bluuebunny/crossref_metadata_2025 huggingface dataset:
Ameliorative effect of taxifolin on gentamicin-induced ototoxicity via down-regulation of apoptotic pathways in mouse cochlear UB/OC-2 cells
Authors: Lin Jia-Ni , Wang Jen-Shu , Lin Chung-Ching , Lin Hui-Yi , Yu Szu-Hui , Wen Yu-Hsuan , Tseng Guo-Fang , Hsu Chuan-Jen , Wu Hung-Pin
Published: March 2022

Background:

Taxifolin is a flavanonol with efficacious cytoprotective properties, such as anti-inflammatory, antioxidant, anticancer, hepatoprotective, and nephroprotective effects. However, the potential protective effects of taxifolin against gentamicin-induced ototoxicity have not been confirmed. In this study, the possible mechanisms underlying the effects of taxifolin on gentamicin-induced death of UB/OC-2 cochlear cells were investigated.

Methods:

Mouse cochlear UB/OC-2 cells with or without taxifolin pretreatment were exposed to gentamicin, and the effects on cytotoxicity, reactive oxygen species (ROS) production, mitochondrial permeability transition, and apoptotic marker expression were examined using biochemical techniques, flow cytometry, western blotting, and fluorescent staining.

Results:

Little or no apparent effect of taxifolin on cell viability was observed at concentrations less than 40 μM. Further investigations showed that gentamicin significantly inhibited cell viability in a concentration-dependent manner. Pretreatment with taxifolin attenuated gentamicin-induced lactate dehydrogenase release, as well as cellular cytotoxicity. In addition, taxifolin significantly prevented gentamicin-induced cell damage by decreasing ROS production, stabilizing mitochondrial membrane potential, and downregulating the mitochondrial pathway of apoptosis.

Conclusion:

In summary, pretreatment with taxifolin is effective for mitigating gentamicin-induced apoptotic cell death mediated by the mitochondrial pathway. Our data suggest that taxifolin provides a new approach to combat gentamicin-induced ototoxicity.
Painful Diabetic Neuropathy as a Cause for Refractory Ear Pain in Type 2 Diabetic Patients
Authors: Attia Tamer M. , Hamdan Ahmad Mahmoud
Published: March 2022

Objective

To assess painful diabetic neuropathy (PDN) as a cause for refractory ear pain in type 2 diabetics.

Design

An observational prospective case series study.

Setting

Otolaryngology departments of tertiary referral hospitals from November 2019 to January 2021.

Patients

Sixty-eight patients with type 2 diabetes with refractory ear pain of more than 1-month duration not responding to the routine analgesics.

Intervention

Diagnostic intervention.

Main Outcome Measure

The primary outcome measure was the prevalence of painful diabetic neuropathy among different causes of ear pain in the study sample of type II diabetics with refractory ear pain with an assessment of the response of these cases to routine neuropathic pain treatment with pregabalin.

Results

Fifteen out of 68 (22.1%) were diagnosed as having painful diabetic neuropathy based on the “Douleur Neuropathique en 4 Questions” (DN4) questionnaire with its mean value being 6.47±1.19. There was a highly significant improvement of the 10 items of painful diabetic neuropathy scales after 1 month of treatment (p < 0.001 for all). There was a significant positive correlation between the Hemoglobin A1c level and duration of diabetes at one hand and intensity of pain derived from the painful diabetic neuropathy scale at the other hand (p = 0.0002, and p = 0.032 respectively).

Conclusion

Painful diabetic neuropathy showed a potential correlation with refractory ear pain in type II diabetic patients with significant improvement after painful diabetic neuropathy treatment. Further studies are needed to confirm these findings.
Dispatching citizens as first responders to out-of-hospital cardiac arrests: a systematic review and meta-analysis
Authors: Scquizzato Tommaso , Belloni Olivia , Semeraro Federico , Greif Robert , Metelmann Camilla , Landoni Giovanni , Zangrillo Alberto
Published: March 2022

Mobile phone technologies to alert citizen first responders to out-of-hospital cardiac arrests (OHCAs) were implemented in numerous countries. This systematic review and meta-analysis aim to investigate whether activating citizen first responders increases bystanders’ interventions and improves outcomes. We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to 24 November 2021, for studies comparing citizen first responders’ activation versus standard emergency response in the case of OHCA. The primary outcome was survival at hospital discharge or 30 days. Secondary outcomes were discharge with favourable neurological outcome, bystander-initiated cardiopulmonary resuscitation (CPR), and the use of automated external defibrillators (AEDs) before ambulance arrival. Evidence certainty was evaluated with GRADE. Our search strategy yielded 1215 articles. After screening, we included 10 studies for a total of 23 351 patients. OHCAs for which citizen first responders were activated had higher rates of survival at hospital discharge or 30 days compared with standard emergency response [nine studies; 903/9978 (9.1%) vs. 1104/13 247 (8.3%); odds ratio (OR), 1.45; 95% confidence interval (CI), 1.21–1.74; P < 0.001], return of spontaneous circulation [nine studies; 2575/9169 (28%) vs. 3445/12 607 (27%); OR, 1.40; 95% CI, 1.07–1.81; P = 0.01], bystander-initiated CPR [eight studies; 5876/9074 (65%) vs. 6384/11 970 (53%); OR, 1.75; 95% CI, 1.43–2.15; P < 0.001], and AED use [eight studies; 654/9132 (7.2%) vs. 624/14 848 (4.2%); OR, 1.82; 95% CI, 1.31–2.53; P < 0.001], but similar rates of neurological intact discharge [three studies; 316/2685 (12%) vs. 276/2972 (9.3%); OR, 1.37; 95% CI, 0.81–2.33; P = 0.24]. Alerting citizen first responders to OHCA patients is associated with higher rates of bystander-initiated CPR, use of AED before ambulance arrival, and survival at hospital discharge or 30 days.
The Relationship Between Self-reported Cognitive Abilities and Psychological Symptoms in Breast Cancer Survivors
Authors: Crouch Adele , Von Ah Diane
Published: March 2022

Background

Many breast cancer survivors (BCSs) report numerous symptoms following cancer treatment, including cognitive concerns and psychological symptoms (anxiety and depression). However, the association among these symptoms is not well understood.

Objectives

The objectives were to, primarily, examine the relationship between self-reported cognitive ability and psychological symptoms (anxiety and depressive symptoms) controlling for potential confounders of age, education, and time posttreatment and, secondarily, examine the relationship between self-reported cognitive domains (attention, language, visuoperception, visual memory, and verbal memory) and psychological symptoms.

Methods

This secondary data analysis pooled data from 2 theoretically and conceptually congruent, institutional review board–approved studies of BCSs. Breast cancer survivors completed the Multiple Ability Self-report Questionnaire (cognitive ability), Spielberger State Trait Anxiety Inventory—State (anxiety), and Center for Epidemiological Studies—Depression Scale (depressive symptoms). Data were analyzed using descriptive statistics, Pearson correlations, and separate linear regression.

Results

One hundred fifty-five BCSs who were on average 54.8 (SD, 8.9) years of age, approximately 5 years (mean, 5.2 [SD, 3.8] years) posttreatment, and well-educated (mean, 15.2 [SD, 2.2] years) completed questionnaires. In bivariate correlations, higher anxiety and depressive symptoms were significantly related to cognitive abilities in all domains (P = <.01). In the regression model, increased anxiety was associated with poorer cognitive abilities in all domains (P < .01).

Conclusions

Anxiety and depressive symptoms were associated with decrements in self-reported cognitive abilities among BCSs.

Implications for Practice

With increasing numbers of BCSs, more research is needed to address psychological symptoms, which correlate with cognitive function. Findings from this analysis can inform clinical BCS survivorship care planning and future interventional research, focused on comprehensive symptom management.
Delayed Presentation, Diagnosis, and Treatment of Breast Cancer Among Chinese Women
Authors: An Jinghua , Hershberger Patricia E. , Ferrans Carol Estwing
Published: March 2022

Background

Delays before treatment initiation increase the likelihood of later-stage diagnosis of breast cancer and reduce survival. Among Chinese women living in mainland China, Hong Kong, and Taiwan, the amount of time lost in delay and the factors influencing it are unclear.

Objective

This integrative review aimed to characterize delay intervals among Chinese women, identify factors contributing to delay, and develop a conceptual model of these factors.

Methods

Using Whittemore and Knafl’s methodology for integrative reviews, PubMed, CINAHL, Web of Science, SCOPUS, PsycINFO, and China National Knowledge Infrastructure were searched for primary research articles. For 15 selected studies, quality evaluation was performed employing the Crowe Critical Appraisal Tool. A narrative synthesis was developed to summarize and explain the findings.

Results

Total delay intervals (from first discovery of breast symptoms to treatment initiation) exceeded 3 months for 50.2% to 52% of breast cancer patients. The greatest delay occurred between symptom discovery and first presentation (patient intervals). Factors affecting delay in presentation, diagnosis, and treatment included symptom appraisal, Chinese cultural factors, knowledge of breast cancer symptoms and screening, health history, personality, social and healthcare factors, and background factors.

Conclusions

Half of Chinese breast cancer patients delayed long enough to lower their chances of survival. Our review sheds light on how the reviewed factors contribute to delay and their unique influences in this population.

Implications for Practice

Factors identified can inform nursing interventions that raise breast cancer awareness and promote timely diagnosis and treatment in Chinese women.
A Systematic Review and Meta-analytic Evaluation of Moral Distress in Oncology Nursing
Authors: Eche Ijeoma Julie , Phillips Carolyn S. , Alcindor Nadia , Mazzola Emanuele
Published: March 2022

Background

Weighing implications of multiple intensive cancer-directed therapies over time, oncology nurses are more prone to intrinsic distress compared to nurses in non-oncologic settings. This vulnerability may give rise to moral distress. Yet, little is known about moral distress experiences of oncology nurses.

Objective

This systematic review and meta-analysis examined the frequency and intensity of moral distress among oncology nurses with an exploratory focus on nurse-level and work-related characteristics.

Methods

We conducted a systematic search of 7 electronic databases (2000–2020) supplemented by hand-search strategy. Means and standard deviations of moral distress scores in the included studies were extracted and pooled in our meta-analysis.

Results

Our sample of 8 cross-sectional studies consisting of 2686 participants with 1654 oncology nurses met criteria for inclusion. A random-effects model was used in our meta-analysis given considerable heterogeneity. Our results suggest that moral distress was of low to moderate frequency, but of high intensity. Moral distress among oncology nurses was a significant predictor for burnout, provider communication, decisions surrounding end-of-life care, work conditions (eg, patient assignment, type of unit), and inability to provide compassionate care.

Conclusion

Moral distress in oncology nurses is associated with burnout syndrome, compassion fatigue, and secondary traumatic stress syndrome, all of which are linked to poor patient care and outcomes. Robust psychological well-being is critical in minimizing unintended consequences of moral distress.

Implications for Practice

Oncology nurses are at high risk for moral distress due to the nature of their work. Future studies should examine the prevalence among oncology nurses to help inform targeted interventions.
“Hard to Say Goodbye Over iPad”
Authors: Lalani Nasreen , Cai Yun , Wang Yitong
Published: March 2022

The need for palliative care (PC) has gained increased attention during the COVID-19 pandemic. Palliative care adds an extra layer of support and care for patients with advanced chronic illnesses and their families. Because of pandemic restrictions, access and provision of PC services were challenging and resulted in huge suffering and caregiving burden among patients with advanced chronic illnesses and their families, especially those living in smaller towns and rural communities. The study aimed to describe the impact of COVID-19 on PC services and examine various ethical, moral, and practice issues and challenges experienced by rural providers. Using a community-based participatory research approach, a purposive sample of health care providers (n = 15) was obtained from smaller towns and rural communities in Indiana, United States. Online individual interviews were used for data collection. Thematic analysis showed several concerns including restricted visitation, communication challenges, “hard to say goodbye over iPad”, moral distress among providers, and preference for home hospice services. Findings call for strategies to implement best PC practices and programs to support providers and families in smaller towns and rural communities.
Outcome of Patients With Head and Neck Squamous Cell Carcinoma Can be Predicted by Expression of eIF4E and Osteopontin in Free Surgical Margins
Authors: Abouhashem Nehal S. , Elwan Amira , Elaidy Noha F.
Published: March 2022

Squamous cell carcinoma of the head and neck (HNSCC) is recognized as the third most common cause of death. Incomplete resection of the primary tumor is the main cause of local recurrence and poor prognosis in HNSCC. Histologic assessment in order to determine “tumor-free” margins could be inadequate because of malignant transformation occurs at the molecular level earlier than the morphologic level. The present study aimed to evaluate the prognostic significance of eukaryotic initiation factor 4E (eIF4E) and Osteopontin in the tumor cells and histologically tumor free surgical margins of HNSCC. This cohort study was performed on 60 cases of HNSCC diagnosed at the Department of Pathology and treated at the Clinical Oncology Department, Faculty of Medicine, Zagazig University. Our enrolled formalin fixed paraffin embedded biopsy specimens with their matched tumor free surgical margins from resected head and neck squamous cell carcinoma were immunostaind for eIF4E and Osteopontin markers. 65% of our HNSCC patients had eIF4 E positive cytoplasmic immunostaining and 70% of them exhibited Osteopontin staining. Two-thirds of the dead patients exhibited high Osteopontin positive staining, whereas the surviving group did not exhibit this high expression. Concerning eIF4E, 85% and 5% of the dead patients showed high and low eIF4E expression, respectively. Disease-free survival (DFS) and overall survival were significantly (P=0.000) different between high and negative expression of Osteopontin, high and negative expression of eIF4E. 84% of patients with eIF4E positive margins and 75% with Osteopontin positive margins had local recurrence. In addition, negative expression of eIF4E is associated with highly significant better DFS and overall survival (P=0.000 and 0.001), respectively, in the margin negative expression status, while negative expression of Osteopontin was significantly associated with better DFS but of no significance in overall survival outcome. Our findings suggest that tumor-free surgical margins in HNSCC may be redefined as histologically Osteopontin and eIF4E negative resection margins. However, multicenter prospective studies are required to further evaluate their clinical utility in the surgical management of primary HNSCC.
Temporal and Spatial Changes in the Microbiome Following Pediatric Severe Traumatic Brain Injury
Authors: Rogers Matthew B. , Simon Dennis , Firek Brian , Silfies Laurie , Fabio Anthony , Bell Michael J. , Yeh Andrew , Azar Justin , Cheek Richard , Kochanek Patrick M. , Peddada Shyamal D. , Morowitz Michael J.
Published: March 2022

OBJECTIVES:

The microbiome may be affected by trauma and critical illness. Many studies of the microbiome in critical illness are restricted to a single body site or time point and confounded by preexisting conditions. We report temporal and spatial alterations in the microbiome of previously healthy children with severe traumatic brain injury (TBI).

DESIGN

We collected oral, rectal, and skin swabs within 72 hours of admission and then twice weekly until ICU discharge. Samples were analyzed by 16S rRNA gene amplicon sequencing. Children undergoing elective outpatient surgery served as controls. Alpha and beta diversity comparisons were performed with Phyloseq, and differentially abundant taxa were predicted using Analysis of Composition of Microbiomes.

SETTING:

Five quaternary-care PICUs.

PATIENTS:

Patients less than 18 years with severe TBI requiring placement of an intracranial pressure monitor.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Three hundred twenty-seven samples were analyzed from 23 children with severe TBI and 35 controls. The community composition of initial oral (F = 3.2756, R
2 = 0.0535, p = 0.012) and rectal (F = 3.0702, R
2 = 0.0649, p = 0.007) samples differed between TBI and control patients. Rectal samples were depleted of commensal bacteria from Ruminococcaceae, Bacteroidaceae, and Lachnospiraceae families and enriched in Staphylococcaceae after TBI (p < 0.05). In exploratory analyses, antibiotic exposure, presence of an endotracheal tube, and occurrence of an infection were associated with greater differences of the rectal and oral microbiomes between TBI patients and healthy controls, whereas enteral nutrition was associated with smaller differences (p < 0.05).

CONCLUSIONS:

The microbiome of children with severe TBI is characterized by early depletion of commensal bacteria, loss of site specificity, and an enrichment of potential pathogens. Additional studies are needed to determine the impact of these changes on clinical outcomes.
Tumor to Tumor Metastasis: A Case Report of Metastatic Angiosarcoma to an Ovarian Brenner Tumor and Review of the Literature
Authors: Dundar Bilge , Alrwashdeh Audai , Dahmoush Laila
Published: March 2022

While angiosarcoma metastatic to the ovary is rare, metastatic angiosarcoma to an ovarian tumor has never been reported in the literature, so far. We report a case of a 61-yr-old postmenopausal woman with history of breast cancer, presenting with metastatic angiosarcoma to an ovarian Brenner tumor. Initially at the frozen section examination, on limited sampling, and without knowledge of the patient’s history, a diagnosis of at least proliferating Brenner tumor was rendered. Upon review of permanent sections, an intermixed angiosarcoma component was identified within Brenner tumor. Tumor to ovarian tumor metastasis is a rare phenomenon, with only 18 cases reported in the last 50 yr. It poses diagnostic challenges during sampling and histopathologic interpretation. Detailed clinical history, careful gross examination and sampling are important to recognize the separate tumor components.
Evaluation of Saccharomyces cerevisiae–like 1 (SEC14L1) in Gynecologic Malignancies Shows Overexpression in Endometrial Serous Carcinoma
Authors: Banet Natalie , Masnick Max , Quddus M. Ruhul
Published: March 2022

Saccharomyces cerevisiae–like 1 (SEC14L1) is a member of the SEC14 family and is involved in liposoluble vitamin transfer, and in a large cohort of breast cancer cases, was one of the genes most significantly associated with lymphovascular invasion (LVI), and had a significant relationship with human epidermal growth factor receptor 2 status, survival, and histologic grade. In this study, 111 separate gynecologic tumors were studied for SEC14L1 protein expression, including: uterine adenosarcoma, ovarian clear cell carcinoma, endometrial stromal sarcoma, endometrioid carcinoma of the uterus, high-grade serous carcinoma, ovarian endometrioid carcinoma, uterine leiomyosarcoma, low-grade serous carcinoma, uterine carcinosarcoma, and uterine serous carcinoma (USC). Overall, LVI was noted in 31/111 (28%) cases, highest in uterine carcinosarcoma (5/11; 45%), high-grade serous carcinoma (9/21; 43%), and ovarian clear cell carcinoma (4/10; 40%). SEC14L1 was positive in 25/111 (23%) cases; the highest percentage and only statistically significant finding by tumor type was USC at 9/12 (75%) cases positive. No relation between LVI or survival and SEC14L1 expression was noted. The relation between USC, a tumor known to show human epidermal growth factor receptor 2 overexpression and SEC14L1 is a novel finding, the significance of which warrants further study.
Social Influences on Perceptions of Sense of Control and Attributed Dignity Among Older People Managing Multiple Chronic Conditions
Authors: LeBlanc Raeann G. , Jacelon Cynthia S.
Published: March 2022

Purpose

The aim of this study was to explore associations between social support, sense of control, and attributed dignity in persons aged 65 years and older who self-manage multiple chronic conditions while living in the community.

Design

A descriptive, nonexperimental, correlational design was used in this study.

Methods

Eighty-nine participants completed telephone surveys that measured social support, sense of control and attributed dignity. Regression analysis was used to identify associations.

Results

Participants were independent in seven of the eight instrumental activities of daily living, with participants having an average of 11 (±4) chronic conditions. Significant positive relationships between social support, perceived sense of control, and attributed dignity were identified.

Conclusions

Positive social support is strongly associated with perceived sense of control and attributed dignity.

Clinical Relevance

Healthcare professionals, especially rehabilitation nurses, can assess social support and offer ways to improve social support, thus enhancing sense of control and attributed dignity. These concepts enhance older individuals’ ability to manage multiple chronic conditions.
The expanding role of synthetic nucleic acids for diagnosis and treatment
Authors: Arinuma Yoshiyuki
Published: March 2022

Purpose of review

The presence of autoantibodies is a characteristic and diagnostic index of systemic lupus erythematosus (SLE). Antidouble-stranded DNA (antids-DNA) antibodies are the most frequent autoantibodies found in SLE related to the diagnosis and disease activity of SLE, and are measured by established methods like ELISA as a polyclonal autoantibody. However, there is no reliable data on the relationship between the respective reactivity of these polyclonal antids-DNA antibodies against different epitopes generated from the original antigen and the disease phenotype. Of the complications in SLE, neuropsychiatric SLE (NPSLE) is a troublesome and frequent phenotype of the disease but no specific diagnostic autoantibodies in serum have been found. First in this review, the possibility of antids-DNA antibodies for identifying primary NPSLE in patients with SLE based on the reactivity of different synthetic nucleic acids is described as a diagnostic marker. The purpose of this review is to examine diagnostic and therapeutic opportunities to modulate autoimmune in the central nervous system (CNS) developing the CNS inflammatory disorders.

Recent findings

Khatri et al. investigated antids-DNA antibodies in order to develop a reliable method based on the application of synthetic nucleic acids and protein-based antigen arrays to characterize autoreactive antibodies specially for NPSLE. They found autoantibodies in three particular synthetic double stranded antigens and the antinuclear antibody patterns in ordinary lupus and NPSLE. These discoveries are leading to precision medicine in the CNS inflammatory disorders.

Verifying the similarity of antids-DNA obtained from patients with NPSLE can be useful as a diagnostic marker. mRNA vaccination can locally suppress autoimmunity in the CNS associated with critical steps for the develop of CNS autoinflammation. Synthetic nuclei acids may provide a diagnostic and therapeutic target in patients with autoimmune CNS inflammatory disorders.
Disrupted default mode network and executive control network are associated with depression severity on structural network
Authors: He Mengxin , Cheng Yuqi , Chu Zhaosong , Xu Jinlei , Lu Yi , Shen Zonglin , Xu Xiufeng
Published: March 2022

Objective

Major depressive disorder (MDD) is a psychiatric disorder with a relatively limited response to treatment. It is necessary to better understand the neuroanatomical mechanisms of structural networks.

Methods

The current study recruited 181 first-onset, untreated adult MDD patients: slight MDD (SD, N = 23), moderate MDD (MD, N = 77), Heavy MDD (HD, N = 81) groups; along with a healthy control group (HC, N = 81) with matched general clinical data. FreeSurfer was used to preprocess T1 images for gray matter volume (GMV), and the default mode network (DMN) and the execution control network (ECN) were analyzed by structural covariance network (SCN).

Results

Present study found that the GMV of brain regions reduced with the severity of the disease. Specifically, the GMV of the left anterior cingulate gyrus (ACC.L) is negatively correlated with MDD severity. In addition, the SCN connectivity of the whole-brain network increases with the increase of severity in MDD. ACC.L is a key brain region with increased connectivity between the left orbitofrontal in DMN and between the right orbitofrontal in ECN, which leads to damage to the balance of neural circuits.

Conclusions

Patients with smaller GMV of ACC.L are more likely to develop severe MDD, and as a key region in both networks which have distinct structural network models in DMN and ECN. MDD patients with different severity have different neuroimaging changes in DMN and ECN.
Estimating data-driven coronavirus disease 2019 mitigation strategies for safe university reopening
Authors: Yang Qihui , Gruenbacher Don M. , Scoglio Caterina M.
Published: March 2022

After one pandemic year of remote or hybrid instructional modes, universities struggled with plans for an in-person autumn (fall) semester in 2021. To help inform university reopening policies, we collected survey data on social contact patterns and developed an agent-based model to simulate the spread of severe acute respiratory syndrome coronavirus 2 in university settings. Considering a reproduction number ofR0= 3 and 70% immunization effectiveness, we estimated that at least 80% of the university population immunized through natural infection or vaccination is needed for safe university reopening with relaxed non-pharmaceutical interventions (NPIs). By contrast, at least 60% of the university population immunized through natural infection or vaccination is needed for safe university reopening when NPIs are adopted. Nevertheless, attention needs to be paid to large-gathering events that could lead to infection size spikes. At an immunization coverage of 70%, continuing NPIs, such as wearing masks, could lead to a 78.39% reduction in the maximum cumulative infections and a 67.59% reduction in the median cumulative infections. However, even though this reduction is very beneficial, there is still a possibility of non-negligible size outbreaks because the maximum cumulative infection size is equal to 1.61% of the population, which is substantial.
Onset of synchronization in coupled Mixmaster oscillators
Authors: Cotsakis Spiros
Published: March 2022

We consider the problem of asymptotic synchronization of different spatial points coupled to each other in inhomogeneous space–time and undergoing chaotic Mixmaster oscillations towards the singularity. We demonstrate that for couplings larger than some threshold value, two Mixmaster spatial points

A
,
B

, with

A

in the past of

B

, synchronize and thereby proceed in perfect unison towards the initial singularity. We further show that there is a Lyapunov function for the synchronization dynamics that makes different spatial points able to synchronize exponentially fast in the past direction. We provide an elementary proof of how an arbitrary spatial point responds to the mean field created by the oscillators, leading to their direct interaction through spontaneous synchronization. These results ascribe a clear physical meaning of early-time synchronization leading to a resetting effect for the two BKL maps corresponding to two distinct oscillating spatial points, as the two maps converge to each other to become indistinguishable at the end of synchronization. Our results imply that the universe generically organizes itself through simpler, synchronized, states as it approaches the initial singularity. A discussion of further implications of early-time inhomogeneous Mixmaster synchronization is also provided.

This article is part of the theme issue ‘The future of mathematical cosmology, Volume 1’.
“I wanna live and not think about the future” What place for advance care planning for people living with severe multiple sclerosis and their families? A qualitative study
Authors: Koffman Jonathan , Penfold Clarissa , Cottrell Laura , Farsides Bobbie , Evans Catherine J , Burman Rachel , Nicholas Richard , Ashford Stephen , Silber Eli
Published: March 2022

Background

Little is known about how people with multiple sclerosis and their families comprehend advance care planning (ACP) and its relevance in their lives.

Aim

To explore under what situations, with whom, how, and why do people with MS and their families engage in ACP

Methods

We conducted a qualitative study comprising interviews with people living with MS and their families followed by an ethical discussion group with five health professionals representing specialties working with people affected by MS and their families. Twenty-seven people with MS and 17 family members were interviewed between June 2019 and March 2020. Interviews and the ethical discussion group were audio-recorded and transcribed verbatim. Data were analysed using the framework approach.

Results

Participants’ narratives focused on three major themes :(i) planning for an uncertain future; (ii) perceived obstacles to engaging in ACP that included uncertainty concerning MS disease progression, negative previous experiences of ACP discussions and prioritising symptom management over future planning; (iii) Preferences for engagement in ACP included a trusting relationship with a health professional and that information then be shared across services. Health professionals accounts from the ethical discussion group departed from viewing ACP as a formal document to that of an ongoing process of seeking preferences and values. They voiced similar concerns to people with MS about uncertainty and when to initiate discussions. Some shared concerns of a lack of confidence when having ACP discussions.

Conclusion

These findings support the need for a whole systems strategic approach where information about the potential benefits of ACP in all its forms can be shared with people with MS. Moreover, they highlight the need for health professionals to be skilled and trained in engaging in ACP discussions and where information is contemporaneously and seamlessly shared across services.
On the normative advantages of dopamine and striatal opponency for learning and choice
Authors: Jaskir Alana , Frank Michael J
Published: March 2022

The basal ganglia (BG) contribute to reward-driven behavior, but it is unclear why such behavior should rely on notoriously complex circuitry involving opponent striatal pathways. Dopamine (DA) nonlinearly modulates activity and plasticity in the BG and is itself dynamically modulated across tasks. We develop the OpAL* model to assess the normative advantages of such circuitry. In OpAL*, dynamic DA modulation differentially amplifies the striatal pathway most tuned to the accumulated history of positive or negative outcomes. This efficient coding mechanism avoids a vexing explore-exploit tradeoff that plagues traditional RL models in sparse reward environments. OpAL* exhibits robust advantages over alternative models across a range of environments, particularly with sparse reward. These advantages depend on opponent and nonlinear Hebbian plasticity mechanisms previously thought to be pathological. Finally, OpAL* captures risky choice patterns arising from DA and environmental manipulations across species, suggesting that they result from a normative biological mechanism.

Everybody wants the most they can possibly get

For the least they can possibly do

– Todd Snider, “Easy Money”
Clinical interpretation of machine learning models for prediction of diabetic complications using electronic health records
Authors: Momenzadeh Amanda , Shamsa Ali , Meyer Jesse G.
Published: March 2022

Type 2 diabetes is a massive public health issue that continues to grow. The rate of diabetic complication progression varies across individuals. Understanding factors that alter the rate of complication onset may uncover new clinical interventions and help prioritize individuals for more aggressive management. Here, we explore how various machine learning models and types of electronic health records can predict fast versus slow diabetic complication onset using only patient data prior to diabetes diagnosis. We find that optimized random forests generally perform best among the tested models and combining all data sources yields the best predictive performance. A key differentiator of our study is our model interpretation, which identifies specific patient metrics from each dataset that play a unique role in the progression of each complication. Overall, our clinical interpretation of machine learning models can identify patients at risk for poorer outcomes years in advance of their diabetic complication.
Biomedical consequences of elevated cholesterol-containing lipoproteins and apolipoproteins
Authors: Schmidt AF , Joshi R , Gordillo-Marañón M , Drenos F , Charoen P , Giambartolomei C , Bis JC , Gaunt TR , Hughes AD , Lawlor DA , Wong A , Price JF , Chaturvedi N , Wannamethee G , Franceschini N , Kivimaki M , Hingorani AD , Finan C
Published: March 2022

Aims

To provide a comprehensive evaluation of the biomedical effects of circulating concentrations of cholesterol-containing lipoproteins and apolipoproteins.

Methods and Results

Nuclear magnetic resonance (NMR) spectroscopy was used to measure the cholesterol content of high density (HDL-C), very low-density (VLDL-C), intermediate-density (IDL-C), and low-density (LDL-C) lipoprotein fractions; apolipoproteins Apo-A1 and Apo-B; as well as total triglycerides (TG), remnant-cholesterol (Rem-chol) and total cholesterol (TC). The causal effects of these exposures were assessed against 33 cardiovascular as well as non-cardiovascular outcomes using two-sample univariable and multivariable Mendelian randomization. We observed that most cholesterol containing lipoproteins and apolipoproteins affected coronary heart disease (CHD), cIMT, carotid plaque, CRP and blood pressure. Through MVMR we showed that many of these exposures acted independently of the more commonly measured blood lipids: HDL-C, LDL-C and TG. We furthermore found that HF risk was increased by higher concentrations of TG, VLDL-C, Rem-Chol and Apo-B, often independently of LDL-C, HDL-C or TG. Finally, a smaller subset of these exposures could be robustly mapped to non-CVD traits such as Alzheimer’s disease (HDL-C, LDL-C, IDL-C, Apo-B), type 2 diabetes (VLDL-C, IDL-C, LDL-C), and inflammatory bowel disease (LDL-C, IDL-C).

Conclusion

The cholesterol content of a wide range of lipoprotein and apolipoproteins affected measures of atherosclerosis and CHD, implicating subfractions beyond LDL-C. Many of the observed effects acted independently of LDL-C, HDL-C, and TG, supporting the potential for additional, non-LDL-C, avenues to disease prevention.
International travel as a risk factor for carriage of extended-spectrum β-lactamase-producing Escherichia coli in a large sample of European individuals - The AWARE Study
Authors: Rodríguez-Molina Daloha , Berglund Fanny , Blaak Hetty , Flach Carl-Fredrik , Kemper Merel , Marutescu Luminita , Gradisteanu Gratiela Pircalabioru , Popa Marcela , Spießberger Beate , Wengenroth Laura , Chifiriuc Mariana Carmen , Larsson D. G. Joakim , Nowak Dennis , Radon Katja , de Roda Husman Ana Maria , Wieser Andreas , Schmitt Heike
Published: March 2022

Antibiotic resistance (AR) is currently a major threat to global health, calling for a One Health approach to be properly understood, monitored, tackled, and managed. Potential risk factors for AR are often studied in specific high-risk populations, but are still poorly understood in the general population. Our aim was to explore, describe, and characterize potential risk factors for carriage of Extended-Spectrum Beta-Lactamase-resistant E. coli (ESBL-EC) in a large sample of European individuals aged between 16 and 67 years recruited from the general population in Southern Germany, the Netherlands, and Romania. Questionnaire and stool sample collection for this cross-sectional study took place from September 2018 to March 2020. Selective culture of participants’ stool samples was performed for detection of ESBL-EC. A total of 1,183 participants were included in the analyses: 333 from Germany, 689 from the Netherlands, and 161 from Romania. Travels to Northern Africa (aOR 4.03, 95% CI 1.67-9.68), Sub-Saharan Africa (aOR 4.60, 95% CI 1.60-13.26), and Asia (aOR 4.08, 95% CI 1.97-8.43) were identified as independent risk factors for carriage of ESBL-EC carriage. Therefore, travel to these regions should continue to be routinely inquired risk factors in clinical practice when considering antibiotic therapy.
OncoPubMiner: A platform for oncology publication mining
Authors: Xu Quan , Liu Yueyue , Sun Dawei , Hu Jifang , Duan Xiaohong , Song Niuben , Zhou Jiale , Su Junyan , Liu Siyao , Chen Fan , Guo Zhongjia , Li Hexiang , Zhou Qiming , Niu Beifang
Published: March 2022

Knowledge bases that are up-to-date and of expert quality are fundamental in biomedical research fields. A knowledge base established with human participation and subjected to multiple inspections is crucial for supporting clinical decision-making, especially in the exponentially growing field of precision oncology. The number of original publications in the field has skyrocketed with the advancement of technology and in-depth research evolved. It has become an increasingly pressing issue that researchers need to consider how to gather and mine these articles accurately and efficiently. In this paper, we present OncoPubMiner (https://oncopubminer.chosenmedinfo.com), a free and powerful system that combines text mining, data structure customization, publication search with online reading, project-centered and team-based data collection to realize a one-stop “keyword in, knowledge out” oncology publication mining platform. It was built by integrating all the open-access abstracts from PubMed and full-text articles from PubMed Central, and is updated on a daily basis. The system makes it straightforward to obtain precision oncology knowledge from scientific articles. OncoPubMiner will assist researchers in developing professional structured knowledge base systems efficiently, and bringing the oncology community closer to achieving precision oncology goals.

Graphical Abstract

OncoPubMiner’s one-stop “keyword in, knowledge out” workflow (A) is built on key features such as text mining (B), publication search (C), form customization (D), and team-based curation (E).
PRState: Incorporating Genetic Ancestry in Prostate Cancer Risk scores for African American Men
Authors: Pagadala Meghana S. , Linscott Joshua A. , Talwar James , Seibert Tyler , Rose Brent , Lynch Julie , Panizzon Matthew , Hauger Richard , Hansen Moritz H. , Sammon Jesse D. , Hayn Matthew H , Kader Karim , Carter Hannah , Ryan Stephen T.
Published: March 2022

Prostate cancer (PrCa) is one of the most genetically driven solid cancers with heritability estimates as high as 57%. African American men are at an increased risk of PrCa; however, current risk prediction models are based on European ancestry groups and may not be broadly applicable. In this study, we define an African ancestry group of 4,533 individuals to develop an African ancestry-specific PrCa polygenic risk score (PRState). We identified risk loci on chromosomes 3, 8, and 11 in the African ancestry group GWAS and constructed a polygenic risk score (PRS) from 10 African ancestry-specific PrCa risk SNPs, achieving an AUC of 0.61 [0.60-0.63] and 0.65 [0.64-0.67], when combined with age and family history. Performance dropped significantly when using ancestry-mismatched PRS models but remained comparable when using trans-ancestry models. Importantly, we validated the PRState score in the Million Veteran Program, demonstrating improved prediction of PrCa and metastatic PrCa in African American individuals. This study underscores the need for inclusion of individuals of African ancestry in gene variant discovery to optimize PRS.
Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture
Authors: Hale Andrew T. , He Jing , Jones Jesse
Published: March 2022

Background

The genetic determinants and mechanisms underlying intracranial aneurysm rupture (rIA) are largely unknown. Given the ∼50% mortality rate of rIA, approaches to identify patients at high-risk will inform screening, diagnostic, and preventative measures.

Objective

Our goal was to identify and characterize the genetic basis of rIA.

Methods

We perform a genome-wide association study (GWAS) use functional genomics approaches to identify and characterize rIA-associated loci and genes. We perform a meta-analysis across 24 published GWAS of rIA. Single nucleotide polymorphisms (SNP), gene-burden analysis, and functional genomics identify and characterize genetic risk factors for rIA.

Results

Our cohort contains 84,353 individuals (7,843 rIA cases and 76,510 controls). We identify 5 independent genetic loci reaching genome-wide significance (p<5.0×10−8) for rIA including rs12310399 (FGD6, OR=1.16), which to our knowledge, has not been implicated in prior GWAS of rIA. We then quantified gene-level mutation-burden across ∼20,000 genes, and only FGD6 (containing 21 rIA-associated SNPs) reached transcriptome-wide significance. Expression quantitative trait loci (eQTL) mapping indicates that rs12310399 causes decreased FGD6 gene expression in arterial tissue. Next, we utilized publicly available single-cell RNA sequencing of normal human cerebrovascular cells obtained during resection surgery and identify high expression of FGD6 in 1 of 3 arterial lineages but absent in perivascular cells. These data suggest how alterations in FGD6 may confer risk to rIA.

Conclusion

We identify and characterize a previously unknown risk loci for rIA containing FGD6. Elucidation of high-risk genetic loci may instruct population-genetic screening and clinical-genetic testing strategies to identify patients predisposed to rIA.

Funding

No funding sources were used for the material presented herein.
Detection of COVID-19 and age-dependent dysosmia with paired crushable odorant ampules
Authors: Wood Ronald W. , Stodgell Christopher J , Linder Mitchell A. , Pressman Eva K.
Published: March 2022

Background

Signs of anosmia can help detect COVID-19 infection when testing for viral positivity is not available. Inexpensive mass-produced disposable olfactory sensitivity tests suitable for worldwide use might serve not only as a screening tool for potential infection but also to identify cases at elevated risk of severe disease as anosmic COVID-19 patients have a better prognosis.

Methods and Findings

We adopted paired crushable ampules with two concentrations of a standard test odorant (n-butanol) as standard of care in several clinics as community prevalence of COVID-19 infection waxed and waned. This was not a clinical trial; a chart review was undertaken to evaluate the operating characteristics and potential utility of the test device as RT-PCR testing became routine. The risk of anosmia was greater in COVID-19 patients. Olfactory sensitivity was concentration-dependent, decreased with aging, and was sex-dependent at the highest concentration. Hyposmia was detected across a wider age range than expected from the literature, and tests can be optimized to characterize different age groups.

Conclusions

n-Butanol at 0.32 and 3.2% in crushable ampules can be used to characterize olfactory function quickly and inexpensively and thus has potential benefits in pandemic screening, epidemiology, and clinical decision-making.
A Hybrid Pipeline for Covid-19 Screening Incorporating Lungs Segmentation and Wavelet Based Preprocessing of Chest X-Rays
Authors: Abdulah Haikal , Huber Benjamin , Abdallah Hassan , Palese Luigi L. , Soltanian-Zadeh Hamid , Gatti Domenico L.
Published: March 2022

We have developed a two-module pipeline for the detection of SARS-CoV-2 from chest X-rays (CXRs). Module 1 is a traditional convnet that generates masks of the lungs overlapping the heart and large vasa. Module 2 is a hybrid convnet that preprocesses CXRs and corresponding lung masks by means of the Wavelet Scattering Transform, and passes the resulting feature maps through an Attention block and a cascade of Separable Atrous Multiscale Convolutional Residual blocks to produce a class assignment as Covid or non-Covid. Module 1 was trained on a public dataset of 6395 CXRs with radiologist annotated lung contours. Module 2 was trained on a dataset of 2362 non-Covid and 1435 Covid CXRs acquired at the Henry Ford Health System Hospital in Detroit. Six distinct cross-validation models, were combined into an ensemble model that was used to classify the CXR images of the test set. An intuitive graphic interphase allows for rapid Covid vs. non-Covid classification of CXRs, and generates high resolution heat maps that identify the affected lung regions.
Prior selection affects phenotypic and transcriptional response to hypoxia
Authors: Ekwudo Millicent N. , Malek Morad C. , Anderson Cora E. , Yampolsky Lev Y.
Published: March 2022

Hypoxia has profound and diverse effects on aerobic organisms, disrupting oxidative phosphorylation and activating several protective pathways. Predictions have been made that exposure to mild intermittent hypoxia may be protective against more severe exposure and may extend lifespan. Both effects are likely to depend on prior selection on phenotypic and transcriptional plasticity in response to hypoxia, and may therefore show signs of local adaptation. Here we report the lifespan effects of chronic, mild, intermittent hypoxia (CMIH) and short-term survival in acute severe hypoxia (ASH) in four clones of Daphnia magna originating from either permanent or intermittent habitats, the latter regularly drying up with frequent hypoxic conditions. We show that CMIH extended the lifespan in the two clones originating from intermittent habitats but had the opposite effect in the two clones from permanent habitats, which also showed lower tolerance to ASH. Exposure to CMIH did not protect against ASH; to the contrary, Daphnia from the CMIH treatment had lower ASH tolerance than normoxic controls. Few transcripts changed their abundance in response to the CMIH treatment in any of the clones. After 12 hours of ASH treatment, the transcriptional response was more pronounced, with numerous protein-coding genes with functionality in mitochondrial and respiratory metabolism, oxygen transport, and gluconeogenesis showing up-regulation. While clones from intermittent habitats showed somewhat stronger differential expression in response to ASH than those from permanent habitats, there were no significant hypoxia-by-habitat of origin or CMIH-by-ASH interactions. GO enrichment analysis revealed a possible hypoxia tolerance role by accelerating the molting cycle and regulating neuron survival through up-regulation of cuticular proteins and neurotrophins, respectively.