bluuebunny/crossref_metadata_2025 huggingface dataset:
Esketamine Nasal Spray for the Rapid Reduction of Depressive Symptoms in Major Depressive Disorder With Acute Suicidal Ideation or Behavior
Authors: Canuso Carla M. , Ionescu Dawn F. , Li Xiang , Qiu Xin , Lane Rosanne , Turkoz Ibrahim , Nash Abigail I. , Lopena Tricia J. , Fu Dong-Jing
Published: August 2021

Purpose/Background

Numerous health authority approvals of esketamine nasal spray, combined with oral antidepressant, to treat depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior were based on 2 identically designed, double-blind, phase 3 studies.

Methods/Procedures

Across both ASPIRE studies (NCT03039192, NCT03097133), patients (N = 456) were randomized to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks plus comprehensive standard of care, including hospitalization and newly initiated or optimized antidepressant(s). In post hoc analyses of pooled data, changes from baseline at 24 hours after the first dose in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression–Severity of Suicidality–Revised, in the full cohort and in subgroups, were analyzed using analysis of covariance.

Findings/Results

Esketamine plus standard of care demonstrated significantly greater improvement in Montgomery-Åsberg Depression Rating Scale total score versus placebo plus standard of care at 24 hours (least square mean difference [95% confidence interval], −3.8 [−5.75 to −1.89]) and at earlier (4 hours: −3.4 [−5.05 to −1.71]) and later time points (day 25: −3.4 [−5.36 to −1.36]). The between-group difference (95% confidence interval) for change in Clinical Global Impression–Severity of Suicidality–Revised at 24 hours was −0.20 (−0.43 to 0.04) for all patients and −0.31 (−0.61 to −0.01) for those with a history of suicide attempt. Common adverse events (≥20%) during esketamine treatment were dizziness, dissociation, nausea, somnolence, and headache.

Implications/Conclusions

Esketamine plus comprehensive standard of care rapidly reduces depressive symptoms in patients with major depressive disorder who have acute suicidal ideation or behavior, especially in those with a history of suicide attempt, providing a new treatment option for this particularly ill and vulnerable population.
The Influence of Chronic Diseases on Self-Reported Work Disability
Authors: Lee June-Hee , Kang Mo-Yeol
Published: August 2021

Objective:

To investigate the relationship between the types of chronic diseases and self-reported work disability.

Methods:

We used data from the Korean Labor and Income Panel Study from waves 6 to 21 conducted from 2003 to 2018. New cases of work disability were defined as those who reported that they had work limitations due to their health problems. Information on chronic disease was collected using a questionnaire during the sixth wave of the survey. To evaluate the effects of chronic disease on self-reporting work disability, Cox proportional hazard models were used.

Results:

The three most influential diseases on work disability were ophthalmologic diseases, chronic kidney diseases, and cardiovascular diseases during the 15-year follow-up period.

Conclusion:

Work disability is strongly and significantly associated with the aforementioned chronic diseases.
Efficacy of a Core Strengthening Program for Diastasis Rectus Abdominis in Postpartum Women: A Prospective Observational Study
Authors: Leopold Madeline , Santiago Kristen , Cheng Jennifer , Keller Leah , Abutalib Zafir , Bonder Jaclyn , Sharma Geeta , Tenforde Adam , Casey Ellen
Published: August 2021

Background:

Diastasis rectus abdominis (DRA) is characterized by a widening between the rectus abdominis muscles and thinning of the linea alba. It is common during pregnancy and may contribute to postpartum low back pain (LBP) and stress urinary incontinence (SUI). Core strengthening is thought to improve DRA, but there is no widely accepted exercise program.

Objectives:

To assess changes in interrectus distance (IRD) and participant-reported outcomes (PROs) after an online core strengthening program in postpartum women with DRA.

Study Design:

Prospective observational study.

Methods:

Forty-three postpartum women (36.7 ± 3.5 years) with DRA, which was diagnosed as an IRD 2.0 cm or more using musculoskeletal ultrasound, participated in a 12-week online core strengthening program focused on daily transversus abdominis activation with coordinated breathing and pelvic floor muscle engagement. IRD and PROs were assessed at baseline and 12 weeks. A subset of 19 women participated in an additional 12-week maintenance phase, and outcomes assessments were performed at 24 weeks.

Results:

The 12-week online core strengthening program significantly decreased IRD above and below the umbilicus at rest (slope [95% confidence interval]: −0.56 [−0.74, −0.38] and −0.26 [−0.45, −0.06]; P < .001 and P = .009, respectively) and below the umbilicus during contraction (−0.39 [−0.58, −0.20]; P < .001). Improvements in LBP-related disability (P = .002) and SUI (P = .001) were also observed. Participation in the maintenance phase significantly improved IRD at 24 weeks compared with 12 weeks (P < .0125). Satisfaction averaged 7.43 ± 2.23.

Conclusions:

The 12-week online core strengthening program reduced IRD and improved LBP-related disability and SUI. Program participation for 12 additional weeks further reduced IRD. These results suggest that the online core strengthening program can be used in postpartum women with DRA.
The incidence rate of herpes zoster in inflammatory bowel disease
Authors: Lai Shih-Wei , Liao Kuan-Fu , Lin Cheng-Li , Kuo Yu-Hung , Liu Chiu-Shong , Hwang Bing-Fang
Published: August 2021

Inflammatory bowel disease is associated with an increased risk of opportunistic infections. This study aimed to investigate the incidence rate of herpes zoster in patients with inflammatory bowel disease.

A meta-analysis was conducted by searching PubMed literature published from January 2000 to July 2019. The main outcome was the incidence rate of a new diagnosis of herpes zoster in patients previously diagnosed with inflammatory bowel disease. The incidence rate ratio (IRR) and 95% confidence interval (95% CI) for herpes zoster associated with inflammatory bowel disease was measured.

A total of 6 eligible cohort studies matching the entry criteria were included in the meta-analysis, providing 216,552 participants with inflammatory bowel disease and 790 events of herpes zoster among these participants with inflammatory bowel disease. The pooled incidence rate of developing herpes zoster was 10.41 per 1000 person-years in the inflammatory bowel disease group and 6.10 per 1000 person-years in the non-inflammatory bowel disease group, respectively. The meta-analysis demonstrated that patients with inflammatory bowel disease were associated with 1.68-fold increased risk of developing herpes zoster when compared to those without inflammatory bowel disease (IRR = 1.68, 95% CI = 1.53–1.84). Crohn disease and ulcerative colitis were associated with an increased risk of developing herpes zoster (IRR = 1.67, 95% CI = 1.40–1.98 for Crohn disease and IRR = 1.49, 95% CI = 1.34–1.65 for ulcerative colitis, respectively).

Patients with inflammatory bowel disease are at increased risk of developing herpes zoster. We suggest that the vaccination should be considered at the time of inflammatory bowel disease being diagnosed.
LEP as a potential biomarker in prognosis of breast cancer
Authors: Jin Tong Yi , Saindane Madhuri , Park Kyoung Sik , Kim SeongHoon , Nam SangEun , Yoo YoungBum , Yang Jung-Hyun , Yun IkJin
Published: August 2021

Purpose

Obesity strongly affects the prognosis of various malignancies, including breast cancer. Leptin (LEP) may be associated with obesity and breast cancer prognosis. The purpose of our study was to determine the prognostic value of LEP in breast cancer.

Method

We conducted a multi-omic analysis to determine the prognostic role of LEP. Different public bioinformatics platforms (Oncomine, Gene Expression Profiling Interactive Analysis, University of California Santa Cruz Xena, bc-GenExMiner, PrognoScan database, R2-Kaplan–Meier Scanner, UALCAN, Search Tool for the Retrieval of Interacting Genes/Proteins database , and The Database for Annotation, Visualization and Integrated Discovery) were used to evaluate the roles of LEP. Clinicopathological variables were evaluated.

Results

LEP was downregulated in breast cancer tissues compared to levels in normal tissues. By co-expressed gene analysis, a positive correlation between LEP and SLC19A3 was observed. Based on the clinicopathological analysis, low LEP expression was associated with older age, higher stage, lymph node status, human epidermal growth factor receptor 2 (HER2) status, estrogen receptor (ER+) positivity, and progesterone receptor (PR+) positivity. Kaplan–Meier survival analysis showed that low LEP expression indicated a poorer prognosis. LEP is hypermethylated in breast cancer tissues in PrognoScan and R2-Kaplan Meier Scanner, and low LEP expression was correlated with poor prognosis. LEP protein–protein interactions were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins database. Gene ontology analysis results showed that cellular component is mainly associated with the endosome lumen, cytosol, and secretory granules and is upregulated. For the biological process energy reserve, metabolic processes exhibited the greatest regulation compared to the others. In molecular function, it was mainly enriched in a variety of combinations, but hormone activity showed the highest regulation.

Conclusion

Our study provides evidence for the prognostic role of LEP in breast cancer and as a novel potential therapeutic target in such malignancies. Nevertheless, further validation is required.
Traditional Chinese medicine for acute coronary syndrome
Authors: Liao Jiangquan , Li Tao , Hua Yingying , Shao Mingjing , Wang Yan , Wang Zhe , Wei Kangkang , Chang Jiangmeng , Zhang Xiaoqiong , Chen Ming , Li Xianlun , Du Jinhang
Published: August 2021

Background:

Modern clinical trials and experimental researches of traditional Chinese medicine (TCM) have been conducted for decades and provided support for the prevention and treatment of acute coronary syndrome (ACS). However the level of evidence and the proper application of TCM were still barely satisfactory.

Methods:

In this study, we divided ACS into 3 different stages, including unstable angina, acute myocardial infarction, and post myocardial infarction. Then we systematically reviewed and meta-analyzed the existing randomized controlled trials on both clinical manifestations and objective indicators, in these 3 aspects.

Results:

The results indicate that TCM can both improve the clinical manifestations and ameliorate the objective parameters in different courses of ACS, including C-reactive protein in unstable angina, left ventricular ejection fraction in acute myocardial infarction and post myocardial infarction. And the incidence of short-term cardiovascular events are lower in TCM intervention group. Some of the improvements lead to potential long-term benefits.

Conclusion:

TCM treatment is beneficial to different courses of ACS. To acquire more solid and comprehensive evidence of TCM in treating ACS, more rigorously designed randomized controlled trials with longer follow-up duration are warranted.
Pulmonary mycobacterial infection is associated with increased mortality in patients with acute respiratory distress syndrome
Authors: Jeong Jong Hwan , Heo Manbong , Ju Sunmi , Lee Seung Jun , Cho Yu Ji , Jeong Yi Yeong , Lee Jong Deog , Yoo Jung-Wan
Published: August 2021

Although pulmonary mycobacterial infection is associated with acute respiratory distress syndrome (ARDS) in critically ill patients, its clinical implication on patients with ARDS has not been clearly elucidated. The aim of study was to investigate the clinical significance of pulmonary mycobacterial infection in patients with ARDS.

Between January 2014 and April 2019, medical records of 229 patients with ARDS who met the Berlin criteria and received invasive mechanical ventilation in medical intensive care unit were reviewed. Clinical characteristics and the rate of mortality between patients with and without pulmonary mycobacterial infection were compared. Factors associated with a 28-day mortality were analyzed statistically.

Twenty two (9.6%) patients were infected with pulmonary mycobacteria (18 with tuberculosis and 4 with non-tuberculous mycobacteria). There were no differences in baseline characteristics, the severity of illness scores. Other than a higher rate of renal replacement therapy required in those without pulmonary mycobacterial infection, the use of adjunctive therapy did not differ between the groups. The 28- day mortality rate was significantly higher in patients with pulmonary mycobacterial infection (81.8% vs 58%, P = .019). Pulmonary mycobacterial infection was significantly associated with 28-day mortality (hazard ratio 1.852, 95% confidence interval 1.108–3.095, P = .019).

Pulmonary mycobacterial infection was associated with increased 28-day mortality in patients with ARDS.
High-impact aerobics programme supplemented by pelvic floor muscle training does not impair the function of pelvic floor muscles in active nulliparous women
Authors: Piernicka Magdalena , Błudnicka Monika , Kortas Jakub , Duda-Biernacka Barbara , Szumilewicz Anna
Published: August 2021

Background:

We aimed to test the hypothesis that high-impact aerobics programme, combined with pelvic floor muscle training does not impair pelvic floor muscle function in young active women.

Methods:

A randomized control trial was conducted among active nulliparous, sport university students (age 23 ± 3 years, mean ± SD). Experimental group (n = 13) attended high-impact aerobics programme, supplemented by pelvic floor muscle training with one biofeedback session, for 6 weeks. The control group (n = 19) did not get any intervention. Before and after the experiment, we assessed pelvic floor muscle function in both groups with surface electromyography using vaginal probes. In both groups, we assessed the participants’ quality of life related to pelvic floor functions with the Incontinence Impact Questionnaires.

Results:

We recorded no impairments in neuromuscular activity of pelvic floor muscles and in quality of life in women regularly performing high-impact aerobics. What is even more positive, after 6 weeks, experimental group presented better skills both in contracting and relaxing their pelvic floor muscles, although the pre-post intervention EMG change was not statistically significant. All participants maintained good quality of life related to pelvic floor functions.

Conclusions:

High-impact aerobics, supplemented by pelvic floor muscle training can be recommended for active nulliparas.
Comparison of palonosetron with combined palonosetron and midazolam for preventing postoperative nausea and vomiting after laparoscopic cholecystectomy
Authors: Choi Eun Kyung , Park Sang-Jin , Park Chanyang , Lim Jung A.
Published: August 2021

Background:

Postoperative nausea and vomiting (PONV) is an undesirable complication in patients undergoing general anesthesia. Combination therapy via different mechanisms of action for antiemetic prophylaxis has been warranted for effective treatment of PONV. This study was designed to compare the prophylactic antiemetic effect between midazolam combined with palonosetron (group MP) and palonosetron alone (group P) after laparoscopic cholecystectomy surgeries.

Methods:

A prospective randomized controlled trial was investigated in non-smoking female. Eighty-eight patients were randomly divided into 2 groups with 44 patients each. Group MP received 0.05 mg/kg of midazolam intravenously before induction of anesthesia whereas group P received the same volume of normal saline. Immediately after anesthetic induction, 0.075 mg of palonosetron was administered to both the groups. The incidence and severity of PONV were assessed during 2 time intervals (0–2 hours, 2–24 hours), postoperatively.

Results:

The incidence of PONV during 24 hours after surgery was lower in group MP as compared to group P. There was also a significant difference in the use of rescue antiemetics. The severity of nausea was significantly lower in group MP as compared to group P, in the initial 2 hours after surgery. The incidence of side effects was similar between the 2 groups.

Conclusion:

In the prevention of PONV, midazolam combined with palonosetron, administered during induction of anesthesia was more effective as compared to palonosetron alone.
Applying Computerized Adaptive Testing to the FACE-Q Skin Cancer Module: Individualizing Patient-Reported Outcome Measures in Facial Surgery
Authors: Ottenhof Maarten J. , Geerards Daan , Harrison Conrad , Klassen Anne F. , Hoogbergen Maarten M. , van der Hulst René R. W. J. , Lee Erica H. , Pusic Andrea L. , Sidey-Gibbons Chris J.
Published: August 2021

Background:

Skin cancer is among the most frequently occurring malignancies worldwide, which creates a great need for an effective patient-reported outcome measure. Providing shorter questionnaires reduces patient burden and increases patients’ willingness to complete forms. The authors set out to use computerized adaptive testing to reduce the number of items needed to predict results for scales of the FACE-Q Skin Cancer Module, a validated patient-reported outcome measure that measures health-related quality of life and patient satisfaction in facial surgery.

Methods:

Computerized adaptive testing generates tailored questionnaires for patients in real time based on their responses to previous questions. The authors used an open-source computerized adaptive testing simulation software to run item responses for the five scales from the FACE-Q Skin Cancer Module (i.e., scar appraisal, satisfaction with facial appearance, appearance-related psychosocial distress, cancer worry, and satisfaction with information about appearance). Each simulation continued to administer items until prespecified levels of precision were met, estimated by standard error. Mean and maximum item reductions between the original fixed-length short forms and the simulated versions were evaluated.

Results:

The number of questions that patients needed to answer to complete the FACE-Q Skin Oncology Module was reduced from 41 items in the original form to a mean of 23 ± 0.55 items (range, 15 to 29) using the computerized adaptive testing version. Simulated computerized adaptive testing scores maintained a high correlation (0.98 to 0.99) with the score from the fixed-length short forms.

Conclusions:

Applying computerized adaptive testing to the FACE-Q Skin Cancer Module can reduce the length of assessment by more than 50 percent, with virtually no loss in precision. It is likely to play a critical role in the implementation in clinical practice.
Leber's Hereditary Optic Neuropathy in Older Individuals Because of Increased Alcohol Consumption During the COVID-19 Pandemic
Authors: Zaslavsky Kirill , Margolin Edward A.
Published: August 2021

Background:

Leber's hereditary optic neuropathy (LHON) is a disorder affecting oxidative phosphorylation in mitochondria. A majority of affected patients are men of 15 to 35 years of age. Phenotypic penetrance of this condition is only 50% in man and 10% in women and increases if the cellular energy demands go up, with the most common risk factors being smoking and alcohol use.

Methods:

Review of clinical features of 3 patients who were diagnosed with LHON in their sixth decade of life after doubling their alcohol intake during the recent COVID-19 pandemic.

Results:

All 3 patients were older than the age of 50 when they developed severe sequential visual loss. All have at least doubled their alcohol intake for at least 4 weeks preceding visual loss, and 2 who were smokers increased the number of cigarettes consumed daily because of the stress and boredom during the lockdowns triggered by the pandemic.

Conclusions:

Significant increase in substance abuse in the general population during the recent lockdowns to combat the COVID-19 pandemic is well documented. We report 3 patients older than the age of 50, one of them a woman, who developed severe bilateral visual loss due to LHON after doubling their alcohol consumption and increasing number of cigarettes smoked daily during the pandemic. Clinicians are reminded to consider LHON in the differential diagnosis when encountering older patients with bilateral sequential visual loss and to specifically inquire about alcohol use and cigarette smoking in these patients.
The Impact of COVID-19 on Neuro-Ophthalmology Office Visits and Adoption of Telemedicine Services
Authors: Moss Heather E. , Ko Melissa W. , Mackay Devin D. , Chauhan Divya , Gutierrez Karen G. , Villegas Natacha C. , Lai Kevin E.
Published: August 2021

Background:

The COVID-19 public health emergency (PHE) has significantly changed medical practice in the United States, including an increase in the utilization of telemedicine. Here, we characterize change in neuro-ophthalmic care delivery during the early COVID-19 PHE, including a comparison of care delivered via telemedicine and in office.

Methods:

Neuro-ophthalmology outpatient encounters from 3 practices in the United States (4 providers) were studied during the early COVID-19 PHE (March 15, 2020–June 15, 2020) and during the same dates 1 year prior. For unique patient visits, patient demographics, visit types, visit format, and diagnosis were compared between years and between synchronous telehealth and in-office formats for 2020.

Results:

There were 1,276 encounters for 1,167 patients. There were 30% fewer unique patient visits in 2020 vs 2019 (477 vs 670) and 55% fewer in-office visits (299 vs 670). Compared with 2019, encounters in 2020 were more likely to be established, to occur via telemedicine and to relate to an efferent diagnosis. In 2020, synchronous telehealth visits were more likely to be established compared with in-office encounters.

Conclusions:

In the practices studied, a lower volume of neuro-ophthalmic care was delivered during the early COVID-19 public health emergency than in the same period in 2019. The type of care shifted toward established patients with efferent diagnoses and the modality of care shifted toward telemedicine.
Detection of Optic Disc Abnormalities in Color Fundus Photographs Using Deep Learning
Authors: Liu T. Y. Alvin , Wei Jinchi , Zhu Hongxi , Subramanian Prem S. , Myung David , Yi Paul H. , Hui Ferdinand K. , Unberath Mathias , Ting Daniel S. W. , Miller Neil R.
Published: August 2021

Background:

To date, deep learning–based detection of optic disc abnormalities in color fundus photographs has mostly been limited to the field of glaucoma. However, many life-threatening systemic and neurological conditions can manifest as optic disc abnormalities. In this study, we aimed to extend the application of deep learning (DL) in optic disc analyses to detect a spectrum of nonglaucomatous optic neuropathies.

Methods:

Using transfer learning, we trained a ResNet-152 deep convolutional neural network (DCNN) to distinguish between normal and abnormal optic discs in color fundus photographs (CFPs). Our training data set included 944 deidentified CFPs (abnormal 364; normal 580). Our testing data set included 151 deidentified CFPs (abnormal 71; normal 80). Both the training and testing data sets contained a wide range of optic disc abnormalities, including but not limited to ischemic optic neuropathy, atrophy, compressive optic neuropathy, hereditary optic neuropathy, hypoplasia, papilledema, and toxic optic neuropathy. The standard measures of performance (sensitivity, specificity, and area under the curve of the receiver operating characteristic curve (AUC-ROC)) were used for evaluation.

Results:

During the 10-fold cross-validation test, our DCNN for distinguishing between normal and abnormal optic discs achieved the following mean performance: AUC-ROC 0.99 (95 CI: 0.98–0.99), sensitivity 94% (95 CI: 91%–97%), and specificity 96% (95 CI: 93%–99%). When evaluated against the external testing data set, our model achieved the following mean performance: AUC-ROC 0.87, sensitivity 90%, and specificity 69%.

Conclusion:

In summary, we have developed a deep learning algorithm that is capable of detecting a spectrum of optic disc abnormalities in color fundus photographs, with a focus on neuro-ophthalmological etiologies. As the next step, we plan to validate our algorithm prospectively as a focused screening tool in the emergency department, which if successful could be beneficial because current practice pattern and training predict a shortage of neuro-ophthalmologists and ophthalmologists in general in the near future.
Telemedicine Evaluations in Neuro-Ophthalmology During the COVID-19 Pandemic: Patient and Physician Surveys
Authors: Conway Jenna , Krieger Penina , Hasanaj Lisena , Sun Linus , Scharf Jackson M. , Odel Jeffrey G. , Dinkin Marc J. , Oliveira Cristiano , Mackay Devin D. , Rasool Nailyn , Ko Melissa , Rucker Janet C. , Galetta Steven L. , Balcer Laura J.
Published: August 2021

Background:

The novel coronavirus 2019 (COVID-19) pandemic has transformed health care. With the need to limit COVID-19 exposures, telemedicine has become an increasingly important format for clinical care. Compared with other fields, neuro-ophthalmology faces unique challenges, given its dependence on physical examination signs that are difficult to elicit outside the office setting. As such, it is imperative to understand both patient and provider experiences to continue to adapt the technology and tailor its application. The purpose of this study is to analyze both neuro-ophthalmology physician and patient satisfaction with virtual health visits during the time of the COVID-19 pandemic.

Methods:

Across three institutions (NYU Langone Health, Indiana University Health, and Columbia University Medical Center), telemedicine surveys were administered to 159 patients. Neuro-ophthalmologists completed 157 surveys; each of these were linked to a single patient visit. Patient surveys consisted of 5 questions regarding visit preparation, satisfaction, challenges, and comfort. The physician survey included 4 questions that focused on ability to gather specific clinical information by history and examination.

Results:

Among 159 patients, 104 (65.4%) reported that they were satisfied with the visit, and 149 (93.7%) indicated that they were comfortable asking questions. Sixty-eight (73.9%) patients found the instructions provided before the visit easy to understand. Potential areas for improvement noted by patients included more detailed preparation instructions and better technology (phone positioning, Internet connection, and software). More than 87% (137/157) of neuro-ophthalmologists surveyed reported having performed an examination that provided enough information for medical decision-making. Some areas of the neuro-ophthalmologic examination were reported to be easy to conduct (range of eye movements, visual acuity, Amsler grids, Ishihara color plates, and pupillary examination). Other components were more difficult (saccades, red desaturation, visual fields, convergence, oscillations, ocular alignment, and smooth pursuit); some were especially challenging (vestibulo-ocular reflex [VOR], VOR suppression, and optokinetic nystagmus). Clinicians noted that virtual health visits were limited by patient preparation, inability to perform certain parts of the examination (funduscopy and pupils), and technological issues.

Conclusions:

Among virtual neuro-ophthalmology visits evaluated, most offer patients with appointments that satisfy their needs. Most physicians in this cohort obtained adequate clinical information for decision-making. Even better technology and instructions may help improve aspects of virtual health visits.
Rare copy number variants in ASTN2 gene in patients with neurodevelopmental disorders
Authors: Bauleo Alessia , Montesanto Alberto , Pace Vincenza , Brando Rossella , De Stefano Laura , Puntorieri Domenica , Cento Luca , Loddo Sara , Calacci Chiara , Novelli Antonio , Falcone Elena
Published: August 2021

Introduction

In humans the normal development of cortical regions depends on the complex interactions between a number of proteins that promote the migrations of neuronal precursors from germinal zones and assembly into neuronal laminae. ASTN2 is one of the proteins implicated in such a complex process. Recently it has been observed that ASTN2 also regulates the surface expression of multiple synaptic proteins resulting in a modulation of synaptic activity. Several rare copy number variants (CNVs) in ASTN2 gene were identified in patients with neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD), attention deficit–hyperactivity disorders and intellectual disability.

Methods

By using comparative genomic hybridization array technology, we analyzed the genomic profiles of five patients of three unrelated families with NDDs. Clinical diagnosis of ASD was established according to the Statistical Manual of Mental Disorders, Fifth Edition (APA 2013) criteria.

Results

We identified new rare CNVs encompassing ASTN2 gene in three unrelated families with different clinical phenotypes of NDDs. In particular, we identified a deletion of about 70 Kb encompassing intron 19, a 186 Kb duplication encompassing the sequence between the 5′-end and the first intron of the gene and a 205 Kb deletion encompassing exons 6–11.

Conclusion

The CNVs reported here involve regions not usually disrupted in patients with NDDs with two of them affecting only the expression of the long isoforms. Further studies will be needed to analyze the impact of these CNVs on gene expression regulation and to better understand their impact on the protein function.
Epigenetic marks in suicide: a review
Authors: Ramos-Rosales Daniel F. , Vazquez-Alaniz Fernando , Urtiz-Estrada Norma , Ramirez-Valles Eda G. , Mendez-Hernádez Edna M. , Salas-Leal Alma C. , Barraza-Salas Marcelo
Published: August 2021

Suicide is a complex phenomenon and a global public health problem that involves several biological factors that could contribute to the pathophysiology of suicide. There is evidence that epigenetic factors influence some psychiatric disorders, suggesting a predisposition to suicide or suicidal behavior. Here, we review studies of molecular mechanisms of suicide in an epigenetic perspective in the postmortem brain of suicide completers and peripheral blood cells of suicide attempters. Besides, we include studies of gene-specific DNA methylation, epigenome-wide association, histone modification, and interfering RNAs as epigenetic factors. This review provides an overview of the epigenetic mechanisms described in different biological systems related to suicide, contributing to an understanding of the genetic regulation in suicide. We conclude that epigenetic marks are potential biomarkers in suicide, and they could become attractive therapeutic targets due to their reversibility and importance in regulating gene expression.
Diminishing immune responses against variants of concern in dialysis patients four months after SARS-CoV-2 mRNA vaccination
Authors: Dulovic Alex , Strengert Monika , Ramos Gema Morillas , Becker Matthias , Griesbaum Johanna , Junker Daniel , Lürken Karsten , Beigel Andrea , Wrenger Eike , Lonnemann Gerhard , Cossmann Anne , Stankov Metodi V. , Dopfer-Jablonka Alexandra , Kaiser Philipp D. , Traenkle Bjoern , Rothbauer Ulrich , Krause Gérard , Schneiderhan-Marra Nicole , Behrens Georg M.N.
Published: August 2021

Patients undergoing chronic hemodialysis were among the first to receive SARS-CoV-2 vaccinations due to their increased risk for severe COVID-19 disease and high case fatality rates. To date, there have been minimal longitudinal studies in hemodialysis patients to ascertain whether protection offered by vaccination is long-lasting. To assess how surrogates for protection changed over time, we examined both the humoral and cellular response in a previously reported cohort of at-risk hemodialysis patients and healthy donors, four months after their second dose of Pfizer BNT162b2. Compared to three weeks post-second vaccination, both cellular and humoral responses against the original SARS-CoV-2 isolate as well as variants of concern were significantly reduced, with some dialyzed individuals having no B- or T-cell response. Our data strongly support the need for a third booster in hemodialysis patients and potentially other at-risk individuals.
Targeted screening for lung cancer with autoantibodies
Authors: Sullivan Frank M. , Mair Frances S. , Anderson William , Armory Pauline , Briggs Andrew , Chew Cindy , Dorward Alistair , Haughney John , Hogarth Fiona , Kendrick Denise , Littleford Roberta , McConnachie Alex , McCowan Colin , McMeekin Nicola , Patel Manish , Rauchhaus Petra , Ritchie Lewis , Robertson Chris , Robertson John , Robles-Zurita Jose , Sarvesvaran Joseph , Sewell Herbert , Sproule Michael , Taylor Thomas , Treweek Shaun , Vedhara Kavita , Schembri Stuart
Published: August 2021

Earlier detection of lung cancer is possible, but difficult and costly to achieve. Screening with Low Dose Computed Tomography (LDCT)scanning has been shown to reduce mortality by 20-25% over the past decade but uptake amongst those most likely to suffer the disease has been slow. Resource constraints and a high false positive rate have also limited adoption of LDCT in many health systems. Targeted screening of people most likely to benefit using a range of biomarkers may be one way to improve the yield and reduce the resource requirements of LDCT. Autoantibodies, which amplify the signal produced by cancer derived proteins, are present in the blood of people mounting an immune response to cancer are a potential way to select those at highest risk. We have followed up 12 208 people enrolled in the ECLS trial for three years and shown that the specificity for early stage (I &II) disease is 90.3% throughout that period. More cancers were detected in the control than the intervention arm of the trial (101V 83). Sensitivity was 77.8% after 6 months and dropped to 46.4% after 3 years. At the end of three years the hazard ratios (95%CI) for All Cause, Cancer Specific and Lung Cancer Mortality was 0.82(0.67-1.01), 0.72(0.54-0.97) and 0.70(0.46-1.08) respectively for those randomised to Early CDT testing. As a range of treatment modalities become increasingly more effective it is even more important to target LDCT on those most likely to have early stage disease. Autoantibody testing may be one method of targeting early detection on those most likely to benefit.
Different adjuvanted pediatric HIV envelope vaccines induced distinct plasma antibody responses despite similar B cell receptor repertoires in infant rhesus macaques
Authors: Berendam Stella J. , Morgan-Asiedu Papa K , Mangan Riley J. , Li Shukhang , Heimsath Holly , Luo Kan , Curtis Alan D. , Eudailey Joshua A. , Fox Christopher B. , Tomai Mark A. , Phillips Bonnie , Itell Hannah L. , Kunz Erika , Hudgens Michael , Cronin Kenneth , Wiehe Kevin , Alam S.Munir , Van Rompay Koen K.A. , De Paris Kristina , Permar Sallie R. , Moody M. Anthony , Fouda Genevieve G.
Published: August 2021

Different HIV vaccine regimens elicit distinct plasma antibody responses in both human and nonhuman primate models. Previous studies in human and non-human primate infants showed that adjuvants influenced the quality of plasma antibody responses induced by pediatric HIV envelope vaccine regimens. We recently reported that use of the 3M052-SE adjuvant and longer intervals between vaccinations are associated with higher magnitude of antibody responses in infant rhesus macaques. However, the impact of different adjuvants in HIV vaccine regimens on the developing infant B cell receptor (BCR) repertoire has not been studied. This study evaluated whether pediatric HIV envelope vaccine regimens with different adjuvants induced distinct antigen-specific memory B cell repertoires and whether specific immunoglobulin (Ig) immunogenetic characteristics are associated with higher magnitude of plasma antibody responses in vaccinated infant rhesus macaques. We utilized archived preclinical pediatric HIV vaccine studies PBMCs and tissue samples from 19 infant rhesus macaques immunized either with (i) HIV Env protein with a squalene adjuvant, (ii) MVA-HIV and Env protein coadministered using a 3-week interval, (iii) MVA-HIV prime/ protein boost with an extended 6-week interval between immunizations, or (iv) with HIV Env administered with 3M-052-SE adjuvant. Frequencies of vaccine-elicited HIV Env-specific memory B cells from PBMCs and tissues were similar across vaccination groups (frequency range of 0.06-1.72%). There was no association between vaccine-elicited antigen-specific memory B cell frequencies and plasma antibody titer or avidity. Moreover, the epitope specificity and Ig immunogenetic features of vaccine-elicited monoclonal antibodies did not differ between the different vaccine regimens. These data suggest that pediatric HIV envelope vaccine candidates with different adjuvants that previously induced higher magnitude and quality of plasma antibody responses in infant rhesus macaques were not driven by distinct antigen-specific memory BCR repertoires.
Microbial communities in retail draft beers and the biofilms they produce
Authors: Bose Nikhil , Auvil Daniel P. , Moore Erica L. , Moore Sean D.
Published: August 2021

In the beer brewing industry, microbial spoilage presents a consistent threat that must be monitored and controlled to ensure the palatability of a finished product. Many of the predominant beer spoilage microbes have been identified and characterized, but the mechanisms of contamination and persistence remain an open area of study. Post-production, many beers are distributed as kegs that are attached to draft delivery systems in retail settings where ample opportunities for microbial spoilage are present. As such, restaurants and bars can experience substantial costs and downtime for cleaning when beer draft lines become heavily contaminated. Spoilage monitoring on the retail side of the beer industry is often overlooked, yet this arena may represent one of the largest threats to the profitability of a beer if its flavor profile becomes substantially distorted. In this study, we sampled and cultured microbial communities found in beers dispensed from a retail draft system to identify the contaminating bacteria and yeasts. We also evaluated their capability to establish new biofilms in a controlled setting. Among four tested beer types, we identified over a hundred different contaminant bacteria and nearly twenty wild yeasts. The culturing experiments demonstrated that most of these microbes were viable and capable of joining new biofilm communities. From these data, we provide an important starting point for the efficient monitoring of beer spoilage in draft systems and provide suggestions for cleaning protocol improvements that can benefit the retail community.

Importance

Beer production, packaging, and service are each vulnerable to contamination by microbes that metabolize beer chemicals and impart undesirable flavors, which can result in the disposal of entire batches. Therefore, great effort is taken by brewmasters to reduce and monitor contamination during production and packaging. A commonly overlooked quality control stage of a beer supply chain is at the retail service end, where beer kegs supply draft lines in bars and restaurants under non-sterile conditions. We found that retail draft line contamination is rampant and that routine line cleaning methods are insufficient to efficiently suppress beer spoilage. Thus, many customers unknowingly experience spoiled versions of the beers they consume. This study identified the bacteria and yeast that were resident in draft beer samples and also assessed their abilities to colonize tubing material as members of stable biofilm communities.
Lifelong single-cell profiling of cranial neural crest diversification
Authors: Fabian Peter , Tseng Kuo-Chang , Thiruppathy Mathi , Arata Claire , Chen Hung-Jhen , Smeeton Joanna , Nelson Nellie , Crump J. Gage
Published: August 2021

The cranial neural crest generates a huge diversity of derivatives, including the bulk of connective and skeletal tissues of the vertebrate head. How neural crest cells acquire such extraordinary lineage potential remains unresolved. By integrating single-cell transcriptome and chromatin accessibility profiles of cranial neural crest-derived cells across the zebrafish lifetime, we observe region-specific establishment of enhancer accessibility for distinct fates. Neural crest-derived cells rapidly diversify into specialized progenitors, including multipotent skeletal progenitors, stromal cells with a regenerative signature, fibroblasts with a unique metabolic signature linked to skeletal integrity, and gill-specific progenitors generating cell types for respiration. By retrogradely mapping the emergence of lineage-specific chromatin accessibility, we identify a wealth of candidate lineage-priming factors, including a Gata3 regulatory circuit for respiratory cell fates. Rather than multilineage potential being an intrinsic property of cranial neural crest, our findings support progressive and region-specific chromatin remodeling underlying acquisition of diverse neural crest lineage potential.

Highlights

Single-cell transcriptome and chromatin atlas of cranial neural crest

Progressive emergence of region-specific cell fate competency

Chromatin accessibility mapping identifies candidate lineage regulators

Gata3 function linked to gill-specific respiratory program

Graphical Abstract
epiRomics: a multi-omics R package to identify and visualize enhancers
Authors: Mawla Alex M. , Huising Mark O.
Published: August 2021

epiRomics is an R package designed to integrate multi-omics data in order to identify and visualize enhancer regions alongside gene expression and other epigenomic modifications. Regulatory network analysis can be done using combinatory approaches to infer regions of significance such as enhancers, when combining ChIP and histone data. Downstream analysis can identify co-occurrence of these regions of interest with other user-supplied data, such as chromatin availability or gene expression. Finally, this package allows for results to be visualized at high resolution in a stand-alone browser.

Availability and Implementation

epiRomics is released under Artistic-2.0 License. The source code and documents are freely available through Github (https://github.com/Huising-Lab/epiRomics).

Contact

ammawla@ucdavis.edu or mhuising@ucdavis.edu

Supplementary information

Supplementary data, and methods are available online on biorxiv or Github.
Stromal-cell deletion of STAT3 protects mice from kidney fibrosis by inhibiting pericytes trans-differentiation and migration
Authors: Ajay Amrendra K. , Zhao Li , Vig Shruti , Fujikawa Mai , Thakurela Sudhir , Jadhav Shreyas , Chiu I-Jen , Ding Yan , Ramachandran Krithika , Mithal Arushi , Bhatt Aanal , Chaluvadi Pratyusha , Gupta Manoj K. , Sabbisetti Venkata S. , Waaga-Gasser Ana Maria , Murugaiyan Gopal , Frank David A. , Bonventre Joseph V. , Hsiao Li-Li
Published: August 2021

Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor implicated in the pathogenesis of kidney fibrosis. Although tubular Stat3 deletion in tubular epithelial cells is known to protect mice from kidney fibrosis, the exact function of STAT3 in stromal cells remains unknown. We utilized stromal-cell Stat3 knock-out (KO) mice, CRISPR and pharmacologic activators and inhibitors of STAT3 to investigate its function in pericyte-like cells. STAT3 is phosphorylated in tubular epithelial cells in acute kidney injury whereas its activation expanded to interstitial cells in chronic kidney disease in mice and humans. Stromal cell-specific deletion of Stat3 protects mice from folic acid- and aristolochic acid-induced kidney fibrosis. Mechanistically, STAT3 directly regulates the inflammatory pathway, differentiation of pericytes into myofibroblasts. Specifically, STAT3 activation leads to an increase in migration and profibrotic signaling in genome-edited pericyte-like cells, 10T1/2. Conversely, Stat3 KO or blocking STAT3 function inhibits detachment, spreading, migration, and profibrotic signaling. Furthermore, STAT3 binds to Collagen1a1 promoter of fibrotic mouse kidneys and in pericyte-like cells. Together, our study identifies a previously unknown function of STAT3 in stromal cells that promotes kidney fibrosis and may have therapeutic value in fibrotic kidney disease.

Graphical Abstract
Gene expression in African Americans and Latinos reveals ancestry-specific patterns of genetic architecture
Authors: Kachuri Linda , Mak Angel C.Y. , Hu Donglei , Eng Celeste , Huntsman Scott , Elhawary Jennifer R. , Gupta Namrata , Gabriel Stacey , Xiao Shujie , Keys Kevin L. , Oni-Orisan Akinyemi , Rodríguez-Santana José R. , LeNoir Michael , Borrell Luisa N. , Zaitlen Noah A. , Williams L. Keoki , Gignoux Christopher R. , Burchard Esteban González , Ziv Elad
Published: August 2021

We analyzed whole genome and RNA sequencing data from 2,733 African American and Hispanic/Latino children to explore ancestry- and heterozygosity-related differences in the genetic architecture of whole blood gene expression. We found that heritability of gene expression significantly increases with greater proportion of African genetic ancestry and decreases with higher levels of Indigenous American ancestry, consistent with a relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of statistically significant ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most of the anc-eQTLs (89%) were driven by population differences in allele frequency, demonstrating the importance of measuring gene expression across multiple populations. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait pairs using models trained in our admixed population than models trained in GTEx. Our study highlights the importance of large and ancestrally diverse genomic studies for enabling new discoveries of complex trait architecture and reducing disparities.
Loneliness is linked to specific subregional alterations in hippocampus-default network co-variation
Authors: Zajner Chris , Spreng Nathan , Bzdok Danilo
Published: August 2021

Social interaction complexity makes humans unique. But in times of social deprivation this strength risks to expose important vulnerabilities. Human social neuroscience studies have placed a premium on the default network (DN). In contrast, hippocampus (HC) subfields have been intensely studied in rodents and monkeys. To bridge these two literatures, we here quantified how DN subregions systematically co-vary with specific HC subfields in the context of subjective social isolation (i.e., loneliness). By co-decomposition using structural brain scans of ∼40,000 UK Biobank participants, loneliness was specially linked to midline subregions in the uncovered DN patterns. These association cortex signatures coincided with concomitant HC patterns implicating especially CA1 and molecular layer. These patterns also showed a strong affiliation with the fornix white-matter tract and the nucleus accumbens. In addition, separable signatures of structural HC-DN co-variation had distinct associations with the genetic predisposition for loneliness at the population level.