bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender-based differences in the job titles and lifestyles in the cataract and refractive surgery society in Japan
Authors: Kato Naoko , Kojima Takashi , Ouchi Masayuki , Nakamura Tomoaki , Tokuda Yoshihiro , Yakushiji Tadayuki , Ichikawa Kazuo
Published: October 2023

To investigate sex differences in the titles and lifestyles of Japanese ophthalmologists, we evaluated work places and private lives. Retrospective cross-sectional study. The study included 1721 members (1344 males and 377 females) of the Japanese Society of Cataract and Refractive Surgery. An online, anonymized questionnaire was distributed to the society members. The questionnaire included 40 questions to collect data on profiles, lifestyles, job title, families, spouses, children, household chores, child-rearing, and work satisfaction. In total, 219 members (144 males and 75 females; 53.4 ± 1.0 and 51.3 ± 9.9 years old, respectively) completed the questionnaire. The job title, working time, annual income, marriage rate, and the number of children significantly differed between male and female respondents. Female respondents had greater responsibilities toward house chores, child care, and nursing, whereas several male doctors had spouses who did not work or worked for shorter times, earned a lower income, and contributed greater toward family responsibilities. Female respondents changed their job titles after having children more frequently than male respondents. Both males and females had limited time available for community activities and volunteer work. There were no significant differences in daily sleep duration. Both sexes were equally satisfied with their career choice of ophthalmology; however, fewer females recommended ophthalmology as a career for students and children compared to males. There are significant sex differences among ophthalmologists in Japan in terms of family responsibilities; this topic has received insufficient attention.
Vascular complications of diabetes: A narrative review
Authors: Lu Yongxia , Wang Wei , Liu Jingyu , Xie Min , Liu Qiang , Li Sufang
Published: October 2023

Diabetes mellitus is a complex chronic metabolic disease characterized by hyperglycemia and various complications. According to the different pathophysiological mechanisms, these complications can be classified as microvascular or macrovascular complications, which have long-term negative effects on vital organs such as the eyes, kidneys, heart, and brain, and lead to increased patient mortality. Diabetes mellitus is a major global health issue, and its incidence and prevalence have increased significantly in recent years. Moreover, the incidence is expected to continue to rise as more people adopt a Western lifestyle and diet. Thus, it is essential to understand the epidemiology, pathogenesis, risk factors, and treatment of vascular complications to aid patients in managing the disease effectively. This paper provides a comprehensive review of the literature to clarify the above content. Furthermore, this paper also delves into the correlation between novel risk factors, such as long noncoding RNAs, gut microbiota, and nonalcoholic fatty liver disease, with diabetic vascular complications.
The association between monocyte to high-density lipoprotein cholesterol ratio and clinical prognosis of acute ischemic stroke after intravenous thrombolysis therapy
Authors: Yang Ning , Hu Liqun , Han Yulong
Published: October 2023

The monocyte-to-high-density lipoprotein cholesterol (HDL) ratio (MHR) is accepted as a novel marker for demonstrating inflammation. We investigated whether the monocyte-to-HDL ratio is related to the 90-day clinical prognosis of acute ischemic stroke (AIS) after intravenous thrombolysis (IVT). Patients with AIS treated with alteplase IVT were included consecutively, and clinical information and laboratory data were collected. The 90-day prognosis of all patients was determined with a clinical assessment using the modified Rankin Scale (mRS). The optimal cutoff values for patients were evaluated by the receiver operating characteristic (ROC) curve method. Then, a multivariate logistic regression model was used to evaluate the risk factors for poor prognosis of IVT in AIS. We retrospectively enrolled 192 patients who were diagnosed with AIS and received IVT between February 2020 and July 2022, with final follow-up on September 30, 2022. The patients in the poor prognosis group had significantly higher monocyte counts, lower HDL levels, and higher MHR values than the good prognosis group. The optimal cutoff value of the MHR for predicting the 3-month outcome of acute pontine infarction was 0.621. Multivariate logistic regression revealed that the MHR (OR = 4.626, 95% CI: 1.156–18.512,P = .030) was strongly associated with poor prognosis in AIS. The MHR is an independent risk factor for the clinical prognosis of AIS patients receiving IVT therapy and shows a certain predictive value.
Risk factors and predictive models for early death in patients with advanced melanoma: A population-based study
Authors: Li Siru , Yin Cunli , Yang Xi , Lu Yingchun , Wang ChunYu , Liu Bin
Published: October 2023

The prognosis for advanced melanoma (AM) is extremely poor. Some patients are already in an advanced stage at the time of their first diagnosis and face a significant risk of early death. This study predicted all-cause early death and cancer-specific early death in patients with AM by identifying independent risk factors, building 2 separate nomogram models, and validating the efficiency of the models. A total of 2138 patients diagnosed with AM from 2010 to 2015 were registered in the Surveillance, Epidemiology and End Results (SEER) database and randomly assigned to a training cohort and a validation cohort. Logistic regression models were used to identify the associated independent risk factors. These factors have also been used to build nomograms for early deaths. Next, we validated the model’s predictive power by examining subject operating characteristic curves, then applied calibration curves to assess the accuracy of the models, and finally, tested the net benefit of interventions based on decision curve analysis. The results of the logistic regression model showed that marital status, primary site, histological type, N stage, surgery, chemotherapy, bone, liver, lung and brain metastases were significant independent risk factors for early death. These identified factors contributed to the creation of 2 nomograms, which predict the risk of all-cause early death and cancer-specific early death in patients with AM. In the all-cause early death model, the area under the curve was 0.751 and 0.759 for the training and validation groups, respectively, whereas in the cancer-specific early death model, the area under the curve was 0.740 and 0.757 for the training and validation groups. Calibration curves indicated a high degree of agreement between the predicted and observed probabilities, and the decision curve analysis demonstrated a high value for the model in terms of its applicability in clinical settings. These nomograms have practical applications in predicting the risk of early death in patients with AM, helping oncologists to intervene early and develop more personalized treatment strategies.
Case report of a young male, with recurrent pneumothorax, hemoptysis and intrapulmonary cavitary lesions
Authors: Junping Sun , Tianyu Sun , Rentao Wang , Shengshu Li , Xiaobo Han , Xinxin Zhang , Mingyue Zhang
Published: October 2023

Rationale:

Primary spontaneous pneumothorax (PSP) is a manifestation of Vascular Ehlers-Danlos syndrome (vEDS) caused by heterozygous mutations in the COL3A1 gene. vEDS is a rare inherited disorder with an prevalence of one in 150,000. It can causes PSP and severe fragility of connective tissues with arterial but it remains poorly defined on clinical grounds and diagnose. Through this report, we hoped to help clinicians further understand the characteristics of vEDS.

Patient concerns:

A 22-year-old man presented with recurrent pneumothorax, hemoptysis, and chest pain. Physical examination revealed remarkable hypermobility of the small joints and translucent skin with visible veins. Chest computed tomography (CT) showed pneumothorax and multiple pulmonary cavities.

Intervention and outcome:

Genomic deoxyribonucleic acid (DNA) was extracted from patients. Heterozygosity was observed in all 3 novel variants. The main variant is COL3A1, c.3256-43T > G(NM_000090.3), which represents a missense mutation in collagen type III alpha 1 that can lead to vEDS. The other 2 mutations were FLNB c.4814G > A(NM_001457.3) and TSC2 c.3145G > A (NM_000548.3). These variants were validated by Sanger sequencing of their parents. COL3A1was not detected in either of the parent strains. FLNB and TSC2 were detected in his mother.

Diagnoses:

Vascular Ehlers-Danlos syndrome.

Lessons:

Both COL3A1 and TSC2 gene mutations can cause PSP; however, to the best of our knowledge, there are no reports on these 2 gene mutations in 1 patient at the same time.
Effect of group sand play therapy on psychopathologies of adolescents with delinquent behaviors
Authors: Lee Sunhwa , Kwak Hyeon Jeong , Ahn Un Kyoung , Kim Kyoung Min , Lim Myung-Ho
Published: October 2023

Prior research has established adolescent vulnerability to delinquent behavior. This single-arm, noninterventional, observational study investigated the effect of sand play therapy on the psychopathologies of adolescents with delinquent behavior. A total of 68 adolescents participated in the study. Participants were treated with 8 weekly sessions of sand play therapy, lasting 50 minutes each and conducted in groups of 3 to 4 members. The psychopathologies of depression, anxiety, self-esteem, impulsiveness, characteristics of attention-deficit hyperactivity disorder (ADHD), and impulsiveness were measured using self-reporting scales. Following therapy, depression (t = 3.28; P = .002; ES = 0.399) and anxiety (t = 4.00; P < .001; ES = 0.485) decreased significantly with moderate effect size. ADHD characteristics (t = 2.73; P = .008) and impulsiveness (t = 2.73; P = .009) also decreased significantly with effect size of 0.330 and 0.327, respectively. Self-esteem (t = −2.06, P = .043; ES = 0.251) was found to have significantly increased. The high-risk group within each psychopathology showed significantly higher improvement than the low-risk group. Results showed that group sand play therapy is effective in improving internalizing problems such as depression and anxiety, as well as externalizing problems of ADHD features and impulsiveness among adolescents with deviant behaviors.
Eligibility of cardiac arrest patients for extracorporeal cardiopulmonary resuscitation and their clinical characteristics: a retrospective two-centre study
Authors: Verdonschot Rob J.C.G. , Buissant des Amorie Floor I. , Koopman Seppe S.H.A. , Rietdijk Wim J.R. , Ko Sindy Y. , Sharma Upasna R.U. , Schluep Marc , den Uil Corstiaan A. , dos Reis Miranda Dinis , Mandigers Loes
Published: October 2023

Background and importance

Sudden cardiac arrest has a high incidence and often leads to death. A treatment option that might improve the outcomes in refractory cardiac arrest is Extracorporeal Cardiopulmonary Resuscitation (ECPR).

Objectives

This study investigates the number of in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA) patients eligible to ECPR and identifies clinical characteristics that may help to identify which patients benefit the most from ECPR.

Design, settings and participants

A retrospective two-centre study was conducted in Rotterdam, the Netherlands. All IHCA and OHCA patients between 1 January 2017 and 1 January 2020 were screened for eligibility to ECPR. The primary outcome was the percentage of patients eligible to ECPR and patients treated with ECPR. The secondary outcome was the comparison of the clinical characteristics and outcomes of patients eligible to ECPR treated with conventional Cardiopulmonary Resuscitation (CCPR) vs. those of patients treated with ECPR.

Main results

Out of 1246 included patients, 412 were IHCA patients and 834 were OHCA patients. Of the IHCA patients, 41 (10.0%) were eligible to ECPR, of whom 20 (48.8%) patients were actually treated with ECPR. Of the OHCA patients, 83 (9.6%) were eligible to ECPR, of whom 23 (27.7%) were actually treated with ECPR. In the group IHCA patients eligible to ECPR, no statistically significant difference in survival was found between patients treated with CCPR and patients treated with ECPR (hospital survival 19.0% vs. 15.0% respectively, 4.0% survival difference 95% confidence interval −21.3 to 28.7%). In the group OHCA patients eligible to ECPR, no statistically significant difference in-hospital survival was found between patients treated with CCPR and patients treated with ECPR (13.3% vs. 21.7% respectively, 8.4% survival difference 95% confidence interval −30.3 to 10.2%).

Conclusion

This retrospective study shows that around 10% of cardiac arrest patients are eligible to ECPR. Less than half of these patients eligible to ECPR were actually treated with ECPR in both IHCA and OHCA.
The Relationship Between Coronavirus Disease 2019 (COVID-19) Pandemic-linked Job Losses and Health Care Access and Household Financial Health in Medicaid Expansion and Nonexpansion States
Authors: Benitez Joseph A. , Huang Huang , Johnson Portia L.
Published: October 2023

Background:

Unemployment associated with the coronavirus disease 2019 (COVID-19) pandemic was linked to financial insecurity and disruptions in access to health care.

Objective:

To explore whether expanded access to Medicaid mitigated the likelihood of health and non-health financial hardship associated with pandemic-linked job loss.

Design:

We estimate linear regression models comparing differences in the levels of outcomes attributable to pandemic-linked joblessness in Medicaid expansion and nonexpansion states.

Observations:

A total of 20,281 adults aged 19–64 were in the 2021 National Financial Capability Study.

Measures:

Our key exposure was job loss, layoffs, and furloughs, attributable to the COVID-19 pandemic. Outcomes under evaluation include indicators of health care access and household financial health.

Results:

Relative to persons reporting pandemic-linked unemployment in nonexpansion states, adults experiencing pandemic-linked job loss in expansion states were less likely to report as uninsured [−6.2 percentage points (PPs); 95% CI: −10.8, −1.6; P < 0.01], having unpaid medical bills (−4.3 PP; 95% CI: −8, −0.6; P < 0.05), having unmet medical needs due to cost (−5.3 PP; 95% CI: −10.1, −0.5; P < 0.05), and having calls from debt collection agencies (−6.9 PP; 95% CI: −10.6, −3.1; P < 0.01). Patterns consistent with Medicaid acting as a safety net for the adverse financial effects of job loss were more pronounced for middle-income households.

Conclusions:

In economic downturns, such as the COVID-19 crisis, Medicaid can help insulate households from diminished health care access and financial distress associated with job loss.
Climate change and its influence in nephron mass
Authors: Alvarez-Elias Ana Catalina , Brenner Barry M. , Luyckx Valerie A.
Published: October 2023

Purpose of review

The consequences of climate change, including heat and extreme weather events impact kidney function in adults and children. The impacts of climate change on kidney development during gestation and thereby on kidney function later in life have been poorly described. Clinical evidence is summarized to highlight possible associations between climate change and nephron mass.

Recent findings

Pregnant women are vulnerable to the effects of climate change, being less able to thermoregulate, more sensitive to the effects of dehydration, and more susceptible to infections. Exposure to heat, wildfire smoke, drought, floods and climate-related infections are associated with low birth weight, preterm birth and preeclampsia. These factors are associated with reduced nephron numbers, kidney dysfunction and higher blood pressures in offspring in later life. Exposure to air pollution is associated with higher blood pressures in children and has variable effects on estimated glomerular filtration rate.

Climate change has important impacts on pregnant women and their unborn children. Being born too small or too soon is associated with life-time risk of kidney disease. Climate change may therefore have a dual effect of impacting fetal kidney development and contributing to cumulative postnatal kidney injury. The impact on population kidney health of future generations may be significant.
Predictive Value of Antithrombin III and d-Dimer in the Development of Moderate-To-Severe Acute Pancreatitis
Authors: Garcia Borobia Francisco , Flores Clotet Roser , Bejarano Gonzalez Natalia , Gonzalez Martinez Sergio , Garcia Monforte Neus , Romaguera Monzonis Andreu , Gonzalez Abos Carolina , Gonzalez Abos Sandra , Lucas Guerrero Victoria , Perez Perarnau Alba , Mota Villaplana Francisco
Published: October 2023

Objectives

To analyze if antithrombin III (AT-III) and d-dimer levels at admission and at 24 hours can predict acute pancreatitis (AP) progression to moderately severe AP (MSAP) to severe AP (SAP) and to determine their predictive value on the development of necrosis, infected necrosis, organ failure, and mortality.

Methods

Prospective observational study conducted in patients with mild AP in 2 tertiary hospitals (2015–2017).

Results

Three hundred forty-six patients with mild AP were included. Forty-four patients (12.7%) evolved to MSAP/SAP. Necrosis was detected in 36 patients (10.4%); in 10 (2.9%), infection was confirmed. Organ failure was recorded in 9 patients (2.6%), all of whom died. Those who progressed to MSAP/SAP showed lower AT-III levels; d-dimer and C-reactive protein (CRP) levels increased. The best individual marker for MSAP/SAP at 24 hours is CRP (area under the curve [AUC], 0.839). Antithrombin III (AUC, 0.641), d-dimer (AUC, 0.783), and creatinine added no benefit compared with CRP alone. Similar results were observed for patients who progressed to necrosis, infected necrosis, and organ failure/death.

Conclusion

Low AT-III and high d-dimer plasma levels at 24 hours after admission were significantly associated with MSAP/SAP, although their predictive ability was low. C-reactive protein was the best marker tested.

Clinical Study Identifier

ClinicalTrials.gov NCT02373293
Start With the Body or the Mind? Differential Benefits of Mindfulness and Qigong Practices for Colorectal Cancer Survivors
Authors: Wan Adrian H. Y. , Ho Rainbow T. H. , Yau Joshua C. Y. , Yau Elzer F. K.
Published: October 2023

Background

Mindfulness and qigong are 2 distinct forms of mind-body practice that have been well-received by cancer survivors. Although there is evidence supporting the effectiveness of mindfulness or qigong in promoting wellness of cancer survivors, little is known about the differential benefits of these common forms of mind-body practices among survivors.

Objective

To compare the potential biopsychosocial-spiritual impacts of mindfulness and Baduanjin (BDJ) qigong on colorectal cancer survivors.

Methods

Sixty cancer survivors who participated in a mindfulness intervention (n = 38) and BDJ qigong (n = 22) intervention were invited to provide qualitative feedback for their experiences. Content analyses were conducted to identify emerging themes from the data, andχ2tests were conducted to compare the responses of the mindfulness and BDJ groups in the major categories.

Results

Both practices positively influenced psychosocial wellness. The practice of BDJ qigong led to more prominent improvements in physical well-being, whereas mindfulness worked best in enhancing spiritual growth and intrapersonal connectedness.

Conclusions

Survivors of colorectal cancer who are looking for ways to enhance their vitality and rejuvenate their physical body may find the practice of BDJ helpful, whereas survivors who are looking for spiritual comfort or growth may consider practicing mindfulness as an entry point toward mind-body unity.

Implications for Practice

Mindfulness and BDJ may be helpful for survivors of colorectal cancer to improve their holistic wellness. Oncology nurses can consider prescription of mindfulness and/or BDJ for patients recovering from colorectal cancer.
Burden of Other Musculoskeletal Disorders in Latin America and the Caribbean
Authors: Mendoza-Pinto Claudia , Etchegaray-Morales Ivet , Munguía-Realpozo Pamela , Rojas-Villarraga Adriana , Osorio-Peña Ángel David , Méndez-Martínez Socorro , García-Carrasco Mario
Published: October 2023

Objective

To describe the results from the Global Burden Disease (GBD) study 2019 on the burden of other musculoskeletal (MSK) disorders in Latin America and the Caribbean (LAC).

Methods

In this cross-sectional study, we analyzed data from all LAC region in the GBD study from 1990 to 2019. Other MSK (other than rheumatoid arthritis, osteoarthritis, gout, low back pain, and neck pain) burden was measured as prevalence, mortality, years lived with disability (YLD), and disability-adjusted life (DALY), by year, sex, and country. We show the counts, rates, and 95% uncertainty intervals (95% UI). Joinpoint regression analysis was used to estimate the average annual percentage change (AAPC) from 1990 to 2019. A correlational analysis between the burden parameters and sociodemographic index (SDI) was performed.

Results

In 2019, there were 52.0 million (95% UI, 44.8–60.1 million) individuals with other MSK disorders in LAC. The age-standardized mortality rate in 2019 was 1.2 (95% UI, 0.8–1.6) per 100,000 inhabitants. The AAPC was estimated as 0.1% (95% confidence interval [CI], 0.1–0.2) and 0.2% (95% CI, 0.1–0.3) for prevalence and mortality rates, respectively. The age-standardized DALY rate was 685.4 (95% UI, 483.6–483.6) per 100,000 inhabitants, representing an AAPC of 0.2% (95% CI, 0.1–0.3). The burden was larger in women and the elderly. The SDI was positively correlated with the prevalence of YLD in 2019.

Conclusions

LAC region has experienced a significant burden of other MSK disorders over the last three decades. To challenge this growing burden, population-based strategies designed to reduce the burden of other MSK and strengthen health systems to contribute effective and cost-efficient care are necessary.
Ultrasound—An Easy Available and Useful Point-of-Care Adjunct for Clinical Decision-Making in Hand Infections
Authors: Mueller Camillo Theo , Aman Martin , Grünfelder Franziska , Haug Valentin , Thomas Benjamin , Bollmann Christoph , Kneser Ulrich , Harhaus Leila
Published: October 2023

Initial findings of hand infections warrant a thorough treatment strategy depending on the progress of the infection. The decision for surgical treatment can be unclear. Searching to improve the quality of diagnostics, we reviewed the literature regarding the use of point-of-care ultrasound (PCUS) in hand infections and analyzed patients undergoing decision-making with PCUS. We searched PubMed, Scopus, Cochrane Register, and Google Scholar for the use of PCUS in therapy planning in infections of the hand. In addition, we screened our patients from July 1, 2020, to November 30, 2020, to validate the potential benefit of ultrasound examination in suspected hand infections. We evaluated initial clinical examinations versus blinded sonographic assessments in the context of correct decision to proceed with surgery or conservative treatment. Two thousand forty-eight studies within the topic were identified, but only 9 studies were found eligible to be included with a total of 88 patients. The studies illustrate that ultrasound can be performed on all patients, including children and pregnant women, and can be performed in a timely manner. In our retrospective analysis of 20 patients with suspected hand infection, the clinical and ultrasound assessment led to surgery in 13 cases. Of those 13 patients, 7 revealed intraoperative pus. By retrospective assessment of solely the ultrasound images, surgery would have been indicated in 9 cases, including all 7 cases with intraoperative pus. Clinical examination and ultrasound can help in detecting infections of the hand. Ultrasound examination, however, seems to yield a lower false-positive rate than clinical examination. Ultrasound could be a valuable addition to clinical examination.
The Buccal Fat Pad as a Primary Flap for the Reconstruction of Intraoral Defect After Resection of Oral Cavity Malignant Tumors: A Retrospective Study
Authors: Jolly Satnam Singh , Singh Apoorva , Rattan Vidya
Published: October 2023

Background:

Among the various local and regional flaps used for the reconstruction of intraoral defects after oral cavity cancer surgery, the pedicled buccal fat pad (BFP) flap is considered a reliable alternative. Reconstruction with a BFP flap is particularly feasible in oral cavity areas, such as the posterior maxilla, buccal mucosa, retromolar trigone, and gingivobuccal sulcus. The purpose of this study was to analyze the outcomes of pedicled BFP as a primary reconstruction flap for small to medium intraoral posterior oral cavity postresection defects operated in our institute.

Methods:

This study was designed as a retrospective study. Thirty-seven patients with oral cavity cancer underwent wide local excision with adequate margins, followed by reconstruction of the defect with a pedicled BFP flap. Defect size, postoperative healing of the surgical site, mouth opening at 6 months, and any associated complications were assessed.

Results:

The mean age of the patients was 47.38±9.95 years with a male-to-female ratio of 3.6:1. Mean defect size at the greatest dimension was 5.01±1.39 cm. The mean preoperative mouth opening of patients was 35±6.4 mm, whereas the mean postoperative mouth opening after 6 months of follow-up was 27.8±9.2 cm.

Conclusion:

The BFP flap is a convenient, reliable, and feasible reconstruction modality after oncological resection of posterior oral cavity cancers. Harvesting a BFP flap is minimally invasive with fewer complications, shorter recovery time, no donor site morbidity, and allows early initiation of adjuvant therapy postoperatively.
In vitro comparison of SARS-CoV-2 variants
Authors: Phadke Kruttika S. , Higdon Nathaniel , Bellaire Bryan H.
Published: October 2023

A myriad of coronaviruses cause diseases from a common cold to severe lung infections and pneumonia. SARS-CoV-2 was discovered to be the etiologic agent of the Coronavirus pandemic and many laboratory techniques were examined for virus culture and basic and applied research. Understanding the replication kinetics and characterizing the effect the virus has on different cell lines is crucial for developing in vitro studies. With the emergence of multiple variants of SARS-CoV-2, a comparison between their infectivity and replication in common cell lines will help give us a clear understanding of their characteristic differences in pathogenicity. In this study we compared the cytopathic effect and replication of Wild Type (WT), Omicron (B.1.1.529), and Delta (B.1.617.2) variants on 5 different cell lines; VeroE6, VeroE6 cells expressing high endogenous ACE2, VeroE6 cells expressing human ACE2 and TMPRSS2, Calu3 cells highly expressing human ACE2 and A549 cells. This data will aid researchers with experimental planning and viral pathogenicity analysis and provide a baseline for testing any future variants.
Clinical and genetic associations of asymmetric apical and septal left ventricular hypertrophy
Authors: Yuan Victoria , Vukadinovic Milos , Kwan Alan C. , Rader Florian , Li Debiao , Ouyang David
Published: October 2023

Increased left ventricular mass has been associated with adverse cardiovascular outcomes including incident cardiomyopathy and atrial fibrillation. Such associations have been studied in relation to total left ventricular hypertrophy, while the regional distribution of myocardial hypertrophy is extremely variable and the clinical significant and genetic associations of such variability requires further study. Here, we use deep learning derived phenotypes of disproportionate patterns of hypertrophy, such as apical hypertrophy and septal hypertrophy, to study genome-wide and clinical associations in addition to and independent from total left ventricular mass within 35,268 UK Biobank participants. Adjusting for total left ventricular mass, apical hypertrophy is associated with elevated risk for cardiomyopathy and atrial fibrillation, and the risk for cardiomyopathy was increased for subjects with increased apical or septal mass even in the absence of global hypertrophy. We identified seventeen genome-wide associations for left ventricular mass, three unique associations with increased apical mass, and three additional unique associations with increased septal mass. Further studies are needed in multi-ethnic cohorts.
Deriving Explainable Metrics of Left Ventricular Flow by Reduced-Order Modeling and Classification
Authors: Borja María Guadalupe , Martinez-Legazpi Pablo , Nguyen Cathleen , Flores Oscar , Kahn Andrew M. , Bermejo Javier , del Álamo Juan C.
Published: October 2023

Background

Extracting explainable flow metrics is a bottleneck to the clinical translation of advanced cardiac flow imaging modalities. We hypothesized that reduced-order models (ROMs) of intraventricular flow are a suitable strategy for deriving simple and interpretable clinical metrics suitable for further assessments. Combined with machine learning (ML) flow-based ROMs could provide new insight to help diagnose and risk-stratify patients.

Methods

We analyzed 2D color-Doppler echocardiograms of 81 non-ischemic dilated cardiomyopathy (DCM) patients, 51 hypertrophic cardiomyopathy (HCM) patients, and 77 normal volunteers (Control). We applied proper orthogonal decomposition (POD) to build patient-specific and cohort-specific ROMs of LV flow. Each ROM aggregates a low number of components representing a spatially dependent velocity map modulated along the cardiac cycle by a time-dependent coefficient. We tested three classifiers using deliberately simple ML analyses of these ROMs with varying supervision levels. In supervised models, hyperparameter gridsearch was used to derive the ROMs that maximize classification power. The classifiers were blinded to LV chamber geometry and function. We ran vector flow mapping on the color-Doppler sequences to help visualize flow patterns and interpret the ML results.

Results

POD-based ROMs stably represented each cohort through 10-fold cross-validation. The principal POD mode captured >80% of the flow kinetic energy (KE) in all cohorts and represented the LV filling/emptying jets. Mode 2 represented the diastolic vortex and its KE contribution ranged from <1% (HCM) to 13% (DCM). Semi-unsupervised classification using patient-specific ROMs revealed that the KE ratio of these two principal modes, the vortex-to-jet (V2J) energy ratio, is a simple, interpretable metric that discriminates DCM, HCM, and Control patients. Receiver operating characteristic curves using V2J as classifier had areas under the curve of 0.81, 0.91, and 0.95 for distinguishing HCM vs. Control, DCM vs. Control, and DCM vs. HCM, respectively.

Conclusions

Modal decomposition of cardiac flow can be used to create ROMs of normal and pathological flow patterns, uncovering simple interpretable flow metrics with power to discriminate disease states, and particularly suitable for further processing using ML.
Nphos: Database and Predictor of ProteinN-phosphorylation
Authors: Zhao Ming-Xiao , Ding Ruo-Fan , Chen Qiang , Meng Junhua , Li Fulai , Fu Songsen , Huang Biling , Liu Yan , Ji Zhi-Liang , Zhao Yufen
Published: October 2023

ProteinN-phosphorylation widely present in nature and participates in various biological functions. However, current knowledge onN-phosphorylation is extremely limited compared to that onO-phosphorylation. In this study, we collected 11,710 experimentally verifiedN-phosphosites of 7344 proteins from 39 species and subsequently constructed the database Nphos to share up-to-date information on proteinN-phosphorylation. Upon these substantial data, we characterized the sequential and structural features of proteinN-phosphorylation. Moreover, after comparing of hundreds of learning models, we chose and optimized gradient boosting decision tree (GBDT) models to predict three types of humanN-phosphorylation, achieving mean areas under the receiver operating characteristic curve (AUC) of 90.56%, 91.24%, and 92.01% for pHis, pLys, and pArg, respectively. Meanwhile, we discovered 488,825 distinctN-phosphosites in the human proteome. The models were also deployed in Nphos for interactiveN-phosphosite prediction. In summary, this work provides new insights and points for both flexible and focused investigations ofN-phosphorylation. It will also facilitate a deeper and more systematic understanding of proteinN-phosphorylation modification by providing a data and technical foundation. Nphos is freely available athttp://www.bio-add.organdhttp://ppodd.org.cn/Nphos/.
The impact of pubertal stress and adult hormone exposure on the transcriptome of the developing hypothalamus
Authors: Gautier Karissa N. , Higley Samantha L. , Mendoza John M. , Morrison Kathleen E.
Published: October 2023

Why individuals suffer negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when in the lifespan the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted hypothalamic-pituitary-adrenal axis glucocorticoid response in peripartum humans and mice. In mice, our prior examination of the paraventricular nucleus (PVN) of the hypothalamus showed that pubertal stress led to an upregulation of baseline mRNA expression of six immediate early genes (IEGs) in the PVN of adult, pregnant mice. Separately, we showed that the pregnancy-associated hormone allopregnanolone is necessary and sufficient to produce the blunted stress response phenotype in pubertally stressed mice. In the current study, we further examined a potential mechanistic role for the IEGs in the PVN. We found that in pubertally stressed adult female, but not male, mice, intra-PVN allopregnanolone was sufficient to recapitulate the baseline IEG mRNA expression profile previously observed in pubertally stressed, pregnant mice. We also examined baseline IEG mRNA expression during adolescence, where we found that IEGs have developmental trajectories that showed sex-specific disruption by pubertal stress. Altogether, these data establish that IEGs may act as a key molecular switch involved in increased vulnerability to negative outcomes in adult, pubertally stressed animals. How the factors that produce vulnerability combine throughout the lifespan is key to our understanding of the etiology of stress-related disorders.
Mice require proprioception to establish long-term visuospatial memory
Authors: Rutler Olivia , Persaud Serena , Kosmidis Stylianos , Park Jung M. , Harano Nina , Bruno Randy M. , Goldberg Michael E.
Published: October 2023

Because the retina moves constantly, the retinotopic representation of the visual world is spatially inaccurate and the brain must transform this spatially inaccurate retinal signal to a spatially accurate signal usable for perception and action. One of the salient discoveries of modern neuroscience is the role of the hippocampus in establishing gaze-independent, long-term visuospatial memories. The rat hippocampus has neurons which report the animal’s position in space regardless of its angle of gaze. Rats with hippocampal lesions are unable to find the location of an escape platform hidden in a pool of opaque fluid, the Morris Water Maze (MWM) based on the visual aspects of their surrounding environment. Here we show that the representation of proprioception in the dysgranular zone of primary somatosensory cortex is equivalently necessary for mice to learn the location of the hidden platform, presumably because without it they cannot create a long-term gaze-independent visuospatial representation of their environment from the retinal signal. They have no trouble finding the platform when it is marked by a flag, and they have no motor or vestibular deficits.
Single-cell chromatin state transitions during epigenetic memory formation
Authors: Fujimori Taihei , Rios-Martinez Carolina , Thurm Abby R. , Hinks Michaela M. , Doughty Benjamin R. , Sinha Joydeb , Le Derek , Hafner Antonina , Greenleaf William J. , Boettiger Alistair N. , Bintu Lacramioara
Published: October 2023

Repressive chromatin modifications are thought to compact chromatin to silence transcription. However, it is unclear how chromatin structure changes during silencing and epigenetic memory formation. We measured gene expression and chromatin structure in single cells after recruitment and release of repressors at a reporter gene. Chromatin structure is heterogeneous, with open and compact conformations present in both active and silent states. Recruitment of repressors associated with epigenetic memory produces chromatin compaction across 10-20 kilobases, while reversible silencing does not cause compaction at this scale. Chromatin compaction is inherited, but changes molecularly over time from histone methylation (H3K9me3) to DNA methylation. The level of compaction at the end of silencing quantitatively predicts epigenetic memory weeks later. Similarly, chromatin compaction at the Nanog locus predicts the degree of stem-cell fate commitment. These findings suggest that the chromatin state across tens of kilobases, beyond the gene itself, is important for epigenetic memory formation.
Benchmark dataset for training machine learning models to predict the pathway involvement of metabolites
Authors: Huckvale Erik D. , Powell Christian D. , Jin Huan , Moseley Hunter N.B.
Published: October 2023

Metabolic pathways are a human-defined grouping of life sustaining biochemical reac-tions, metabolites being both the reactants and products of these reactions. But many public datasets include identified metabolites whose pathway involvement is unknown, hindering metabolic inter-pretation. To address these shortcomings, various machine learning models, including those trained on data from the Kyoto Encyclopedia of Genes and Genomes (KEGG), have been developed to pre-dict the pathway involvement of metabolites based on their chemical descriptions; however, these prior models are based on old metabolite KEGG-based datasets, including one benchmark dataset that is invalid due to the presence of over 1500 duplicate entries. Therefore, we have developed a new benchmark dataset derived from the KEGG following optimal standards of scientific compu-tational reproducibility and including all source code needed to update the benchmark dataset as KEGG changes. We have used this new benchmark dataset with our atom coloring methodology to develop and compare the performance of Random Forest, XGBoost, and multilayer perceptron with autoencoder models generated from our new benchmark dataset. Best overall weighted average performance across 1000 unique folds was an F1-score of 0.8180 and Matthews correlation coeffi-cient of 0.7933, which was provided by XGBoost binary classification models for 11 KEGG-defined pathway categories.
Type I IFN signaling in the absence of IRGM1 promotesM. tuberculosisreplication in immune cells by suppressing T cell responses
Authors: Naik Sumanta K. , McNehlan Michael E. , Mreyoud Yassin , Kinsella Rachel L. , Smirnov Asya , Chowdhury Chanchal Sur , McKee Samuel R. , Dubey Neha , Woodson Reilly , Kreamalmeyer Darren , Stallings Christina L.
Published: October 2023

Polymorphisms in theIRGMgene are associated with susceptibility to tuberculosis in humans. A murine ortholog ofIrgm,Irgm1, is also essential for controllingMycobacterium tuberculosis(Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells. However, what IRGM1-mediated pathway is necessary to control Mtb infectionin vivoand the mechanistic basis for this control remains unknown. We dissected the contribution of IRGM1 to immune control of Mtb pathogenesisin vivoand found thatIrgm1deletion leads to higher levels of IRGM3-dependent type I interferon signaling. The increased type I interferon signaling precludes T cell expansion during Mtb infection. The absence of Mtb-specific T cell expansion inIrgm1-/-mice results in uncontrolled Mtb infection in neutrophils and alveolar macrophages, which directly contributes to susceptibility to infection. Together, our studies reveal that IRGM1 is required to promote T cell-mediated control of Mtb infection in neutrophils, which is essential for the survival of Mtb-infected mice. These studies also uncover new ways type I interferon signaling can impact TH1 immune responses.
Consequences of directly- and indirectly-experienced heat stress in a mutagenic environment
Authors: Feugere Lauric , De Freitas Claudio Silva , Bates Adam , Storey Kenneth B. , Beltran-Alvarez Pedro , Valero Katharina C. Wollenberg
Published: October 2023

Climate change increases the frequency and duration of heat events. Negative effects of heat stress may be exacerbated through the action of social metabolites between aquatic animals. Whilst early life stages are vulnerable to stress-induced damage, they deploy cellular mechanisms to protect cells against mutagens such as ultraviolet rays (UV). Little is known about the fate of fish embryos which have experienced heat stress in a mutagenic environment. The present study exposed zebrafish embryos to one of three stress history treatments consisting of direct heat stress (TS+UV), the social context of heat stress via social metabolites (SM+UV), and their combination in TS+SM+UV before a UVB/UVA damage/repair assay. We measured phenotypic and transcriptomic responses to these treatments, and estimated mutational damage through DNA mutation frequencies and RNA integrity values. Compared to UV-treated controls (C+UV), the social context of heat stress history preceding the UV assay altered keratin and cell structuring-related pathways, associated with longer embryos with over-developed pericardia displaying behavioural hypoactivity. Relative to C+UV, direct heat stress history preceding UV exposure had a hormetic effect by stimulating the cellular stress response and facilitating DNA repair, which rescued embryos from subsequent UV damage and improved their apparent fitness. However, heat stress combined with social metabolites overwhelmed embryos in the UV assay, which annihilated the hormetic effect, introduced mutations, and lowered their apparent fitness. Whilst generated in the laboratory, these findings provide an important baseline for understanding the consequences of heat stress history in natural environments, where heat stress occurs within a social context.

Highlights

Heat stress had a hormetic effect against UV damage, by stimulating the heat shock response, antioxidants, and DNA repair.

The heat hormetic effect protected and/or rescued embryos from UV damage by reducing single nucleotide variants observed in RNA, lowering malformations, and accelerating development.

Heat-stressed embryos released social metabolites that initiated keratin, immune, and cellular structuring responses in receivers, in turn increasing body sizes but without reducing UV-induced malformations.

Heat combined with social metabolites overwhelmed embryos in response to UV, reducing fitness-relevant performance.

Heat stress during early embryogenesis led to differential fitness-relevant outcomes showing a nonlinear relationship with stress intensity.

Summary statement

Sublethal heat stress protects zebrafish embryos in a mutagenic environment, but this protective effect is lost when zebrafish embryos additionally stress each other via chemical cues.

Graphical abstract
Integrating Genomics, Collections, and Community Science to Reveal Speciation in a Variable Monitor Lizard (Varanus tristis)
Authors: Pavón-Vázquez Carlos J. , Fitch Alison J. , Doughty Paul , Donnellan Stephen C. , Keogh J. Scott
Published: October 2023

—The accurate characterization of species diversity is a vital prerequisite for ecological and evolutionary research, as well as conservation. Thus, it is necessary to generate robust hypotheses of species limits based on the inference of evolutionary processes. Integrative species delimitation, the inference of species limits based on multiple sources of evidence, can provide unique insight into species diversity and the processes behind it. However, the application of integrative approaches in non-model organisms is often limited by the amount of data that is available. Here, we show how data relevant for species delimitation can be bolstered by incorporating information from tissue collections, museum specimens, and observations made by the wider community. We show how to integrate these data under a hypothesis-driven, integrative framework by identifying the processes generating genetic and phenotypic variation inVaranus tristis, a widespread and variable complex of Australian monitor lizards. Using genomic, morphometric (linear and geometric), coloration, spatial, and environmental data we show that disparity in this complex is inconsistent with intraspecific variation and instead suggests that speciation has occurred. Based on our results, we identify the environmental factors that may have been responsible for the geographic sorting of variation. Our workflow provides a guideline for the integrative analysis of several types of data to identify the occurrence and causes of speciation. Furthermore, our study highlights how community science and machine learning—two tools used here—can be used to accelerate taxonomic research.
CellPLM: Pre-training of Cell Language Model Beyond Single Cells
Authors: Wen Hongzhi , Tang Wenzhuo , Dai Xinnan , Ding Jiayuan , Jin Wei , Xie Yuying , Tang Jiliang
Published: October 2023

The current state-of-the-art single-cell pre-trained models are greatly inspired by the success of large language models. They trained transformers by treating genes as tokens and cells as sentences. However, three fundamental differences between single-cell data and natural language data are overlooked: (1) scRNA-seq data are presented as bag-of-genes instead of sequences of RNAs; (2) Cell-cell relations are more intricate and important than inter-sentence relations; and (3) The quantity of single-cell data is considerably inferior to text data, and they are very noisy. In light of these characteristics, we propose a new pre-trained modelCellPLM, which takes cells as tokens and tissues as sentences. In addition, we leverage spatially-resolved transcriptomic data in pre-training to facilitate learning cell-cell relationships and introduce a Gaussian mixture prior distribution as an additional inductive bias to overcome data limitation.CellPLMis the first single-cell pre-trained transformer that encodes cell-cell relations and it consistently outperforms existing pre-trained and non-pre-trained models in diverse downstream tasks, with 100x times higher inference speed compared to existing pre-trained models.