care of cystinuria patients. However, these guidelines were largely based on retrospective data from adults and children presenting with stones. Significant questions remain about the natural history of cystinuria in presymptomatic children.

Recent findings

We review the natural history of cystinuria in presymptomatic children followed from birth. In total, 130 pediatric patients were assigned putative genotypes based on parental urinary phenotype: type A/A (N = 23), B/B (N = 6), and B/N (N = 101). Stones were identified in 12/130 (4% of A/A, 17% of B/B, and 1% of B/N patients). Type B/B patients had lower cystine excretion than type A/A patients. Although urine cystine/creatinine fell with age, urine cystine/l rose progressively in parallel with the risk of nephrolithiasis. Each new stone was preceded by 6–12 months of urine specific gravity of more than 1.020. However, average urine specific gravity and pH were not different in stone formers vs. nonstone formers, suggesting that intrinsic stone inhibitors or other unknown factors may be the strongest determinants of individual risk.

The current study reviews the clinical evolution of cystinuria in a cohort of children identified by newborn screening, who were categorized by urinary phenotype and followed from birth.
Intersectionality and adolescent medicine: an overview
Authors: Mazon Candice , Jimenez-Maldonado Jacqueline , Walters Frinny Polanco
Published: April 2023

Purpose of review

This review defines intersectionality, discusses recent studies that use an intersectional framework in adolescent health research, and outlines ways where clinicians can use intersectionality to address health disparities in youth of color through clinical practice, research, and advocacy.

Recent findings

Research using an intersectional framework can identify populations at risk for certain disorders or behaviors. Recent studies in adolescent health research using an intersectional lens identified lesbian girls of color as an at-risk population for e-cigarette use, demonstrated lower skin color satisfaction among Black girls of all ages predicted greater binge-eating disorder symptoms, and showed that two-thirds of Latine (gender-neutral term that refers to people with Latin American roots) youth who recently immigrated to the United States experienced at least one traumatic event during their migration journey, putting them at risk for PTSD and other mental health disorders.

Intersectionality refers to how multiple social identities intersect to produce a specific experience that reflects overlapping systems of oppression. Diverse youth contain multiple identities that intersect to produce unique experiences and health inequities. Using an intersectional framework acknowledges that youth of color are not homogenous. Intersectionality becomes an important tool to care for marginalized youth and advance health equity.
Role of lymphadenectomy during primary surgery for kidney cancer
Authors: Bekku Kensuke , Kawada Tatsushi , Yanagisawa Takafumi , Karakiewicz Pierre I. , Shariat Shahrokh F.
Published: April 2023

Purpose of review

Lymph node dissection (LND) during radical nephrectomy (RN) for renal cell carcinoma (RCC) is not considered as a standard. The emergence of robot-assisted surgery and effective immune checkpoint inhibitors (ICI) in recent years may change this and lymph node (LN) staging has become easier and has a clinical impact. In this review, we aimed to reconsider the role of LND today.

Recent findings

Although the extent of LND has still not been well established, removal of more LN seems to provide better oncologic outcomes for a select group of patients with high-risk factors such as clinical T3-4. Adjuvant therapy using pembrolizumab has been shown to improve disease free survival if complete resection of metastatic lesions as well as the primary site is obtained in combination. Robot assisted RN for localized RCC has been widespread and the studies regarding LND for RCC has been recently appeared.

The staging and surgical benefits and its extent of LND during RN for RCC remains unclear, but it is becoming increasingly important. Technologies that allow an easier LND and adjuvant ICI that improve survival in LN-positive patients are engaging the role of LND, a procedure that was needed, but almost never done, is now indicated sometimes. Now, the goal is to identify the clinical and molecular imaging tools that can help identify with sufficient accuracy who needs a LND and which LNs to remove in a targeted personalized approach.
External Scholarship Mentors for DNP-Prepared Faculty
Authors: Dunlap Jayne Jennings , Brewer Tracy L. , Mainous Rosalie O.
Published: April 2023

Background:

Variability surrounding what practice scholarship should entail and how to incorporate into academic life exists among DNP-prepared faculty teaching across nursing programs.

Problem:

DNP-prepared faculty entering an academic role are expected to maintain a clinical practice, teach/advise students, and fulfill service obligations, often leaving minimal time to build a program of scholarship.

Approach:

Building upon the archetype of external mentors for PhD researchers, we introduce a new model for external mentorship for DNP-prepared faculty to facilitate scholarship.

Outcomes:

In the first dyad to use this model, the mentor-mentee met/exceeded all contractual goals, including presentations, manuscripts, leadership behaviors, and role navigation within higher education. More external dyads are currently in development.

Conclusions:

Securing an external, seasoned mentor as a match for a junior member of the faculty in a yearlong partnership demonstrates promise for positive change in the scholarship trajectory of DNP-prepared faculty in higher education.
The impact of prehospital whole blood on hemorrhaging trauma patients: A multi-center retrospective study
Authors: Braverman Maxwell A. , Schauer Steven G. , Ciaraglia Angelo , Brigmon Erika , Smith Alison A. , Barry Lauran , Bynum James , Cap Andrew D. , Corral Hannah , Fisher Andrew D. , Epley Eric , Jonas Rachelle B. , Shiels Michael , Waltman Elizabeth , Winckler Christopher , Eastridge Brian J. , Stewart Ronald M. , Nicholson Susannah E. , Jenkins Donald H.
Published: April 2023

BACKGROUND

Whole blood (WB) use has become increasingly common in trauma centers across the United States for both in-hospital and prehospital resuscitation. We hypothesize that prehospital WB (pWB) use in trauma patients with suspected hemorrhage will result in improved hemodynamic status and reduced in-hospital blood product requirements.

METHODS

The institutional trauma registries of two academic level I trauma centers were queried for all patients from 2015–2019 who underwent transfusion upon arrival to the trauma bay. Patients who were dead on arrival or had isolated head injuries were excluded. Demographics, injury and shock characteristics, transfusion requirements, including massive transfusion protocol (MTP) (>10 U in 24 hours) and rapid transfusion (CAT3+) and outcomes were compared between pWB and non-pWB patients. Significantly different demographic, injury characteristics and pWB were included in univariate followed by stepwise logistic regression analysis to determine the relationship with shock index (SI). Our primary objective was to determine the relationship between pWB and improved hemodynamics or reduction in blood product utilization.

RESULTS

A total of 171 pWB and 1391 non-pWB patients met inclusion criteria. Prehospital WB patients had a lower median Injury Severity Score (17 vs. 21, p < 0.001) but higher prehospital SI showing greater physiologic disarray. Prehospital WB was associated with improvement in SI (−0.04 vs. 0.05, p = 0.002). Mortality and (LOS) were similar. Prehospital WB patients received fewer packed red blood cells, fresh frozen plasma, and platelets units across their LOS but total units and volumes were similar. Prehospital WB patients had fewer MTPs (22.6% vs. 32.4%, p = 0.01) despite a similar requirement of CAT3+ transfusion upon arrival.

CONCLUSION

Prehospital WB administration is associated with a greater improvement in SI and a reduction in MTP. This study is limited by its lack of power to detect a mortality difference. Prospective randomized controlled trials will be required to determine the true impact of pWB on trauma patients.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
Blood component resuscitative strategies to mitigate endotheliopathy in a murine hemorrhagic shock model
Authors: Baucom Matthew R. , Wallen Taylor E. , Ammann Allison M. , England Lisa G. , Schuster Rebecca M. , Pritts Timothy A. , Goodman Michael D.
Published: April 2023

BACKGROUND

Resuscitation with plasma components has been shown to improve endotheliopathy induced by hemorrhagic shock, but the optimal resuscitation strategy to preserve the endothelial glycocalyx has yet to be defined. The aim of this study was to determine if resuscitation with lactated Ringer's (LR), whole blood (WB), packed red blood cells (RBCs), platelet-rich plasma (PRP), platelet poor plasma, balanced RBC:PRP (1:1), or day 14 (d14) RBC would best minimize endothelial damage following shock.

METHODS

Male C57BL/6 mice were hemorrhaged to a goal mean arterial pressure of 25 mm Hg for 1 hour. Unshocked sham mice served as controls. Mice were then resuscitated with equal volumes of LR, WB, RBC, PRP, platelet poor plasma, 1:1, or d14 RBC and then sacrificed at 1, 4, or 24 hours (n = 5). Serum was analyzed for syndecan-1, ubiquitin C-terminal hydrolase L1, and cytokine concentrations. Lungs underwent syndecan-1 immunostaining, and lung injury scores were calculated after hematoxylin and eosin. Proteolytic cleavage of the endothelial glycocalyx was assessed by serum matrix metalloprotease 9 levels.

RESULTS

Serum syndecan-1 and ubiquitin C-terminal hydrolase L1 levels were significantly increased following resuscitation with d14 RBC compared with other groups. Early elevation in lung syndecan-1 staining was noted in LR-treated mice, while d14 mice showed decreased staining compared with sham mice following shock. Lung injury scores were significantly elevated 4 hours after resuscitation with LR and d14 RBC compared with WB. Serum matrix metalloprotease 9 levels were significantly increased at 1 and 4 hours in d14 mice compared with sham mice. Systemic inflammation was increased in animals receiving LR, 1:1, or d14 RBC.

CONCLUSION

Resuscitation with WB following hemorrhagic shock reduces endothelial syndecan-1 shedding and mitigates lung injury. Aged RBC and LR fail to attenuate endothelial injury following hemorrhagic shock. Further research will be necessary to determine the effect of each of these resuscitative fluids in a hemorrhagic shock model with the addition of tissue injury.
Number of Hepatic Resections and Association with Complication after Metastatic Neuroendocrine Tumor Debulking: An American College of Surgeons NSQIP Database Study
Authors: Schwarz Jason L , Kuchta Kristine M , Rojas Aram , Mehdi Syed , Hoon Choi Sung , Keutgen Xavier M , Talamonti Mark S , Hogg Melissa E
Published: April 2023

Introduction:

Neuroendocrine tumor liver metastases (NELM) are a major source of morbidity and mortality in neuroendocrine tumor patients and can be treated with hepatic debulking surgery (HDS). This study aims to identify variables associated with postoperative morbidity in NELM HDS.

Methods:

This analysis uses the ACS-NSQIP targeted hepatectomy-specific Participant User File from 2014-2020. Surgeries were grouped by number of hepatic resections performed (1-5, 6-10, >10). Multivariable logistic regression (MVA) and matching was used to identify prognostic factors of morbidity.

Results:

1,163 patients were included. 1,011 (87%) had 1-5 hepatic resections, 101 (8.7%) had 6-10 resections, and 51 (4.4%) had >10 resections. Overall complication rate was 35% while surgical and medical complications reached 30% and 13%, respectively. Mortality occurred in 11 patients (0.9%). Significantly higher rates of any (34% vs 35% vs 53%, p = .021) and surgical complications (29% vs 28% vs 49%, p = .007) were noted for those undergoing >10 resections (1-5 resections, 6-10, >10). “Bleeding requiring transfusion” (p < .0001) occurred more frequently in the >10 resection group. On MVA, >10 resections was an independent risk factor for any (OR 2.53, p = .002; OR 2.52, p = .013) and surgical (OR 2.53, p = .003; OR 2.88, p = .005) complications compared to 1-5 resections and 6-10 resections, respectively. Medical complications (OR 2.34, p = .020) and length of stay (LOS) > 5 days (OR 1.98, p = .032) were also increased with >10 vs 1-5 resections.

Conclusion:

As reported by NSQIP, NELM HDS were performed safely with low mortality. However, more hepatic resections, especially >10, was associated with increased postoperative morbidity and LOS.
Modelling planar kirigami metamaterials as generalized elastic continua
Authors: Zheng Y. , Niloy I. , Tobasco I. , Celli P. , Plucinsky P.
Published: April 2023

Kirigami metamaterials dramatically change their shape through a coordinated motion of nearly rigid panels and flexible slits. Here, we study a model system for mechanism-based planar kirigami featuring periodic patterns of quadrilateral panels and rhombi slits, with the goal of predicting their engineering scale response to a broad range of loads. We develop a generalized continuum model based on the kirigami’s effective (cell-averaged) nonlinear deformation, along with its slit actuation and gradients thereof. The model accounts for three sources of elasticity: a strong preference for the effective fields to match those of a local mechanism, inter-panel stresses arising from gradients in slit actuation, and distributed hinge bending. We provide a finite-element formulation of this model and implement it using the commercial software Abaqus. Simulations of the model agree quantitatively with experiments across designs and loading conditions.
Actomyosin-mediated cellular tension promotes Yap nuclear translocation and myocardial proliferation through α5 integrin signaling
Authors: Li Xiaofei , McLain Callie , Samuel Michael S. , Olson Michael F. , Radice Glenn L.
Published: April 2023

The cardiomyocyte phenotypic switch from a proliferative to terminally differentiated state results in the loss of regenerative potential of the mammalian heart shortly after birth. Yet, the molecular mechanisms that regulate this critical developmental process are incompletely understood. Nonmuscle myosin IIB (NM IIB)-mediated actomyosin contractility regulates cardiomyocyte cytokinesis in the embryonic heart, and NM IIB levels decline after birth suggesting a role for cellular tension in the regulation of cardiomyocyte cell cycle activity in the postnatal heart. The Rho kinase (ROCK) serine/threonine protein kinases that act downstream of the RhoA small GTP-binding protein regulate nonmuscle myosin contractile force generation. To investigate the role of actomyosin contractility in cardiomyocyte maturation and cell cycle arrest, we conditionally-activated ROCK2 kinase domain (ROCK2:ER) in the murine postnatal heart. Here we show that cardiac-specific activation of actomyosin contractility shifts the balance from cell-cell to cell-matrix adhesions. Specifically, α5/β1 integrin and fibronectin matrix increase in response to actomyosin-mediated tension. Moreover, activation of ROCK2:ER promotes nuclear translocation of Yap, a mechanosensitive transcriptional co-activator, and enhances cardiomyocyte proliferation. Finally, we show that reduction of myocardial α5 integrin rescues the myocardial proliferation phenotype in ROCK2:ER hearts. These data demonstrate that cardiomyocytes respond to increase intracellular tension by altering their intercellular contacts in favor of cell-matrix interactions leading to Yap nuclear translocation, thus uncovering a novel function for nonmuscle myosin contractility in promoting cardiomyocyte cell cycle activity in the postnatal heart.
Knowledge and Attitude Towards Palliative Care Among Clinical Undergraduate Students of Physiotherapy in Nigerian Universities: A Cross-Sectional Study
Authors: Odetunde Marufat Oluyemisi , Nwankwo Jessie Chiamaka , Owojuyigbe Afolabi Muyiwa , Aaron Olurotimi I. , Okonji Adaobi Magraet
Published: April 2023

Introduction

Palliative care demands a special skill from health care providers which begins with the right attitude and adequate knowledge during training. Little is known about knowledge and attitude of physiotherapy undergraduates towards palliative care. Objective of this study was to assess knowledge and attitude of clinical undergraduates of physiotherapy in Nigerian universities towards palliative care.

Method

This was a cross sectional survey involving 281 (132 females and 149 males) clinical physiotherapy undergraduates from 10 purposively selected universities across Nigeria. Palliative care knowledge was assessed with a structured questionnaire while attitude was assessed using FROMMELT attitude towards care of the dying scale. Both questionnaires were administered online via Google forms. Socio-demographic data of each respondent was also collected. Data were analyzed using descriptive and inferential statistics. Level of significance was set at p<0.05.

Results

Majority of respondents were males (53%) aged 21-25 years (87.9%) from Obafemi Awolowo University (40.3%) and had above average knowledge (62%). Almost all, (99.6%) of the respondents displayed favourable attitude. There were significant associations between knowledge and university of respondents (p=0.001), attitude and age of respondents (p=0.003), as well as attitude and geopolitical zone of origin of respondents (p=0.006). There was significant correlation between knowledge and attitude of respondents (r =0.441, p =0.001).

Conclusion

There are knowledge gaps, but positive attitudes towards palliative care among clinical physiotherapy undergraduates in Nigeria. This signifies an essential and urgent need for inclusion, reform or improvement in palliative care education in the curriculum of undergraduate physiotherapy training in Nigerian universities.
Epidural stimulation restores muscle synergies by modulating neural drives in participants with motor/sensory complete spinal cord injuries
Authors: Singh Rajat Emanuel , Ahmadi Aliya , Parr Ann , Samadani Uzma , Krassioukov Andrei V. , Netoff Theoden I , Darrow David P.
Published: April 2023

Multiple studies have corroborated restored volitional motor control after motor-complete spinal cord injury (SCI) through the use of spinal cord stimulation (SCS/eSCS) but rigorous quantitative descriptions have been lacking. Using a structured surface electromyogram based (sEMG) task with and without SCS during the Epidural Stimulation After Neurological Damage (ESTAND) study in participants with chronic, motor and sensory complete SCI, we investigated muscle activity complexity and muscle synergies to better characterize neuro-muscular control.

In addition, competition exists between the task and neural origin hypotheses underlying muscle synergies, and this analysis in humans with motor and sensory complete chronic injury provided an opportunity to test these hypotheses. Muscle activity complexity was computed with Higuchi Fractal Dimensional analysis (HFD), and muscle synergies were estimated using non-negative matrix factorization (NNMF) in six participants with AIS A chronic SCI. We found that the complexity of muscle activity is immediately reduced with SCS in the SCI participants. We also found that over the follow-up sessions, the muscle synergy structure of the SCI participants became more defined, and the number of synergies decreased over time, indicating improved coordination between the muscle groups. Lastly, we found that the muscle synergies were restored with SCS, supporting the neural hypothesis of muscle synergies. We conclude that SCS restores muscle movements and muscle synergies that are distinct from healthy, able-bodied controls.
Epigenetic inheritance of gene-silencing is maintained by a self-tuning mechanism based on resource competition
Authors: Karin Omer , Miska Eric A. , Simons Benjamin D.
Published: April 2023

Biological systems can maintain memories over long timescales, with examples including memories in the brain and immune system. It is currently unknown how functional properties of memory systems, such as memory persistence, can be established by biological circuits. To address this question, we focus on transgenerational epigenetic inheritance in C. elegans. In response to a trigger, worms silence a target gene for multiple generations, resisting strong dilution due to growth and reproduction. Silencing may also be maintained indefinitely upon selection according to silencing levels. We show that these properties imply fine-tuning of biochemical rates in which the silencing system is positioned near the transition to bistability. We demonstrate that this behavior emerges from a generic mechanism based on competition for synthesis resources, which leads to self-organization around a critical state with broad silencing timescales. The theory makes distinct predictions and offers insights into the design principles of long-term memory systems.
Pan-cancer whole genome comparison of primary and metastatic solid tumors
Authors: Martínez-Jiménez Francisco , Movasati Ali , Brunner Sascha , Nguyen Luan , Priestley Peter , Cuppen Edwin , Van Hoeck Arne
Published: April 2023

Metastatic cancer remains almost inevitably a lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here, we characterize the genomic differences between early-stage untreated primary tumors and late-stage treated metastatic tumors using a harmonized pan-cancer (re-)analysis of 7,152 whole-genome-sequenced tumors. In general, our analysis shows that metastatic tumors have a low intra-tumor heterogeneity, high genomic instability and increased frequency of structural variants with comparatively a modest increase in the number of small genetic variants. However, these differences are cancer type specific and are heavily impacted by the exposure to cancer therapies. Five cancer types, namely breast, prostate, thyroid, kidney clear carcinoma and pancreatic neuroendocrine, are a clear exception to the rule, displaying an extensive transformation of their genomic landscape in advanced stages. These changes were supported by increased genomic instability and involved substantial differences in tumor mutation burden, clock-based molecular signatures and the landscape of driver alterations as well as a pervasive increase in structural variant burden. The majority of cancer types had either moderate genomic differences (e.g., cervical and colorectal cancers) or highly consistent genomic portraits (e.g., ovarian cancer and skin melanoma) when comparing early- and late-stage disease. Exposure to treatment further scars the tumor genome and introduces an evolutionary bottleneck that selects for known therapy-resistant drivers in approximately half of treated patients. Our data showcases the potential of whole-genome analysis to understand tumor evolution and provides a valuable resource to further investigate the biological basis of cancer and resistance to cancer therapies.
The Pandemic Response Commons
Authors: Trunnell Matthew , Frankenberger Casey , Hota Bala , Hughes Troy , Martinov Plamen , Ravichandran Urmila , Shah Nirav S. , Grossman Robert L. ,   The Pandemic Response Commons Consortium
Published: April 2023

Objective

A data commons is a software platform for managing, curating, analyzing, and sharing data with a community. The Pandemic Response Commons is a data commons designed to provide a data platform for researchers studying an epidemic or pandemic.

Methods

The pandemic response commons was developed using the open source Gen3 data platform and is based upon consortium, data, and platform agreements developed by the not-for-profit Open Commons Consortium. A formal consortium of Chicagoland area organizations was formed to develop and operate the pandemic response commons.

Results

We developed a general pandemic response commons and an instance of it for the Chicagoland region called the Chicagoland COVID-19 Commons. A Gen3 data platform was set up and operated with policies, procedures and controls based upon NIST SP 800-53. A consensus data model for the commons was developed, and a variety of datasets were curated, harmonized and ingested, including statistical summary data about COVID cases, patient level clinical data, and SARS-CoV-2 viral variant data.

Discussion and conclusion

Given the various legal and data agreements required to operate a data commons, a pandemic response commons is designed to be in place and operating at a low level prior to the occurrence of an epidemic, with the activities increasing as required during an epidemic. A regional instance of a Pandemic Response Commons is designed to be part of a broader data ecosystem or data mesh consisting of multiple regional commons supporting pandemic response through sharing of regional data.
Multi-omics analysis reveals a crucial role for Retinoic Acid in promoting epigenetic and transcriptional competence of anin vitromodel of human Pharyngeal Endoderm
Authors: Cipriano Andrea , Colantoni Alessio , Gomes Danielle , Moqri Mahdi , Parker Alexander , Caldwell Matthew , Briganti Francesca , Fiorentino Jonathan , Roncarolo Maria Grazia , Baldini Antonio , Weinacht Katja G , Tartaglia Gian Gaetano , Sebastiano Vittorio
Published: April 2023

In vitrodifferentiation of human Pluripotent Stem Cells (hPSCs) into different cell types has enabled the study of developmental processes that are impossible to dissectin vivo. This innovation has allowed for the derivation of therapeutically relevant cell types that can be used for downstream applications and studies. The Pharyngeal Endoderm (PE) is considered an extremely relevant developmental tissue since it acts as a precursor to a plethora of organ systems such as Esophagus, Parathyroids, Thyroids, Lung, and Thymus. While several studies have highlighted the importance of these cells, anin vitroplatform to generate human PE cells is still missing. Here we fill this knowledge gap, by providing a novelin vitroprotocol for the derivation ofbona fidePE cells from hPSCs. We demonstrated that our PE cells robustly express Pharyngeal Endoderm markers, they are transcriptionally similar to PE cells isolated fromin vivomouse development and represent a transcriptionally homogeneous population. Importantly, we elucidated the contribution of Retinoic Acid in promoting a transcriptional and epigenetic rewiring of PE cells. In addition, we defined the epigenetic landscape of PE cells by combining ATAC-Seq and ChIP-Seq of histone modifications. The integration of these data led to the identification of new putative regulatory regions and to the generation of a gene regulatory network orchestrating the development of PE cells. By combining hPSCs differentiation with computational genomics, our work reveals the epigenetic dynamics that occur during human PE differentiation, providing a solid resource and foundation for research focused on the development of PE derivatives and modeling of their developmental defects in genetic syndromes.
Structural Thalamocortical Network Atrophy in Sporadic Behavioural Variant Frontotemporal Dementia
Authors: Jakabek David , Power Brian D. , Spotorno Nicola , Macfarlane Matthew D. , Walterfang Mark , Velakoulis Dennis , Nilsson Christer , Waldö Maria Landqvist , Lätt Jimmy , Nilsson Markus , van Westen Danielle , Lindberg Olof , Looi Jeffrey C. L. , Santillo Alexander F.
Published: April 2023

Using multi-block methods we combined multimodal neuroimaging metrics of thalamic morphology, thalamic white matter tract diffusion metrics, and cortical thickness to examine changes in behavioural variant frontotemporal dementia. (bvFTD). Twenty-three patients with sporadic bvFTD and 24 healthy controls underwent structural and diffusion MRI scans. Clinical severity was assessed using the Clinical Dementia Rating scale and behavioural severity using the Frontal Behaviour Inventory by patient caregivers. Thalamic volumes were manually segmented. Anterior and posterior thalamic radiation fractional anisotropy and mean diffusivity were extracted using Tract-Based Spatial Statistics. Finally, cortical thickness was assessed using Freesurfer. We used shape analyses, diffusion measures, and cortical thickness as features in sparse multi-block partial least squares (PLS) discriminatory analyses to classify participants within bvFTD or healthy control groups. Sparsity was tuned with five-fold cross-validation repeated 10 times. Final model fit was assessed using permutation testing. Additionally, sparse multi-block PLS was used to examine associations between imaging features and measures of dementia severity. The main features predicting bvFTD group membership were bilateral anterior-dorsal thalamic atrophy, increase in mean diffusivity of thalamic projections, and frontotemporal cortical thinning. The model had a sensitivity of 96%, specificity of 68%, and was statistically significant using permutation testing (p = 0.012). For measures of dementia severity, we found similar involvement of regional thalamic and cortical areas as in discrimination analyses, although more extensive thalamo-cortical white matter metric changes. Using multimodal neuroimaging, we demonstrate combined structural network dysfunction of anterior cortical regions, cortical-thalamic projections, and anterior thalamic regions in sporadic bvFTD.
Predicting climate-driven distribution shifts inHyalomma marginatum(Ixodidae)
Authors: Hekimoglu Olcay , Elverici Can , Kuyucu Arda Cem
Published: April 2023

Hyalomma marginatumis an important tick species which is the main vector of Crimean-Congo haemorrhagic fever (CCHF) and spotted fever. The species is predominantly distributed in parts of Southern Europe, North Africa and West Asia. However, due to ongoing climate change and increasing reports ofH. marginatumin central and northern Europe, the expansion of this range poses a potential future risk. In this study, we employed an Ecological Niche Modelling (ENM) approach to model the current and future climatic suitability ofH. marginatum. Using high resolution climatic variables from the Chelsa dataset and an updated list of locations forH. marginatum, we constructed 2 models under current environmental conditions using MaxEnt: a more specific model for only current conditions, and a more general model for both current conditions and future projections under the ssp370 and ssp585 scenarios. Our models show that the climatically suitable region forH. marginatummatches the current distributional area in the Mediterranean basin and West Asia. When applied to future projections, our models suggest a considerable expansion ofH. marginatum’s range in the north in Europe as a result of rising temperatures. However, they also predict a decline in central Anatolia, potentially due to the exacerbation of drought conditions in that region.

Subjects

Ecology, Entomology, Epidemiology, Infectious Diseases, Climate Change Biology
Progranulin maintains blood pressure and vascular tone dependent on EphrinA2 and Sortilin1 receptors and eNOS activation
Authors: Bruder-Nascimento Ariane , Awata Wanessa M.C. , Alves Juliano V. , Singh Shubhnita , Costa Rafael M. , Bruder-Nascimento Thiago
Published: April 2023

Background

The mechanisms determining vascular tone are still not completely understood, even though it is a significant factor in blood pressure management. Many circulating proteins have a significant impact on controlling vascular tone. Progranulin (PGRN) displays anti-inflammatory effects and has been extensively studied in neurodegenerative illnesses. We investigated whether PGRN sustains the vascular tone that helps regulate blood pressure.

Methods

We used male and female C57BL6/J wild type (PGRN+/+) and B6(Cg)-Grntm1.1Aidi/J (PGRN-/-) to understand the impact of PGRN on vascular contractility and blood pressure.

Results

We found that male and female PGRN-/- mice display elevated blood pressure followed by hypercontractility to noradrenaline in mesenteric arteries, which are restored by supplementing the mice with recombinant PGRN (rPGRN). Inex vivoexperiments, rPGRN attenuated the vascular contractility to noradrenaline in male and female PGRN+/+ arteries, which was blunted by blocking EphrinA2 or Sortlin1. To understand the mechanisms whereby PGRN evokes anti-contractile effects, we inhibited endothelial factors. L-NAME [nitric oxide (NO) synthase (NOS) inhibitor] prevented the PGRN effects, whereas indomethacin (cyclooxygenases inhibitor) only affected the contractility in arteries incubated with vehicle, indicating the PGRN increases nitric oxide and decreases contractile prostanoids. Finally, rPGRN induced endothelial NOS (eNOS) phosphorylation and NO production in isolated mesenteric endothelial cells.

Conclusion

Circulating PGRN regulates vascular tone and blood pressure via EphrinA2 and Sortlin1 receptors and eNOS activation. Collectively, our data suggest that deficiency in PGRN is a cardiovascular risk factor and that PGRN might be a new therapeutic avenue to treat high blood pressure.

Clinical Perspective

What is new?

PGRN displays vascular anti-contractile effects dependent on EphrinA2 and Sortilin1 receptors and nitric oxide formation in male and female

Deficiency in PGRN triggers high blood pressure and induces vascular dysfunction characterized by hypercontractility to noradrenaline

PGRN supplementation restores blood pressure and vascular dysfunction in PGRN-deficient mice

What are the clinical implications?

PGRN deficiency is associated with neurodegenerative diseases including neuronal ceroid lipofuscinosis and frontotemporal dementia (FTD). Our study reveals that a lack of PGRN might be associated with vascular dysfunction and high blood pressure

Supplementation with PGRN might be a potential therapeutic route to treat high blood pressure and diseases associated with vascular dysfunction

Reduction in PGRN might be a target to screen for higher cardiovascular risk
The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors
Authors: Hardy Rachel E. , Chung Injae , Yu Yizhou , Loh Samantha H.Y. , Morone Nobuhiro , Soleilhavoup Clement , Travaglio Marco , Serreli Riccardo , Panman Lia , Cain Kelvin , Hirst Judy , Martins Luis M. , MacFarlane Marion , Pryde Kenneth R
Published: April 2023

Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder and major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority of patients. The majority of antipsychotic drugs function as dopamine receptor antagonists in the brain while the most recent ‘third’-generation, such as aripiprazole, act as partial agonists. Despite showing good clinical efficacy, these newer agents are still associated with EPS in ∼5-15% of patients. However, it is not fully understand how these movement disorders develop. Here, we combine clinically-relevant drug concentrations with mutliscale model systems to show that aripiprazole and its primary active metabolite induce mitochondrial toxicity inducing robust declines in cellular ATP and viability. Aripiprazole, brexpiprazole and cariprazine were shown to directly inhibit respiratory complex I through its ubiquinone-binding channel. Importantly, all three drugs induced mitochondrial toxicity in primary embryonic mouse neurons, with greater bioenergetic inhibition in ventral midbrain neurons than forebrain neurons. Finally, chronic feeding with aripiprazole resulted in structural damage to mitochondria in the brain and thoracic muscle of adultDrosophila melanogasterconsistent with locomotor dysfunction. Taken together, we show that antipsychotic drugs acting as partial dopamine receptor agonists exhibit off-target mitochondrial liabilities targeting complex I.
Improved inference of population histories by integrating genomic and epigenomic data
Authors: Sellinger Thibaut , Johannes Frank , Tellier Aurélien
Published: April 2023

Abstract

With the availability of high quality full genome polymorphism (SNPs) data, it becomes feasible to study the past demographic and selective history of populations in exquisite detail. However, such inferences still suffer from a lack of statistical resolution for recent, e.g. bottlenecks, events, and/or for populations with small nucleotide diversity. Additional heritable (epi)genetic markers, such as indels, transposable elements, microsatellites or cytosine methylation, may provide further, yet untapped, information on the recent past population history. We extend the Sequential Markovian Coalescent (SMC) framework to jointly use SNPs and other hyper-mutable markers. We are able to 1) improve the accuracy of demographic inference in recent times, 2) uncover past demographic events hidden to SNP-based inference methods, and 3) infer the hyper-mutable marker mutation rates under a finite site model. As a proof of principle, we focus on demographic inference inA. thalianausing DNA methylation diversity data from 10 European natural accessions. We demonstrate that segregating Single Methylated Polymorphisms (SMPs) satisfy the modelling assumptions of the SMC framework, while Differentially Methylated Regions (DMRs) are not suitable as their length exceeds that of the genomic distance between two recombination events. Combining SNPs and SMPs while accounting for site-and region-level epimutation processes, we provide new estimates of the glacial age bottleneck and post glacial population expansion of the EuropeanA. thalianapopulation. Our SMC framework readily accounts for a wide range of heritable genomic markers, thus paving the way for next generation inference of evolutionary history by combining information from several genetic and epigenetic markers.
Bidirectional transcription at thePPP2R2Bgene locus in spinocerebellar ataxia type 12
Authors: Zhou Chengqian , Liu Hans B. , Bakhsh Fatemeh J. , Wu Bin , Ying Mingyao , Margolis Russell L. , Li Pan P.
Published: April 2023

OBJECTIVE

Spinocerebellar ataxia type 12 (SCA12) is a neurodegenerative disease caused by expansion of a CAG repeat in thePPP2R2B gene. Here we tested the hypothesis that thePPP2R2B antisense(PPP2R2B-AS1) transcript containing a CUG repeat is expressed and contributes to SCA12 pathogenesis.

METHODS

Expression ofPPP2R2B-AS1transcript was detected in SCA12 human induced pluripotent stem cells (iPSCs), iPSC-derived NGN2 neurons, and SCA12 knock-in mouse brains using strand-specific RT-PCR (SS-RT-PCR). The tendency of expandedPPP2R2B-AS1(expPPP2R2B-AS1) RNA to form foci, a marker of toxic processes involving mutant RNAs, was examined in SCA12 cell models by fluorescencein situhybridization. The toxic effect ofexpPPP2R2B-AS1transcripts on SK-N-MC neuroblastoma cells was evaluated by caspase 3/7 activity. Western blot was used to examine the expression of repeat associated non-ATG-initiated (RAN) translation ofexpPPP2R2B-AS1transcript in SK-N-MC cells.

RESULTS

The repeat region inPPP2R2Bgene locus is bidirectionally transcribed in SCA12 iPSCs, iPSC-derived NGN2 neurons, and SCA12 mouse brains. TransfectedexpPPP2R2B-AS1transcripts are toxic to SK-N-MC cells, and the toxicity may be mediated, at least in part, by the RNA secondary structure. TheexpPPP2R2B-AS1transcripts form CUG RNA foci in SK-N-MC cells.expPPP2R2B-AS1transcript is translated in the Alanine ORF via repeat-associated non-ATG (RAN) translation, which is diminished by single nucleotide interruptions within the CUG repeat, and MBNL1 overexpression.

INTERPRETATION

These findings suggest thatPPP2R2B-AS1contributes to SCA12 pathogenesis, and may therefore provide a novel therapeutic target for the disease.
Bridging the gap from knowledge to action: Implementation of the data to policy (D2P) training program at sub-national levels in Zambia
Authors: Banda Kutha , Zimba Rabson , Chilengi-Sakala Sandra , Shakwelele Hilda , Akinola Olatubosun Akinnola
Published: April 2023

Knowledge translation is the synthesis, exchange, and application of knowledge by relevant stakeholders to accelerate the benefits of global and local innovation in strengthening health systems. In Zambia, research evidence is recognized as a critical element for the development of sound policies. This requires deliberate efforts towards generating, harvesting, and utilizing evidence from research and program data to inform decision-making. In response, the National Health Research Authority with support from the Clinton Health Access Initiative adapted a data to policy curriculum for use at sub-national levels and conducted training for 17 healthcare workers. The objectives of the training were to build the capacity of healthcare workers in analyzing research and other data to inform policy and programming as well as to develop six policy briefs for presentation to policymakers.

The curriculum combines epidemiology with economic analysis and modeling to develop informative policy briefs. Sixteen modules were covered and delivered during periodic interactive workshops led by facilitators and mentorship was done in-between sessions. This was done within 6 months from February to August 2022. To assess the participants understanding, Kirkpatrick learning evaluation model was adapted upto level 3; we utilized a pre and posttest method of assessment.

At pre-test, about 71% of the participants scored below 50 percent, while at posttest, all the participants scored above 50%. Six policy briefs were successfully developed covering Sexual Reproductive Maternal Newborn Child Adolescent Health and Nutrition topics. Implementation of this program provided a lot of learnings for programs aimed at improving uptake of evidence into action. One of the key learnings was that conducting economic evaluations and mathematical modelling of proposed policy interventions was critical in informing the decision-makers of the cost and benefits of the interventions. Policy options proposed in the policy brief were largely accepted by key stakeholders and proposed for piloting.
Enhancing Infectious Intestinal Disease diagnosis through metagenomic and metatranscriptomic sequencing of over 1000 human diarrhoeal samples
Authors: Cunningham-Oakes Edward , Perez-Sepulveda Blanca M. , Li Yan , Hinton Jay C. D. , Nelson Charlotte A. , McIntyre K. Marie , Wardeh Maya , Haldenby Sam , Gregory Richard , Iturriza-Gómara Miren , Hertz-Fowler Christiane , O’Brien Sarah J. , Cunliffe Nigel A. , Darby Alistair C.
Published: April 2023

Fundamental issues in the traditional surveillance of diarrhoeal disease need to be addressed. The limitations of traditional microbiological diagnostic methods often mean that the cause of diarrhoea remains unknown, especially for novel or difficult-to-isolate pathogens. Sequencing samples directly, without isolating pathogens, would address this issue. However, we must ensure that sequencing also captures pathogens that are detectable using current diagnostic methods.

We show that metagenomic and metatranscriptomic approaches can effectively detect nine gastrointestinal pathogens in the UK. Metatranscriptomics shows increased sensitivity of detection for pathogens likeCampylobacter,Clostridioides difficile,CryptosporidiumandGiardia, while metagenomics is more effective for detecting pathogens such asAdenovirus, pathogenicEscherichia coli,Salmonella,Shigella, andYersinia enterocolitica. Certain pathogens were detected by both metagenomic and metatranscriptomic sequencing. Metatranscriptomics gave near-complete genome coverage for Human mastadenovirus F and detectedCryptosporidiumvia capture ofCryptosporidium parvumvirus (CSpV1). A comprehensive transcriptomic profile ofSalmonellaEnteritidis was recovered from the stool of a patient with a laboratory-confirmedSalmonellainfection.

This study highlights the power of direct sequencing of human samples to augment GI pathogen surveillance and clinical diagnostics. Metatranscriptomics was best for capturing a wide breadth of pathogens and was more sensitive for this purpose. We propose that metatranscriptomics should be considered for future surveillance of gastrointestinal pathogens. This study has generated a rich data resource of paired metagenomic and metatranscriptomic datasets, direct from over 1000 patient stool samples. We have made these data publicly available to promote the improved understanding of pathogens associated with infectious intestinal diseases.