bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the feasibility and outcomes of a resident-led school-based pediatric clinic
Authors: D’Arienzo David , Xu Shiqi , Shahid Abeera , Meloche David , Hebert Julie , Dougherty Geoffrey , Li Patricia , Sternszus Robert
Published: May 2023

Objective

A resident-led school-based clinic to serve low-income populations was established in 2019 and served as a continuity clinic for pediatric residents at a single university. Our aim was to assess the feasibility, clinic outcomes, and resident experience of a resident-led school-based clinic (RLSBC), established in an elementary school that serves an underserved population.

Methods

A retrospective chart review for the first 6 months (October 2019 to March 2020) of clinic operations was conducted. Feasibility metrics included the number of patients, visits and planned follow-ups; clinic outcomes included the number and type of presenting complaint, new diagnoses and interventions. Residents were also surveyed to assess their satisfaction and perceived learning in training at the school-based clinic.

Results

Over the first 19 clinic days, 48 children were seen at the school-based clinic. Of the clinic users, 60% did not have a primary care physician, 46% received a new diagnosis, 46% received an intervention in the form of medication prescription, laboratory/imaging requisitions or referrals, and 96% received a treatment plan. Residents positively rated the experience of staffing the school-based clinic in all aspects, including learning environment, clinic and team environment, teaching obtained, practice management, and overall experience.

Conclusion

A RLSBC is feasible and our outcomes suggest that such clinics may address health care needs of low-income families and children, while being a positively rated educational experience for pediatric residents.
Prophylactic mastectomy and bilateral salpingo-oophorectomy in patients with breast cancer: a systematic review of postsurgical sexual function and menopausal hormone therapy symptom mitigation
Authors: Morgan Orly , Belda Rocio , Schnur Julie , Montgomery Guy , Parmar Shivangi , Chirivella Isabel , Cano Antonio
Published: May 2023

Introduction

Preventative surgical procedures for patients who are breast cancer (BRCA) positive—namely, bilateral salpingo-oophorectomy and mastectomy—have been linked to changes in sexual function, including surgically induced menopause. A patient’s decision to undergo preventive surgery as opposed to high-risk screening is heavily reliant on advice received from one’s health care provider. Quality of life should be considered when shared decision making is conducted with patients.

Objectives

To assemble and analyze findings related to patient-reported sexual function after these surgical procedures, to see if and how either procedure affects sexual function from patient baseline, and to determine whether the effects can be mitigated with menopausal hormone therapy.

Methods

A literature review based on the PubMed, Embase, and MEDLINE databases was conducted from inception through January 25, 2022. To be included, studies had to meet an a priori list of Medical Subject Headings: “BRCA” AND “sexual dysfunction” OR “dyspareunia.” GRADE criteria were used to determine the quality of studies relating to menopause hormone therapy.

Results

The search yielded 14 results, and 11 reported sufficient data for systematic review. Sexual function was measured via validated and investigator-generated surveys. All studies, no matter the survey metric, found significant reduction in sexual function with bilateral salpingo-oophorectomy; no studies revealed sexual function changes associated with mastectomy postsurgery. Few studies indicated that menopause hormone therapy resulted in significant improvement in sexual function, and all studies reported that postoperative sexual function could not reach baseline levels with therapy. No studies were high quality by GRADE metrics.

Conclusion

Prophylactic mastectomies and bilateral salpingo-oophorectomies among patients who are BRCA positive cause SF changes postprocedure. Menopausal hormone therapy offers little help in mediating symptoms. Significantly more research is needed to explore potential changes in sexual function, as it is an important aspect of quality of life for patients with BRCA positivity.
The Extensile Lateral Approach to the Calcaneus
Authors: Bhimani Rohan , Shah Kush C. , Kadakia Rishin J.
Published: May 2023

Accounting for 1% to 2% of all fractures, calcaneus fractures are the most common tarsal bone fracture. Although often managed nonoperatively, operative management is preferred for cases that involve significant displacement, joint height loss, and malalignment in patients with limited complication profiles. The extensile lateral approach has historically been a commonly utilized approach for the operative management of displaced calcaneus fractures. Although minimally invasive approaches, such as the sinus tarsi approach, have gained recent traction, they have inherent limitations that result in the extensile lateral approach being the preferable technique in certain cases. In this technique guide, we outline the surgical technique for calcaneus fracture repair using the extensile lateral approach and reported outcomes in the literature.

Level of Evidence:

Level V.
Well-Being and Professional Fulfillment in Mohs Surgeons: An Explanatory Sequential Mixed-Method Design Study
Authors: Lam Charlene , Kim Yesul , Costigan Heather J. , Stuckey Heather , Vidimos Allison T. , Billingsley Elizabeth M. , Albertini John G. , Miller Jeffrey J. , Shanafelt Tait D.
Published: May 2023

BACKGROUND

There are limited data evaluating specific themes of well-being and professional fulfillment in Mohs surgeons.

OBJECTIVE

To identify factors that drive occupational distress and those that promote well-being and professional fulfillment among Mohs surgeons.

METHODS

This is an explanatory sequential mixed-method study, using semistructured individual interviews. Common drivers of physician well-being and fulfillment were identified based on the independent assessment of the coding in the interview transcripts.

RESULTS

This study reports the following qualitative themes: (1) gratitude for the chosen profession and relationships, (2) unrealistic standards of perfection that may have contributed to past career success but are unattainable and create emotional burden, and (3) ability to practice in a manner aligned with personal values promotes professional fulfillment.

CONCLUSION

This study suggests that gratitude, self-compassion, and ability to practice in a manner aligned with personal values promote well-being and professional fulfillment in Mohs surgeons. Notably, we found that unrealistic standards of perfection and personal-organization practice incongruences contribute to burnout.
Relationship between Total Expenditure on Cosmetic Procedures in the United States and NASDAQ 100 Index
Authors: Moon Jiyeon , Ha Jisoo , Kang Daihun
Published: May 2023

Background:

The volume of cosmetic procedures and expenditures has increased over the past 15 years. Recent studies have shown that the market for cosmetic procedures follows the standard laws of economics. However, no studies published in the literature have found a direct correlation between US stock market indices and expenditures on cosmetic surgery and minimally invasive procedures.

Methods:

The authors analyzed annual cosmetic procedure statistics from the American Society of Plastic Surgeons for 2005–2020 against economic indices, including major US stock market indices [NASDAQ 100, S&P 500, Dow Jones Industrial Average (DJIA), Russell 2000 indices from the New York Stock Exchange, gross domestic product (GDP)], median income of US citizens, and the US population from the Federal Reserve Bank of St. Louis. Pearson correlation coefficient and multiple regression analysis were used for the statistical analysis.

Results:

Total expenditure on cosmetic surgery and minimally invasive procedures (TECP) has more than doubled since 2005 to 2020. TECP revealed statistically significant correlations with all other indicators. TECP had the greatest correlation with DJIA (r = 0.952, P < 0.001). In the multiple regression analysis, the increase in TECP led to the rise of the NASDAQ 100 index (adjusted R2 was 0.790, P < 0.001).

Conclusions:

There was a statistically significant correlation between the TECP in USA and the major indices of the US stock market. In particular, the increase in TECP led to the rise of the NASDAQ 100 index.
The prevalence and factors associated with acute postoperative pain in elective gynecologic surgical patients at two referral hospitals in Addis Abeba, Ethiopia, 2021: a cross-sectional study
Authors: Amberbir Wubet Dessie , Bayable Samuel Debas , Fetene Melaku Bantie
Published: May 2023

Background:

Postoperative pain is an expected and undesirable by-product of all surgical procedures. The provision of effective and safe postoperative pain management should be one of the top priorities of any healthcare, where surgical procedures are carried out. Major abdominal surgical operations require pain management services, regular pain assessment, and timely management of breakthrough pains in the postoperative period.

Objective:

This study aimed to determine the prevalence and factors associated with acute postoperative pain.

Methods:

A cross-sectional study was conducted at Minilik and Zewditu Referral hospitals from October to December 2021 and chart review and face-to-face interviews were the methods of data collection. The pain was measured at the 2, 12, and 24 h postoperatively through a numerical rating scale, and the pain was categorized as no pain (score=0), mild pain (score 1–3), moderate pain (score 4–6), or severe pain (score 7–10). All independent variables with P less than or equal to 0.2 in the univariable logistic regression were reanalyzed with multivariable logistic regression at 95% CI to determine predictive factors and a P-value of less than 0.05 was considered statistically significant.

Results:

In the study period, a total of 368 eligible patients were involved, out of this 11 patients were discharged before 24 h, four patients refuse to participate two incomplete documentation and one patient was ICU admitted, therefore 350 patients were involved with a response rate of 95.1%. Among those patients 73.1% of respondents’ experience at least one episodes of moderate to severe postoperative pain within the first 24 h. Preoperative anxiety (AOR: 2.2, 95% CI: 1.2, 5.1), urban residency (AOR: 2.3, 95% CI: 1.2, 50), participants who have not formal education (AOR: 2.5, 95% CI: 1.3, 4.1), surgical patients without pre-emptive analgesia (AOR: 2.7, 95% CI: 1.3, 3.6), abdominal incision greater than 10 cm (AOR: 3.5, 95% CI: 2.1, 7.2), and surgical duration greater than or equal to 60 min (AOR: 2.3, 95% CI: 1.1, 3.1) were factors associated with acute postoperative pain following elective gynecologic surgery.

Conclusion:

In this study, the overall incidence of moderate to severe postoperative pain after gynecologic surgery was unacceptably high, and patients undergoing gynecologic surgical procedures suffer sufficient postoperative pain need of intervention.
Comparison of SARS-CoV-2 virus detection using the Xpert Xpress rapid molecular test on Abbott M2000 Real-Time System: a cross-sectional study
Authors: Hasanah Miftah , Aulia Fauqa Arinil , Wardhani Puspa , Aryati
Published: May 2023

Introduction:

Emergency use of molecular rapid test kits approved by the Food and Drug Administration (FDA) includes the Xpert Xpress SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) kit. The rapid molecular test is one of the examinations using the reverse transcription-polymerase chain reaction (RT-PCR) method. Compared to conventional PCR, the examination time is faster, so it is suitable for diagnostic purposes.

Objectives:

Determining the diagnostic capabilities of the Xpert Xpress SARS-CoV-2 rapid molecular test in detecting the SARS-CoV-2 virus in the Indonesian population.

Methods:

A cross-sectional study was conducted with consecutive sampling, in which participants were diagnosed with coronavirus disease 2019 (COVID-19) infection using the RT-PCR Abbott M2000 SARS-CoV-2 System. A molecular rapid test examination was carried out using the Xpert Xpress SARS-CoV-2 kit. Assessing the correlation between the cycle threshold (CT) value of Xpert Xpress SARS-CoV-2 and the Abbott M2000 SARS-CoV-2 System using the Pearson and Spearmen test with P<0.05.

Results:

Molecular rapid test using Xpert Xpress has a compatibility of 100% with RT-PCR using Abbott M2000 SARS-CoV-2 and a sensitivity and specificity value of 100%. The Xpert Xpress SARS-CoV-2 CT value had a significant correlation with the Abbott M2000 SARS-CoV-2 System CT value, with moderate correlation strength for the CT protein E value (r=0.444; P=0.007) and robust correlation for CT value of protein N2 (r=0.829; P<0.001). The negative predictive and positive predictive values were 100% each.

Conclusion:

The Xpert Xpress SARS-CoV-2 molecular rapid test has a sensitivity and specificity of 100% and can be recommended for diagnosing COVID-19.
Does Linear or Spot Injection Technique Matter in Upper Face Botulinum Toxin Type A Application? A Split-Face Randomized Trial
Authors: Li Yunzhu , Sun Yixin , Lan Xinze , Wu Tingting , Xiao Yiding , Xia Zenan , Wang Hayson Chenyu , Yu Nanze , Wang Xiaojun , Long Xiao
Published: May 2023

Background:

Although the efficacy of botulinum toxin type A (BoNTA) has been shown to vary depending on injection layer, reconstitution volume, and BoNTA formulation, the effect of injection pattern has rarely been mentioned. The authors compared the therapeutic effects in patients treated with BoNTA with retrograde linear and traditional spot injection techniques.

Methods:

Twenty-eight participants were enrolled in a split-face, patient-blinded randomized clinical trial. Each patient received BoNTA injected with linear injection technique on one side and with spot injection technique on the other side. Outcomes included wrinkle improvement rates (WIRs) of the 2 injection techniques determined by wrinkle scores derived from an Antera 3-dimensional camera, muscle activity assessed by ultrasound, and patient-reported pain rating on a numeric rating scale.

Results:

All participants completed the study. For forehead wrinkles, WIR on the linear side was significantly larger than that on the spot side at 1 week and 1 month (P < 0.02). For glabellar wrinkles, WIR on the linear injection side was significantly larger than that on the spot side at 1 week (P = 0.04). However, for periorbital wrinkles, WIR on the spot side was significantly larger than that on the linear side at 1 week (P < 0.03). No significant difference was observed between the injection patterns in terms of muscle contraction and numeric rating scale pain scores.

Conclusions:

Compared with the traditional spot injection, retrograde linear injection was superior in reducing forehead lines and glabellar lines, but less effective in reducing periorbital lines when identical dosages were injected.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.
Patient Safety Climate, Quality of Care, and Intention of Nursing Professionals to Remain in Their Job During the COVID-19 Pandemic
Authors: Herrera Claire Nierva , Guirardello Edinêis de Brito
Published: May 2023

Objective

This study aimed to examine the relationship between patient safety climate, quality of care, and intention of nursing professionals to remain in their job.

Methods

A cross-sectional study was carried out in a teaching hospital in Brazil wherein nursing professionals were surveyed. The Brazilian version of the Patient Safety Climate in Healthcare Organizations tool was applied to measure the patient safety climate. Spearman correlation coefficient and multiple linear regression models were applied for the analysis.

Results

A high percentage of problematic response was observed for most dimensions, except for fear of shame. Quality of care resulted in a strong correlation with organizational resources for safety and with overall emphasis on patient safety, and the nurse-perceived staffing adequacy was strongly correlated with organizational resources for safety. The multiple linear regression model showed higher scores in quality of care in dimensions related to organizational, work unit, and interpersonal aspects as well as in the adequacy of the number of professionals. A higher score in intention to stay in one’s job was also found in the dimensions of fear of blame and punishment, provision of safe care, and adequacy of the number of professionals.

Conclusions

The organizational and work unit aspects can lead to a better perception of the quality of care. Improving interpersonal relationships and increasing the number of professionals on staff were found to increase nurses’ intention to remain in their jobs. Assessing a hospital’s patient safety climate will enable improvement in the provision of safe and harm-free health care assistance.
Chemical Bowel Preparation Exerts an Independent Preventive Effect Against Surgical Site Infection Following Elective Laparoscopic Colorectal Surgery
Authors: Ichimura Kentaro , Imaizumi Ken , Kasajima Hiroyuki , Sato Aya , Sato Kentaro , Yamana Daisuke , Tsuruga Yosuke , Umehara Minoru , Kurushima Michihiro , Nakanishi Kazuaki
Published: May 2023

Background:

We investigated the independent clinical value of mechanical bowel preparations (MBP) and chemical bowel preparations (CBP) for preventing surgical site infection (SSI) in patients undergoing elective laparoscopic colorectal surgery.

Materials and Methods:

This retrospective cohort study included 475 patients who underwent elective laparoscopic colorectal surgery between January 2018 and March 2022. CBP was introduced in January 2021 and included kanamycin (1 g) and metronidazole (1 g) 2 times a day, the day before surgery. In some cases, MBP was omitted in patients who planned to undergo right-sided colectomy, those with tumor obstruction, and those with poor general conditions, depending on the judgment of the physician. The primary endpoint was the overall SSI incidence, while the secondary endpoints were the incidences of incisional SSI and organ-space SSI, culture from the surgical site, and length of postoperative hospital stay.

Results:

In total, 136 patients underwent CBP. MBP was omitted in 53 patients. Overall, SSI occurred in 80 patients (16.8%), including 61 cases of incisional SSI (12.8%) and 36 cases of organ-space SSI (7.6%). Multivariate logistic regression revealed that CBP exerted an independent preventive effect on overall and incisional SSI, whereas MBP did not. However, CBP was not associated with a decreased risk of overall SSI in patients who had undergone preoperative therapy, those with benign disease, and those with stoma formation in the subgroup analysis. Levels of Bacteroides species at the surgical site were significantly lower in the CBP group than in the non-CBP group. Postoperative hospital stay was significantly longer in the incisional SSI group than in the non-SSI group and was significantly longer in the organ-space SSI group than in the other groups.

Conclusions:

CBP, but not MBP, exerts an independent preventive effect on SSI, especially incisional SSI, in patients undergoing elective laparoscopic colorectal surgery.
Evolutionary mechanisms modulating the mammalian skull development
Authors: Kyomen Stella , Murillo-Rincón Andrea P. , Kaucká Markéta
Published: May 2023

Mammals possess impressive craniofacial variation that mirrors their adaptation to diverse ecological niches, feeding behaviour, physiology and overall lifestyle. The spectrum of craniofacial geometries is established mainly during embryonic development. The formation of the head represents a sequence of events regulated on genomic, molecular, cellular and tissue level, with each step taking place under tight spatio-temporal control. Even minor variations in timing, position or concentration of the molecular drivers and the resulting events can affect the final shape, size and position of the skeletal elements and the geometry of the head. Our knowledge of craniofacial development increased substantially in the last decades, mainly due to research using conventional vertebrate model organisms. However, how developmental differences in head formation arise specifically within mammals remains largely unexplored. This review highlights three evolutionary mechanisms acknowledged to modify ontogenesis: heterochrony, heterotopy and heterometry. We present recent research that links changes in developmental timing, spatial organization or gene expression levels to the acquisition of species-specific skull morphologies. We highlight how these evolutionary modifications occur on the level of the genes, molecules and cellular processes, and alter conserved developmental programmes to generate a broad spectrum of skull shapes characteristic of the class Mammalia.

This article is part of the theme issue ‘The mammalian skull: development, structure and function’.
Evolution, conservatism and overlooked homologies of the mammalian skull
Authors: Koyabu Daisuke
Published: May 2023

In the last decade, studies integrating palaeontology, embryology and experimental developmental biology have markedly altered our homological understanding of the mammalian skull. Indeed, new evidence suggests that we should revisit and restructure the conventional anatomical terminology applied to the components of the mammalian skull. Notably, these are classical problems that have remained unresolved since the ninteenth century. In this review, I offer perspectives on the overlooked problems associated with the homology, development, and conservatism of the mammalian skull, aiming to encourage future studies in these areas. I emphasise that ossification patterns, bone fusion, cranial sutures and taxon-specific neomorphic bones in the skull are virtually unexplored, and further studies would improve our homological understanding of the mammalian skull. Lastly, I highlight that overlooked bones may exist in the skull that are not yet known to science and suggest that further search is needed.

This article is part of the theme issue ‘The mammalian skull: development, structure and function’.
Mandibular characteristics of early Glires (Mammalia) reveal mixed rodent and lagomorph morphotypes
Authors: Fostowicz-Frelik Łucja , Cox Philip G. , Li Qian
Published: May 2023

Glires (rodents, lagomorphs and their fossil kin) is the most speciose and arguably most diversified clade of living placentals. Different lineages within the Glires evolved basically opposite chewing movements: a mostly transversal power stroke in lagomorphs, and a mostly proal power stroke in rodents, but the ancestral condition for Glires is still unclear. To address this knowledge gap, we studied the mandibles of Chinese Palaeocene Glires representing the duplicidentate (lagomorph-like;
Mimotona
) and simplicidentate (rodent-like;
Eomylus
and
Heomys
) lineages. To assess the mechanical resistance of mandibles to bending and torsion, we calculated the section modulus. The dentaries differ greatly in morphology and the region where the maximum grinding force was likely applied. The early Palaeocene
Mimotona lii
and the middle Palaeocene
Mimotona robusta
and
Heomys orientalis
all show a pattern of increasing strength moving posteriorly along the mandible, similar to sciurids and the mountain beaver. By contrast, the late Palaeocene
Eomylus
sp. mandible was strongest in the m1 region, a pattern seen in lagomorphs and the stem placental
Zofialestes
. Our results indicate the early diversification of mandible structure of Glires, demonstrate a mixture of duplicidentate and simplicidentate characters among the basal Glires and suggest an early occurrence of a lagomorph-like morphotype.

This article is part of the theme issue ‘The mammalian skull: development, structure and function’.
Composite interventions on outcomes of severely and critically ill patients with COVID-19 in Shanghai, China
Authors: Shao Jiasheng , Fan Rong , Guo Chengnan , Huang Xuyuan , Guo Runsheng , Zhang Fengdi , Hu Jianrong , Huang Gang , Cao Liou
Published: May 2023

Background

The sixty-day effects of initial composite interventions for the treatment of severely and critically ill patients with COVID-19 are not fully assessed.

Methods

Using a bayesian piecewise exponential model, we analyzed the 60-day mortality, health-related quality of life (HRQoL) and disability in 1082 severely and critically patients with COVID-19 between December 8, 2022 and February 9, 2023 in Shanghai, China. The final 60-day follow-up was completed on April 10, 2023.

Results

Among 1082 patients (mean age, 78.0 years), 421 [38.9%] women), 139 patients (12.9%) died within 60 days. Azvudine had a 99.8% probability of improving 2-month survival (adjusted HR, 0.44 [95% credible interval, 0.24-0.79]) and Paxlovid had a 91.9% probability of improving 2-month survival (adjusted HR, 0.71 [95% credible interval, 0.44-1.14]) compared with the control. IL-6 receptor antagonist, Baricitinib, and a-thymosin each had a high probability of benefit (99.5%, 99.4%, and 97.5%, respectively) compared to their controls, while the probability of trail-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.8%; HR, 1.64 [95% CrI, 1.06-2.50]), and glucocorticoid (91.4%; HR, 1.20 [95% CrI, 0.71-2.16]). Paxlovid, Azvudine and therapeutic anticoagulation showed significant reduction in disability (p<0.05)

Conclusions

Among severely and critically ill patients with COVID-19 who received 1 or more therapeutic interventions, treatment with Azvudine had a high probability of improved 60-day mortality compared with the control, indicating its potential in resource-limited scenario. Treatment with IL-6 receptor antagonist, Baricitinib, and a-thymosin also had high probabilities of benefit of improving 2-month survival, among which a-thymosin could improve HRQoL. Treatment with Paxlovid, Azvudine and therapeutic anticoagulation could significantly reduce disability at day 60.
The effect of genetic predisposition to Alzheimer’s disease and related traits on recruitment bias in a study of cognitive ageing
Authors: Gomez Lina M. , Mitchell Brittany L. , McAloney Kerrie , Adsett Jessica , Garden Natalie , Wood Madeline , Diaz-Torres Santiago , Garcia-Marin Luis M. , Breakspear Michael , Martin Nicholas G. , Lupton Michelle K.
Published: May 2023

The recruitment of participants for research studies may be subject to bias due to an overrepresentation of those more willing to participate voluntarily. No study has analysed the effect of genetic predisposition to Alzheimer’s disease (AD) on study participation. The Prospective Imaging Study of Ageing (PISA), aims to characterise the phenotype and natural history of healthy adult Australians at high future risk of AD. Participants approached to take part in PISA were selected from existing cohort studies with available genome-wide genetic data for both successfully and unsuccessfully recruited participants, allowing us to investigate the genetic contribution to voluntary recruitment. From a recruitment pool of 13,432 individuals (age 40-80), 64% of participants were successfully recruited into the study. Polygenic risk scores (PRS) were computed in order to test to what extent the genetic risk for AD, and related risk factors (including educational attainment, household income and IQ), predicted participation in PISA. We examined the associations between PRS andAPOEε4 with recruitment using logistic regression models. We found significant associations of age and sex with study participation, where older and female participants were more likely to complete the core module. We did not identify a significant association of genetic risk for AD with study participation. Nonetheless, we identified significant associations with genetic scores for key causal risk factors for AD, such as IQ, household income and years of education. Our findings highlight the importance of considering bias in key risk factors for AD in the recruitment of individuals for cohort studies.
OPTIMIZING THERAPEUTIC TARGETS FOR BREAST CANCER USING BOOLEAN NETWORK MODELS
Authors: Sgariglia Domenico , Gonçalves Carneiro Flavia Requel , Vidal de Carvalho Luis Alfredo , Pedreira Carlos Eduardo , Carels Nicolas , Barbosa da Silva Fabricio Alves
Published: May 2023

Studying gene regulatory networks associated with cancer provides valuable insights for therapeutic purposes, given that cancer is fundamentally a genetic disease. However, as the number of genes in the system increases, the complexity arising from the interconnections between network components grows exponentially. In this study, using Boolean logic to adjust the existing relationships between network components has facilitated simplifying the modeling process, enabling the generation of attractors that represent cell phenotypes based on breast cancer RNA-seq data. A key therapeutic objective is to guide cells, through targeted interventions, to transition from the current cancer attractor to a physiologically distinct attractor unrelated to cancer. To achieve this, we developed a computational method that identifies network nodes whose inhibition can facilitate the desired transition from one tumor attractor to another associated with apoptosis, leveraging transcriptomic data from cell lines. To validate the model, we utilized previously published in vitro experiments where the downregulation of specific proteins resulted in cell growth arrest and death of a breast cancer cell line. The method proposed in this manuscript combines diverse data sources, conducts structural network analysis, and incorporates relevant biological knowledge on apoptosis in cancer cells. This comprehensive approach aims to identify potential targets of significance for personalized medicine.
Optical nanosensor passivation enables highly sensitive detection of the inflammatory cytokine IL-6
Authors: Gaikwad Pooja , Rahman Nazifa , Parikh Rooshi , Crespo Jalen , Cohen Zachary , Williams Ryan
Published: May 2023

Interleukin-6 (IL-6) is known to a play critical role in the progression of inflammatory diseases such as cardiovascular disease, cancer, sepsis, viral infection, neurological disease, and autoimmune diseases. Emerging diagnostic and prognostic tools, such as optical nanosensors, experience challenges in successful clinical application in part due to protein corona formation dampening their selectivity and sensitivity. To address this problem, we explored the rational screening of several classes of biomolecules to be employed as agents in non-covalent surface passivation as a strategy to screen interference from non-specific proteins. Findings from this screening were applied to the detection of IL-6 by a fluorescent antibody-conjugated single-walled carbon nanotube (SWCNT)-based nanosensor. The IL-6 nanosensor exhibited highly sensitive and specific detection after passivation with a polymer, poly-L-lysine, as demonstrated by IL-6 detection in human serum within a clinically relevant range of 25 pg/mL to 25,000 pg/mL, exhibiting a limit of detection over three orders of magnitude lower than prior antibody-conjugated SWCNT sensors. This work holds the potential for rapid and highly sensitive detection of IL-6 in clinical settings with future application to other cytokines or disease-specific biomarkers.
Quantify nanoscopic alterations associated with mitochondrial dysfunctions using three-dimensional single-molecule localization microscopy
Authors: Brenner Benjamin , Zhang Yang , Kweon Junghun , Fang Raymond , Sheibani Nader , Zhang Sarah X. , Sun Cheng , Zhang Hao F.
Published: May 2023

The morphology of mitochondria provides insights into their functions. Three-dimensional (3D) single-molecule localization microscopy (SMLM) uniquely enables the analysis of mitochondrial morphological features individually, thanks to its high resolution. However, nearly all reported studies of mitochondrial morphology have been qualitative and without statistical analysis. We report a quantitative method to extract mitochondrial morphological metrics, including volume, aspect ratio, and local protein density, from 3D SMLM images, with single-mitochondrion sensitivity. We validated our approach using simulated ground-truth SMLM images of mitochondria. We further tested our morphological analysis on mitochondria that have been altered functionally and morphologically in controlled manners. This work sets the stage to analyze mitochondrial morphological alterations associated with disease progression quantitatively.
The kinetics and basal levels of the transcriptome response during Effector-Triggered Immunity in Arabidopsis are mainly controlled by four immune signaling sectors
Authors: Hillmer Rachel A. , Igarashi Daisuke , Stoddard Thomas , Lu You , Liu Xiaotong , Tsuda Kenichi , Katagiri Fumiaki
Published: May 2023

To observe the transcriptome response during Effector-Triggered Immunity (ETI) without complications from any other pathogen factors or heterogeneously responding cell populations, we transgenically and conditionally expressed thePseudomonas syringaeeffector AvrRpt2 in Arabidopsis leaves. We studied this ETI-specific, cell-autonomous transcriptome response in 16 exhaustively combinatorial genetic backgrounds for the jasmonate (JA), ethylene (ET), PAD4, and salicylate (SA) immune signaling sectors. Removal of some or all four sectors had relatively small impacts on the intensity of the overall ETI transcriptome response (1972 upregulated and 1290 downregulated genes). Yet, we found that the four signaling sectors strongly affect the kinetics of the ETI transcriptome response based on analysis of individual genes via time-course modeling and of the collective behaviors of the genes via a PCA-based method: the PAD4 sector alone and the JA;SA sector interaction (defined by the averaging model) accelerated the response, while the ET;SA sector interaction delayed it. The response acceleration by the PAD4 sector or the JA;SA sector interaction was consistent with their positive contributions to ETI measured by pathogen growth inhibition. The responsive genes overlapping between ETI and Pattern-Triggered Immunity (PTI) had distinct regulatory trends regarding the four sectors, indicating different regulatory circuits in upstream parts of ETI and PTI signaling. The basal mRNA levels of most ETI-upregulated genes, but not downregulated genes, were predominantly positively regulated by the PAD4;SA sector interaction. This detailed mechanistic decomposition of the roles of four signaling sectors allowed us to propose a potential regulatory network involved in ETI signaling.
SMYD5 is a regulator of the mild hypothermia response
Authors: Rafnsdottir Salvor , Jang Kijin , Halldorsdottir Sara Tholl , Vinod Meghna , Tomasdottir Arnhildur , Moller Katrin , Halldorsdottir Katrin , Reynisdottir Tinna , Atladottir Laufey Halla , Allison Kristin Elisabet , Ostacolo Kevin , He Jin , Zhang Li , Northington Frances J. , Magnusdottir Erna , Chavez-Valdez Raul , Anderson Kimberley Jade , Bjornsson Hans
Published: May 2023

The mild hypothermia response (MHR) maintains organismal homeostasis during cold exposure and is thought to be critical for the neuroprotection documented with therapeutic hypothermia. To date, little is known about the transcriptional regulation of the MHR. We utilize a forward CRISPR-Cas9 mutagenesis screen to identify the histone lysine methyltransferase SMYD5 as a regulator of the MHR. SMYD5 represses the key MHR gene SP1 at euthermia. This repression correlates with temperature-dependent levels of H3K36me3 at the SP1-locus and globally, indicating that the mammalian MHR is regulated at the level of histone modifications. We have identified 37 additional SMYD5 regulated temperature-dependent genes, suggesting a broader MHR-related role for SMYD5. Our study provides an example of how histone modifications integrate environmental cues into the genetic circuitry of mammalian cells and provides insights that may yield therapeutic avenues for neuroprotection after catastrophic events.
Pregnancy and postpartum dynamics revealed by millions of lab tests
Authors: Bar Alon , Moran Ron , Mendelsohn-Cohen Netta , Kohanim Yael Korem , Mayo Avi , Toledano Yoel , Alon Uri
Published: May 2023

Pregnancy and delivery involve dynamic alterations in many physiological systems. However, the physiological dynamics during pregnancy and after delivery have not been systematically analyzed at high temporal resolution in a large human population. Here we present the dynamics of 76 lab tests based on a cross-sectional analysis of roughly 41 million measurements from over 300,000 pregnancies. We analyzed each test at weekly intervals from 20 weeks preconception to 80 weeks postpartum, providing detailed temporal profiles. About half of the tests take three months to a year to return to baseline during postpartum, highlighting the physiological load of childbirth. The precision of the data revealed effects of preconception supplements, overshoots after delivery and intricate temporal responses to changes in blood volume and renal filtration rate. Pregnancy complications – gestational diabetes, pre-eclampsia and postpartum hemorrhage – showed distinct dynamical changes. These results provide a comprehensive dynamic portrait of the systems physiology of pregnancy.
Initial platelet aggregation in the complex shear environment of a punctured vessel model
Authors: Spieker Christian J. , Závodszky Gábor , Mouriaux Clarisse , Mangin Pierre H. , Hoekstra Alfons G.
Published: May 2023

To analyze flow conditions and cellular behavior at the onset of a hemostatic response in the injury of a microneedle-induced vessel puncture, a combinedin silicoandin vitroplatform is created. A cell-resolved blood flow model is utilized for in-depth flow profile and cell distribution analyses and a novel punctured vessel flow chamber is set up to complement the simulations with the evaluation of platelet aggregation around the wound neck of the puncture. The respective setups of the platform are explained and the results of both experiments and simulations with various puncture diameters and pressure drops are combined, providing detailed insight into the basic processes of platelet transport and aggregation in the wound area. A special emphasis of the simulation evaluation is put on the cell distributions and the magnitude of shear rate and elongational flow in the wound neck area, as well as downstream from the puncture. Additionally, possible implications of wound size and pressure difference on the hemostatic response are discussed. The simulations display asymmetric cell distributions between the proximal and distal side of the wound neck in regards to flow direction. The flow chamber with the puncture diameter closest to the simulated domains confirms this asymmetry by displaying increased platelet aggregation at the wound neck’s distal side. The presented punctured vesselin silicoandin vitroexperimental setups offer a platform to analyze the hemostatic environment of a vessel injured by a puncture and might assist in identifying differentiating factors between primary hemostasis and arterial thrombosis.
A phylogenomic perspective on interspecific competition
Authors: Louw Nicolas , Wolfe Benjamin E. , Uricchio Lawrence H.
Published: May 2023

Evolutionary processes may have substantial impacts on community assembly, but evidence for phylogenetic relatedness as a determinant of interspecific interaction strength remains mixed. In this perspective, we consider a possible role for discordance between gene trees and species trees in the interpretation of phylogenetic signal in studies of community ecology. Modern genomic data show that the evolutionary histories of many taxa are better described by a patchwork of histories that vary along the genome rather than a single species tree. If a subset of genomic loci harbor trait-related genetic variation, then the phylogeny at these loci may be more informative of interspecific trait differences than the genome background. We develop a simple method to detect loci harboring phylogenetic signal and demonstrate its application through a proof of principle analysis ofPenicilliumgenomes and pairwise interaction strength. Our results show that phylogenetic signal that may be masked genome-wide could be detectable using phylogenomic techniques and may provide a window into the genetic basis for interspecific interactions.

Data & code accessibility

Data and code for this project are freely available in the repository linked below and will be permanently archived upon publication.

Statement of authorship

NL, BEW, and LHU designed the research; NL performed experiments; NL and LHU performed computational analyses; NL, BEW, and LHU wrote the manuscript.

Code repository

https://github.com/uricchio/ILSComp
Exploring the utility of regulatory network-based machine learning for gene expression prediction in maize
Authors: Ferebee Taylor H. , Buckler Edward S.
Published: May 2023

Genomic selection and gene editing in crops could be enhanced by multi-species, mechanistic models predicting effects of changes in gene regulation. Current expression abundance prediction models require extensive computational resources, hard-to-measure species-specific training data, and often fail to incorporate data from multiple species. We hypothesize that gene expression prediction models that harness the regulatory network structure ofArabidopsis thalianatranscription factor-target gene interactions will improve on the present maize models. To this end, we collect 147Oryza sativaand 99Sorghum bicolorgene expression assays and assign them to maize family-based orthologous groups. Using three popular graph-based machine learning frameworks, including a shallow graph convolutional autoencoder, a deep graph convolutional autoencoder, and the inductive GraphSage strategy, we encode anArabidopsis thalianaintegrated gene regulatory network (iGRN) structure and TF gene expression values to predict gene expression both within and between species. We then evaluate the network methods against a partial least-squares baseline. We find that the baseline gives the best predictions within species, with Spearman correlations averaging between 0.74 and 0.78. The graph autoencoder methods were more variable with correlations between -0.1 and 0.65. In particular, the GraphSage and deep autoencoders performed the worst, and the shallow autoencoders performed the best. In the most challenging prediction context, where predictions were in new species and on genes that were not seen, we found that the shallow graph autoencoder framework averaged around 0.65. Unlike initial thoughts about preserved network structure improving gene expression predictions, this study shows that within-species predictions only need simple models, such as partial least squares, to capture expression variations. In cross-species predictions, the best model is often a more complex strategy utilizing regulatory network structure and other studies’ expressions.
Anex vivomodel of interactions between extracellular vesicles and peripheral mononuclear blood cells in whole blood
Authors: Rodriguez Blanca V. , Wen Yi , Shirk Erin N. , Vazquez Samuel , Gololobova Olesia , Maxwell Amanda , Plunkard Jessica , Castell Natalie , Carlson Bess , Queen Suzanne E. , Izzi Jessica M. , Driedonks Tom A.P. , Witwer Kenneth W.
Published: May 2023

Extracellular vesicles (EVs) can be loaded with therapeutic cargo and engineered for retention by specific body sites; therefore, they have great potential for targeted delivery of biomolecules to treat diseases. However, the pharmacokinetics and biodistribution of EVs in large animals remain relatively unknown, especially in primates. We recently reported that when cell culture-derived EVs are administered intravenously toMacaca nemestrina(pig-tailed macaques), they differentially associate with specific subsets of peripheral blood mononuclear cells (PBMCs). More than 60% of CD20+B cells were observed to associate with EVs for up to 1 hr post-intravenous administration. To investigate these associations further, we developed anex vivomodel of whole blood collected from healthy pig-tailed macaques. Using thisex vivosystem, we found that labeled EVs preferentially associate with B cells in whole blood at levels similar to those detectedin vivo. This study demonstrates thatex vivoblood can be used to study EV-blood cell interactions.
Co-engagement of TIGIT+immune cells to PD-L1+tumours by a bispecific antibody potentiates T-cell response and tumour control
Authors: Cui Xiaopei , Zhu Xi , Yu Haijia , Xu Jingen , Wei Xiaoyue , Chen Shi , Wang Yangtin , Chen Xiaofang , Feng Yujie , Ren Xiaochen , Fei Liyang , Xie Bin , Li Mingwei , Li Xue , Jia Huifeng , Xie Simin , Chen Li , Cheng Yong , Zhang Lei , Li Haidong , Zhu Xiangyang , Zhan Yifan
Published: May 2023

Co-targeting PD-1/PD-L1 and TIGIT/CD226 is being pursued to broaden the efficacy of current immunotherapy. Here we demonstrate that a bispecific antibody (BsAb) targeting PD-L1 and TIGIT, HB0036, shows major advantages over the combination of the two parental monoclonal Abs (mAbs). We demonstrated that HB0036 co-engages PD-L1+tumour cells and TIGIT+T cells, and thereby upregulates CD226 on T cells and induces a greater T-cell proliferative response compared to the combination of the parental antibodiesin vitro.In vivo, HB0036 recruits greater amounts of TIGIT antibody in PD-L1+tumours but not in PD-L1-tumours, compared with therapy using the two parental antibodies. We also observed improved tumour control and favourable immunological signatures with HB0036 in syngeneic and xenograft tumour models. Collectively, these findings demonstrate that bispecific antibodies targeting PD-L1 and TIGIT offer superior benefits in cancer immunotherapy compared with therapy using the two parental antibodies. Based on these studies, a phase I clinical trial with HB0036 has been initiated in patients with solid tumours (NCT05417321).