bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of the active ingredients and pharmacological effects of Kuntai capsules in the treatment of primary ovarian insufficiency: A review
Authors: Liu Feng-Xia , Sun Yan
Published: June 2023

Kuntai capsules are effective in controlling primary ovarian insufficiency (POI). However, the precise mechanisms underlying the pharmacological effects of Kuntai capsules remain unclear. This study aimed to screen the active components and underlying mechanisms of Kuntai capsules for POI treatment using network pharmacology protocols and molecular docking technology. Potential active constituents in the chemical composition of Kuntai capsules were obtained from the Traditional Chinese Medicine System Pharmacology Database. Targets for POI were obtained from the Online Mendelian Inheritance in Man and Gene Cards database. All target data were integrated to identify the active ingredients of POI treatment. Enrichment analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery database. The STRING database and Cytoscape software were used for protein-protein interaction network construction and core target identification. Finally, a molecular docking analysis of the active components and core targets was performed. A total of 157 ingredients related to POI were identified. Enrichment analysis showed that these components might participate in the mitogen-activated protein kinase, tumor necrosis factor, phosphoinositide-3-kinase/AKT serine/threonine kinase 1, and forkhead box O signaling pathways. Further protein-protein interaction network analysis revealed that the core targets were Jun proto-oncogene, AKT serine/threonine kinase 1, tumor protein P53, interleukin 6, and the epidermal growth factor receptor. Molecular docking analysis showed that baicalein was the most active ingredient with the highest affinity for the core targets. This study identified baicalein as the core functional component and elucidated the potential pharmacological effects of Kuntai capsule in the treatment of POI.
Psychological intervention for career self-esteem among students of agricultural education programme
Authors: Ifeanyieze Florence O. , Ede Kelechi R. , Ejiofor Toochukwu E. , Onah Ogechukwu , Isiwu Edward C. , Nwankwo Clara U. , Okadi Ashagwu O. , Ezebuiro Felicia , Omeje Benedicta Anene , Okwo Chinyere , Nwachukwu Christiana Ukamaka , Ali Chinedu C. , Okeme Isaac , Nyakuwa Robert
Published: June 2023

Background:

This study determined the efficacy of rational career intervention on career self-esteem of students of Agricultural education programmed in Universities in Southeast Nigeria.

Methods:

Data were collected from a sample of 54 students. The sampled students were allocated to 2 (treatment and control) groups using the sequence allocation software package. Students in the treatment group were counseled through a rational career intervention programmed that lasted for 12 sessions while similar students in the control group were not treated. The 2 groups of students were then assessed 3 times based on a career self-esteem scale. Data collected were analyzed using Analysis of variance and partial eta square statistical tools.

Results:

The study’s findings indicated a strong impact of rational career intervention on career self-esteem levels. The findings also showed that group and gender interaction effects had a substantial impact on the professional self-esteem scores of students in agricultural education. The findings also indicated a statistically significant relationship between time and students career self-esteem in agricultural education. The findings also showed that the group and time interaction effect had a substantial impact on the professional self-esteem scores of students in agricultural education. The follow-up findings showed that the rational career intervention has a long-term impact on career self-esteem among students in Agricultural Education.

Conclusion:

It was concluded that rational career intervention is useful in improving self-esteem among students of agricultural education in universities in Southeast Nigeria. It was then recommended that year-1 students should be counseled immediately after registration.
Acute kidney injury in diabetic patients: A narrative review
Authors: Kaur Amninder , Sharma Gaurav Shekhar , Kumbala Damodar R
Published: June 2023

Diabetes mellitus (DM) is the most common cause of chronic kidney disease, which leads to end-stage renal failure worldwide. Glomerular damage, renal arteriosclerosis, and atherosclerosis are the contributing factors in diabetic patients, leading to the progression of kidney damage. Diabetes is a distinct risk factor for acute kidney injury (AKI) and AKI is associated with faster advancement of renal disease in patients with diabetes. The long-term consequences of AKI include the development of end-stage renal disease, higher cardiovascular and cerebral events, poor quality of life, and high morbidity and mortality. In general, not many studies discussed extensively “AKI in DM.” Moreover, articles addressing this topic are scarce. It is also important to know the cause of AKI in diabetic patients so that timely intervention and preventive strategies can be implemented to decrease kidney injury. Aim of this review article is to address the epidemiology of AKI, its risk factors, different pathophysiological mechanisms, how AKI differs between diabetic and nondiabetic patients and its preventive and therapeutic implications in diabetics. The increasing occurrence and prevalence of AKI and DM, as well as other pertinent issues, motivated us to address this topic.
Comparison of child abuse history in patients with and without overactive bladder: a case-control study
Authors: Rahmanipur Akram , Sarmadian Roham , Salehi Bahman , Yousefichaijan Parsa , Habibi Danial
Published: June 2023

Background:

Child abuse is a major global concern in terms of healthcare and social welfare. Child abuse is associated with numerous physical and mental health issues, including anxiety and depression. Overactive bladder (OAB) is a bladder storage functional disease defined by urine urgency with or without urge incontinence and is frequently accompanied by frequency and nocturia. This disorder’s origin is not entirely understood. Since OAB can be caused by problems of nervous system maturation or behavioural disorders, its correlation with child maltreatment is possible.

Objective:

This study aimed to compare the occurrence of maltreatment in children with OAB to healthy children referred to Amirkabir hospital, Arak.

Method:

This study included 100 children with overactive bladder and 100 healthy children without overactive bladder (ages 5–12 years) as case and control groups, respectively. Children referred to paediatric clinic at Amirkabir hospital in Arak, were selected as participants. Child abuse domains including psychological/emotional, physical, and neglect were diagnosed using a standardized child abuse questionnaire answered by the children. Data were analyzed by SPSS version χ2 test, t-test, and Pearson’s χ2 test.

Results:

The Prevalence of child maltreatment was significantly greater in the case group (31 cases) than in the control group (12 cases) (P<0.0001). The psychological/emotional domain of child abuse was observed in 19 case group participants and 4 control group participants (P=0.001), and the physical domain was observed in 29 case group participants and 11 control group participants (P<0.0001). Despite this considerable difference, 10 and 8 children in the case and control groups, respectively, scored positively for the neglect domain (P=0.112).

Conclusion:

Child abuse is considerably more common in children with OAB than in healthy children, especially in the psycho-emotional and physical domains, and it is possible to prevent and treat this condition by notifying parents. Children with OAB should also be subjected to child abuse screening.
Abandoning Blue-Collar Management
Authors: Porter-O'Grady Tim
Published: June 2023

Leading professionals require a different set of skills from those used for most employee work groups. This article reviews the reasons why nursing professionals need different leadership capacity and what some of those changes might be.
Leadership Development Recommendations for Clinical Nurse Managers to Bolster the Postpandemic Workforce
Authors: Buck Carrie K. , Dorrell Jolene J. , Winslow Susan A.
Published: June 2023

The postpandemic atmosphere has created a perfect storm that has necessitated a renewed prioritization to bolster support for the role of the clinical nurse manager. Role transition, competencies, mentorship, and ongoing development for the clinical nurse manager have been solidly supported in nursing leadership literature for decades. Preparing competent, ready-to-respond, people-oriented, transformational nurse leaders for these positions is essential to survival of our health care workforce. This article includes a summative review of comprehensive published findings related to nurse manager competency, development, and support. Findings have been correlated with one health system's postpandemic internal surveys, focus groups, reaction panels, and gap analysis to validate historic recommendations and prepare for program development. The purpose of this project was to endorse manager support and development recommendations and implement an evidence-based program to better prepare clinical nurse managers in today's health care leadership reality.
Closing the Workforce Staffing Chasm by Breaking Boundaries
Authors: Tellson Alaina , Murray Cindy , Boysen Carrie , Dodd Jamie , Maldonado Lauren , Mohl Christine , Walker Janice
Published: June 2023

As hospitals are experiencing a nursing shortage, nursing leaders must build innovative partnerships and strategies between nursing and recruitment to close the workforce gap. One large health care system was experiencing a high vacancy rate. To improve recruitment and retention efforts, nursing leaders partnered with the recruitment department and other key stakeholders to develop strategies. Together, they designed a candidate-centric recruiting and hiring process, designed innovative recruitment campaigns including recruiting former employed nurses, recruitment of traveling nurses into employees, increased graduate nurse recruitment efforts, and implementation of a registered nurse (RN) Ambassador program. The team improved work process efficiency for recruiters and candidates. Retention efforts focused on engaging nurses in the work environment, decreasing nurse leader workload to allow a focus on staff relationships, and improving exit processes in an effort to retain the nurse. The actual vacancy rate was as high as 20.9% in July 2021 to 8% in September 2022, indicating the system is closing the vacancy rate and nearing the goal of 5%.
Exploration of System Chief Nurse Executive's Leadership Practices to Support, Mentor, Develop, and Retain Nurse Leaders
Authors: Lyle-Edrosolo Giancarlo , Saria Marlon Garzo , Bailey K. David
Published: June 2023

In 2019, the National Academy of Science identified clinician burnout as a growing public health concern. The COVID-19 pandemic has only compounded this crisis and transformed it into an escalating fracture within the US health care system. Concurrently evolving with this emergency is a rise in the number of nurses who intend to leave the profession. Frontline nurse leaders are the lynchpin in ensuring health care systems function. These leaders have accountability over patient care and clinician well-being. Focused efforts must address clinician burnout. However, without addressing the well-being of frontline nurse leaders, the fault line in our health care system becomes a vast chasm. Recently, published literature began to emerge describing and addressing frontline clinician burnout. Unfortunately, only a few, if any, address issues related to leaders. The aim of this qualitative case study research was to explore and discover general themes in system chief nurse executive leadership practices that support, mentor, develop, and retain nurse leaders as a basis for future research. Three major themes were identified for future study and exploration: enhancing leadership development programs; improving leader work environments; and focusing on leader well-being and support. Further research is needed to evaluate the effectiveness of these themes.
Distribution, Consequences, and Determinants of Time to Antibiotics in Children With Community-Onset Severe Bacterial Infection: A Secondary Analysis of a Prospective Population-Based Study
Authors: Malorey David , Lorton Fleur , Chalumeau Martin , Bourgoin Pierre , Boussicault Gérald , Chantreuil Julie , Gaillot Théophile , Roué Jean-Michel , Martinot Alain , Assathiany Rémy , Saulnier Jean-Pascal , Caillon Jocelyne , Grain Audrey , Gras-Le Guen Christèle , Launay Elise
Published: June 2023

OBJECTIVES:

To describe the distribution, consequences and potential determinants of time to antibiotics administration in children with community-onset severe bacterial infections (COSBIs).

DESIGN:

Secondary analysis of the available data from a prospective population-based study from 2009 to 2014.

SETTING:

An administrative area in western France accounting for 13% of the national pediatric population.

PATIENTS:

All children from 1 month to 16 years old admitted to a PICU or who died before admission and had a COSBI.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

The time to antibiotics was divided into patient interval (from first signs of COSBI to the first medical consultation) and medical interval (from the first consultation to appropriate antibiotics administration). The association between the medical interval and child outcome was studied by a multinomial logistic regression model and the potential determinants of the patient and medical intervals were by a Cox proportional-hazards model. Of the 227 children included (median age 2.1 yr), 22 died (9.7%), and 21 (9.3%) had severe sequelae at PICU discharge. Median patient and medical intervals were 7.0 hours (interquartile range [IQR], 2.0–16.5 hr) and 3.3 hours (IQR, 1.1–12.2 hr), respectively. The last quartile of medical interval was not associated with death (adjusted odds ratio [aOR], 3.7; 95% CI, 0.8–17.5) or survival with severe sequelae (aOR, 1.3; 95% CI, 0.4–4.0) versus survival without severe sequelae. Patient interval was shorter in younger children (adjusted hazard ratio [aHR], 0.95; 95% CI, 0.92–0.99), and medical interval was reduced when the first consultation was conducted in a hospital (aHR, 1.5; 95% CI, 1.1–2.0) versus outpatient medicine.

CONCLUSIONS:

For children with COSBI, we found no significant association between medical interval and mortality or severe sequelae. An initial hospital referral could help reduce the time to antibiotics in COSBIs.
Incidence of hypertension in people with HIV infection: a longitudinal observational study
Authors: Gelpi Marco , Karvig Luanna Uchoa , Knudsen Andreas Dehlbæk , Sørensen Edith Wolder , Benfield Thomas , Afzal Shoaib , Nielsen Susanne Dam
Published: June 2023

Objective:

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in people with HIV (PWH). Although hypertension is a well-known risk factor for CVD, studies investigating incident hypertension in PWH and its risk factors are scarce. In the present study we set out to investigate incident hypertension and its predictors in the context of well-treated HIV infection.

Methods:

We included 532 PWH from the Copenhagen Comorbidity in HIV (COCOMO study). All included individuals took part in both baseline and 2.5 years follow-up examinations. Linear and Poisson regression were used to test our hypotheses, both before and after adjusting for confounders.

Results:

105 (19.7%) cases of incident hypertension occurred during 1217 person-years of follow-up (PYFU), corresponding to 8.5 cases per 100 PYFU. Waist-hip-ratio (relative risk (RR) 1.61 [1.34- 1.94] and adjusted RR (aRR) 1.54 [1.24–1.91]) and central obesity (RR 2.41 [1.61–3.61] and aRR 2.29 [1.49, 3.52]) were significantly associated with this condition. No HIV-specific factors were found to be associated with incident hypertension.

Conclusions:

In the present study the incidence rate of hypertension in well-treated PWH was comparable to that of the general population from similar socio-economic settings. Traditional risk factors, in particular age and indices of adipose tissue accumulation, were associated with incident hypertension.

Our results may further underline the pivotal importance of focusing on lifestyle changes and weight loss, rather than on HIV-specific factors, in order to prevent incident hypertension in well-treated PWH.
Anatomical and Histological Study of the Upper Tarsus in Asian
Authors: Gao Shenzhen , Lu Baixue , Zhou Rong , Gao Weicheng
Published: June 2023

Objective:

The aim of this study was to observe and analyze the anatomical and histological characteristics of the upper tarsus in Asian.

Methods:

A total of 15 Asians (14 adults, 1 child) were used. The sagittal sections with thickness of 3 μm in the middle of the upper eyelid were prepared and stained with hematoxylin-eosin, Masson trichrome and anti-smooth muscle actin antibody staining, and then were observed and photographed under light microscopy.

Results:

On the sagittal section, the upper end of the tarsus was connected with the Müller muscle and the part of the posterior layer of the levator aponeurosis; the lower end was the inflated part of the palpebral margin; the superficial surface was connected with the pretarsal fascia; and the deep surface was connected with Müller muscle aponeurosis and palpebral conjunctiva. Histologically, the tarsus was similar to the structure between dense fibrous connective tissue and cartilage, and its main structures include meibomian glands and its ducts, accessory lacrimal glands, glands of Moll, glands of Zeis, eyelash hair follicles, Riolan muscle, blood vessels, and collagen fibers. Through the observation of the tarsus of a child, compared with the adult specimen, the meibomian gland tissue was more abundant; the collagen fibers density was significantly lower and arranged orderly; the blood vessel density was significantly higher; α-SMA positive smooth muscle cells could be seen in the upper end of the tarsus and its superficial and deep surfaces.

Conclusions:

In this study, the internal and adjacent anatomical structures of the upper tarsus in Asians were observed under a microscope, and according to the histological characteristics, the tarsus was divided into 3 parts and 3 types. Through the preliminary analysis, the tarsus was likely to show different histological characteristics in different individuals and age groups of Asians. There was a certain correlation between the degree of meibomian gland atrophy, the degree of collagen fibrosis and the density of blood vessel in the tarsus.
Effectiveness of Spreader Graft Versus Autospreader Flap in Reducing Nasal Air Resistance
Authors: Cemiloglu Muhammed , Aricigil Mitat , Bayrakci Erdem , Acar Gülay , Arbag Hamdi
Published: June 2023

Objective:

The authors aimed to compare the functional outcomes of 2 different techniques, spreader graft and autospreader flap, by using them for nasal valve surgery in cadavers using acoustic rhinometry (AR).

Method:

Ten frozen cadavers who underwent nasal valve surgery between May 2017 and August 2018 were randomly divided into 2 groups. Spreader grafts were applied to 10 nasal valve regions in 1 group, while the autospreader flap method was used on the other 10 nasal valve regions. The effectiveness of the surgical techniques was evaluated utilizing AR.

Result:

We objectively evaluated the effect of surgery on nasal air resistance by comparing the preoperative and postoperative AR values (MCA1, MCA2, volume) in both the spreader graft and the autospreader flap groups. In addition, the differences in nasal potency gain after the application of both techniques were compared and the superiority of the 2 surgeries in terms of functional gains was evaluated. A statistically significant difference was observed in preoperative and postoperative MCA1, MCA2, and volume values in both the techniques and sides. The authors found more significant nasal valve opening for the spreader graft technique using acoustic rhinometric values when compared with the autospreader flap technique.

Conclusions:

In both methods, the air resistance was observed to decrease objectively in the nasal valve region. Autospreader flaps increase the nasal valve angle without the need for additional cartilage tissue, and it could be an alternative to spreader grafts.
Distal Pancreatectomy
Authors: Loos Martin , Mack Claudia E. , Xu An Ting L. , Hassenpflug Matthias , Hinz Ulf , Mehrabi Arianeb , Berchtold Christoph , Schneider Martin , Al-Saeedi Mohammed , Roth Susanne , Hackert Thilo , Büchler Markus W.
Published: June 2023

Background:

Recently, subclassification of pancreatoduodenectomy in 4 differing types has been reported, because additional major vascular and multivisceral resections have been shown to be associated with an increased risk of postoperative morbidity and mortality.

Objective:

To classify distal pancreatectomy (DP) based on the extent of resection and technical difficulty and to evaluate postoperative outcomes with regards to this classification system.

Methods:

All consecutive patients who had undergone DP between 2001 and 2020 in a high-volume pancreatic surgery center were included in this study. DPs were subclassified into 4 distinct categories reflecting the extent of resection and technical difficulty, including standard DP (type 1), DP with venous (type 2), multivisceral (type 3), or arterial resection (type 4). Patient characteristics, perioperative data and postoperative outcomes were analyzed and compared among the 4 groups.

Results:

A total of 2,135 patients underwent DP. Standard DP was the most frequently performed procedure (64.8%). The overall 90-day mortality rate was 1.6%. Morbidity rates were higher in patients with additional vascular or multivisceral resections, and 90-day mortality gradually increased with the extent of resection from standard DP to DP with arterial resection (type 1: 0.7%; type 2: 1.3%; type 3: 3%; type 4: 8.7%; P<0.0001). Multivariable analysis confirmed the type of DP as an independent risk factor for 90-day mortality.

Conclusion:

Postoperative outcomes after DP depend on the extent of resection and correlate with the type of DP. The implementation of the 4-type classification system allows standardized reporting of surgical outcomes after DP improving comparability of future studies.
Evaluation of novel hemostatic agents in a coagulopathic swine model of junctional hemorrhage
Authors: Gerling Kimberly A. , Kersey Alexander J. , Lauria Alexis L. , Mares John A. , Hutzler Justin D. , White Paul W. , Abel Biebele , Burmeister David M. , Propper Brandon , White Joseph M.
Published: June 2023

BACKGROUND

Hemostatic dressings are used extensively in both military and civilian trauma to control lethal noncompressible hemorrhage. The ideal topical hemostatic agent would provide reliable hemostasis in patients with profound acidosis, coagulopathy, and shock. This study aimed to compare next-generation hemostatic agents against the current military standard in a translational swine model of vascular injury and coagulopathy.

METHODS

Female Yorkshire swine were randomized to eight groups (total n = 63; control n = 14, per group n = 7) of hemostatic agents and included: QuikClot Combat Gauze (Teleflex, Morrisville, NC), which served as the control; BloodSTOP IX (LifeScience Plus, Mountain View, CA); Celox Rapid (Medtrade Product, Crewe, United Kingdom); ChitoSAM 100 (Sam Medical, Tualatin, OR); EVARREST Fibrin Sealant Patch (Ethicon, Raritan, NJ); TAC Wrapping Gauze (H&H Medical, Williamsburg, VA); ChitoGauze XR Pro (Tricol Biomedical, Portland, OR); and X-Stat 30 (RevMedX, Wilsonville, OR). Hemodilution via exchange transfusion of 6% hetastarch was performed to induce acidosis and coagulopathy. An arteriotomy was created, allowing 30 seconds of free bleeding followed by application of the hemostatic agent and compression via an external compression device. A total of three applications were allowed for continued/recurrent bleeding. All blood loss was collected, and hemostatic agents were weighed to calculate blood volume loss. Following a 180-minute observation period, angiography was completed to evaluate for technical complication and distal perfusion of the limb. Finally, the limb was ranged five times to assess for rebleeding and clot stability.

RESULTS

All swine were confirmed coagulopathic with rotational thromboelastography and acidotic (pH 7.2 ± 0.02). BloodSTOP IX allowed a significant increase in blood loss and number of applications required to obtain hemostasis compared with all other groups. BloodSTOP IX demonstrated a decreased survival rate (29%, p = 0.02). All mortalities were directly attributed to exsanguination as a result of device failure. In surviving animals, there was no difference in extravasation. BloodSTOP IX had an increased rebleeding rate after ranging compared with QuikClot Combat Gauze (p = 0.007).

CONCLUSION

Most novel hemostatic agents demonstrated comparable efficacy compared with the currently military standard hemostatic dressing, CG.
Low-pass whole genome sequencing is a reliable and cost-effective approach for copy number variant analysis in the clinical setting
Authors: Mazzonetto Patricia C. , Villela Darine , da Costa Silvia Souza , Krepischi Ana C. V. , Milanezi Fernanda , Migliavacca Michele P. , Pierry Paulo M. , Bonaldi Adriano , Almeida Luiz Gustavo D. , De Souza Camila Alves , Kroll José Eduardo , Paula Marcelo G. , Guarischi-Sousa Rodrigo , Scapulatempo-Neto Cristovam , Rosenberg Carla
Published: June 2023

We evaluated the performance of low-pass whole genome sequencing (LP-WGS) to detect copy number variants (CNVs) in clinical cytogenetics. DNA samples with known CNVs detected by chromosomal microarray analyses (CMA) were selected for comparison; our panel included 44 DNA samples (12 prenatal and 32 postnatal), comprising a total of 55 chromosome imbalances. The selected cases were chosen to provide a wide range of clinically relevant CNVs, being the vast majority associated with intellectual disability or recognizable syndromes. The chromosome imbalances ranged in size from 75 kb to 90.3 Mb, including aneuploidies and two cases of mosaicism. All CNVs were successfully detected by LP-WGS, showing a high level of consistency and robust performance of the sequencing method. Notably, the size of chromosome imbalances detected by CMA and LP-WGS were compatible between the two different platforms, which indicates that the resolution and sensitivity of the LP-WGS approach are at least similar to those provided by CMA. Our data show the potential use of LP-WGS to detect CNVs in clinical diagnosis and confirm the method as an alternative for chromosome imbalances detection. The diagnostic effectiveness and feasibility of LP-WGS, in this technical validation study, were evidenced by a clinically representative dataset of CNVs that allowed a systematic assessment of the detection power and the accuracy of the sequencing approach. Further, since the software used in this study is commercially available, the method can be easily tested and implemented in a routine diagnostic setting.
Ovarian carcinoma patients with a tumorBRCA-like genomic copy number aberration profile benefit from maintenance olaparib/bevacizumab therapy in the PAOLA-1 randomized controlled trial
Authors: Schouten Philip C. , Schmidt Sandra , Becker Kerstin , Thiele Holger , Nürnberg Peter , Richters Lisa , Ernst Corinna , Treilleux Isabelle , Medioni Jacques , Heitz Florian , Pisano Carmela , Garcia Yolanda , Petru Edgar , Hietanen Sakari , Colombo Nicoletta , Vergote Ignace , Nagao Shoji , Linn Sabine C. , Pujade Lauraine Eric , Ray-Coquard Isabelle , Harter Philip , Hahnen Eric , Schmutzler Rita K.
Published: June 2023

Background

We previously established an ovarian carcinoma (OC)BRCA-like genomic copy number aberration profile classifier (“BRCA-like classifier”), which identifies tumors with deleterious mutations and epigenetic alterations in the homologous recombination pathway (1). We explored whether the classifier may also be predictive for therapies targeting tumors with homologous recombination deficiency (HRD) such as olaparib, a PARP inhibitor with synthetic lethal interaction with HRD, in combination with bevacizumab.

Methods

As part of the ENGOT (European Network of Gynaecological Oncological Trial groups) HRD initiative, the OCBRCA-like classifier was evaluated using tumor-derived DNA samples from 469 out of 806 patients enrolled in the PAOLA-1/ENGOT-ov25 trial. PAOLA-1 is a randomized, double-blind, international phase 3 trial (NCT02477644) including advanced high grade OC patients. Prolonged progression-free survival (PFS) and overall survival (OS) was observed for patients treated with maintenance olaparib and bevacizumab versus placebo and bevacizumab, and particularly for those patients tested HRD positive according to Myriad MyChoice® CDx HRD test.

Results

Results were obtained for 442 patients (failure rate of 6%, 27 of 469 samples). A survival benefit from adding maintenance olaparib was observed in the 298 (67%) patients with aBRCA-like tumor (hazard ratio (HR) for PFS: 0.49, 95% confidence interval (CI) 0.37-0.65, p = 0.01; OS: 0.64, 95% CI 0.45-0.90, p < 0.01). No benefit was detected in patients with a non-BRCA-like tumor when treated with olaparib (HR for PFS: 1.02, 95% CI 0.68-1.51, p = 0.93; OS 1.48, 95% CI 0.94-2.33, p = 0.09). P values for interaction betweenBRCA-like status and olaparib for PFS and OS were both 0.004. Multivariate analysis revealed comparable results. The concordance rate with the Myriad test was 77% in samples that were successfully analysed with both assays. In the survival analyses, the CIs of theBRCA-like classifier and the Myriad test overlap.

Conclusion

TheBRCA-like classifier is a high-sensitive predictive biomarker for survival benefit of olaparib/bevacizumab as maintenance therapy in advanced ovarian carcinoma with a low drop-out rate.
Preventable deaths involving falls in England and Wales, 2013-2022: a systematic case series of coroners’ reports
Authors: Song Kaiyang , Portwood Clara , Jindal Jessy , Launer David , France Harrison S , Hey Molly , Richards Georgia , Dernie Francesco
Published: June 2023

Background

Falls in older people are common, but can lead to significant harm including death. Coroners in England and Wales have a duty to report cases where action should be taken to prevent deaths, but dissemination of their findings remains poor.

Objective

To identify preventable fall-related deaths, classify coroners’ concerns, and explore organisational responses.

Design

Retrospective case series.

Setting

Coroners’ reports to Prevent Future Deaths (PFD) in England and Wales.

Methods

Web scraping was used to screen and read PFDs from the Courts and Tribunals Judiciary website from July 2013 (inception) to November 2022. Demographic information, coroners’ concerns and responses from organisations were extracted. Descriptive statistics and content analysis were used to synthesise data.

Results

527 PFDs (12.5% of all PFDs) involved a fall that contributed to death. These deaths predominantly affected older people (median 82 years) in the community (72%), with subsequent death in hospital (70.8%). A high proportion of cases experienced fractures, major bleeding or head injury. Coroners frequently raised concerns regarding falls risks assessments, failures in communication, and documentation issues. Only 56.7% of PFDs received a response from the intended recipients. Organisations produced new protocols, improved training, and commenced audits in response to PFDs.

Conclusions

One in eight preventable deaths reported in England and Wales involved a fall. Addressing concerns raised by coroners should improve falls prevention and care following falls especially for older adults. Poor responses to coroners may indicate that actions are not being taken. Wider learning from PFD findings may help reduce preventable fall-related deaths.
Heterogeneous genomic architecture of skeletal armour traits in sticklebacks
Authors: Yi Xueling , Kemppainen Petri , Reid Kerry , Chen Ying , Rastas Pasi , Fraimout Antoine , Merilae Juha
Published: June 2023

Whether populations adapt to similar selection pressures using the same underlying genetic variants depends on population history and the distribution of standing genetic variation at the metapopulation level. Studies of sticklebacks provide a case in point: when colonising and adapting to freshwater habitats, three-spined sticklebacks (Gasterosteus aculeatus; TSSs) with high gene flow tend to fix the same adaptive alleles in the same major loci, whereas nine-spined sticklebacks (Pungitius pungitius; NPSs) with limited gene flow tend to utilize a more heterogeneous set of loci. In accordance with this, we report results of quantitative trait locus (QTL) analyses using a F2back-cross design showing that lateral plate number variation in the western European lineage of NPSs mapped to three moderate-effect QTL, contrary to one major QTL in TSSs and these QTL were different from the four previously identified QTL in the eastern European lineage of NPSs. Furthermore, several QTL were identified associated with variation in lateral plate size, and three moderate-effect QTL with body size. Together, these findings indicate that genetic underpinnings of skeletal armour variation inPungitiussticklebacks are more polygenic and heterogenous than those in three-spined sticklebacks, indicating limited genetic parallelism underlying armour trait evolution in the family Gasterostidae.
Modelling axonal loss caused by chronic demyelination and slow-burning inflammation at the rim of chronic lesions in MS patients
Authors: Klistorner Samuel , Klistorner Alexander
Published: June 2023

Objectives

Slow-burning inflammation at the edge of chronic multiple sclerosis lesions and loss of myelin in the depths of the lesions have emerged as a key components of disease progression. However, their relative contribution to progressive axonal damage has not been investigated. Therefore, the aim of the study was to examine relative weight of those factors in axonal attrition inside the chronic MS lesions by measuring tissue rarefication of the lesion core.

Methods

Pre- and post-gadolinium 3D-T1, 3D FLAIR, diffusion tensor images, Optical Coherence tomography and multifocal visual evoked potentials were acquired from 52 patients. Analysis was performed between baseline and 48 months. Lesion expansion was measured using in-house software. The degree of lesional tissue damage was determined by measuring increase of Mean Diffusivity (MD) in lesion core normalised over MD dynamic range.

Results

There were 104 expanding and 257 stable lesions. Rate of normalised MD (nMD) increase was several folds higher in expanding vs stable lesions (0.21% vs 1.12% per year, p=0.01). The magnitude of nMD change was significantly associated with the rate of lesion expansion (r=0.4, p<0.001). Analysis of visual system revealed the rate of axonal loss similar to the degree of tissue rarefication in stable lesions.

Interpretation

The current study demonstrated a significant increase in water content in chronic MS lesions, which was, however, markedly higher in slowly expanding compared to stable lesions. This suggests that slow-burning inflammation at the lesion rim, when present, is likely to play a more significant role in axonal attrition than chronic demyelination.
Co-enrichment of cancer-associated bacterial taxa is correlated with immune cell infiltrates in esophageal tumor tissue
Authors: Greathouse KL , Stone JK , Vargas AJ , Choudhury A , Padgett N , White JR , Jung A , Harris CC
Published: June 2023

Esophageal carcinoma (ESCA) is a leading cause of cancer-related death worldwide, and Barrett’s esophagus (BE) is a strong risk factor along with smoking. Smoking is well-known to induce microbial dysbiosis and we asked if BE and esophageal microbiomes had shared microbial alterations that could provide novel biomarkers. We extracted DNA from BE tissues (n=5) and tumors of 158 patients in the NCI-MD case control study and sequenced the 16S rRNA gene (V3-4), with TCGA ESCA RNAseq (n = 173) and WGS (n = 139) non-human reads used as validation. We identified four taxa,Campylobacter, Prevotella, Streptococcus, andFusobacteriumas highly enriched in esophageal cancer across all cohorts. Using SparCC, we discovered thatFusobacteriumandPrevotellawere also co-enriched across all cohorts. We then analyzed immune cell infiltration to determine if these dysbiotic taxa were associated with immune signatures. Using xCell to obtain predicted immune infiltrates, we identified a depletion of megakaryocyte-erythroid progenitor (MEP) cells in tumors with presence of any of the four taxa, along with enrichment of platelets in tumors withCampylobactororFusobacterium. Taken together, our results suggest that intratumoral presence of these co-occurring bacterial genera may confer tumor promoting immune alternations that allow disease progression in esophageal cancer.
Bridging the gap between movement data and connectivity analysis using the time-explicit Step Selection Function (tSSF)
Authors: Valle Denis , Attias Nina , Cullen Joshua A. , Hooten Mevin B. , Giroux Aline , Oliveira-Santos Luiz Gustavo R. , Desbiez Arnaud L. J. , Fletcher Robert J.
Published: June 2023

Background

Understanding how to connect habitat remnants to facilitate the movement of species is a critical task in an increasingly fragmented world impacted by human activities. The identification of dispersal routes and corridors through connectivity analysis requires measures of landscape resistance but there has been no consensus on how to calculate resistance from habitat characteristics, potentially leading to very different connectivity outcomes.

Methods

We propose a new model called the time-explicit step selection function (tSSF) that can be directly used for connectivity analysis in the context of the spatial absorbing Markov chain (SAMC) framework without requiring arbitrary transformations. The tSSF model combines a time model with a standard selection function and can provide complementary information regarding how animals use landscapes by separately assessing the drivers of time to traverse the landscape and the drivers of habitat selection. These models are illustrated using GPS-tracking data from giant anteaters (Myrmecophaga tridactyla) in the Pantanal wetlands of Brazil.

Results

The time model revealed that the fastest movements tended to occur between 8 pm and 5 am, suggesting a crepuscular/nocturnal behavior. Giant anteaters moved faster over wetlands while moving much slower over forests and savannas, in comparison to grasslands. We found that wetlands were consistently avoided whereas forest and savannas tended to be selected. Importantly, this model revealed that selection for forest increased with temperature, suggesting that forests may act as important thermal shelters when temperatures are high. Finally, the tSSF results can be used to simulate movement and connectivity within a fragmented landscape, revealing that giant anteaters will often not use the shortest-distance path to the destination patch (because that would require traversing a wetland, an avoided habitat) and that approximately 90% of the individuals will have reached the destination patch after 49 days.

Conclusions

The approach proposed here can be used to gain a better understanding of how landscape features are perceived by individuals through the decomposition of movement patterns into a time and a habitat selection component. This approach can also help bridge the gap between movement-based models and connectivity analysis, enabling the generation of time-explicit results.
Coupling of renal sodium and calcium transport: A modeling analysis
Authors: Hakimi Shervin , Dutta Pritha , Layton Anita T.
Published: June 2023

Calcium (Ca2+) transport along the nephron occurs via specific transcellular and paracellular pathways, and is coupled to the transport of other electrolytes. Notably sodium (Na+) transport establishes an electrochemical gradient to drive Ca2+reabsorption. Hence, alterations in renal Na+handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca2+transport. An important class of pharmacological agent is diuretics, which are commonly prescribed for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate Na+transport, but also indirectly affect renal Ca2+handling. To better understand the underlying mechanisms, we have developed a computational model of electrolyte transport along the superficial nephron in the kidney of a male and female rat. Sex differences in renal Ca2+handling are represented. Model simulations predict in the female rat nephron lower Ca2+reabsorption in the proximal tubule and thick ascending limb, but higher reabsorption in the late distal convoluted tubule and connecting tubule, compared to the male nephron. The male rat kidney model yields a higher urinary calcium excretion than female, consistent with animal experiments. Additionally, we conducted simulations of inhibition of channels and transporters that play a major role in Na+and Ca2+transport. Model results indicate that along the proximal tubule and ascending thick ascending limb, Ca2+and Na+transport occurs in parallel, but those processes are dissociated in the distal convoluted tubule. Simulations also reveal sex-specific responses to different pharmacological manipulations.
Combinatorial chloride and calcium channelopathy in myotonic dystrophy
Authors: Cisco Lily A. , Sipple Matthew T. , Edwards Katherine M. , Thornton Charles A. , Lueck John D.
Published: June 2023

Myotonic dystrophy type 1 (DM1) involves misregulated alternative splicing for specific genes. We used exon or nucleotide deletion to mimic altered splicing of genes central to muscle excitation-contraction coupling processes in mice. Mice with forced-skipping of exon 29 in CaV1.1 calcium channel combined with loss of ClC-1 chloride channel function showed a markedly reduced lifespan, whereas other combinations of splicing mimics did not affect survival. The Ca2+/Cl-bi-channelopathy mice exhibited myotonia, weakness, and impairment of mobility and respiration. Chronic administration of the calcium channel blocker verapamil rescued survival and improved force generation, myotonia, and respiratory function. These results suggest that Ca2+/Cl-bi-channelopathy contributes to muscle impairment in DM1 and is potentially mitigated by common clinically available calcium channel blockers.

Repurposing of a calcium channel blocker extends life and mitigates muscle and respiratory dysfunction in a myotonic dystrophy type 1 Ca2+/Cl-bi-channelopathy mouse model.
Efficient multi-fidelity computation of blood coagulation under flow
Authors: Guerrero-Hurtado Manuel , Garcia-Villalba Manuel , Gonzalo Alejandro , Martinez-Legazpi Pablo , Kahn Andy M. , McVeigh Elliot , Bermejo J. , del Alamo Juan C. , Flores Oscar
Published: June 2023

Clot formation is a crucial process that prevents bleeding, but can lead to severe disorders when imbalanced. This process is regulated by the coagulation cascade, a biochemical network that controls the enzyme thrombin, which converts soluble fibrinogen into the fibrin fibers that constitute clots. Coagulation cascade models are typically complex and involve dozens of partial differential equations (PDEs) representing various chemical species’ transport, reaction kinetics, and diffusion. Solving these PDE systems computationally is challenging, due to their large size and multi-scale nature.

We propose a multi-fidelity strategy to increase the efficiency of coagulation cascade simulations. Leveraging the slower dynamics of molecular diffusion, we transform the governing PDEs into ordinary differential equations (ODEs) representing the evolution of species concentrations versus blood residence time. We then Taylor-expand the ODE solution around the zero-diffusivity limit to obtain spatiotemporal maps of species concentrations in terms of the statistical moments of residence time,, and provide the governing PDEs for. This strategy replaces a high-fidelity system ofNPDEs representing the coagulation cascade ofNchemical species byNODEs andpPDEs governing the residence time statistical moments. The multi-fidelity order(p) allows balancing accuracy and computational cost, providing a speedup of overN/pcompared to high-fidelity models.

Using a simplified coagulation network and an idealized aneurysm geometry with a pulsatile flow as a benchmark, we demonstrate favorable accuracy for low-order models ofp= 1 andp= 2. These models depart from the high-fidelity solution by under 16% (p= 1) and 5% (p= 2) after 20 cardiac cycles.

The favorable accuracy and low computational cost of multi-fidelity models could enable unprecedented coagulation analyses in complex flow scenarios and extensive reaction networks. Furthermore, it can be generalized to advance our understanding of other systems biology networks affected by blood flow.
Androgenic Steroids Induce Pathologic Scarring in a Preclinical Swine Model Via Dysfunctional Extracellular Matrix Deposition
Authors: Reiche Erik , Keller Patrick R , Soares Vance , Schuster Calvin R , Rahmayanti Siti , Mroueh Jessica , Mroueh Vanessa , Billaud Marie , Hu Sophia , Hoover-Watson Hunter , Lian Christine G , Tan Yu , Doloff Joshua C , Newell-Fugate Annie E , Coon Devin
Published: June 2023

Background

Hypertrophic scarring is a major source of morbidity for surgery patients. Sex hormones are not classically considered to be modulators of scarring. However, based on clinical observations of increased frequency of hypertrophic scarring in patients on testosterone, we hypothesized that androgenic steroids induce abnormal scarring and developed a preclinical swine model to explore these effects.

Methods

A total of six male (XY) and female (XX) mini-swine underwent castration and were randomly assigned to no testosterone (noT) or biweekly testosterone therapy (+T). Ten dorsal excisional wounds were created on each pig. To mimic a chronic wound, a subset of wounds were re-excised at two weeks. Scars (POD42) and chronic wounds (POD28) were harvested six weeks after initial wounding for analysis via histology, RNA-seq, and mechanical testing.

Results

Histologic analysis of POD42 scars from +T swine showed increased mean fibrosis area (16mm2noT, 28mm2+T; p=0.007) and thickness (0.246mm2noT, 0.406mm2+T; p<0.001) compared to noT swine. Scars in XX+T and XY+T pigs had greater tensile burst strength (p=0.024 and p=0.013 respectively) compared to scars in noT swine. Color deconvolution analysis showed greater deposition of type I and type III collagen as well as increased type I to type III collagen ratio in +T scars. Dermatopathologist scores of POD42 scars show +T exposure was associated with worse overall scarring scores compared to controls (p<0.05). On RNAseq, gene ontology analysis showed testosterone exposure was associated with significant upregulation of cellular metabolism and immune response gene sets. Pathway analysis showed testosterone upregulated Reactome pathways related to keratinization and formation of collagen and laminin.

Conclusion

We developed a novel preclinical porcine model to study the effects of the sex hormone testosterone on scarring. Testosterone induces early proliferation of excessive granulation tissue, which eventually leads to increased scar tissue. T also appears to increase the physical strength of scars via supraphysiologic deposition of collagen and other ECM factors. The increase in burst strength observed for both XX and XY suggests that hormonal administration has a stronger influence on mechanical properties than chromosomal sex. Antiandrogen topical therapies may be a promising future area of research.