bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the Dietary Intake of Children With Esophageal Atresia: A Prospective, Controlled, Observational Study
Authors: Traini Isabelle , Chan Sin Yee , Menzies Jessica , Hughes Jennifer , Coffey Michael J. , Katz Tamarah , McKay Isabelle R. , Ooi Chee Y. , Leach Steven T. , Krishnan Usha
Published: June 2022

Objectives:

Children with esophageal atresia (EA) often have feeding difficulties and dysphagia, which may compromise their nutritional status. This study aimed to compare dietary intake between children with EA and matched healthy controls (HC) and to investigate the relationship between dietary factors, growth, dysphagia, and feeding difficulties in the EA cohort.

Methods:

This cross-sectional cohort study recruited children with EA and HC aged 2–17 years from a tertiary pediatric hospital in Australia. Growth parameters were measured. Dietary intake was assessed using the validated Australian Child and Adolescent Eating Survey. Dysphagia and feeding difficulties were assessed using objective questionnaires.

Results:

Twenty-one children with EA were matched for age and sex with 21 HC. Compared to HC, children with EA had lower meanzscores for height-for-age, but mean weight-for-age and body mass index-for-age z scores were similar. Energy intake was similar between the groups. The diet of children with EA consisted of a higher proportion of fats and lower proportion of carbohydrates compared to matched HC. Dysphagia severity in children with EA positively correlated with proportion of energy from fats and saturated fats.

Conclusions:

Children with EA have similar energy intake and growth parameters to HC, but their diet consists of a higher proportion of fats and lower proportion of carbohydrates compared to HC. Targeted dietary interventions and parental education are necessary.
The Role of the Urban Exposome in the Increasing Global Rates of Pediatric Inflammatory Bowel Disease
Authors: Kuenzig M. Ellen , Benchimol Eric I.
Published: June 2022

Pediatric inflammatory bowel disease (IBD) is becoming increasingly common around the world, rapidly accelerating in regions undergoing rapid economic development. IBD is more common among those living in cities, and the association between the urban environment and IBD incidence is strongest in children. The “urban exposome” is defined as the totality of environmental exposures associated with urban living: air pollution, water contamination, green and blue space, nighttime light, noise, and availability of pre-processed and packaged foods. Investigation of the role of the urban exposome and IBD is in its infancy. Existing research has reached heterogeneous conclusions, and most studies have focused specifically on adult-onset disease and environmental exposures in isolation rather than the interaction between exposures. By better understanding the impact of the urban exposome on pediatric IBD, we can work to minimize these exposures and decrease the future burden of IBD in children.
Antibiotic Therapy for Culture-Proven Bacterial Overgrowth in Children With Intestinal Failure Results in Improved Symptoms and Growth
Authors: Culbreath Katherine , Knell Jamie , Keefe Gregory , Han Sam M. , Hong Charles R. , Riley Heather B. , Liu Enju , McAdam Alexander J. , Modi Biren P. , Jaksic Tom , Duggan Christopher P. , Carey Alexandra N.
Published: June 2022

Objectives:

To evaluate symptoms, enteral tolerance, growth, and antibiotic regimens in pediatric intestinal failure (IF) patients after treated with antibiotic therapy for small bowel bacterial overgrowth (SBBO).

Methods:

Single-center retrospective review of children 0–18 years with IF with endoscopic cultures demonstrating >105 CFU/mL from 2010 to 2017. Symptoms, enteral tolerance, growth, and antibiotic regimens were evaluated at the time of endoscopy and 6 months later.

Results:

Of 505 patients followed in our intestinal rehabilitation program, 104 underwent upper gastrointestinal endoscopy and 78 had positive duodenal cultures. Clinical data pre- and post-endoscopy were available for 56 patients. Compared to baseline, in the 6 months following targeted antibiotic treatment, children showed significant improvement in emesis or feeding intolerance (58.9% vs 23.2%, P < 0.001), abdominal pain (16.1% vs 7.1%, P = 0.02), high stool output (42.9% vs 19.6%, P = 0.002), and gross GI bleeding (19.6% vs 3.6%, P = 0.003). Mean BMI-for-age z scores increased significantly (−0.03 ± 0.94 vs 0.27 ± 0.82, P = 0.03); however, height-for-age z scores, weight-for-age z scores, and percent of calories from enteral intake were not significantly different after therapy. Antibiotic regimens remained highly variable.

Conclusions:

Children with IF and culture-positive SBBO showed significant improvement in symptoms and BMI-for-age z scores after duodenal culture with subsequent targeted antibiotic therapy. Longer follow-up may be needed to detect improvements in linear growth and percent of calories from enteral feeds. Antibiotic regimens remain highly variable. Long-term consequences of chronic antimicrobial therapy, including antimicrobial resistance, remain unknown. Prospective studies focused on standardizing duodenal sampling technique, correlating culture and pathology data, and evaluating antibiotic resistance patterns are needed.
Clinicopathologic and Molecular Characterization of Epstein-Barr Virus–positive Plasmacytoma
Authors: Zhou Ting , Cheng Jinjun , Karrs Jeremiah , Davies-Hill Theresa , Pack Svetlana D. , Xi Liqiang , Tyagi Manoj , Kim Jung , Jaffe Elaine S. , Raffeld Mark , Pittaluga Stefania
Published: June 2022

Epstein-Barr virus (EBV)-positive plasmacytoma is a rare plasma cell neoplasm. It remains unclear whether EBV-positive plasmacytoma represents a distinct entity or a variant of plasmacytoma. It shares morphologic features with plasmablastic lymphoma (PBL) and may cause diagnostic uncertainty. To better understand EBV-positive plasmacytoma and explore diagnostic criteria, this study describes 19 cases of EBV-positive plasmacytoma, compared with 27 cases of EBV-negative plasmacytoma and 48 cases of EBV-positive PBL. We reviewed the clinicopathologic findings and performed immunohistochemistry, in situ hybridization for EBV, fluorescence in situ hybridization for MYC, and next-generation sequencing. We found that 63.2% of patients with EBV-positive plasmacytoma were immunocompromised. Anaplastic features were observed in 7/19 cases. MYC rearrangement was found in 25.0% of them, and extra copies of MYC in 81.3%. EBV-positive and EBV-negative plasmacytomas possessed similar clinicopathologic features, except more frequent cytologic atypia, bone involvement and MYC aberrations in the former group. The survival rate of patients with EBV-positive plasmacytoma was comparable to that of patients with EBV-negative plasmacytoma. In comparison to PBL, EBV-positive plasmacytoma is less commonly associated with a “starry-sky” appearance, necrosis, absence of light chain expression, and a high Ki67 index (>75%). The most recurrently mutated genes/signaling pathways in EBV-positive plasmacytoma are epigenetic regulators, MAPK pathway, and DNA damage response, while the most frequently reported mutations in PBL are not observed. Collectively, EBV-positive plasmacytoma should be regarded as a biological variant of plasmacytoma. Thorough morphologic examination remains the cornerstone for distinguishing EBV-positive plasmacytoma and PBL, and molecular studies can be a valuable complementary tool.
Innervation of the Female Breast and Nipple: A Systematic Review and Meta-Analysis of Anatomical Dissection Studies
Authors: Smeele Hansje P. , Bijkerk Ennie , van Kuijk Sander M. J. , Lataster Arno , van der Hulst René R. W. J. , Tuinder Stefania M. H.
Published: June 2022

Background:

Primary cadaveric studies were reviewed to give a contemporary overview of what is known about innervation of the female breast and nipple/nipple-areola complex.

Methods:

The authors performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses–compliant systematic review and meta-analysis. The authors searched four electronic databases for studies investigating which nerve branches supply the female breast and nipple/nipple-areola complex or describing the trajectory and other anatomical features of these nerves. Inclusion criteria for meta-analysis were at least five studies of known sample size and with numerical observed values. Pooled prevalence estimates of nerve branches supplying the nipple/nipple-areola complex were calculated using random-effects meta-analyses; the remaining results were structured using qualitative synthesis. Risk of bias within individual studies was assessed with the Anatomical Quality Assurance checklist.

Results:

Of 3653 studies identified, 19 were eligible for qualitative synthesis and seven for meta-analysis. The breast skin is innervated by anterior cutaneous branches and lateral cutaneous branches of the second through sixth and the nipple/nipple-areola complex primarily by anterior cutaneous branches and lateral cutaneous branches of the third through fifth intercostal nerves. The anterior cutaneous branch and lateral cutaneous branch of the fourth intercostal nerve supply the largest surface area of the breast skin and nipple/nipple-areola complex. The lateral cutaneous branch of the fourth intercostal nerve is the most consistent contributory nerve to the nipple/nipple-areola complex (pooled prevalence, 89.0 percent; 95 percent CI, 0.80 to 0.94).

Conclusions:

The anterior cutaneous branch and lateral cutaneous branch of the fourth intercostal nerve are the most important nerves to spare or repair during reconstructive and cosmetic breast surgery. Future studies are required to elicit the course of dominant nerves through the breast tissue.
Magnetic Resonance Imaging Screening after Silicone Implant Breast Surgery: Patient Survey of Adherence to U.S. Food and Drug Administration Recommendations
Authors: Copeland-Halperin Libby R. , Wampler Ariel T. , Doughty Hayden , Shank Nina , Levy Joshua J. , Reategui Via y Rada Maria L. , Rosen Joseph M.
Published: June 2022

Background:

The U.S. Food and Drug Administration recommends women with silicone breast implants undergo magnetic resonance imaging surveillance to detect asymptomatic rupture. Screening is costly and often not covered by insurance. The authors assessed awareness of and adherence to these recommendations among patients with silicone breast implants.

Methods:

The authors searched electronic medical records for patients aged 18 years or older with silicone breast implants placed between 2011 and 2016. Consenting patients were surveyed by telephone using a standardized script to assess awareness of U.S. Food and Drug Administration recommendations, whether they had undergone magnetic resonance imaging screening, and barriers to testing. Patients who declined to participate or could not be contacted were excluded. Demographics and operative data were collected. Odds ratios were calculated with one-sample 95 percent confidence intervals, and Fisher exact tests of independence were conducted under assumptions of normality. Multivariable logistic regression analysis was performed to test for confounding.

Results:

Of 370 patients meeting inclusion criteria, 109 consented to participate. Adherence to U.S. Food and Drug Administration recommendations was 5.9 percent (95 percent CI, 0.15 to 28.7 percent). There was no difference in adherence between patients undergoing cosmetic versus reconstructive surgery (p = 1.00; OR, 0.80; 95 percent CI, 1.17 to 2.93), having health insurance (p = 0.58), or residing in a county with median annual household income greater than that of the state of residence (p = 0.33).

Conclusions:

A small proportion of respondents had undergone magnetic resonance imaging in accordance with U.S. Food and Drug Administration recommendations. Low adherence highlights a potential limitation of current federal surveillance recommendations. Additional research is needed to better characterize adherence to magnetic resonance imaging surveillance recommendations, identify barriers to implementation, and determine whether this recommendation remains valid.
HIV Risk Factors and Risk Perception Among Adolescent Girls and Young Women: Results From a Population-Based Survey in Western Kenya, 2018
Authors: Kamire Vivienne , Magut Faith , Khagayi Sammy , Kambona Caroline , Muttai Hellen , Nganga Lucy , Kwaro Daniel , Joseph Rachael H.
Published: June 2022

Background:

In sub-Saharan Africa, HIV prevalence in adolescent girls and young women (AGYW) is 2-fold to 3-fold higher than that in adolescent boys and young men. Understanding AGYW's perception of HIV risk is essential for HIV prevention efforts.

Methods:

We analyzed data from a HIV biobehavioral survey conducted in western Kenya in 2018. Data from AGYW aged 15–24 years who had a documented HIV status were included. We calculated weighted prevalence and evaluated factors associated with outcomes of interest (HIV infection and high risk perception) using generalized linear models to calculate prevalence ratios.

Results:

A total of 3828 AGYW were included; 63% were aged 15–19 years. HIV prevalence was 4.5% and 14.5% of sexually active AGYW had high risk perception. Over 70% of participants had accessed HIV testing and counseling in the past 12 months. Factors associated with both HIV infection and high risk perception included having an HIV-positive partner or partner with unknown status and having a sexually transmitted infection in the past 12 months. Having an older (by ≥10 years) partner was associated with HIV infection, but not high risk perception. Less than 30% of sexually active AGYW with 3 or more HIV risk factors had high perception of HIV risk.

Conclusion:

Gaps in perceived HIV risk persist among AGYW in Kenya. High access to HIV testing and prevention services in this population highlights platforms through which AGYW may be reached with improved risk counseling, and to increase uptake of HIV prevention strategies.
Postoperative Utilization of Opioids After Midurethral Sling Surgery: A Prospective Clinical Practice Study
Authors: Ramaseshan Aparna S. , O'Meara Amanda , O'Sullivan David M. , Tunitsky-Bitton Elena
Published: June 2022

Importance

This study was performed to understand opioid consumption after midurethral sling (MUS) procedures to provide surgeons with guidelines on appropriate prescription regimens.

Objective

This study aimed to evaluate postdischarge narcotic use (PDNU) after MUS surgery using a restrictive postdischarge opioid regimen.

Study Design

This prospective clinical practice study included women undergoing MUS surgery from December 2018 to October 2019. Patients were discharged with an electronic prescription for 5 tablets of an oral narcotic. Brief Pain Inventory (BPI) surveys were collected preoperatively. Patients answered questions regarding remaining number of opioid tablets, BPI scores, and patient satisfaction on day 1, week 1 (postoperative week [POW] 1), and 4–6 weeks (POW4–6) postoperatively. Electronic records were reviewed to determine narcotic refills. Primary outcome was PDNU measured in morphine milligram equivalents (MME). Secondary outcomes evaluated refill rate, BPI scores, and patient satisfaction. Standard statistical tests were applied.

Results

Fifty-six patients were included in the analysis. Total median (interquartile range) PDNU was 12.5 (0–37.5) MME at POW1 and 15.0 (0–37.5) MME at POW4–6, which is approximately equivalent to 2 oxycodone (5 mg) tablets. Eighteen patients (32.1%) took 0 narcotics postdischarge. Brief Pain Inventory scores showed that “worst pain” was highest on postoperative day 1 with a median (interquartile range) score of 6 (4–8). At the POW1 and POW4–6 mark, 94.3% and 92% of patients, respectively, were satisfied or extremely satisfied with their pain control. Seven patients (11.8%) required a refill.

Conclusions

Most patients undergoing MUS surgery used no more than 2 oxycodone (5 mg) tablets during their 6-week postoperative course, with almost a third not requiring any narcotics. Low pain scores and high patient satisfaction rates were noted.
Barriers and Promotors to Health Service Utilization for Pelvic Floor Disorders in the United States: Systematic Review and Meta-analysis of Qualitative and Quantitative Studies
Authors: Mou Tsung , Gonzalez Javier , Gupta Ankita , O’Shea Michele , Thibault Mary Duarte , Gray Elizabeth L. , Beestrum Molly , Brown Oluwateniola , Cichowski Sara
Published: June 2022

Importance

We need a systematic approach to understanding health service utilization behavior in women with pelvic floor symptoms in the United States.

Objectives

The aim of this study was to determine the prevalence of pelvic floor care utilization and identify its barriers and promotors using Andersen’s model, which theorizes care-seeking behavior with individual care needs, resources, predispositions, and macrostructures.

Design

This was a systematic search of studies on care-seeking patterns in women with symptomatic pelvic floor disorders, which included pelvic organ prolapse, lower urinary tract symptoms, and anal incontinence. We then performed meta-analyses with random-effects models and descriptive analysis to determine utilization rate and the impact of each identified determinant.

Results

The pooled utilization rate was 37% (95% confidence interval [CI], 30%–45%). Determinants were identified across all domains except at the macrostructure level. For individual care needs, increased symptom severity or duration and a history of depression (odds ratio [OR], 1.27; 95% CI, 1.07–1.51) were associated with higher utilization. In the resources domain, having social support and established primary/secondary care were promotors, whereas higher income and employed status trended as barriers. Under predispositions, age ≥50 years (OR, 1.29; 95% CI, 1.05–1.60), and pelvic floor awareness were associated with utilization, whereas Asian (OR, 0.60; 95% CI, 0.51–0.72) and Black (OR, 0.77; 95% CI, 0.55–1.08) women as well as women experiencing fear, misinformation, or normalization of pelvic floor disorders had decreased utilization.

Conclusions

This review identified a low utilization rate for pelvic floor care and revealed multilayered, actionable items affecting care-seeking behavior. It highlights the need for more inclusive and multifaceted approaches in future pelvic floor disparity research and equity interventions.
Running-specific prosthesis model, stiffness and height affect biomechanics and asymmetry of athletes with unilateral leg amputations across speeds
Authors: Tacca Joshua R. , Beck Owen N. , Taboga Paolo , Grabowski Alena M.
Published: June 2022

Athletes with transtibial amputation (TTA) use running-specific prostheses (RSPs) to run. RSP configuration likely affects the biomechanics of such athletes across speeds. We determined how the use of three RSP models (Catapult, Sprinter and Xtend) with three stiffness categories (recommended, ±1), and three heights (recommended, ±2 cm) affected contact length (

L
c

), stance average vertical ground reaction force (
F
avg
), step frequency (
f
step
) and asymmetry between legs for 10 athletes with unilateral TTA at 3–7 m s
−1
. The use of the Xtend versus Catapult RSP decreased

L
c

(
p
= 2.69 × 10
−7
) and
F
avg
asymmetry (
p
= 0.032); the effect on

L
c

asymmetry diminished with faster speeds (
p
= 0.0020). The use of the Sprinter versus Catapult RSP decreased
F
avg
asymmetry (
p
= 7.00 × 10
−5
); this effect was independent of speed (
p
= 0.90). The use of a stiffer RSP decreased

L
c

asymmetry (
p
≤ 0.00033); this effect was independent of speed (
p
≥ 0.071). The use of a shorter RSP decreased

L
c

(
p
= 5.86 × 10
−6
),
F
avg
(
p
= 8.58 × 10
−6
) and
f
step
asymmetry (
p
= 0.0011); each effect was independent of speed (
p
≥ 0.15). To minimize asymmetry, athletes with unilateral TTA should use an Xtend or Sprinter RSP with 2 cm shorter than recommended height and stiffness based on intended speed.
Personality, sperm traits and a test for their combined dependence on male condition in guppies
Authors: Galluccio Edward , Lymbery Rowan A. , Wilson Alastair , Evans Jonathan P.
Published: June 2022

There is evidence that animal personality can affect sexual selection, with studies reporting that male behavioural types are associated with success during pre- and post-copulatory sexual selection. Given these links between personality and sexual traits, and the accumulating evidence that their expression can depend on an individual's dietary status (i.e. condition), a novel prediction is that changes in a male's diet should alter both the average expression of personality and sexual traits, and their covariance. We tested these predictions using the guppyPoecilia reticulata, a species previously shown to exhibit strong condition dependence in ejaculate traits and a positive correlation between sperm production and individual variation in boldness. Contrary to expectation, we found that dietary restriction—when administered in mature adult males—did not affect the expression of either behavioural (boldness and activity) or ejaculate traits, although we did find that males subjected to dietary stress exhibited a positive association between sperm velocity and boldness that was not apparent in the unrestricted diet group. This latter finding points to possible context-dependent patterns of covariance between sexually selected traits and personalities, which may have implications for patterns of selection and evolutionary processes under fluctuating environmental conditions.
Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder
Authors: Siecinski Stephen K , Giamberardino Stephanie N , Spanos Marina , Hauser Annalise C , Gibson Jason R , Chandrasekhar Tara , Trelles M D Pilar , Rockhill Carol M , Palumbo Michelle L , Cundiff Allyson Witters , Montgomery Alicia , Siper Paige , Minjarez Mendy , Nowinski Lisa A , Marler Sarah , Kwee Lydia C , Shuffrey Lauren C , Alderman Cheryl , Weissman Jordana , Zappone Brooke , Mullett Jennifer E , Crosson Hope , Hong Natalie , Luo Sheng , She Lilin , Bhapkar Manjushri , Dean Russell , Scheer Abby , Johnson Jacqueline L , King Bryan H , McDougle Christopher J , Sanders Kevin B , Kim Soo-Jeong , Kolevzon Alexander , Veenstra-VanderWeele Jeremy , Hauser Elizabeth R , Sikich Linmarie , Gregory Simon G
Published: June 2022

Oxytocin (OT), the brain’s most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD’s complex etiology. We hypothesized that genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To test this hypothesis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis shows subtle, but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. We also identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions.
Adipose-derived stromal cells preserve pancreatic islet function in a transplantable 3D bioprinted scaffold
Authors: Abadpour Shadab , Niemi Essi M. , Orrhult Linnea Strid , Hermanns Carolin , de Vries Rick , Nogueira Liebert Parreiras , Haugen Håvard Jostein , Josefsen Dag , Krauss Stefan , van Apeldoorn Aart , Gatenholm Paul , Scholz Hanne
Published: June 2022

Intra-portal islet transplantation is the method of choice for treatment of insulin dependent type 1 diabetes, but its outcome is hindered by limited islet survival due to the immunological and metabolic stress post transplantation. Adipose-derived stromal cells (ASCs) promise to improve significantly the islet micro-environment but an efficient long-term delivery method has not been achieved. We therefore explore the potential of generating ASC enriched islet transplant structure by 3D bioprinting. Here, we fabricate a double-layered 3D bioprinted scaffold for islets and ASCs by using alginate-nanofibrillated cellulose bioink. We demonstrate the diffusion properties of the scaffold and report that human ASCs increase the islet viability, preserve the endocrine function, and reduce pro-inflammatory cytokines secretionin vitro. Intraperitoneal implantation of the ASCs and islets in 3D bioprinted scaffold improve the long-term function of islets in diabetic mice. Our data reveals an important role for ASCs on the islet micro-environment. We suggest a novel cell therapy approach of ASCs combined with islets in a 3D structure with a potential for clinical beta cell replacement therapies at extrahepatic sites.
Are Brain Responses to Emotion a Reliable Endophenotype of Schizophrenia? An Image-based fMRI Meta-analysis
Authors: Fiorito Anna M. , Aleman André , Blasi Giuseppe , Bourque Josiane , Cao Hengyi , Chan Raymond C. K. , Chowdury Asadur , Conrod Patricia , Diwadkar Vaibhav A. , Goghari Vina M. , Guinjoan Salvador , Gur Raquel E. , Gur Ruben C. , Kwon Jun Soo , Lieslehto Johannes , Lukow Paulina B. , Meyer-Lindenberg Andreas , Modinos Gemma , Quarto Tiziana , Spilka Michael J. , Shivakumar Venkataram , Venkatasubramanian Ganesan , Villarreal Mirta , Wang Yi , Wolf Daniel H. , Yun Je-Yeon , Fakra Eric , Sescousse Guillaume
Published: June 2022

Background

Impaired emotion processing constitutes a key dimension of schizophrenia and a possible endophenotype of this illness. Empirical studies consistently report poorer emotion recognition performance in patients with schizophrenia as well as in individuals at enhanced risk of schizophrenia (“at risk”). fMRI studies also report consistent patterns of abnormal brain activation in response to emotional stimuli in patients, in particular decreased amygdala activation. In contrast, brain-level abnormalities in at-risk individuals are more elusive. We address this gap using an image-based meta-analysis of the fMRI literature.

Methods

fMRI studies investigating brain responses to negative emotional stimuli and reporting a comparison between at-risk individuals and healthy controls were identified. Frequentist and Bayesian voxel-wise meta-analyses were performed separately, by implementing a random effect model with unthresholded group-level T-maps from individual studies as input.

Results

Seventeen studies with a cumulative total of 677 at-risk individuals and 805 healthy controls were included. Frequentist analyses did not reveal significant differences between at-risk individuals and healthy controls. Similar results were observed with Bayesian analyses, which provided strong evidence for the absence of meaningful brain activation differences across the entire brain. Region of interest analyses specifically focusing on the amygdala confirmed the lack of group differences in this region.

Conclusions

These results suggest that brain activation patterns in response to emotional stimuli are unlikely to constitute a reliable endophenotype of schizophrenia. We suggest that future studies rather focus on impaired functional connectivity as an alternative and promising endophenotype.
The global prevalence and ethnic heterogeneity of iron-refractory iron deficiency anaemia
Authors: Fan Shanghua , Zhao Ting , Sun Liu
Published: June 2022

Background

Iron-refractory iron deficiency anaemia (IRIDA) is an autosomal recessive iron deficiency anaemia caused by mutations in theTMPRSS6gene. Iron deficiency anaemia is common, whereas IRIDA is rare. The prevalence of IRIDA is unclear. This study aimed to estimate the carrier frequency and genetic prevalence of IRIDA using Genome Aggregation Database (gnomAD) data.

Methods

The pathogenicity ofTMPRSS6variants was interpreted according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) standards and guidelines. The minor allele frequency (MAF) ofTMPRSS6gene disease-causing variants in 141456 unique individuals was examined to estimate the global prevalence of IRIDA in seven ethnicities: African/African American (afr), American Admixed/Latino (amr), Ashkenazi Jewish (asj), East Asian (eas), Finnish (fin), Non-Finnish European (nfe) and South Asian (sas). The global and population-specific carrier frequencies and genetic prevalence of IRIDA were calculated using the Hardy-Weinberg equation.

Results

In total, 86 pathogenic/likely pathogenic variants (PV/LPV) were identified according to ACMG/AMP guideline. The global carrier frequency and genetic prevalence of IRIDA were 2.02 per thousand and 1.02 per million, respectively.

Conclusions

The prevalence of IRIDA is greater than previous estimates.
Levels and determinants of quality of antenatal care in Bangladesh: Evidence from the Bangladesh Demographic and Health Survey
Authors: Akter Ema , Hossain Aniqa Tasnim , Rahman Ahmed Ehsanur , Ahmed Anisuddin , Tahsina Tazeen , Tanwi Tania Sultana , Nusrat Nowrin , Nahar Quamrun , Arifeen Shams El , Chowdhury Mahbub Elahi
Published: June 2022

Background

Assessing the quality of antenatal care (ANC) is imperative for improving care provisions during pregnancy to ensure the health of mother and baby. In Bangladesh, there is a dearth of research on the quality of ANC using nationally representative data to understand its levels and determinants. The current study aims to assess the quality of ANC and identify the sociodemographic factors associated with the usage of quality ANC services in Bangladesh.

Methods

We conducted secondary data analysis using the last two Bangladesh Demographic and Health Surveys (BDHS) (2014 and 2017–18). A total of 8,277 ever-married women were included in the analysis (3,631 from 2014 and 4,646 from 2017–18 BDHS). We constructed the quality ANC index using a principal component analysis on different ANC components: weight, blood pressure measurement, blood and urine tests, counseling about pregnancy complications and a minimum of four ANC visits of which one is by a medically trained provider. Multinomial logistic regression was used to determine the strength of association.

Results

Receiving all the six components of quality ANC increased from about 13% in 2014 (BDHS 2014) to 18% in 2017/18 (BDHS 2017–18) with a significant difference of p < 0.001. Women from the poorest group, being rural areas, with no education, high birth order and unexposed to media were less likely to receive high-quality ANC than women from the richest group, from urban areas, with a higher level of education, low birth order and exposure to media.

Conclusion

There is a need to improve the quality of ANC services in Bangladesh. An education program for women, with regular knowledge-enhancing sessions for pregnant mothers, may help them understand the value of ANC visits. Documentaries about maternal and child healthcare can be broadcast on television, YouTube, Facebook, radio and other digital platforms regularly.
SARS-CoV-2 impacts the transcriptome and epigenome at the maternal-fetal interface in pregnancy
Authors: Gao Lin , Mathur Vrinda , Tam Sabrina Ka Man , Zhou Xuemeng , Cheung Ming Fung , Chan Lu Yan , Estrada-Gutiérrez Guadalupe , Leung Bo Wah , Moungmaithong Sakita , Wang Chi Chiu , Poon Liona C. , Leung Danny
Published: June 2022

During pregnancy, the maternal-fetal interface plays vital roles in fetal development. Its disruption is frequently found in pregnancy complications. Recent works show increased incidences of adverse pregnancy outcomes in COVID-19 patients; however, the mechanism remains unclear. Here, we analyzed the molecular impacts of SARS-CoV-2 infection on the maternal-fetal interface. Generating bulk and single-nucleus transcriptomic and epigenomic profiles from COVID-19 patients and control samples, we discovered aberrant immune activation and angiogenesis patterns in patients. Surprisingly, retrotransposons were dysregulated in specific cell types. Notably, reduced enhancer activities of LTR8B elements were functionally linked to the downregulation of Pregnancy-Specific Glycoprotein genes in syncytiotrophoblasts. Our findings revealed that SARS-CoV-2 infection induced significant changes to the epigenome and transcriptome at the maternal-fetal interface, which may be associated with pregnancy complications.

One-Sentence Summary

Pregnant COVID-19 patients show placental epigenetic and transcriptional changes, associated with adverse pregnancy outcomes.
FBXO11 deficiency in mice impairs lung development and aggravates cigarette smoke-induced airway fibrosis
Authors: Shenoy Anitha , Luo Huacheng , Lulu Sarah , Li Jennifer W. , Jin Yue , Yu Qin , Guo Shu , Shenoy Vinayak , Chen Hao , Bryant Andrew , Wu Lizi , Chang Jia , Mohammed Kamal , Lu Jianrong
Published: June 2022

Small airway fibrosis is a common pathology of chronic obstructive pulmonary disease (COPD) and contributes to airflow obstruction. However, the underlying fibrogenic mechanism is poorly understood. Epithelial-mesenchymal transition (EMT) has been proposed as a driver of fibrosis. EMT occurs in the airways of COPD patients and smokers, but it remains elusive whether EMT may contribute to airway fibrosis. We previously reported that FBXO11 is a critical suppressor of EMT and Fbxo11 deficiency in mice causes neonatal lethality and EMT in epidermis. Here, we found that Fbxo11-deficient mouse embryonic lungs showed impaired epithelial differentiation, excess fibroblast cells surrounding the airways, and thickened interstitial mesenchyme. We further generated conditional mutant mice to ablate Fbxo11 selectively in the club airway epithelial cells in adult mice, which induced partial EMT in the airways. To determine the effect of EMT on airway fibrosis, Fbxo11 conditional mutant mice were exposed to cigarette smoke. Airway-specific loss of Fbxo11 markedly enhanced smoking-induced airway fibrotic remodeling and collagen deposition. Taken together, our study suggests that EMT in the airway epithelium exacerbates cigarette smoke-induced airway fibrosis.
Validation of scRNA-seq by scRT-ddPCR using the example ofErbB2in MCF7 cells
Authors: Lange Tobias , Groß Tobias , Jeney Ábris , Scherzinger Julia , Sinkala Elly , Niemöller Christoph , Zimmermann Stefan , Koltay Peter , Stetten Felix von , Zengerle Roland , Jeney Csaba
Published: June 2022

Single-cell RNA sequencing (scRNA-seq) can unmask transcriptional heterogeneity facilitating the detection of rare subpopulations at unprecedented resolution. In response to challenges related to coverage and quantity of transcriptome analysis, the lack of unbiased and absolutely quantitative validation methods hampers further improvements. Digital PCR (dPCR) represents such a method as we could show that the inherent partitioning enhances molecular detections by increasing effective mRNA concentrations. We developed a scRT-ddPCR method and validated it using two breast cancer cell lines, MCF7 and BT-474, and bulk methods.ErbB2, a low-abundant transcript in MCF7 cells, suffers from dropouts in scRNA-seq and thus calculated fold changes are biased. Using our scRT-ddPCR, we could improve the detection ofErbB2and based on the absolute counts obtained we could validate the scRNA-seq fold change. We think this workflow is a valuable addition to the single-cell transcriptomic research toolbox and could even become a new standard in fold change validation because of its reliability, ease of use and increased sensitivity.
Discrimination of conspecific head orientations and learning set formation in Bengalese finches
Authors: Chen Wei , Kamijo Makiko , okanoya Kazuo
Published: June 2022

Animals detect others’ gaze direction, such as predators, prey, and courtship mates, to enable adaptive behavior. However, head movements play a more significant role in gaze shifts in birds than eye movement because of the flat eye shape. Additionally, most birds with laterally placed eyes usually turn the lateral face to the target. Therefore, we used Bengalese finches to examine whether songbirds can discriminate between conspecific frontal and lateral faces and divide head orientations in different angles into two categories. In experiments, birds were trained by operant conditioning to discriminate stimuli consisting of conspecific frontal and lateral head images. Eight out of nine birds finished discrimination training and test sessions. The results indicate that Bengalese finches can discriminate gaze direction by the head orientations. Furthermore, as the number of stimuli set increased, fewer trials were needed to achieve the criteria, which suggests that birds have developed a learning set during the training. However, we did not find a clear discrimination boundary for head orientation categorization.
Structure-based identification of novel histone deacetylase 4 (HDAC4) inhibitors
Authors: Agarwal Rupesh , Pattarawat Pawat , Duff Michael R. , Wang Hwa-Chain Robert , Baudry Jerome , Smith Jeremy C.
Published: June 2022

Histone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. Here, we use molecular modeling approaches to identify and target potential novel pockets specific to Class IIA HDAC-HDAC4 at the interface between HDAC4 and the NCOR protein. These pockets were then targeted using an ensemble docking approach combined with consensus scoring to identify compounds with a different mechanism of binding than the currently known HDAC modulators. Using this approach, 18 compounds predicted in silico to bind to HDAC4’s novel pockets were tested in vivo testing on two cancer cell lines. Of these, 5 compounds decreased cell viability to less than 60%. One inhibited the catalytic activity of HDAC4 but not HDAC3, which belongs to a different family of HDACs (Class I). The most potent compound has an IC50 comparable to the FDA-approved compound SAHA (Vorinostat). While there are currently no known inhibitors reported to bind highly selectively to HDAC4, the present result suggests potential mechanistic and chemical approaches for the development of selective HDAC4 modulators.
Spatiotemporal modeling reveals geometric dependence of AMPAR dynamics on dendritic spine morphology
Authors: Bell M. K. , Lee C. T. , Rangamani P.
Published: June 2022

The modification of neural circuits depends on the strengthening and weakening of synaptic connections. Synaptic strength is often correlated to the density of the ionotropic, glutamateric receptors, AMPAR, (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) at the postsynaptic density (PSD). While AMPAR density is known to change based on complex biological signaling cascades, the effect of geometric factors such as dendritic spine shape, size, and curvature remain poorly understood. In this work, we developed a deterministic, spatiotemporal model to study the dynamics of AMPAR during long term potentiation (LTP). This model includes a minimal set of biochemical events that represent the upstream signaling events, trafficking of AMPAR to and from the PSD, lateral diffusion in the plane of the spine membrane, and the presence of an extrasynaptic AMPAR pool. Using idealized and realistic spine geometries, we show that the dynamics and increase of bound AMPAR at the PSD depends on a combination of endo- and exocytosis, membrane diffusion, availability of free AMPAR, and intracellular signaling interactions. We also found non-monotonic relationships between spine volume and change in AMPAR at the PSD, suggesting that spines restrict changes in AMPAR to optimize resources and prevent runaway potentiation.

Significance Statement

Synaptic plasticity involves dynamic biochemical and physical remodeling of small protrusions called dendritic spines along the dendrites of neurons. Proper synaptic functionality within these spines requires changes in receptor number at the synapse, which has implications for down-stream neural functions, such as learning and memory formation. In addition to being signaling subcompartments, spines also have unique morphological features that can play a role in regulating receptor dynamics on the synaptic surface. We have developed a spatiotemporal model that couples biochemical signaling and receptor trafficking modalities in idealized and realistic spine geometries to investigate the role of biochemical and biophysical factors in synaptic plasticity. Using this model, we highlight the importance of spine size and shape in regulating bound AMPAR dynamics that govern synaptic plasticity, and predict how spine shape might act to reset synaptic plasticity as a built-in resource optimization and regulation tool.
Achieving single nucleotide sensitivity in direct hybridization genome imaging
Authors: Wang Yanbo , Cottle Wayne T. , Wang Haobo , Gavrilov Momcilo , Zou Roger S. , Bailey Scott , Ha Taekjip
Published: June 2022

Direct visualization of point mutations in situ can be informative for studying genetic diseases and nuclear biology. We describe a direct hybridization genome imaging method with single-nucleotide sensitivity, sgGOLDFISH, which leverages the high cleavage specificity of enhanced Cas9 combined with a single extended guide RNA to load a superhelicase and reveal probe binding sites through local denaturation. Using sgGOLDFISH, we identified base-editor-modified and unmodified progeroid fibroblasts from a heterogeneous population, validated the identification through progerin immunofluorescence, and demonstrated accurate sub-nuclear localization of point mutations.
Working memory and reaction time variability mediate the relationship between polygenic risk and ADHD traits in a general population sample
Authors: Moses Mia , Tiego Jeggan , Demontis Ditte , Walters G. Bragi , Stefansson Hreinn , Stefansson Kari , Børglum Anders D. , Arnatkeviciute Aurina , Bellgrove Mark A.
Published: June 2022

Endophenotypes are heritable and quantifiable traits indexing genetic liability for a disorder. Here, we examined three potential endophenotypes, working memory function, response inhibition and reaction time variability, for attention-deficit hyperactivity disorder (ADHD) measured as a dimensional latent trait in a large general population sample derived from the Adolescent Brain and Cognition Developmental study. The genetic risk for ADHD was estimated using polygenic risk scores (PRS) whereas ADHD traits were quantified as a dimensional continuum using Bartlett factor score estimates, derived from Attention Problems items from the Child Behaviour Checklist and Effortful Control items from the Early Adolescent Temperament Questionnaire-Revised. The three candidate cognitive endophenotypes were quantified using task-based performance measures. Higher ADHD PRSs were associated with higher ADHD traits, as well as poorer working memory performance and increased reaction time variability. Lower working memory performance, poorer response inhibition, and increased reaction time variability were associated with more pronounced ADHD traits. Working memory and reaction time variability partially statistically mediated the relationship between ADHD PRS and ADHD traits, explaining 14% and 16% of the association, respectively. The mediation effect was specific to the genetic risk for ADHD and did not generalise to genetic risk for four other major psychiatric disorders. Together, these findings provide robust evidence from a large general population sample that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.
Whole-genome and mitogenome based in silico analysis of select Plasmodium and identification of a novel drug molecule against the malaria parasite
Authors: Sarkar Indrani , Rathore Saurabh Singh , Singh Gyan Dev , Singh Ram Pratap
Published: June 2022

Malaria, caused by a parasite known as Plasmodium, is one of the leading causes of death, worldwide, especially in the third world countries of Africa and Asia. Plasmodium does not only infect humans but also reptiles, birds and other mammals. However, they are the secondary hosts for this parasite. The primary host of Plasmodium is female Anopheles mosquitoes. Long term researchers have formulated drugs against this deadly pathogen but the current emergence of multi-drug resistance strains of Plasmodium has created a recurring concern. Identification of new drug molecules and understanding their mechanism of action is an urgent need to combat this battle. However, for that, we need to first understand the genomic strategies taken up by Plasmodium to survive the host immune system. With the advancement of high-throughput sequencing techniques, the whole genomes of Plasmodium have been sequenced which can help us in advancing our strategies against Plasmodium. In this study, we performed a thorough analysis of the genomic features of Plasmodium along with its evolution. This revealed a codon biased co-evolution among the parasite and respective hosts. Reverse ecology and protein-protein interactions were studied among Plasmodium and Homo sapiens revealing a complex biological interaction among them governing the host-parasite interaction as well as drug resistance capability among Plasmodium. The molecular docking and simulation studies have found a new drug-target site within mitogenome coding proteins. Those sites were targeted with Cymbopogonol, a phyto-compound derived from Cymbopogon (Lemongrass). Along with Cymbopogonol few other Cymbopogon derived compounds were also found to be effective as new anti-malarial drug molecules. This is the first report on the effect of Cymbopogon derived compounds on Plasmodium and is open for a clinical trial.
Role of the drug efflux pump in the intrinsic cefiderocol resistance of Pseudomonas aeruginosa
Authors: Ikawa Sota , Yamasaki Seiji , Morita Yuji , Nishino Kunihiko
Published: June 2022

Cefiderocol is a novel siderophore cephalosporin antibiotic exhibiting activities against carbapenem-resistant Gram-negative bacteria including Pseudomonas aeruginosa and Enterobacteriaceae. Drug efflux pumps are reportedly involved in both intrinsic and acquired drug resistance, although their role in bacterial cefiderocol susceptibility remains poorly understood. In this study, we investigated how drug efflux pumps contribute to bacterial cefiderocol susceptibility using the efflux pump(s)-deficient and overexpressing strains of P. aeruginosa, Escherichia coli, and Salmonella enterica. We observed that the mexAB-oprM-deficient P. aeruginosa mutant displayed increased cefiderocol susceptibility compared to the wild-type strain. The overexpression of mexAB-oprM or mexXY-oprM in the mexAB-oprM-deficient mutant increased the MIC value of cefiderocol. Furthermore, the pump inhibitor phenylalanine-arginine β-naphthylamide increased cefiderocol susceptibility in wild-type P. aeruginosa whereas it did not affect the susceptibility of the mexAB-oprM-deficient mutant. These data indicate that the MexAB-OprM drug efflux system contributes to the intrinsic cefiderocol resistance of P. aeruginosa. In addition, MexXY-OprM partially complemented the function of MexAB-OprM in the cefiderocol susceptibility, when expressed.