bluuebunny/crossref_metadata_2025 huggingface dataset:
Management and Follow-up of Massive Fetomaternal Hemorrhage Requiring High-Dose Rh Immune Globulin: A Case Report
Authors: Fortes Precious Ann , Gnass Esteban D , Baez Janet , Bayati Banafsheh , Mei Zhen , McGonigle Andrea M , Ziman Alyssa , Ward Dawn C
Published: March 2023

Objectives

Massive fetomaternal hemorrhage (FMH) is rare and reported to be the cause in approximately 3% of all fetal deaths. Maternal management of massive FMH includes prevention of Rh(D) alloimmunization in Rh(D)-negative mothers by administration of Rh(D) immune globulin (RhIG).

Methods

We describe a case of a 30-year-old O-negative, primigravida woman who presented at 38 weeks of gestation with decreased fetal movements. She underwent an emergency cesarean section and delivered an O-positive baby girl who died shortly after birth.

Results

The patient’s FMH screen was positive, with a Kleihauer-Betke test demonstrating 10.7% fetal blood in maternal circulation. The calculated dose of 6,300 µg RhIG was given prior to discharge over 2 days using an intravenous (IV) preparation. Antibody screening a week after discharge showed anti-D and anti-C. The anti-C was attributed to acquired passive immunity from the large dose of RhIG. Anti-C reactivity waned and was negative at 6 months, but the anti-D pattern persisted at 9 months postdelivery. Negative antibody screens were noted at 12 and 14 months.

Conclusions

This case highlights the immunohematology challenges of IV RhIG as well as the success in preventing alloimmunization with IV RhIG given the patient’s complete resolution of anti-C and no anti-D formation, with a subsequent healthy pregnancy.
Wind-farm and hydrogen-storage co-location system optimization for dynamic frequency response in the UK
Authors: Fan Fulin , Skellern Shanay , Campos-Gaona David , Nwobu John
Published: March 2023

The continuous development of hydrogen-electrolyser and fuel-cell technologies not only reduces their investment and operating costs but also improves their technical performance to meet fast-acting requirements of electrical grid balancing services such as frequency-response services. In order to project the feasibility of co-locating a hydrogen-storage system with a wind farm for the dynamic regulation frequency-response provision in Great Britain, this paper develops a modelling framework to coordinate the wind export and frequency responses to the main grid and manage the interaction of the electrolyser, compressor, storage tank and fuel cell within the hydrogen-storage system by respecting the market mechanisms and the balance and conversion of power and hydrogen flows. Then the revenue of frequency-response service provision and a variety of costs induced by the hydrogen-storage system are translated into the net profit of the co-location system, which is maximized by optimizing the capacities of hydrogen-storage-system components, hydrogen-storage levels that guide the hydrogen restoration via operational baselines and the power interchange between a wind-farm and hydrogen-storage system, as well as the capacities tendered for low- and high-frequency dynamic regulation services. The developed modelling framework is tested based on a particular 432-MW offshore wind farm in Great Britain combined with the techno-economics of electrolysers and fuel cells projected for 2030 and 2050 scenarios. The optimized system configuration and operation are compared between different operating scenarios and discussed alongside the prospect of applying hydrogen-storage systems for frequency-response provision.
Ozone pollution and hospital admissions for cardiovascular events
Authors: Jiang Yunxing , Huang Jing , Li Guoxing , Wang Wanzhou , Wang Kai , Wang Jinxi , Wei Chen , Li Yinxiang , Deng Furong , Baccarelli Andrea A , Guo Xinbiao , Wu Shaowei
Published: March 2023

Aims

The available literature on morbidity risk of cardiovascular diseases associated with ambient ozone pollution is still limited. This study examined the potential acute effects of exposure to ambient ozone pollution on hospital admissions of cardiovascular events in China.

Methods and results

A two-stage multi-city time-series study approach was used to explore the associations of exposure to ambient ozone with daily hospital admissions (n = 6 444 441) for cardiovascular events in 70 Chinese cities of prefecture-level or above during 2015–17. A 10 μg/m3 increment in 2-day average daily 8 h maximum ozone concentrations was associated with admission risk increases of 0.46% [95% confidence interval (CI): 0.28%, 0.64%] in coronary heart disease, 0.45% (95% CI: 0.13%, 0.77%) in angina pectoris, 0.75% (95% CI: 0.38%, 1.13%) in acute myocardial infarction (AMI), 0.70% (95% CI: 0.41%, 1.00%) in acute coronary syndrome, 0.50% (95% CI: 0.24%, 0.77%) in heart failure, 0.40% (95% CI: 0.23%, 0.58%) in stroke and 0.41% (95% CI: 0.22%, 0.60%) in ischemic stroke, respectively. The excess admission risks for these cardiovascular events associated with high ozone pollution days (with 2-day average 8-h maximum concentrations ≥100 µg/m3 vs. < 70 µg/m3) ranged from 3.38% (95% CI: 1.73%, 5.06%) for stroke to 6.52% (95% CI: 2.92%, 10.24%) for AMI.

Conclusion

Ambient ozone was associated with increased hospital admission risk for cardiovascular events. Greater admission risks for cardiovascular events were observed under high ozone pollution days. These results provide evidence for the harmful cardiovascular effects of ambient ozone and call for special attention on the control of high ozone pollution.
Efficacy of ceftazidime/avibactam in various combinations for the treatment of experimental osteomyelitis in rabbits caused by OXA-48-/ESBL-producing Escherichia coli
Authors: Davido Benjamin , Crémieux Anne-Claude , Vaugier Isabelle , De Truchis Pierre , Hamami Kamel , Laurent Frédéric , Saleh-Mghir Azzam
Published: March 2023

Background

While the treatment of ESBL-producing Enterobacterales osteomyelitis relies on carbapenems, the optimal regimen for OXA48 types remains unclear. We evaluated the efficacy of ceftazidime/avibactam in different combinations in an experimental model of OXA-48-/ESBL-producing Escherichia coli osteomyelitis.

Methods

E. coli pACYC184 is a clinical strain harbouring blaOXA-48 and blaCTX-M-15 inserts, with ‘increased exposure susceptibility’ to imipenem (MIC, 2 mg/L), gentamicin (MIC, 0.5 mg/L), colistin (MIC, 0.25 mg/L), ceftazidime/avibactam (MIC, 0.094 mg/L) and fosfomycin (MIC, 1 mg/L), and resistance to ceftazidime (MIC, 16 mg/L). Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu of OXA-48/ESBL E. coli. Treatment started 14 days later for 7 days in six groups: (1) control, (2) colistin 150.000 IU/kg subcutaneously (SC) q8h, (3) ceftazidime/avibactam 100/25 mg/kg SC q8h, (4) ceftazidime/avibactam + colistin, (5) ceftazidime/avibactam + fosfomycin 150 mg/kg SC q12h, (6) ceftazidime/avibactam + gentamicin 15 mg/kg intramuscularly (IM) q24h. Treatment was evaluated at Day 24 according to bone cultures.

Results

In vitro, time–kill curves of ceftazidime/avibactam in combination showed a synergistic effect. In vivo, compared with controls, rabbits treated with colistin alone had similar bone bacterial density (P = 0.50), whereas ceftazidime/avibactam alone or in combinations significantly decreased bone bacterial densities (P = 0.004 and P < 0.0002, respectively). Bone sterilization was achieved using ceftazidime/avibactam in combination with colistin (91%) or fosfomycin (100%) or gentamicin (100%) (P < 0.0001), whereas single therapies were not different from controls. No ceftazidime/avibactam-resistant strains emerged in rabbits treated, regardless of the combination.

Conclusions

In our model of E. coli OXA-48/ESBL osteomyelitis, ceftazidime/avibactam in combination was more effective than any single therapy, whatever the companion drug used (gentamicin or colistin or fosfomycin).
Stellar prospects for FRB gravitational lensing
Authors: Connor Liam , Ravi Vikram
Published: March 2023

Gravitational lensing of fast radio bursts (FRBs) offers an exciting avenue for several cosmological applications. However, it is not yet clear how many such events future surveys will detect nor how to optimally find them. We use the known properties of FRBs to forecast detection rates of gravitational lensing on delay time-scales from microseconds to years, corresponding to lens masses spanning 15 orders of magnitude. We highlight the role of the FRB redshift distribution on our ability to observe gravitational lensing. We consider cosmological lensing of FRBs by stars in foreground galaxies and show that strong stellar lensing will dominate on microsecond time-scales. Upcoming surveys such as DSA-2000 and CHORD will constrain the fraction of dark matter in compact objects (e.g. primordial black holes) and may detect millilensing events from intermediate mass black holes (IMBHs) or small dark matter halos. Coherent all-sky monitors will be able to detect longer-duration lensing events from massive galaxies, in addition to short time-scale lensing. Finally, we propose a new application of FRB gravitational lensing that will measure directly the circumgalactic medium of intervening galaxies.
Priorities in gravitational waveforms for future space-borne detectors: vacuum accuracy or environment?
Authors: Zwick Lorenz , Capelo Pedro R , Mayer Lucio
Published: March 2023

In preparation for future space-borne gravitational-wave (GW) detectors, should the modelling effort focus on high-precision vacuum templates or on the astrophysical environment of the sources? We perform a systematic comparison of the phase contributions caused by (1) known environmental effects in both gaseous and stellar matter backgrounds, or (2) high-order post-Newtonian (PN) terms in the evolution of mHz GW sources during the inspiral stage of massive binaries. We use the accuracy of currently available analytical waveform models as a benchmark value, finding the following trends: the largest unmodelled phase contributions are likely environmental rather than PN for binaries lighter than ∼107/(1 + z)2 M⊙, where z is the redshift. Binaries heavier than ∼108/(1 + z) M⊙ do not require more accurate inspiral waveforms due to low signal-to-noise ratios (SNRs). For high-SNR sources, environmental phase contributions are relevant at low redshift, while high-order vacuum templates are required at z ≳ 4. Led by these findings, we argue that including environmental effects in waveform models should be prioritized in order to maximize the science yield of future mHz detectors.
Intraocular Pressure Spikes Following iStent Inject and the Relationship to Aqueous Outflow in Open Angle Glaucoma
Authors: Lusthaus Jed A. , McCluskey Peter J. , Martin Keith R.
Published: March 2023

Précis:

Adding trabecular bypass surgery (TBS) to phacoemulsification creates unpredictable short-term intraocular pressure (IOP) control that may be undesirable for patients with advanced glaucoma. Aqueous outflow (AO) responses after TBS are complex and probably multifactorial.

Purpose:

To assess IOP spikes in patients with open angle glaucoma up to 1 month after iStent inject and their relationship to AO patterns measured by hemoglobin video imaging (HVI).

Participants and Methods:

We studied IOP for 4 weeks after TBS with iStent inject in 105 consecutive eyes with open angle glaucoma (6 TBS only and 99 combined with phacoemulsification). The change in IOP after surgery at each time point was compared with baseline measurements and the prior postoperative visit. IOP-lowering medications were stopped on the day of surgery in all patients. A smaller pilot study of 20 eyes (TBS only = 6 and combined = 14) underwent concurrent HVI to observe and quantify perioperative AO. Aqueous column cross-sectional area (AqCA) of one nasal and one temporal aqueous vein was calculated at each time point, and qualitative observations were documented. An additional 5 eyes were studied after phacoemulsification only.

Results:

Mean IOP for the entire cohort (preoperative 17.3 ± 5.6 mm Hg) was lowest the day after TBS (13.1 ± 5.0 mm Hg) and peaked at 1 week (17.2 ± 8.0 mm Hg), before stabilizing by 4 weeks (15.2 ± 5.2 mm Hg;P< 0.00001). The same IOP pattern was seen when separating the group into a larger cohort without HVI (respectively 15.9 ± 3.2 mm Hg, 12.8 ± 4.9 mm Hg, 16.4 ± 7.4 mm Hg, and 14.1 ± 4.1 mm Hg; N = 85,P< 0.00001) and the smaller HVI pilot study (respectively 21.4 ± 9.9 mm Hg, 14.2 ± 4.9 mm Hg, 20.2 ± 9.7 mm Hg, and 18.9 ± 7.6 mm Hg; N = 20,P< 0.001). More than 30% IOP elevation above baseline occurred in 13.3% of the entire cohort at 1 week after surgery. This increased to 46.7% when IOP was compared with 1 day after surgery. Inconsistent AqCA values and patterns of aqueous flow were demonstrated after TBS. AqCA after phacoemulsification alone was maintained or increased within 1 week in all 5 eyes.

Conclusion:

After iStent inject surgery in patients with open angle glaucoma, intraocular spikes were most commonly seen at 1 week. AO patterns were variable and additional studies are needed to understand the pathophysiology underlying IOP responses after this procedure.
The Diagnostic Value of Optical Coherence Tomography for Detecting Glaucoma in High Myopia
Authors: Zhang Yan , Wang Wenxing , Chen Jiawei , Huang Chukai
Published: March 2023

Précis:

Glaucomatous changes in high myopia are difficult to detect due to the similarity of functional and structural alteration in both disease. Optical coherence tomography (OCT) shows relatively high diagnostic accuracy in glaucoma with high myopia (HM).

Purpose:

This study aims to evaluate the thickness differences of OCT parameters between HM and HM with glaucoma (HMG), and to verify which parameters have a higher diagnostic value on this issue according to area under the receiver operating characteristic (AUROC) curve.

Materials and Methods:

A comprehensive literature search was performed on PubMed, Embase, Medline, Cochrane, CNKI, and Wanfang. Eligible articles were identified by reviewing the retrieved results. The weighted mean difference and 95% CI for continuous outcomes and pooled AUROC were calculated.

Results:

Fifteen studies with a total of 1304 eyes, including 569 high myopia and 735 HMG were comprised in this meta-analysis. Our results showed that, in comparison with HM, HMG had a significantly thinner thickness for retinal nerve fiber layer except for nasal sector, macular ganglion cell inner plexiform layer thickness except for superior sector and macular ganglion cell complex thickness. In contrast, the inferior sector and average thickness of retinal nerve fiber layer, macular ganglion cell complex and ganglion cell inner plexiform layer had relatively high AUROC.

Conclusion:

Based on the current study of retinal OCT measurement differences between HM and HMG, ophthalmologists should pay more attention to the thinning in inferior sector and the average thickness of macular and optic disc during the management of HM.
Effects of COVID-19 on Retinal and Choroidal Thickness by Optical Coherence Tomography
Authors: Sumer Fatma , Subasi Sevgi
Published: March 2023

Précis:

The aim of our study was to evaluate the subclinical changes in the macula, retinal nerve fiber layer (RNFL), and choroidal thickness after coronavirus disease 2019 (COVID-19) infection using spectral domain optical coherence tomography.

Methods:

Our study was prospectively designed and involved 170 eyes of 85 patients. Patients with polymerase chain reaction (PCR)-positive COVID-19 infection were examined in the ophthalmology clinic before and after infection were included. All included patients had mild COVID-19 with no hospitalization and no need for intubation. Control ophthalmic examination was repeated at least 6 months after PCR positivity. Macular and choroidal thickness and RNFL parameters were compared before and at least 6 months after PCR-positive COVID-19 infection using optical coherence tomography.

Results:

When the mean macular thickness data were evaluated, a significant decrease was detected in the inner (mean difference, −3.37 µm; 95% CI: −6.09 to −0.65, P = 0.021) and outer (mean difference, −6.56 µm; 95% CI: −9.26 to −3.86, P < 0.001) temporal segments and the inner (mean difference, −3.39 µm; 95% CI: −5.46 to −1.32, P = 0.002) and outer (mean difference, −2.01 µm; 95% CI, −3.70 to −0.31, P = 0.018) superior segments in the post-COVID-19 measurements compared with pre–COVID-19 measurements. Similarly, on RNFL evaluation, some thinning was evident in the temporal superior (mean = 1.14 µm, P = 0.004) and temporal inferior (mean = 1.30 µm, P = 0.032) regions. All choroidal regions, including central, nasal 500 µm and 1500 µm and temporal 500 µm and 1500 µm, exhibited significant thinning (P < 0.001).

Conclusion:

At least 6 months after mild COVID-19 infection, significant thinning was seen in the temporal and superior quadrants of the macula, the temporal superior and temporal inferior regions of the RNFL, and all measured areas of choroidal regions.
Assessment of bone lesions with 18F-FDG PET/MRI in patients with nasopharyngeal carcinoma
Authors: Fang Yuting , Chen Shoucong , Xu Yuanfan , Qiang Mengyun , Tao Changjuan , Huang Shuang , Wang Lei , Chen Xiaozhong , Cao Caineng
Published: March 2023

Purpose

The purpose of this study is to evaluate the role of 18 fluorodeoxyglucose (18F) PET/MRI (18F-FDG PET/MRI) for detecting bone metastasis in nasopharyngeal carcinoma (NPC).

Patients and methods

Between May 2017 and May 2021, 58 histologically proven NPC patients who underwent both 18F-FDG PET/MRI and 99mTc-MDP planar bone scintigraphy (PBS) for tumor staging were included. With the exception of the head, the skeletal system was classified into four groups: the spine, the pelvis, the thorax and the appendix.

Results

Nine (15.5 %) of 58 patients were confirmed to have bone metastasis. There was no statistical difference between PET/MRI and PBS in patient-based analysis (P = 0.125). One patient with a super scan was confirmed to have extensive and diffuse bone metastases and excluded for lesion-based analysis. Of the 57 patients, all 48 true metastatic lesions were positive in PET/MRI whereas only 24 true metastatic lesions were positive in PBS (spine: 8, thorax: 0, pelvis: 11 and appendix: 5). PET/MRI was observed to be more sensitive than PBS in lesion-based analysis (sensitivity 100.0% versus 50.0 %; P < 0.001).

Conclusions

Compared with PBS for tumor staging of NPC, PET/MRI was observed to be more sensitive in the lesion-based analysis of bone metastasis.
A Cross-sectional Survey to Review Food Safety Practices Within Pediatric Oncology and Stem Cell Transplant Centers in the United Kingdom
Authors: Morris Alisa , O’ Connor Graeme , Renshaw Gemma
Published: March 2023

Food Safety and Pediatric Cancer:

Neutropenia is a common complication of chemotherapy, which poses a high risk of infection and mortality. Neutropenic diet has historically been recommended for those undergoing chemotherapy. The rationale is to reduce the risk of foodborne infection by avoiding foods considered to be of high microbial risk. However, evidence for this diet is limited, and there is a lack of national consensus guidelines.

Aim:

Ascertain food safety advice across specialist centers providing high-dose chemotherapy for malignancy or stem cell transplants in the United Kingdom.

Materials and Methods:

Dietitians at 22 centers were contacted to complete a questionnaire regarding food safety guidance implemented at their center for pediatric patients undergoing high-dose chemotherapy or stem cell transplants. Questions related to restricted foods, specific guidelines implemented, ward food provision, and timings of food provision.

Results:

Sixteen centers responded (73%). Many aspects of neutropenic diet were consistent across centers; avoidance of unpasteurized dairy products (94%), raw/undercooked meat (94%), and unpasteurized pâté (88%). There was a lack of consistency regarding water sources used on wards and unpeeled fruits and vegetables.

Conclusions:

Food safety guidance for neutropenic patients differs across centers, with some practices seeming outdated and nonevidence based. A national review of food safety guidance should be considered to provide a standardized approach.
Circulation of enterotoxigenic Escherichia coli (ETEC) isolates expressing CS23 from the environment to clinical settings
Authors: Toledo Carla Calderon , von Mentzer Astrid , Agramont Jorge , Thorell Kaisa , Zhou Yingshun , Szabó Miklós , Colque Patricia , Kuhn Inger , Gutiérrez-Cortez Sergio , Joffré Enrique
Published: March 2023

EnterotoxigenicEscherichia coli(ETEC) is one of the leading causes of infant diarrhea in low- and middle-income countries (LMICs). Diarrheal pathogens are transmitted through environmental reservoirs; however, the bacterial clones that spread across the human-environment interphases remind unexplored. We aimed to determine the relationship and clonal dissemination of ETEC between children with diarrhea (> 5 years of age) and polluted water samples from local river in La Paz, Bolivia. Our study used whole genome sequencing and phenotypic fingerprinting system (PhenePlates) to analyze ETEC strains. We showed that ST218 and ST410 LT+STh CS23 ETEC were found with high frequency in both samples. The CS23 ETEC isolates were found within several STs,E. coliphylogroups A, B1, C, and D, and across ETEC lineages. Our comparative genomic analysis and PhenePlate screening of globally distributed clinical ETEC strains suggested that virulent CS23 plasmids acquisition occurs independently of the bacterial chromosomal background. Environmental strains were more often multidrug-resistant (MDR) than clinical isolates and harbored the class 1 integron-integrase geneintI1next to the MDR cassettes. Retrospective analysis of antibiotic resistance in ETEC revealed a high frequency of MDR in clinical isolates. The LT+STh CS23 ETEC isolates showed an increased biofilm ability at environmental temperature, equal cytotoxicity, and significantly lower adherence to human epithelial cells compared to ETEC expressing other CFs. Together, our findings suggest that CS23 is more prevalent in ETEC than previously estimated, and the Choqueyapu River is a reservoir for LT+STh CS23 ETEC containing strains capable of causing diarrheal cases in children.

Importance

The importance of clean water cannot be overstated. It is a vital resource for maintaining health and well-being. Unfortunately, water sources contaminated with fecal discharges from animal and human origin due to a lack of wastewater management poses a significant risk to communities, as they can become a means of transmission pathogenic bacteria like enterotoxigenicE. coli(ETEC). ETEC is frequently found in polluted water in countries with a high prevalence of diarrheal diseases, such as Bolivia. This study provides novel insights into the circulation of ETEC between diarrheal cases and polluted water sources in areas with high rates of diarrheal disease. The findings highlight the Choqueyapu River as a potential reservoir for emerging pathogens carrying antibiotic-resistance genes, making it a crucial area for monitoring and intervention. Furthermore, the results demonstrate the feasibility of a low-cost, high-throughput method for tracking bacterial pathogens in low- and middle-income countries, making it a valuable tool for One Health monitoring efforts.
Characterization of Long COVID among U.S. Medicare Beneficiaries using Claims Data
Authors: Lu Yun , Lindaas Arnstein , Izurieta Hector S , Cozen Myrna , Menis Mikhail , Shi Xiangyu , Steele Whitney , Wernecke Michael , Chillarige Yoganand , Kelman Jeffrey A , Forshee Richard A
Published: March 2023

This retrospective study utilized healthcare claims data to investigate the incidence, patient demographics, and concurrent diagnoses associated with long COVID in the U.S. Medicare population. Nearly 194,000 (0.6%) beneficiaries had post-COVID condition diagnoses, with higher rates among nursing home residents. Of those medically attended for COVID-19, 3-5% were diagnosed with post-COVID conditions. We observed minimal demographic differences between those with and without long COVID. When comparing diagnoses concurrent with long COVID and COVID-19, certain codes (G72 and J84) for myopathies and interstitial pulmonary diseases were disproportionately present with long COVID.
Variants inACTC1underlie distal arthrogryposis accompanied by congenital heart defects
Authors: Chong Jessica X. , Childers Matthew Carter , Marvin Colby T. , Marcello Anthony J. , Gonorazky Hernan , Hazrati Lili-Naz , Dowling James J. , Amrani Fatema Al , Alanay Yasemin , Nieto Yolanda , Marín Gabriel Miguel Á , Aylsworth Arthur S. , Buckingham Kati J. , Shively Kathryn M. , Sommers Olivia , Anderson Kailyn ,   University of Washington Center for Mendelian Genomics,   University of Washington Center for Rare Disease Research, Regnier Michael , Bamshad Michael J.
Published: March 2023

Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such asMYH7,TPM1, andTNNI3that encode parts of the cardiac sarcomere cause muscle diseases that affect the heart, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In contrast, pathogenic variants in homologous genesMYH2,TPM2, andTNNI2, that encode parts of the skeletal muscle sarcomere, cause muscle diseases affecting skeletal muscle, such as the distal arthrogryposis (DA) syndromes and skeletal myopathies. To date, there have been few reports of genes (e.g.,MYH7) encoding sarcomeric proteins in which the same pathogenic variant affects both skeletal and cardiac muscle. Moreover, none of the known genes underlying DA have been found to contain mutations that also cause cardiac abnormalities. We report five families with DA due to heterozygous missense variants in the geneactin, alpha, cardiac muscle 1(ACTC1).ACTC1encodes a highly conserved actin that binds to myosin in both cardiac and skeletal muscle.

Mutations inACTC1have previously been found to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction. Our discovery delineates a new DA condition due to mutations inACTC1and suggests that some functions ofactin, alpha, cardiac muscle 1are shared in cardiac and skeletal muscle.
Pharmacogenetics of SGLT2 Inhibitors: Validation of a sex-agnostic pharmacodynamic biomarker
Authors: Taylor Simeon I. , Cherng Hua-Ren , Yazdi Zhinous Shahidzadeh , Montasser May E. , Whitlatch Hilary B. , Mitchell Braxton D. , Shuldiner Alan R. , Streeten Elizabeth A. , Beitelshees Amber L.
Published: March 2023

Aim

SGLT2 inhibitors provide multiple benefits to patients with type 2 diabetes – including improved glycemic control and decreased risks of cardiorenal disease. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses.

Methods

Canagliflozin (300 mg) was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses – including drug-induced increases in urinary excretion of glucose, sodium, and uric acid.

Results

This pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (−4.1 mg/dL; p=6x10), serum creatinine (+0.05 mg/dL; p=8×10-4), and serum uric acid (−0.90 mg/dL; p=5×10-10). The effects of sex on glucosuria depended upon how data were normalized. Whereas males’ responses were ∼60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated GFR, or age in these healthy non-diabetic individuals with estimated GFR>60 mL/min/1.73m2.

Conclusions

Normalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study (NCT02891954) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as age and renal function.

Registration

NCT02462421 (clinicaltrials.gov)

Funding

Research grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488.
A geopositioned, evidence-graded, pan-species compendium of Mayaro Virus occurrence
Authors: Celone Michael , Potter Alex , Han Barbara A. , Beeman Sean P. , Okech Bernard , Forshey Brett , Dunford James , Rutherford George , Mita-Mendoza Neida Karen , Estallo Elizabet Lilia , Khouri Ricardo , de Siqueira Isadora Cristina , Petersen Kyle , Maves Ryan C. , Anyamba Assaf , Pollett Simon
Published: March 2023

Mayaro Virus (MAYV) is an emerging health threat in the Americas that can cause febrile illness as well as debilitating arthralgia or arthritis. To better understand the geographic distribution of MAYV risk, we developed a georeferenced database of MAYV occurrence based on peer-reviewed literature and unpublished reports. Here we present this compendium, which includes both point and polygon locations linked to occurrence data documented from its discovery in 1954 until 2022. We describe all methods used to develop the database including data collection, georeferencing, management and quality-control. We also describe a customized grading system used to assess the quality of each study included in our review. The result is a comprehensive, evidence-graded database of confirmed MAYV occurrence in humans, non-human animals, and arthropods to-date, containing 266 geo-positioned occurrences in total. This database - which can be updated over time - may be useful for local spill-over risk assessment, epidemiological modelling to understand key transmission dynamics and drivers of MAYV spread, as well as identification of major surveillance gaps.
Single Nucleus Transcriptomics Reveals Pervasive Glial Activation in Opioid Overdose Cases
Authors: Wei Julong , Lambert Tova Y. , Valada Aditi , Patel Nikhil , Walker Kellie , Lenders Jayna , Schmidt Carl J. , Iskhakova Marina , Alazizi Adnan , Mair-Meijers Henriette , Mash Deborah C. , Luca Francesca , Pique-Regi Roger , Bannon Michael J , Akbarian Schahram
Published: March 2023

Dynamic interactions of neurons and glia in the ventral midbrain (VM) mediate reward and addiction behavior. We studied gene expression in 212,713 VM single nuclei from 95 human opioid overdose cases and drug-free controls. Chronic exposure to opioids left numerical proportions of VM glial and neuronal subtypes unaltered, while broadly affecting glial transcriptomes, involving 9.5 - 6.2% of expressed genes within microglia, oligodendrocytes, and astrocytes, with prominent activation of the immune response including interferon, NFkB signaling, and cell motility pathways, sharply contrasting with down-regulated expression of synaptic signaling and plasticity genes in VM non-dopaminergic neurons. VM transcriptomic reprogramming in the context of opioid exposure and overdose included 325 genes with genetic variation linked to substance use traits in the broader population, thereby pointing to heritable risk architectures in the genomic organization of the brain’s reward circuitry.
Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer’s disease
Authors: Green Gilad Sahar , Fujita Masashi , Yang Hyun-Sik , Taga Mariko , McCabe Cristin , Cain Anael , White Charles C. , Schmidtner Anna K. , Zeng Lu , Wang Yangling , Regev Aviv , Menon Vilas , Bennett David A. , Habib Naomi , De Jager Philip L.
Published: March 2023

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brain’s cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We identified two distinct lipid-associated microglial subpopulations, one contributed to amyloid-β proteinopathy while the other mediated the effect of amyloid-β in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities. Older individuals are engaged in one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging. Thus, we provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.
The ability to sense the environment is heterogeneously distributed in cell populations
Authors: Goetz Andrew , Akl Hoda , Dixit Purushottam
Published: March 2023

Channel capacity of signaling networks quantifies their fidelity in sensing extracellular inputs. Low estimates of channel capacities for several mammalian signaling networks suggest that cells can barely detect the presence/absence of environmental signals. However, given the extensive heterogeneity and temporal stability of cell state variables, we hypothesize that the sensing ability itself may depend on the state of the cells. In this work, we present an information theoretic framework to quantify the distribution of sensing abilities from single cell data. Using data on two mammalian pathways, we show that sensing abilities are widely distributed in the population and most cells achieve better resolution of inputs compared to an “average cell”. We verify these predictions using live cell imaging data on the IGFR/FoxO pathway. Importantly, we identify cell state variables that correlate with cells’ sensing abilities. This information theoretic framework will significantly improve our understanding of how cells sense in their environment.
β-carotene accelerates the resolution of atherosclerosis in mice
Authors: Pinos Ivan , Coronel Johana , Albakri Asma’a , Blanco Amparo , McQueen Patrick , Molina Donald , Sim JaeYoung , Fisher Edward A , Amengual Jaume
Published: March 2023

β-carotene oxygenase 1 (BCO1) catalyzes the cleavage of β-carotene to form vitamin A. Besides its role in vision, vitamin A regulates the expression of genes involved in lipid metabolism and immune cell differentiation. BCO1 activity is associated with the reduction of plasma cholesterol in humans and mice, while dietary β-carotene reduces hepatic lipid secretion and delays atherosclerosis progression in various experimental models. Here we show that β-carotene also accelerates atherosclerosis resolution in two independent murine models, independently of changes in body weight gain or plasma lipid profile. Experiments inBco1-/-mice implicate vitamin A production in the effects of β-carotene on atherosclerosis resolution. To explore the direct implication of dietary β-carotene on regulatory T cells (Tregs) differentiation, we utilized anti-CD25 monoclonal antibody infusions. Our data show that β-carotene favors Treg expansion in the plaque, and that the partial inhibition of Tregs mitigates the effect of β-carotene on atherosclerosis resolution. Our data highlight the potential of β-carotene and BCO1 activity in the resolution of atherosclerotic cardiovascular disease.
Advanced variant classification framework reduces the false positive rate of predicted loss of function (pLoF) variants in population sequencing data
Authors: Singer-Berk Moriel , Gudmundsson Sanna , Baxter Samantha , Seaby Eleanor G. , England Eleina , Wood Jordan C. , Son Rachel G. , Watts Nicholas A. , Karczewski Konrad J. , Harrison Steven M. , MacArthur Daniel G. , Rehm Heidi L. , O’Donnell-Luria Anne
Published: March 2023

Predicted loss of function (pLoF) variants are highly deleterious and play an important role in disease biology, but many of these variants may not actually result in loss-of-function. Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines’s PVS1 criterion. Applying this framework to all high-confidence pLoF variants in 22 autosomal recessive disease-genes from the Genome Aggregation Database (gnomAD, v2.1.1) revealed predicted LoF evasion or potential artifacts in 27.3% (304/1,113) of variants. The major reasons were location in the last exon, in a homopolymer repeat, in low per-base expression (pext) score regions, or the presence of cryptic splice rescues. Variants predicted to be potential artifacts or to evade LoF were enriched for ClinVar benign variants. PVS1 was downgraded in 99.4% (162/163) of LoF evading variants assessed, with 17.2% (28/163) downgraded as a result of our framework, adding to previous guidelines. Variant pathogenicity was affected (mostly from likely pathogenic to VUS) in 20 (71.4%) of these 28 variants. This framework guides assessment of pLoF variants beyond standard annotation pipelines, and substantially reduces false positive rates, which is key to ensure accurate LoF variant prediction in both a research and clinical setting.
Prospective Bidirectional Relations Between Depression and Metabolic Health: 30 Year Follow-up from the NHLBI CARDIA Study
Authors: Moorehead Nicholas R. , Goodie Jeffrey L. , Krantz David S.
Published: March 2023

Objective

This study investigated prospective bidirectional relationships between depression and metabolic syndrome (MetS), and the moderating effects of race, sex, and health behaviors in a diverse cohort followed for 30 years.

Methods

Data were analyzed from the NHLBI CARDIA study, a 30 year-prospective study of young adults (N= 5113;Mage = 24.76 (SD= 3.63) at baseline; 45% male) who were tested every 5 years between 1985-2015. Measures included biological assessments of MetS components, and self-reported depressive symptoms based on the Center for Epidemiologic Studies Depression (CESD) scale. Data analyses included bi-directional general estimating equations analyses of time-lagged associations between depressive symptoms and MetS.

Results

There was a consistent, bi-directional relationship between depressive symptoms and MetS over time. Individuals with more CESD depressive symptoms were more likely to develop MetS over time compared to those reporting fewer symptoms (Wald Chi-Square = 7.09 (1),p <0.008), and MetS was similarly predictive of CESD. MetS more consistently predicted depressive symptoms at each 5-year exam than depressive symptoms predicted MetS. Race and sex moderated relationships between depression and MetS, with White females, White individuals overall, and females overall demonstrating significant relationships. Health behaviors were not related to depression-MetS associations.

Conclusion

In a diverse young adult population prospectively followed into late middle age, MetS more consistently predicted depression over time than depression predicted MetS. The relation between MetS and depressive symptoms was moderated by race and sex, but not health behaviors.
Influence of socioeconomic status on the presence of obstructive coronary artery disease and cardiovascular outcomes in patients undergoing invasive coronary angiography
Authors: Chung Jaehoon , Kim Hack-Lyoung , Joh Hyun Sung , Lim Woo-Hyun , Seo Jae-Bin , Kim Sang-Hyun , Zo Joo-Hee , Kim Myung-A
Published: March 2023

Background

Although it has been documented that low socioeconomic status (SES) is associated with increased risk of mortality and cardiovascular disease (CVD), this issue has not been addressed in patients at high CVD risk. This study was performed to investigate the association of the patient’s SES with the presence of obstructive coronary artery disease (CAD) and long-term cardiovascular outcomes who undergo invasive coronary angiography (ICA).

Methods

A total of 9,530 patients who underwent ICA for the evaluation and treatment of CAD (66.0±12.3 years and 60.2% male) were retrospectively reviewed. The patients were divided into two groups according to the health insurance type: those with low SES who had the Medical aid program (Medical aid beneficiary [MAB] group; n=1,436) and those with high SES who had the National Health Insurance program (National Health Insurance beneficiary [NHIB] group; n=8,094). The primary outcome was a composite of cardiac death, acute myocardial infarction, coronary revascularization, and ischemic stroke.

Results

Of the study patients, 1,436 (15.1%) were in the MAB group. The prevalence of cardiovascular risk factors was higher in the MAB group compared to the NHIB group. However, the prevalence of obstructive CAD was similar between the two groups (62.8% vs. 64.2%;P=0.306). During a median follow-up period of 3.5 years (interquartile range, 1.0 to 5.9 years), the incidence of the composite cardiovascular event was significantly higher in the MAB group than in the NHIB group (20.2% vs. 16.2%,P<0.001). In multivariable Cox regression analysis, compared to the NHIB group, the MAB group was independently associated with worse clinical outcomes even after controlling for potential confounders (adjusted odds ratio, 1.28; 95% confidence interval, 1.07 to 1.54;P=0.006).

Conclusions

Although CAD prevalence was similar, MABs showed an increased risk of composite cardiovascular events than NHIBs in Korean adults undergoing ICA. This provides additional evidence for the association between low SES and an increased risk of CVD, even in high-risk subjects.

Clinical perspective

What is new?

This study provided evidence for a relationship between low socioeconomic status and increased cardiovascular disease risk in a high-risk population.

What are the clinical implications?

Subjects with low socioeconomic status are more likely to develop cardiovascular disease and to have a higher frequency of related risk factors, so cardiovascular disease tests and treatments should be performed more aggressively.

Appropriate risk stratification of low socioeconomic status patients with traditional risk factors for cardiovascular disease is important for identifying high-risk patients.
Causal Effect ofHelicobacter PyloriInfection on Coronary Heart Disease is mediated by Body Mass Index: A Mendelian Randomization Study
Authors: Li Bing , Zhang Yaoting , Zheng Yang , Cai He
Published: March 2023

Background

More than half of the world’s population have been infected withH. pylori, however the relationship betweenH. pyloriinfection and coronary heart disease (CHD) is unknown.

Methods

This study used mendelian randomization (MR) analyses. The instrument variables forH. pyloriinfection were genetic variables (rs10004195 and rs368433) obtained from a published study. The outcome data included diagnosis, prognosis, and pathogenesis data for CHD, which were extracted from the public genome-wide association studies database, mainly from the CARDIoGRAMplusC4D consortium, UK Biobank, IEU database, and FinnGen database. MR analyses were performed per outcome database and were conducted by reverse analysis. Two step MR analyses were used to explore indirect pathogenic factors ofH. pyloriinfection.

Results

Genetically-predictedH. pyloriinfection was causally associated with body mass index (BMI) (β, 0.022; 95% CI, 0.008–0.036;p-value = 0.001), but not with the diagnosis of CHD (OR, 0.991; 95%CI, 0.904–1.078;p-value = 0.842, IEU database; OR, 1.049; 95% CI, 0.980–1.118;p-value = 0.178, FinnGen database) and prognosis of CHD (OR, 0.999; 95% CI, 0.997–1.001;p-value = 0.391, IEU database; OR, 1.022; 95% CI, 0.922–1.123;p-value = 0.663, FinnGen database). The causal effect ofH. pyloriinfection on CHD is mediated by BMI. Inverse MR showed no causal effect of CHD onH. pyloriinfection.

Conclusions

Our findings confirm the causal effect ofH. pyloriinfection on CHD is mediated by BMI. Eradication or prevention ofH. pyloriinfection may have a clinical benefit for patients with CHD indirectly.

Clinical Perspective

What Is New?

Genetically-predictedH. pyloriinfection was causally associated with body mass index, but not with the diagnosis and prognosis (major adverse cardiovascular events) of coronary heart disease.

The causal effect ofH. pyloriinfection on coronary heart disease is mediated by body mass index. Inverse mendelian randomization analyses showed no causal effect of coronary heart disease onH. pyloriinfection.

What Are the Clinical Implications?

Our findings confirm that the causal effect of H. pylori infection on coronary heart disease is partially mediated by body mass index.

Eradication or prevention of H. pylori infection may have a clinical benefit for patients with CHD indirectly.
Further evidences of an emerging stingless bee-yeast symbiosis
Authors: de Paula Gabriela Toninato , da Paixão Melo Weilan Gomes , de Castro Ivan , Menezes Cristiano , Paludo Camila Raquel , Rosa Carlos Augusto , Pupo Mônica Tallarico
Published: March 2023

Symbiotic interactions between microorganisms and social insects have been described as crucial for the maintenance of these multitrophic systems, as observed for the stingless beeScaptotrigona depilisand the yeastZygosaccharomycessp. The larvae ofS. depilisingest fungal filaments ofZygosaccharomycessp. to obtain ergosterol, which is the precursor for the biosynthesis of ecdysteroids that modulate insect metamorphosis. In this work we verified that nutritional fungal symbioses also occur in other species of stingless bees. We analyzed brood cell samples from 19 species of stingless bees collected in Brazil. The osmophilic yeastZygosaccharomycesspp. was isolated from eight bee species, namelyScaptotrigona bipuctata, S. postica, S. tubiba, Tetragona clavipes, Melipona quadrifasciata, M. fasciculata, M. bicolorandPartamona helleri. These yeasts form pseudohyphae and also accumulate ergosterol in lipid droplets, similar to the pattern observed forS. depilis. The phylogenetic analyses including variousZygosaccharomycesrevealed that strains isolated from the brood cells formed a branch separated from the previously describedZygosaccharomycesspecies, suggesting that they are new species of this genus and reinforcing the symbiotic interaction with the host insects.

Importance

Benefits exchanged in insect–fungus mutualisms include nutrition, protection, and dispersal. Fungal nutritional roles are well described for some eusocial insects, such as fungus growing ants and termites, but similar interaction in stingless bees was so far observed just inScaptotrigona depilis. Here we expand the knowledge of yeast-bee symbiosis by analyzing the presence, cell morphologies, lipid accumulation and phylogenetic relationships of fungi isolated from brood cells and other locations of bee colonies.Zygosaccharomycesisolates were recovered from 42% of the bee species assessed, and probably represent new species showing pseudohyphae formation and lipid accumulation similar toS. depilisassociatedZygosaccharomycesstrains. The phylogenetic analyses suggested an evolutionary adaptation ofZygosaccharomycesspp. to the brood cell environment to provide nutritional benefits for the developing insect. Stingless bees play important ecosystem services, and our results raise the concern that fungicidal agents used in agriculture could disrupt this symbiosis, impacting bee health.