bluuebunny/crossref_metadata_2025 huggingface dataset:
The endosomal pH regulator NHE9 is a driver of stemness in glioblastoma
Authors: Ko Myungjun , Makena Monish R , Schiapparelli Paula , Suarez-Meade Paola , Mekile Allatah X , Lal Bachchu , Lopez-Bertoni Hernando , Kozielski Kristen L , Green Jordan J , Laterra John , Quiñones-Hinojosa Alfredo , Rao Rajini
Published: March 2022

A small population of self-renewing stem cells initiate tumors and maintain therapeutic resistance in glioblastoma (GBM). Given the limited treatment options and dismal prognosis for this disease, there is urgent need to identify drivers of stem cells that could be druggable targets. Previous work showed that the endosomal pH regulator NHE9 is upregulated in GBM and correlates with worse survival prognosis. Here, we probed for aberrant signaling pathways in patient-derived GBM cells and found that NHE9 increases cell surface expression and phosphorylation of multiple receptor tyrosine kinases (RTKs) by promoting their escape from lysosomal degradation. Downstream of NHE9-mediated receptor activation, oncogenic signaling pathways converged on the JAK2-STAT3 transduction axis to induce pluripotency genes Oct4 and Nanog and suppress markers of glial differentiation. We used both genetic and chemical approaches to query the role of endosomal pH in GBM phenotypes. Loss-of-function mutations in NHE9 that failed to alkalinize endosomal lumen did not increase self-renewal capacity of gliomaspheres in vitro. However, monensin, a chemical mimetic of Na+/H+ exchanger activity, and the H+ pump inhibitor bafilomycin bypassed NHE9 to directly alkalinize the endosomal lumen resulting in stabilization of RTKs and induction of Oct4 and Nanog. Using orthotopic models of primary GBM cells we found that NHE9 increased tumor initiation in vivo. We propose that NHE9 initiates inside-out signaling from the endosomal lumen, distinct from the established effects of cytosolic and extracellular pH on tumorigenesis. Endosomal pH may be an attractive therapeutic target that diminishes stemness in GBM, agnostic of specific receptor subtype.
Isotopic evidence for pallasite formation by impact mixing of olivine and metal during the first 10 million years of the Solar System
Authors: Windmill Richard J , Franchi Ian A , Hellmann Jan L , Schneider Jonas M , Spitzer Fridolin , Kleine Thorsten , Greenwood Richard C , Anand Mahesh
Published: March 2022

Pallasites are mixtures of core and mantle material that may have originated from the core–mantle boundary of a differentiated body. However, recent studies have introduced the possibility that they record an impact mix, in which case an isotopic difference between metal and silicates in pallasites may be expected. We report a statistically significant oxygen isotope disequilibrium between olivine and chromite in main group pallasites that implies the silicate and metal portions of these meteorites stem from distinct isotopic reservoirs. This indicates that these meteorites were formed by impact mixing, during which a planetary core was injected into the mantle of another body. The impactor likely differentiated within ∼1–2 Myr of the start of the Solar System based on Hf–W chronology of pallasite metal, and we infer the age of the impact based on Mn–Cr systematics and cooling rates at between ∼1.5 and 9.5 Myr after Ca–Al-rich inclusions (CAIs). When combined with published slow subsolidus cooling rates for these meteorites and considering that several pallasite groups exist, our results indicate that such impacts may be an important stage in the evolution of planetary bodies.
Troll and divide: the language of online polarization
Authors: Simchon Almog , Brady William J , Van Bavel Jay J
Published: March 2022

The affective animosity between the political left and right has grown steadily in many countries over the past few years, posing a threat to democratic practices and public health. There is a rising concern over the role that “bad actors” or trolls may play in the polarization of online networks. In this research, we examined the processes by which trolls may sow intergroup conflict through polarized rhetoric. We developed a dictionary to assess online polarization by measuring language associated with communications that display partisan bias in their diffusion. We validated the polarized language dictionary in 4 different contexts and across multiple time periods. The polarization dictionary made out-of-set predictions, generalized to both new political contexts (#BlackLivesMatter) and a different social media platform (Reddit), and predicted partisan differences in public opinion polls about COVID-19. Then we analyzed tweets from a known Russian troll source (N = 383,510) and found that their use of polarized language has increased over time. We also compared troll tweets from 3 countries (N = 79,833) and found that they all utilize more polarized language than regular Americans (N = 1,507,300) and trolls have increased their use of polarized rhetoric over time. We also find that polarized language is associated with greater engagement, but this association only holds for politically engaged users (both trolls and regular users). This research clarifies how trolls leverage polarized language and provides an open-source, simple tool for exploration of polarized communications on social media.
The Good, the Bad, and the Missed Boom
Authors: Perotti Enrico , Rola-Janicka Magdalena
Published: March 2022

Some credit booms result in financial crises. While excessive risk-taking could plausibly explain the boom-to-bust cycle, many investors do not anticipate increasing risk. We show that credit booms may be misunderstood as being driven by high productivity because opaque bank assets disguise risk incentives. Balanced funding relative to productive prospects can sustain prudent lending (good boom), whereas funding imbalances may induce high risk exposure and boost asset prices (bad boom) or lead to asset underpricing and insufficient lending (missed boom). Rational agents drawing inference from prices make mistakes that can amplify the effect of funding imbalances and propagate risk.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Multi-Omics Strategies for Investigating the Microbiome in Toxicology Research
Authors: Morgan Ethan W , Perdew Gary H , Patterson Andrew D
Published: March 2022

Microbial communities on and within the host contact environmental pollutants, toxic compounds, and other xenobiotic compounds. These communities of bacteria, fungi, viruses, and archaea possess diverse metabolic potential to catabolize compounds and produce new metabolites. Microbes alter chemical disposition thus making the microbiome a natural subject of interest for toxicology. Sequencing and metabolomics technologies permit the study of microbiomes altered by acute or long-term exposure to xenobiotics. These investigations have already contributed to and are helping to re-interpret traditional understandings of toxicology. The purpose of this review is to provide a survey of the current methods used to characterize microbes within the context of toxicology. This will include discussion of commonly used techniques for conducting omic-based experiments, their respective strengths and deficiencies, and how forward-looking techniques may address present shortcomings. Finally, a perspective will be provided regarding common assumptions that currently impede microbiome studies from producing causal explanations of toxicologic mechanisms.
Expanding the RNA virome of nematodes and other soil-inhabiting organisms
Authors: Vieira Paulo , Subbotin Sergei A , Alkharouf Nadim , Eisenback Jonathan , Nemchinov Lev G
Published: March 2022

In recent years, several newly discovered viruses infecting free-living nematodes, sedentary plant-parasitic nematodes, and migratory root lesion nematodes have been described. However, to the best of our knowledge, no comprehensive research focusing exclusively on metagenomic analysis of the soil nematode community virome has thus far been carried out. In this work, we have attempted to bridge this gap by investigating viral communities that are associated with soil-inhabiting organisms, particularly nematodes. This study demonstrates a remarkable diversity of RNA viruses in the natural soil environment. Over 150 viruses were identified in different soil-inhabiting hosts, of which more than 139 are potentially new virus species. Many of these viruses belong to the nematode virome, thereby enriching our understanding of the diversity and evolution of this complex part of the natural ecosystem.
Known Benefits and Unknown Risks of Active Surveillance of Cervical Intraepithelial Neoplasia Grade 2
Authors: Lycke Kathrine D. , Petersen Lone K. , Gravitt Patti E. , Hammer Anne
Published: March 2022

Cervical intraepithelial neoplasia grade 2 (CIN 2) is an equivocal diagnosis with high interobserver variation. Owing to high regression rates of 50%, many countries recommend active surveillance of CIN 2, especially in women younger than age 25–30 years, where regression rates are even higher (ie, 60%). Additionally, excisional treatment is associated with increased risk of reproductive harm, particularly preterm birth. Active surveillance typically consists of semi-annual follow-up visits for up to 2 years, including colposcopy and either cytology, testing for human papillomavirus, or both. Excisional treatment is recommended for progression or persistent disease after 2 years. Because active surveillance in younger women is relatively new, knowledge on subsequent risk of cervical cancer is limited. Considering human papillomavirus latency, women undergoing active surveillance might be at higher risk of cervical cancer than women undergoing excisional treatment. Furthermore, there are limited data describing preferences of women for the management of CIN 2, and it is also unclear how active surveillance may affect planning for future pregnancy. In this context, biomarkers for risk stratification of CIN 2 into either high or low probability of progression would allow for targeted treatment. Currently, immunohistochemical staining for p16 is used to clarify the histologic diagnosis, but whether it or other biomarkers can be used for risk-stratification in clinical management of women with CIN 2 remains unknown. In conclusion, active surveillance of CIN 2 needs further investigation, including understanding the long-term cervical cancer risk and evaluation of markers that may enable risk stratification of CIN 2.
Health Disparities in Uterine Cancer
Authors: Whetstone Sara , Burke William , Sheth Sangini S. , Brooks Rebecca , Cavens Arjeme , Huber-Keener Kathryn , Scott Dana M. , Worly Brett , Chelmow David
Published: March 2022

The Centers for Disease Control and Prevention recognized the need for educational materials for clinicians on the prevention and early diagnosis of gynecologic cancers. The American College of Obstetricians and Gynecologists convened a panel of experts in evidence review from the Society for Academic Specialists in General Obstetrics and Gynecology and content experts from the Society of Gynecologic Oncology to review relevant literature, best practices, and existing practice guidelines for the development of evidence-based educational materials for women's health care clinicians about uterine cancer. This article is the evidence summary of the literature review of health disparities and inequities related to uterine cancer. Substantive knowledge gaps are noted and summarized to provide guidance for future research.
Executive Summary of the Uterine Cancer Evidence Review Conference
Authors: Chelmow David , Brooks Rebecca , Cavens Arjeme , Huber-Keener Kathryn , Scott Dana M. , Sheth Sangini S. , Whetstone Sara , Worly Brett , Burke William
Published: March 2022

The Centers for Disease Control and Prevention recognized the need for educational materials for clinicians on the prevention and early diagnosis of gynecologic cancers. The American College of Obstetricians and Gynecologists convened a panel of experts in evidence review from the Society for Academic Specialists in General Obstetrics and Gynecology and content experts from the Society of Gynecologic Oncology to review relevant literature, best practices, and existing practice guidelines as a first step toward developing evidence-based educational materials for women's health care clinicians about uterine cancer. Panel members conducted structured literature reviews, which were then reviewed by other panel members and discussed at a virtual meeting of stakeholder professional and patient advocacy organizations in January 2021. This article is the evidence summary of the relevant literature and existing recommendations to guide clinicians in the prevention, early diagnosis, and special considerations of uterine cancer. Substantive knowledge gaps are noted and summarized to provide guidance for future research.
State-Mandated Insurance Coverage and Preimplantation Genetic Testing in the United States
Authors: Bedrick Bronwyn S. , Tipping Andrew D. , Nickel Katelin B. , Riley Joan K. , Jain Tarun , Jungheim Emily S.
Published: March 2022

OBJECTIVE:

To examine the association between state-mandated insurance coverage for infertility treatment in the United States and the utilization of and indication for preimplantation genetic testing.

METHODS:

This was a retrospective cohort study of 301,465 in vitro fertilization (IVF) cycles reported to the Society for Assisted Reproductive Technology between 2014 and 2016. Binomial logistic regression was performed to examine associations between state-mandated insurance coverage and preimplantation genetic testing use. The neonate’s sex from each patient's first successful cycle was used to calculate sex ratios. Sex ratios then were compared by state mandates and preimplantation genetic testing indication for elective sex selection.

RESULTS:

The proportion of IVF cycles using preimplantation genetic testing increased from 17% in 2014 to 34% in 2016. This increase was driven largely by preimplantation genetic testing for aneuploidy testing. Preimplantation genetic testing was less likely to be performed in states with mandates for insurance coverage than in those without mandates (risk ratio [RR] 0.69, 95% CI 0.67–0.71, P<.001). Preimplantation genetic testing use for elective sex selection was also less likely to be performed in states with mandates (RR 0.44, 95% CI 0.36–0.53, P<.001). Among liveborn neonates, the male/female sex ratio was higher for IVF cycles with preimplantation genetic testing for any indication (115) than for those without preimplantation genetic testing (105) (P<.001), and the use of preimplantation genetic testing specifically for elective sex selection had a substantially higher (164) male/female sex ratio than preimplantation genetic testing for other indications (112) (P<.001).

CONCLUSION:

The proportion of IVF cycles using preimplantation genetic testing in the United States is increasing and is highest in states where IVF is largely self-funded. Preimplantation genetic testing for nonmedical sex selection is also more common in states where IVF is self-funded and is more likely to result in male offspring. Continued surveillance of these trends is important, because these practices are controversial and could have implications for future population demographics.
Robot-assisted (RA) versus conventional total knee replacement: a 2-year clinical comparison
Authors: Boucher Henry R. , Abraham Nijo , Lee Ji Won , Grieme Caleb , Rigor Paolo Diaz , Markel Michael J. , Szakiel Paulina , Desale Sameer
Published: March 2022

Background:

Robotic-assisted (RA) technology is becoming increasingly popular in total knee arthroplasty (TKA) due to its improved alignment, accuracy, and precision compared with the conventional TKA. Despite reported benefits, disagreements exist regarding patient-reported outcomes and complication rates comparing RA TKA and conventional TKA. Thus, the purpose of the study is to report differences in patient outcomes and complication rates between patients who underwent RA versus conventional TKA.

Methods:

The authors retrospectively reviewed 239 primary knee arthroplasty cases (n=137 robot-assisted and n=102 conventional TKA) performed by a single fellowship-trained orthopaedic surgeon from January 1, 2016 to February 26, 2019. The electronic medical record and patient outcomes database were reviewed for demographic characteristics (age, sex, body mass index, and comorbidities), patient-reported outcomes (Short Form Health Survey and Oxford Knee Score), 90-day complications, and revision rates.

Results:

There was no statistically significant difference in patient-reported outcomes between conventional versus RA groups at two time points: preoperative and 2-year. Differences remained insignificant after controlling for age, sex, body mass index, and comorbidities. There was no statistically significant difference between the conventional and RA groups in revision rates (0.7% and 1%, respectively; P=1.00) or complication rates (1.5% and 3.9%, respectively; P=0.406).

Conclusions:

There were no differences in 90-day complications, revisions, and patient-reported outcome scores between RA TKA and conventional TKA groups at short-term follow-up. Surgeons can expect similar clinical outcomes without an increase in complications while taking advantage of increased accuracy in alignment and component placement. Further long-term study of RA TKA outcomes is warranted.

Level of Evidence:

Level III.
Optimizing the prescription doses and tolerability of systemic therapy in head and neck cancer patients
Authors: Fuereder Thorsten
Published: March 2022

Purpose of review

Squamous cell carcinoma of the head and neck accounts for 330 000 deaths and 650 000 cases worldwide annually. Systemic therapy is an essential pillar of multimodal therapy despite being accompanied with substantial toxicity. This article reviews the latest advances in systemic therapy for the treatment of locoregionally advanced and reccurent/metastatic head and neck cancer from a tolerability perspective.

Recent findings

Multiple recent attempts have been made to optimize tolerability (and efficacy) of systemic therapy utilizing new regimens, modified prescription doses, drugs such as immunotherapies or genotyping to tailor the systemic therapy to the individual patient.

Although treatment benefit has to be weighed against potential toxicity, it is reasonable to anticipate potential side effects of systemic therapies. In a vulnerable elderly or Asian patient population upfront dose modifications of cytotoxic chemotherapies might be reasonable. Special attention should be laid on the patient's nutritional status and early intervention recommended. Dihydropyrimidine dehydrogenase genotyping can predict 5-fluorouracil toxicity and identify patients for whom alternative regimens are more suitable. As for immune checkpoint inhibitor therapy, despite being well tolerated, the identification of biomarkers to predict reduced tolerability or severe toxicity would be highly desirable.
Effectiveness of the Use of Animation and Gamification in Online Distance Education During Pandemic
Authors: Inangil Demet , Dincer Berna , Kabuk Ayşe
Published: March 2022

The study aimed to determine the effects on knowledge and motivation of animation and gamification in online distance education for a diabetes nursing course. This study was a randomized, controlled, prospective study implemented with 70 nursing students. The animation and gamification were applied to the experimental group. Data were collected using the “Diabetes Nursing Knowledge Test,” “Instructional Materials Motivation Survey,” and “Opinion Form on Diabetes Education Supported by Digital Instruments.” There was a statistical difference between the Diabetes Nursing knowledge scores of the groups after the course (P < .05). The students in the experimental group had significantly higher attention and satisfaction and total scores from the Motivation Scale for Teaching Material sub-dimensions compared with the control group (P < .001). The results of our study in generation Z nursing students demonstrated that the use of animation and gamification in online distance learning in nursing students increased their knowledge as well as motivation.
Uptake of Adjuvant Durvalumab After Definitive Concurrent Chemoradiotherapy for Stage III Nonsmall-cell Lung Cancer
Authors: Bryant Alex K. , Yin Huiying , Schipper Matthew J. , Paximadis Peter A. , Boike Thomas P. , Bergsma Derek P. , Movsas Benjamin , Dess Robert T. , Mietzel Melissa A. , Kendrick Randi , Seferi Merita , Dominello Michael M. , Matuszak Martha M. , Jagsi Reshma , Hayman James A. , Pierce Lori J. , Jolly Shruti ,   on behalf of the Michigan Radiation Oncology Quality Consortium
Published: March 2022

Objectives:

The addition of adjuvant durvalumab improves overall survival in locally advanced nonsmall-cell lung cancer (NSCLC) patients treated with definitive chemoradiation, but the real-world uptake of adjuvant durvalumab is unknown.

Materials and Methods:

We identified patients with stage III NSCLC treated with definitive concurrent chemoradiation from January 2018 to October 2020 from a statewide radiation oncology quality consortium, representing a mix of community (n=22 centers) and academic (n=5) across the state of Michigan. Use of adjuvant durvalumab was ascertained at the time of routine 3-month or 6-month follow-up after completion of chemoradiation.

Results:

Of 421 patients with stage III NSCLC who completed chemoradiation, 322 (76.5%) initiated adjuvant durvalumab. The percentage of patients initiating adjuvant durvalumab increased over time from 66% early in the study period to 92% at the end of the study period. There was substantial heterogeneity by treatment center, ranging from 53% to 90%. In multivariable logistic regression, independent predictors of durvalumab initiation included more recent month (odds ratio [OR]: 1.05 per month, 95% confidence interval [CI]: 1.02-1.08, P=0.003), lower Eastern Cooperative Oncology Group score (OR: 4.02 for ECOG 0 vs. 2+, 95% CI: 1.67-9.64, P=0.002), and a trend toward significance for female sex (OR: 1.66, 95% CI: 0.98-2.82, P=0.06).

Conclusion:

Adjuvant durvalumab for stage III NSCLC treated with definitive chemoradiation was rapidly and successfully incorporated into clinical care across a range of community and academic settings in the state of Michigan, with over 90% of potentially eligible patients starting durvalumab in more recent months.
Complications of intravitreal injections: 2022
Authors: Patel Dillan , Patel Samir N. , Chaudhary Varun , Garg Sunir J.
Published: March 2022

Purpose of review

This review highlights the complications of both intravitreal injection procedure as well as different intravitreal medications including antivascular endothelial growth factors, antibiotics, antivirals, antifungals, methotrexate, and steroids. Techniques for reducing rates of endophthalmitis will also be discussed.

Recent findings

Intravitreal vancomycin can cause hemorrhagic occlusive retinal vasculitis resulting in severe vision loss. Intravitreal brolucizumab is associated with intraocular inflammation and retinal vasculitis resulting in significant vision loss. Face mask use by both patient and physician is not associated with increased risk of endophthalmitis and may decrease culture positive endophthalmitis.

Intravitreal injections continue to be one of the most commonly performed procedures by ophthalmologists. Although the injections are generally well tolerated, sight-threatening complications can occur including endophthalmitis, retinal detachment, and/or retinal vasculitis. Adverse events associated with specific medications are outlined below. Several safety measures have been shown to reduce rates of endophthalmitis, the most concerning complication of this procedure.
Indiana Sexual Assault Nurse Examiner Training Initiative: Positive Impacts for Medical Forensic Care
Authors: Morris Angela , Goletz Sarah , Friona Jane
Published: March 2022

Background

Indiana ranks among the highest in the nation for child abuse and neglect reports. Already facing a persistent shortage of sexual assault nurse examiners (SANEs) to serve patients across the life span, residents with medical forensic needs were often being referred to other hospitals across the state for care or simply were not receiving medical forensic examinations because of lack of access to trained examiners. The Indiana SANE Training Project was established to evaluate the forensic nursing workforce throughout Indiana and work to expand access to qualified SANEs through training and collaboration with stakeholders, with a focus on rural and underserved areas of the state.

Methods

The Project gathered information from nurses who participated in activities during the first Project year. This information was evaluated for service gaps and ongoing training needs. The project coordinator then convened a workgroup of stakeholders and subject matter experts to evaluate and respond to the most immediate need—limited access to pediatric medical forensic providers.

Results

From September 2018 to December 2019, nurses were trained by the Project (n = 160). Of those, 86% indicated that their hospital did not provide medical forensic examinations to pediatric patients. The Pediatric SANE Intensive was launched in October 2020 and trained pediatric SANEs (n = 28). Upon completion, participants reported 47% increase in confidence and 56% increase in competence related to caring for pediatric patients.

Discussion

Statewide collaboration is a critical component of establishing a consistent approach to care, strengthening multidisciplinary partnerships, increasing access to medical forensic services across the life span and in rural and underserved areas, and promoting the Indiana Guidelines for Medical Forensic Examination of Pediatric Sexual Abuse Patients.
Evaluation of Electromagnetic Navigational Bronchoscopy Using Tomosynthesis-Assisted Visualization, Intraprocedural Positional Correction and Continuous Guidance for Evaluation of Peripheral Pulmonary Nodules
Authors: Dunn Bryan K. , Blaj Michael , Stahl Jennifer , Speicher James , Anciano Carlos , Hudson Suzanne , Kragel Emily A. , Bowling Mark R.
Published: March 2022

Background:

Electromagnetic navigational bronchoscopy (ENB) has been shown to have variable diagnostic accuracy for the assessment of peripheral pulmonary nodules. This may be because of discrepancies between the preplanned computed tomography of chest target lesion location versus actual target location (computed tomography-to-body divergence), and the lack of a continuous navigational image. The ILLUMISITE (Medtronic, Minneapolis, MN) is a newly developed ENB platform that utilizes tomosynthesis, an imaging technology that can visualize the target location using fluoroscopy (F-ENB). This new system also allows for intraprocedural positional correction and continuous navigation guidance during sampling to overcome these limitations and improve diagnostic yield. We report our first experience in a single center, single proceduralist using this new technology.

Methods:

We conducted a retrospective, single center, single operator study reviewing 72 consecutive patients (78 nodules) over a 3-month period. We investigated the overall diagnostic yield and diagnostic yield by nodule location, size, and sedation type using this new F-ENB system.

Results:

The overall diagnostic yield was 87% and pnemothoraces occurred in 2/78 procedures. We did not find any statistically significant difference when comparing pulmonary nodule location, size or sedation method utilized (P=0.231, 0.338, and 0.112, respectively). Sixty-nine percent of the pulmonary nodules biopsied were 2 to 3 cm in size. The average distance corrected after tomosynthesis visualization was 15.4 mm (0.4 to 29.8 mm).

Conclusion:

We report our initial experience with the ILLUMISITE system using fluoroscopic tomosynthesis-assisted visualization with continuous navigational guidance at our institution. This new technology allows the operator to correct for better target lesion alignment and real time positional correction and may improve diagnostic yields with minimal complications for evaluation of peripheral pulmonary nodules.
Current concepts in fracture healing: temporal dynamization and applications for additive manufacturing
Authors: Schmidt Elaine C. , Judkins Lauren M. , Monogharan Guha , Mehta Samir , Hast Michael W.
Published: March 2022

Objectives:

Current surgical fracture treatment paradigms, which use rigid metallic constructs to heal bones, provide reasonable clinical outcomes; however, they do not leverage recent advances in our understanding of bone healing and mechanotransduction throughout bone healing. The objective of this review was to investigate the efficacy and potential clinical applicability of surgical techniques and implants that deliberately introduce interfragmentary motion throughout the healing process.

Methods:

The authors searched PubMed and Google Scholar databases for articles reporting on fracture repair using dynamic locking plates, dynamized surgical techniques, and reverse dynamization. Data collection also included assessment of additively manufactured (AM) implants that provide dynamic mechanical behaviors.

Results:

Forty articles were included for final review. It was found that accelerated rates of fracture healing can be achieved with staged 2-part surgeries or dynamic implant designs. Temporal dynamization, where static fixation of bones is followed by the introduction of micromotion and controlled loading, has been shown to improve callus volume and accelerate the healing response. Reverse dynamization, where micromotion is encouraged during early callus formation and arrested later, may represent a significant advance for the treatment of critical defect injuries. Advances in AM techniques will likely provide the ability to create high-resolution implants capable of dynamized and reverse dynamized modalities.

Conclusions:

There is no one-size-fits-all approach to optimization of fracture healing. However, it has been clearly demonstrated that fracture treatment can be enhanced by systematically altering the construct stiffness throughout the different phases of healing, which may be achieved with AM implant designs.
Factors Impacting the Success of Free Functioning Gracilis Muscle Transfer for Elbow Flexion in Brachial Plexus Reconstruction
Authors: Hinchcliff Katharine M. , Kircher Michelle F. , Bishop Allen T. , Spinner Robert J. , Shin Alexander Y.
Published: March 2022

Background:

Free functioning muscle transfer is a reconstructive option to restore elbow flexion in brachial plexus injuries. The authors determined the impact of body mass index, age, and location of distal tendon attachment on elbow flexion strength after free functioning muscle transfer in traumatic brachial plexus injury patients.

Methods:

A retrospective review of patients who underwent free functioning muscle transfer for elbow flexion as part of their brachial plexus injury reconstruction with a minimum 2-year follow-up were evaluated. Outcomes assessed included elbow flexion strength (British Medical Research Council grade) and change in Disabilities of the Arm, Shoulder and Hand questionnaire and visual analogue scale pain scores.

Results:

One hundred six patients met inclusion criteria. The average age was 32 years, and the average body mass index was 27.1 kg/m2; 56.5 percent of patients achieved M3 or greater muscle grade using the authors’ strict modification of the British Medical Research Council scale. Disabilities of the Arm, Shoulder and Hand questionnaire scores improved from 45.7 to 38.8 (p < 0.05). Visual analogue scale pain scores decreased, but this trend did not obtain significance. Age and body mass index both had a significant negative impact on final free functioning muscle transfer grade (p < 0.05). Use of a distal tendon insertion led to improved muscle grade outcomes, with targeting of wrist extension being superior to finger flexion (p < 0.05). Simultaneous musculocutaneous nerve grafting did not significantly alter final elbow flexion strength.

Conclusions:

Increasing age and body mass index both imparted a deleterious effect on free functioning muscle transfer muscle grade. Distal muscle targets had better strength outcomes than when the biceps tendon was used.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Prospective Multicenter Observational Cohort Study on Time to Death in Potential Controlled Donation After Circulatory Death Donors—Development and External Validation of Prediction Models: The DCD III Study
Authors: Kotsopoulos Angela , Vos Piet , Witjes Marloes , Volbeda Meint , Franke Hildegard , Epker Jelle , Sonneveld Hans , Simons Koen , Bronkhorst Ewald , Mullers Ruud , Jansen Nichon , van der Hoeven Hans , Abdo Wilson F.
Published: March 2022

Background.

Acceptance of organs from controlled donation after circulatory death (cDCD) donors depends on the time to circulatory death. Here we aimed to develop and externally validate prediction models for circulatory death within 1 or 2 h after withdrawal of life-sustaining treatment.

Methods.

In a multicenter, observational, prospective cohort study, we enrolled 409 potential cDCD donors. For model development, we applied the least absolute shrinkage and selection operator (LASSO) regression and machine learning–artificial intelligence analyses. Our LASSO models were validated using a previously published cDCD cohort. Additionally, we validated 3 existing prediction models using our data set.

Results.

For death within 1 and 2 h, the area under the curves (AUCs) of the LASSO models were 0.77 and 0.79, respectively, whereas for the artificial intelligence models, these were 0.79 and 0.81, respectively. We were able to identify 4% to 16% of the patients who would not die within these time frames with 100% accuracy. External validation showed that the discrimination of our models was good (AUCs 0.80 and 0.82, respectively), but they were not able to identify a subgroup with certain death after 1 to 2 h. Using our cohort to validate 3 previously published models showed AUCs ranging between 0.63 and 0.74. Calibration demonstrated that the models over- and underestimated the predicted probability of death.

Conclusions.

Our models showed a reasonable ability to predict circulatory death. External validation of our and 3 existing models illustrated that their predictive ability remained relatively stable. We accurately predicted a subset of patients who died after 1 to 2 h, preventing starting unnecessary donation preparations, which, however, need external validation in a prospective cohort.
Regional variation in cardiovascular genes enables a tractable genome editing strategy
Authors: Krysov Vikki A. , Wilson Rachel H. , Ten Nicholas S. , Youlton Nathan , De Jong Hannah N. , Sutton Shirley , Huang Yong , Reuter Chloe , Grove Megan E. , Wheeler Matthew T. , Ashley Euan A. , Parikh Victoria N.
Published: March 2022

Recent rise in the number and therapeutic potential of genome engineering technologies has generated excitement in cardiovascular genetics. One significant barrier to their implementation is costly and time consuming reagent development for novel unique variants. Prior data have illuminated the potential for regional clustering of disease-causing genetic variants in known and potential novel functional protein domains. We hypothesized that most cardiovascular disease-relevant genes in ClinVar would display regional variant clustering, and that multiple variants within a regional hotspot could be targeted with limited prime editing reagents. We collated 2,471 high confidence pathogenic or likely pathogenic (P/LP) missense and truncating variants from 111 cardiovascular disease genes. We then defined a regional clustering index (RCI), the percent of P/LP variants in a given gene located within a pre-specified window around each variant. At a window size commensurate with maximally reported prime editing extension length, 78bp, we found that missense variants displayed a higher mean RCI than truncating variants. We next identified genes particularly attractive for pathogenic hotspot-targeted prime editing with at least 20 P/LP variants and observed that the mean RCI in missense variants remained higher than for truncating variants and for rare variants observed in the same genes in gnomAD (Mean±SD RCI78bp: P/LP ClinVar Missense=5.2±5.9%; P/LP ClinVar Truncating=2.1±3.2%, gnomAD Missense=2±3.2%, gnomAD Truncating=1.1±2.4%. p<2.2e-16; ANOVA with post hoc Bonferroni correction). Further, we tested the feasibility of prime editing for multiple variants in a single hotspot in KCNH2, a gene with a high mean missense variant RCI. Sixty variants were induced in this hotspot in HEK293 cells with CRISPR-X. Correction of these variants was attempted with prime editing using two overlapping prime editing guide RNA extensions. The mean prime editing efficiency across CRISPR-X-enriched variants within this hotspot was 57±27%, including 3 P/LP variants. These data underscore the utility of pathogenic variant hotspots in the diagnosis and treatment of inherited cardiovascular disease.
Regional, circuit, and network heterogeneity of brain abnormalities in psychiatric disorders
Authors: Segal Ashlea , Parkes Linden , Aquino Kevin , Kia Seyed Mostafa , Wolfers Thomas , Franke Barbara , Hoogman Martine , Beckmann Christian F. , Westlye Lars T. , Andreassen Ole A. , Zalesky Andrew , Harrison Ben J. , Davey Christopher , Soriano-Mas Carles , Cardoner Narcís , Tiego Jeggan , Yücel Murat , Braganza Leah , Suo Chao , Berk Michael , Cotton Sue , Bellgrove Mark A. , Marquand Andre F. , Fornito Alex
Published: March 2022

The substantial individual heterogeneity that characterizes mental illness is often ignored by classical case-control designs that rely on group mean comparisons. Here, we present a comprehensive, multiscale characterization of individual heterogeneity of brain changes in 1294 cases diagnosed with one of six conditions and 1465 matched healthy controls. Normative models identified that person-specific deviations from population expectations for regional grey matter volume were highly heterogeneous, affecting the same area in <7% of people with the same diagnosis. However, these deviations were embedded within common functional circuits and networks in up to 56% of cases. The salience/ventral attention system was implicated transdiagnostically, with other systems selectively involved in depression, bipolar disorder, schizophrenia, and ADHD. Our findings indicate that while phenotypic differences between cases assigned the same diagnosis may arise from heterogeneity in the location of regional deviations, phenotypic similarities are attributable to dysfunction of common functional circuits and networks.
Female Zebrafish (Danio rerio) Demonstrate Stronger Preference for Established Shoals over Newly-Formed Shoals in the Three-Tank Open-Swim Preference Test
Authors: Velkey Andrew J. , Koon Caroline H. , Danstrom Isabel A. , Wiens Katie M.
Published: March 2022

Zebrafish (Danio rerio) share a considerable amount of biological similarity with mammals, including identical or homologous gene expression pathways, neurotransmitters, hormones, and cellular receptors. Zebrafish also display complex social behaviors like shoaling and schooling, making them an attractive model for investigating normal social behavior as well as exploring impaired social function conditions such as autism spectrum disorders. Newly-formed and established shoals exhibit distinct behavior patterns and inter-member interactions that can convey the group’s social stability. We used a three-chamber open-swim preference test to determine whether individual zebrafish show a preference for an established shoal over a newly-formed shoal. Results indicated that both sexes maintained greater proximity to arena zones nearest to the established shoal stimulus. In addition, we report the novel application of Shannon entropy to discover sex differences in systematicity of responses not revealed by unit-based measurements; male subjects spent more time investigating between the two shoals than female subjects. This novel technique using established versus newly-formed shoals can be used in future studies testing transgenics and pharmacological treatments that mimic autism spectrum disorder and other disorders that affect social interaction.
Safety and immunogenicity of a hybrid-type vaccine booster in BBIBP-CorV recipients: a randomized controlled phase 2 trial
Authors: Kaabi Nawal Al , Yang Yun Kai , Du Li Fang , Xu Ke , Shao Shuai , Liang Yu , Kang Yun , Su Ji Guo , Zhang Jing , Yang Tian , Hussein Salah , ElDein Mohamed Saif , Yang Sen Sen , Lei Wenwen , Gao Xue Jun , Jiang Zhiwei , Cong Xiangfeng , Tan Yao , Wang Hui , Li Meng , Mekki Hanadi Mekki , Zaher Walid , Mahmoud Sally , Zhang Xue , Qu Chang , Liu Dan Ying , Zhang Jing , Yang Mengjie , Eltantawy Islam , Hou Jun Wei , Lei Ze Hua , Xiao Peng , Wang Zhao Nian , Yin Jin Liang , Mao Xiao Yan , Zhang Jin , Qu Liang , Zhang Yun Tao , Yang Xiao Ming , Wu Guizhen , Li Qi Ming
Published: March 2022

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with immune escape ability raises the urgent need for developing cross-neutralizing vaccines against the virus. NVSI-06-08 is a potential broad-spectrum recombinant COVID-19 vaccine that integrates the antigens from multiple SARS-CoV-2 strains into a single immunogen. Here, we evaluated the safety and immunogenicity of NVSI-06-08 as a heterologous booster dose in adults previously vaccinated with the inactivated vaccine BBIBP-CorV in a randomized, double-blind, controlled, phase 2 trial conducted in the United Arab Emirates (NCT05069129). Three groups of healthy adults over 18 years of age (600 participants per group) who had administered two doses of BBIBP-CorV 4-6-month, 7-9-month and >9-month earlier, respectively, were vaccinated with either a homologous booster of BBIBP-CorV or a heterologous booster of NVSI-06-08. The primary outcome was immunogenicity and safety of booster vaccinations. The exploratory outcome was cross-reactive immunogenicity against multiple SARS-CoV-2 variants of concerns (VOCs). The incidence of adverse reactions was low in both booster vaccinations, and the overall safety profile of heterologous boost was quite similar to that of homologous boost. Heterologous NVSI-06-08 booster was immunogenically superior to homologous booster of BBIBP-CorV. Both Neutralizing and IgG antibodies elicited by NVSI-06-08 booster were significantly higher than by the booster of BBIBP-CorV against not only SARS-CoV-2 prototype strain but also multiple VOCs. Especially, the neutralizing activity induced by NVSI-06-08 booster against the immune-evasive Beta variant was no less than that against the prototype strain, and a considerable level of neutralizing antibodies against Omicron (GMT: 367.67; 95%CI, 295.50-457.47) was induced by heterologous booster, which was substantially higher than that boosted by BBIBP-CorV (GMT: 45.03; 95%CI, 36.37-55.74). Our findings showed that NVSI-06-08 was safe and immunogenic as a booster dose following two doses of BBIBP-CorV, which was immunogenically superior to homologous boost with another dose of BBIBP-CorV. Our study also indicated that the design of hybrid antigen may provide an effective strategy for broad-spectrum vaccine developments.
Sex differences in functional network topology over the course of aging in 37543 UK Biobank participants
Authors: Mijalkov Mite , Veréb Dániel , Jamialahmadi Oveis , Canal-Garcia Anna , Gómez-Ruiz Emiliano , Vidal-Piñeiro Didac , Romeo Stefano , Volpe Giovanni , Pereira Joana B.
Published: March 2022

Aging is a major risk factor for cardiovascular and neurodegenerative disorders, with considerable societal and economic implications. Healthy aging is accompanied by changes in connectivity between and within resting-state functional networks, however, there is no consensus on the impact of sex on these age-related alterations. Here, in a large cross-sectional sample of 37543 UK Biobank participants, we show that multilayer measures that capture the interaction between positive and negative connections provide crucial information on the impact of sex on age-related changes in network topology, being closely related to cognitive, structural, and cardiovascular risk factors that have been shown to differ between men and women. We also provide additional insights into the genetic influences on multilayer connectivity changes that occur during aging. Our findings indicate that multilayer measures contain previously unknown information on the relationship between sex and age, opening up new avenues for research into functional brain connectivity in aging.
Interferon regulatory factor 3 upregulates the Treg recruitment factor CCL22 in response to double-stranded DNA in cancer cells
Authors: Kim Jihyun G. , Peña Jocelyn V. , McQueen Hannah P. , Kong Lingwei , Michael Dina , Cook Pamela R.
Published: March 2022

Cancer immunotherapy holds great promise for the treatment of solid tumors, but its effectiveness is hindered by the recruitment of regulatory T cells (Tregs), which inhibit anti-tumor immune responses. We report here that cytosolic dsDNA, a characteristic of many cancer cells, upregulates expression of the Treg-recruitment chemokine CCL22 in multiple types of malignant epithelial cells. We also identified that interferon regulatory factor 3 (IRF3) is a key regulator of CCL22 in response to dsDNA. Both IRF3 and NF-κB are activated downstream of the stimulator of interferon genes (STING), a primary effector protein responding to multiple cytosolic dsDNA sensors. IRF3 activation by STING triggers robust expression of type I interferons, which can boost anti-tumor immune responses. Thus, STING agonists have been used clinically to activate IRF3 during immunotherapy. However, STING activation in some cases is reported to paradoxically foster a pro-tumor, immunosuppressive environment. Our finding that IRF3 regulates CCL22 in response to dsDNA suggests a possible mechanism contributing to STING-mediated immunosuppression. In addition, we found that cultured cancer cells appear able to evolve mechanisms to co-opt nucleic acid sensing pathways to upregulate CCL22, suggesting that these pathways may contribute to acquired immune evasion in tumors with increased cytosolic dsDNA.
Correlation of biomechanics and cancer cell phenotype by combined Brillouin and Raman spectroscopy of U87-MG glioblastoma cells
Authors: Rix Jan , Uckermann Ortrud , Kirsche Katrin , Schackert Gabriele , Koch Edmund , Kirsch Matthias , Galli Roberta
Published: March 2022

The elucidation of biomechanics furthers understanding of brain tumor biology. Brillouin spectroscopy is a new optical method that addresses viscoelastic properties down to subcellular resolution in contact-free manner. Moreover, it can be combined with Raman spectroscopy to obtain co-localized biochemical information. Here, we applied co-registered Brillouin and Raman spectroscopy to U87-MG human glioblastoma cells in vitro. Using 2D and 3D cultures, we related biomechanical properties with local biochemical composition at subcellular level, as well as cell phenotype. Brillouin and Raman mapping of adherent cells showed that the nucleus and nucleoli are stiffer than the perinuclear region and the cytoplasm. The biomechanics of cell cytoplasm is affected by culturing conditions, i.e. cells grown as spheroids being stiffer than adherent cells. Inside the spheroids, the presence of lipid droplets as assessed by Raman spectroscopy reveals higher Brillouin shifts which is not related to local stiffness increase, but due to a higher refractive index combined with a lower mass density. This highlights the importance of locally defined biochemical reference data for a correct interpretation of the Brillouin shift of cells and tissue in future studies investigating the biomechanics of brain tumor models by Brillouin spectroscopy.