bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of the Hierarchical Nature of the AO Spine Sacral Classification and the Development of the Sacral AO Spine Injury Score
Authors: Karamian Brian A. , Schroeder Gregory D. , Lambrechts Mark J. , Canseco Jose A. , Vialle Emiliano N. , Kandziora Frank , Benneker Lorin M. ,   AO Spine Sacral Classification Group Members, Shanmuganathan Rajasekaran , Öner F. Cumhur , Schnake Klaus J. , Kepler Christopher K. , Vaccaro Alexander R.
Published: March 2023

Study Design:

Global cross-sectional survey.

Objective:

The objective of this study was to validate the hierarchical nature of the AO Spine Sacral Classification System and develop an injury scoring system.

Summary of Background Data:

Although substantial interobserver and intraobserver reliability of the AO Spine Sacral Classification System has been established, the hierarchical nature of the classification has yet to be validated.

Methods:

Respondents numerically graded each variable within the classification system for severity. Based on the results, a Sacral AO Spine Injury Score (AOSIS) was developed.

Results:

A total of 142 responses were received. The classification exhibited a hierarchical Injury Severity Score (ISS) progression (A1: 8 to C3: 95) with few exceptions. Subtypes B1 and B2 fractures showed no significant difference in ISS (B1 43.9 vs. B2 43.4, P=0.362). In addition, the transitions A3→B1 and B3→C0 represent significant decreases in ISS (A3 66.3 vs. B1 43.9, P<0.001; B3 64.2 vs. C0 46.4, P<0.001). Accordingly, A1 injury was assigned a score of 0. A2 and A3 received scores of 1 and 3 points, respectively. Posterior pelvic injuries B1 and B2 both received a score of 2. B3 received a score of 3 points. C0, C1, C2, and C3 received scores of 2, 3, 5, and 6 points, respectively. The scores assigned to neurological modifiers N0, N1, N2, N3, and NX were 0, 1, 2, 4, and 3, respectively. Case-specific modifiers M1, M2, M3, and M4 received scores of 0, 0, 1, and 2 points, respectively.

Conclusions:

The results of this study validate the hierarchical nature of the AO Spine Sacral Classification System. The Sacral AOSIS sets the foundation for further studies to develop a universally accepted treatment algorithm for the treatment of complex sacral injuries.

Level of Evidence:

Level IV—Diagnostic.
Cataract surgery in patients with retinitis pigmentosa: systematic review
Authors: Khojasteh Hassan , Riazi-Esfahani Hamid , Mirghorbani Masoud , Khalili Pour Elias , Mahmoudi Alireza , Mahdizad Zahra , Akhavanrezayat Amir , Ghoraba Hashem , Do Diana V. , Nguyen Quan Dong
Published: March 2023

Retinitis pigmentosa (RP) is an inherited bilateral retinal degenerative disease with an incidence of 1 in 4000 people. RP affects more than 1 million individuals worldwide. Although night blindness and restricted visual field are the most typical symptoms of these individuals, generalized vision loss due to cataracts can be expected in the latter stages of the disease. It has been demonstrated that posterior subcapsular cataract is the most prevalent cataract in younger individuals with RP, as opposed to age-related cataracts. Although most ophthalmologists may have a negative view of cataract surgery in patients with RP, it appears that it can play an important role in the visual restoration of patients with RP. However, there are concerns about performing cataract surgery for patients with RP. Herein, a systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses on databases of MEDLINE and Scopus.
Biomarkers for Bile Acid Malabsorption in Diarrhea-predominant Irritable Bowel Syndrome
Authors: Liu Tianxu , Ma Muyuan , Li Kelei , Tan Wei , Yu Han , Wang Ling
Published: March 2023

Background and Aim:

A clear relationship of biological indexes between bile acid malabsorption (BAM) and diarrhea-predominant irritable bowel syndrome (IBS-D) has not been well analyzed. This meta-analysis aimed to establish a more convenient method to diagnose BAM in IBS-D patients by comparing the differences in biomarkers between IBS-D patients and healthy people.

Methods:

Multiple databases were searched for relevant case-control studies. Indicators used to diagnose BAM included 75Se-homocholic acid taurine (SeHCAT), 7α-hydroxy-4-cholesten-3-one(C4), fibroblast growth factor-19 and 48-hour fecal bile acid (48FBA). The rate of BAM (SeHCAT) was calculated by using a random-effect model. The levels of C4, FGF19, and 48FBA were compared, and the overall effect size was combined by a fixed effect model.

Results:

The search strategy identified 10 relevant studies comprising 1034 IBS-D patients and 232 healthy volunteers. The pooled rate of BAM in IBS-D patients was 32% (according to SeHCAT; 95% CI: 24%–40%). The level of C4 in IBS-D patients was significantly higher than that in the control group (2.86 ng/mL; 95% CI: 1.09, 4.63); The level of FGF19 was significantly lower than that in the control group (−33.97 pg/mL; 95% CI: −51.13, −16.82); The level of 48FBA was significantly higher than that in the control group (0.059; 95% CI: 0.41, 0.77).

Conclusions:

The results mainly concluded serum C4 and FGF19 levels in IBS-D patients. Most of the studies have different normal cutoff points of serum C4 and FGF19 levels; the performance of each test should be further estimated. By comparing the levels of these biomarkers, BAM in patients with IBS-D could be identified more accurately, which would lead to more effective treatment.
Cost Analysis of the Positive Health Check Intervention to Suppress HIV Viral Load and Retain Patients in HIV Clinical Care
Authors: Shrestha Ram K. , Galindo Carla A. , Courtenay-Quirk Cari , Harshbarger Camilla , Abdallah Iddrisu , Marconi Vincent C. , DallaPiazza Michelle , Swaminathan Shobha , Somboonwit Charurut , Lewis Megan A. , Khavjou Olga A.
Published: March 2023

Context:

Digital video-based behavioral interventions are effective tools for improving HIV care and treatment outcomes.

Objective:

To assess the costs of the Positive Health Check (PHC) intervention delivered in HIV primary care settings.

Design, Setting, and Intervention:

The PHC study was a randomized trial evaluating the effectiveness of a highly tailored, interactive video-counseling intervention delivered in 4 HIV care clinics in the United States in improving viral suppression and retention in care. Eligible patients were randomized to either the PHC intervention or the control arm. Control arm participants received standard of care (SOC), and intervention arm participants received SOC plus PHC. The intervention was delivered on computer tablets in the clinic waiting rooms. The PHC intervention improved viral suppression among male participants. A microcosting approach was used to assess the program costs, including labor hours, materials and supplies, equipment, and office overhead.

Participants:

Persons with HIV infection, receiving care in participating clinics.

Main Outcome Measures:

The primary outcome was the number of patients virally suppressed, defined as having fewer than 200 copies/mL by the end of their 12-month follow-up.

Results:

A total of 397 (range across sites [range], 95-102) participants were enrolled in the PHC intervention arm, of whom 368 participants (range, 82-98) had viral load data at baseline and were included in the viral load analyses. Of those, 210 (range, 41-63) patients were virally suppressed at the end of their 12-month follow-up visit. The overall annual program cost was $402 274 (range, $65 581-$124 629). We estimated the average program cost per patient at $1013 (range, $649-$1259) and the cost per patient virally suppressed at $1916 (range, $1041-$3040). Recruitment and outreach costs accounted for 30% of PHC program costs.

Conclusions:

The costs of this interactive video-counseling intervention are comparable with other retention in care or reengagement interventions.
Evaluation of an Emergency Department Visit Data Mental Health Dashboard
Authors: Ising Amy , Waller Anna , Frerichs Leah
Published: March 2023

Context:

Local health departments (LHDs) need timely county-level and subcounty-level data to monitor health-related trends, identify health disparities, and inform areas of highest need for interventions as part of their ongoing assessment responsibilities; yet, many health departments rely on secondary data that are not timely and cannot provide subcounty insights.

Objective:

We developed and evaluated a mental health dashboard in Tableau for an LHD audience featuring statewide syndromic surveillance emergency department (ED) data in North Carolina from the North Carolina Disease Event Tracking and Epidemiologic Collection Tool (NC DETECT).

Design:

We developed a dashboard that provides counts, crude rates, and ED visit percentages at statewide and county levels, as well as breakdowns by zip code, sex, age group, race, ethnicity, and insurance coverage for 5 mental health conditions. We evaluated the dashboards through semistructured interviews and a Web-based survey that included the standardized usability questions from the System Usability Scale.

Participants:

Convenience sample of LHD public health epidemiologists, health educators, evaluators, and public health informaticians.

Results:

Six semistructured interview participants successfully navigated the dashboard but identified usability issues when asked to compare county-level trends displayed in different outputs (eg, tables vs graphs). Thirty respondents answered all questions on the System Usability Scale for the dashboard, which received an above average score of 86.

Conclusions:

The dashboards scored well on the System Usability Scale, but more research is needed to identify best practices in disseminating multiyear syndromic surveillance ED visit data on mental health conditions to LHDs.
Assessment and Identification of Skin Disorders in Skin of Color
Authors: Francis Kathleen F.
Published: March 2023

Skin assessment in patients with dark skin tones (DST) continues to be a challenge for many healthcare providers (HCP) because the visual cues are not always readily identified. For example, identification of early signs of pressure injury when subtle skin color changes are missed has the potential to cause harm and contribute to healthcare disparities. Appropriate wound management can begin only when the wound is correctly identified. For HCPs to identify early signs of skin conditions in DST patients, they must be provided education and effective tools enabling them to identify clinically relevant signs of skin damage in all patients. This article reviews basic anatomy of the skin; it focuses on differences seen in DST and reviews assessment strategies to assist the HCP to identify skin changes and conditions.
Genetic characterization of Escherichia coli and Klebsiella spp. from Humans and Poultry in Nigeria
Authors: Jesumirhewe Christiana , CABAL-ROSEL Adriana , ALLERBERGER Franz , SPRINGER Burkhard , RUPPITSCH Werner
Published: March 2023

The emergence of antibiotic resistance in food producing animals is of major public health significance arising from the risk of these bacteria entering the food chain. In this study, the genetic characteristics of antibiotic resistant Escherichia coli and Klebsiella spp. isolates from humans and poultry in Edo state, Nigeria were investigated. In April 2017, 45 Klebsiella spp. and 46 Escherichia coli isolates were obtained from urine, clinical wounds, nasal and chicken fecal samples. Isolates were recovered and identified as previously described. Species identification was achieved by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry and ribosomal multilocus sequence typing. Antimicrobial susceptibility testing was carried out using the Kirby-Bauer method for 12 antibiotics. Double disc synergy test was used to screen for ESBL production. Whole genome sequencing was performed for strain characterization of the isolates. Thirteen Klebsiella spp. isolates yielded positive results by the ESBL phenotypic test and harbored ESBL genes. Out of the 46 E. coli isolates, 21 human and 13 poultry isolates were resistant to at least one of the tested antibiotics. Four human E. coli isolates harbored ESBL genes and revealed positive results when applying ESBL double disc synergy tests. ESBL genes in the Klebsiella spp. and E. coli isolates include bla CTX-M-15 and bla SHV-28 . Whole genome based cgMLST of the Klebsiella spp. and E. coli isolates revealed a close relatedness among the isolates. An integrated “One Health” surveillance system is required to monitor transmission of antimicrobial resistance in Nigeria.
Genetic variation for plant growth traits in a common wheat population is dominated by known variants and novel QTL
Authors: DeWitt Noah , Guedira Mohammed , Lauer Edwin , Murphy J. Paul , Marshall David , Mergoum Mohamed , Johnson Jerry , Holland James B. , Brown-Guedira Gina
Published: March 2023

Genetic variation in growth over the course of the season is a major source of grain yield variation in wheat, and for this reason variants controlling heading date and plant height are among the best-characterized in wheat genetics. While the major variants for these traits have been cloned, the importance of these variants in contributing to genetic variation for plant growth over time is not fully understood. Here we develop a biparental population segregating for major variants for both plant height and flowering time to characterize the genetic architecture of the traits and identify additional novel QTL. We find that additive genetic variation for both traits is almost entirely associated with major and moderate-effect QTL, including four novel heading date QTL and four novel plant height QTL.FT2andVrn-A3are proposed as candidate genes underlying QTL on chromosomes 3A and 7A, whileRht8is mapped to chromosome 2D. These mapped QTL also underlie genetic variation in a longitudinal analysis of plant growth over time. The oligogenic architecture of these traits is further demonstrated by the superior trait prediction accuracy of QTL-based prediction models compared to polygenic genomic selection models. In a population constructed from two modern wheat cultivars adapted to the southeast U.S., almost all additive genetic variation in plant growth traits is associated with known major variants or novel moderate-effect QTL. Major transgressive segregation was observed in this population despite the similar plant height and heading date characters of the parental lines. This segregation is being driven primarily by a small number of mapped QTL, instead of by many small-effect, undetected QTL. As most breeding populations in the southeast U.S. segregate for known QTL for these traits, genetic variation in plant height and heading date in these populations likely emerges from similar combinations of major and moderate effect QTL. We can make more accurate and cost-effective prediction models by targeted genotyping of key SNPs.
Association of Select Psychiatric Disorders with Incident Brain Aneurysm and Subarachnoid Hemorrhage among Veterans
Authors: Cooke Daniel L , Shen Hui , Duvvuri Madhavi , Thompson Daniel , Neylan Thomas , Wolfe William , Hetts Steven , Ovbiagele Bruce , Whooley Mary , Cohen Beth
Published: March 2023

Background

Brain aneurysms represent a significant cause of hemorrhagic stroke. Prior research has demonstrated links between stress and stroke, including brain aneurysms. We aimed to determine relationships between select psychiatric disorders and aneurysms and aneurysmal SAH.

Methods

We performed retrospective, case-control study of a National Veterans Affairs population with two experimental groups (aneurysm-only and aneurysmal SAH) and 10-fold controls per group matched by age, date, and clinical data source. The studied the presence of 4 psychiatric disorders: Posttraumatic stress disorder (PTSD), major depressive disorder (MDD), generalized anxiety disorder (GAD), and other mood disorders. Our main outcomes Unadjusted and multivariable adjusted ORs of PTSD, MDD, GAD, and mood disorders within aneurysm-only and aSAH groups.

Results

In 6,320,789 US Veterans who were enrolled for at least 5 years in Medicare and/or the Veterans Health Administration, we identified 35,094 cases of aneurysm without SAH and 5749 cases of aneurysm with SAH between 1/2005 and 12/2019. In analyses adjusted for sex, hypertension, and tobacco use, patients with aneurysm were more likely than matched controls to have a history of PTSD (OR 1.48), MDD (OR 1.33), GAD (OR 1.26), and other mood disorders (OR 1.34) (all p values <0.0001). Similarly, patients with aSAH were more likely than controls to have a history of PTSD (OR 1.35), MDD (OR 1.38), GAD (OR 1.18), and other mood disorders (OR 1.30) (all p values <0.0001).

Conclusions

The study, the largest of its kind, further suggests links between psychiatric disorders and stroke. This is important as patients with aneurysms are not routinely screened for such psychiatric risk factors. Additional research on this topic could lead to novel strategies to improve stroke prevention.
A Phylogenomic Analysis of HIV Transmission Pattern among High Risk Groups of North-West India
Authors: Chauhan Chandar Kanta , Lakshmi P.V.M. , Sarma Phulen , Sagar Vivek , Sharma Aman , K.Arora Sunil , Kumar Rajesh
Published: March 2023

Background

Molecular techniques can enhance the power of epidemiological investigations for tracing HIV transmission networks. This information could be useful for developing strategies for prevention of HIV transmission. Hence, we carried out to a study on the transmission patterns among newly diagnosed HIV cases among High-Risk Groups (HRGs) of North-West India using phylogenomic methods.

Methods

Phylogenomic analysis was carried out among 37 randomly selected samples of recently infected HRGs identified through Recent Infections Testing Algorithm (RITA) using Limiting Antigen Avidity Assay. Amplification of the reverse transcriptase region ofpolgene (540 base pairs) and sequencing was done. Reference sequences were extracted from HIV Los Alamos database. Sequences aligned by Clustal W and HIV-1 subtype were determined on the basis of phylogenomic analysis of thepolsequence. Phylogenetic trees were constructed using the MEGA (version 11.0).

Results

The phylogeny clearly depicts that the study isolates RTFSWCHD and RTFSWPB007 cluster with and are related to the Indian reference sequences AY746371 and EU683781 and a Nepalese sequence KX430115.The other study isolates (RTFSWCHD001, RTFSWPB005, RTFSWCHD002, RTFSWPB006, RTFSWHR008, RTFSWHR 009) clustered uniquely among themselves without any interlinking with other references. One study isolate (RTFSWHP004) clustered closely with Zimbabwian isolate AY998351. The phylogeny shows that the study isolate MSMCHD005 clades separately with the Indian references (DQ838761, EU683781and AY746371), but is also very closely related to the references from China (HG421606, JQ658754), Nepal(JN023039) and Myanmar (N223216, JN223183, KC913773). Other study isolates (MSMCHD003, MSMHP007, MSMCHD004, MSMPB001, MSMPB002, and MSMHR006) are highly interrelated among themselves and form a separate unique clade together. The evolutionary tree shows that all the sequences from current study formed a monophyletic lineage, i.e., sequences from India clustered together more than with sequences from any other country. The study sequences showed relatedness only to the Nepal references KX430115 and JN023035. The South African, UK, Norway, China, and Myanmar references are grouped into aseparate clade.

Conclusion

Molecular epidemiologic methods were able to reveal transmission networks; hence, phylogenomic methods can be used in HIV Sentinel Surveillance to monitor transmission networks.
Emulator-based Bayesian calibration of the CISNET colorectal cancer models
Authors: Pineda-Antunez Carlos , Seguin Claudia , van Duuren Luuk A , Knudsen Amy B. , Davidi Barak , Nascimento de Lima Pedro , Rutter Carolyn , Kuntz Karen M. , Lansdorp-Vogelaar Iris , Collier Nicholson , Ozik Jonathan , Alarid-Escudero Fernando
Published: March 2023

Purpose

To calibrate Cancer Intervention and Surveillance Modeling Network (CISNET) ’s SimCRC, MISCAN-Colon, and CRC-SPIN simulation models of the natural history colorectal cancer (CRC) with an emulator-based Bayesian algorithm and internally validate the model-predicted outcomes to calibration targets.

Methods

We used Latin hypercube sampling to sample up to 50,000 parameter sets for each CISNET-CRC model and generated the corresponding outputs. We trained multilayer perceptron artificial neural networks (ANN) as emulators using the input and output samples for each CISNET-CRC model. We selected ANN structures with corresponding hyperparameters (i.e., number of hidden layers, nodes, activation functions, epochs, and optimizer) that minimize the predicted mean square error on the validation sample. We implemented the ANN emulators in a probabilistic programming language and calibrated the input parameters with Hamiltonian Monte Carlo-based algorithms to obtain the joint posterior distributions of the CISNET-CRC models’ parameters. We internally validated each calibrated emulator by comparing the model-predicted posterior outputs against the calibration targets.

Results

The optimal ANN for SimCRC had four hidden layers and 360 hidden nodes, MISCAN-Colon had 4 hidden layers and 114 hidden nodes, and CRC-SPIN had one hidden layer and 140 hidden nodes. The total time for training and calibrating the emulators was 7.3, 4.0, and 0.66 hours for SimCRC, MISCAN-Colon, and CRC-SPIN, respectively. The mean of the model-predicted outputs fell within the 95% confidence intervals of the calibration targets in 98 of 110 for SimCRC, 65 of 93 for MISCAN, and 31 of 41 targets for CRC-SPIN.

Conclusions

Using ANN emulators is a practical solution to reduce the computational burden and complexity for Bayesian calibration of individual-level simulation models used for policy analysis, like the CISNET CRC models. In this work, we present a step-by-step guide to constructing emulators for calibrating three realistic CRC individual-level models using a Bayesian approach.
Endovascular thrombectomy for the treatment of large ischemic stroke: a systematic review and meta-analysis of randomized control trials
Authors: Atchley Travis J. , Estevez-Ordonez Dagoberto , Laskay Nicholas M.B. , Tabibian Borna E. , Harrigan Mark R.
Published: March 2023

Importance

Endovascular thrombectomy (ET) has previously been reserved for patients with small to medium acute ischemic strokes. Three recent randomized control trials (RCTs) have demonstrated functional benefit and risk profiles for ET in large volume ischemic strokes.

Objective

The primary objective of the meta-analysis was to determine the combined benefit of ET in adult patients with large volume acute ischemic strokes and to better determine the risk of adverse events following ET.

Data Sources

We systematically searched MEDLINE, EMBASE, SCOPUS, the Cochrane Central Register of Controlled, and Google Scholar for all RCTs published in English language between January 1, 2010, to February 19, 2023.

Study Selection

We included only RCTs specifically comparing ET to medical therapy in patients with acute ischemic stroke with large volume infarctions as defined by Alberta Stroke Program Early Computed Tomography Score (ASPECTS) 3-5 or calculated infarct volume of > 50-70mL. Two independent reviewers screened potential studies for full text review and metaanalysis inclusion with conflicts being resolved by consensus or third reviewer.

Data Extraction and Synthesis

Data was extracted based on pre-specified variables on study methods and design, participant characteristics, analysis approach, as well as efficacy and safety outcomes. Results were combined using a restricted maximum-likelihood estimation random-effects model. Studies were assessed for potential bias and quality of evidence.

Main Outcome(s) and Measure(s)

The prespecified primary outcome was an overall ordinal shift across the range of modified Rankin scale scores toward a better outcome at 90 days following either ET or medical management for patients with large volume ischemic strokes.

Results

A total of 3044 studies were screened, and 29 underwent full text review. 3 RCTs (1011 patients) were included in the analysis. The pooled random effects model for the primary outcome of mRS improvement favored ET over medical management, generalized odds ratio 1.55 [95% CI 1.25 – 1.91, T2= 0.01, I2= 42.84%]. There was a trend toward increased risk of symptomatic ICH in the ET group, relative risk 1.85 [95% CI 0.94 – 3.63, T2= 0.00, I2= 0.00%].

Conclusions and Relevance

In patients with large volume ischemic strokes, ET has a clear functional benefit and does not confer increased risk of significant complications compared to medical management alone.
Impact of Synchronized Left Ventricular Pacing in Cardiac Resynchronization Therapy
Authors: Miyazaki Yuichiro , Ishibashi Kohei , Ueda Nobuhiko , Oka Satoshi , Wakamiya Akinori , Shimamoto Keiko , Nakajima Kenzaburo , Kamakura Tsukasa , Wada Mitsuru , Inoue Yuko , Miyamoto Koji , Nagase Satoshi , Aiba Takeshi , Kusano Kengo
Published: March 2023

Background

The adaptive cardiac resynchronization therapy (aCRT) algorithm enables synchronized left ventricular pacing (sLVP) to produce fusion with intrinsic right ventricular activation in normal atrioventricular (AV) conduction. Although sLVP presents benefits over biventricular pacing (BVP), the adequate sLVP rate for better clinical outcomes remains unclear. This study aimed to assess the association between sLVP rates and clinical outcomes.

Methods

Among our cohort of 271 consecutive patients who underwent CRT implantation between April 2016 and August 2021, we evaluated 63 patients who underwent CRT without considerably prolonged AV conduction and applied the aCRT algorithm (48 men, mean age: 64 ± 14 years; median follow-up period: 316 days [interquartile range: 212–809 days]).

Results

At the 6-month follow-up after CRT implantation, the frequency of CRT responders was 71% (n = 45). The sLVP rate was significantly higher in responders than in non-responders (75 ± 30 vs. 47 ± 40 %,p= 0.003). Receiver operating characteristics (ROC) curve analysis revealed that the optimal cut-off value during the sLVP rate was 59.4% for prediction of CRT responders (area under the curve, 0.70; sensitivity, 80%; specificity, 61%; positive predictive value, 84%; and negative predictive value, 55%). Kaplan–Meier analysis demonstrated that the higher sLVP group (sLVP ≥59.4%, n = 43) had better prognosis (cardiac death and heart failure hospitalization) than the lower sLVP group (sLVP <59.4%, n = 20) (log-rankp<0.001), and multivariate Cox hazard analysis revealed that a higher sLVP rate was associated with good prognosis (p<0.001).

Conclusion

sLVP was associated with CRT response, and higher sLVP rate (≥59.4%) is important for good prognosis in patients with aCRT.

CLINICAL PERSPECTIVE

What Is New?

Synchronized left ventricular pacing(sLVP) >59.4% was a significant predictor of cardiac resynchronization therapy(CRT) responders and better clinical outcomes, evidenced by the results of the multivariate analysis.

In this study, which included patients with moderately prolonged PR intervals, high sLVP rates were associated with better clinical outcomes.

What Are the Clinical Implications?

sLVP rate was associated with the improvement of cardiac function after CRT implantation.

A higher sLVP rate was associated with a lower risk of cardiac death and heart failure hospitalization.
Bearded or smooth? Awns improve yield when wheat experiences heat stress during grain fill
Authors: DeWitt Noah , Lyerly Jeanette , Guedira Mohammed , Holland James B. , Ward Brian P. , Murphy J. Paul , Boyles Richard E. , Mergoum Mohamed , Babar Md. Ali , Shakiba Ehsan , Sutton Russel , Ibrahim Amir , Tiwari Vijay , Santantonio Nicholas , Van Sanford David A. , Howell Kimberly , Smith Jared H. , Harrison Stephen A. , Brown-Guedira Gina
Published: March 2023

The presence or absence of awns – whether wheat heads are ”bearded” or ”smooth”– is the most visible phenotype distinguishing wheat cultivars. Previous studies suggest that awns may improve yields in heat or water-stressed environments, but the exact contribution of awns to yield differences remains unclear. Here we leverage historical phenotypic, genotypic, and climate data to estimate the yield effects of awns under different environmental conditions over a 12-year period in the Southeast US. Lines were classified as awned or awnless based on sequence data, and observed heading dates were used to associate grain fill periods of each line in each environment with climatic data and grain yield. In most environments, awn suppression was associated with higher yields, but awns were associated with better performance in heat-stressed environments more common at southern locations. Wheat breeders in environments where awns are only beneficial in some years may consider selection for awned lines to reduce year-to-year yield variability, and with an eye towards future climates.
Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse
Authors: Muroňová Jana , Kherraf Zine-Eddine , Giordani Elsa , Lambert Emeline , Eckert Simon , Cazin Caroline , Amiri-Yekta Amir , Court Magali , Chevalier Geneviève , Martinez Guillaume , Neirijnck Yasmine , Kühne Francoise , Wehrli Lydia , Klena Nikolai , Hamel Virginie , De Macedo Lisa , Escoffier Jessica , Guichard Paul , Coutton Charles , Mustapha Selima Fourati Ben , Kharouf Mashmoud , Bouin Anne-Pascale , Zouari Raoudha , Thierry-Mieg Nicolas , Nef Serge , Geimer Stefan , Loeuillet Corinne , Ray Pierre , Arnoult Christophe
Published: March 2023

Genetic mutations are a recurrent cause of male infertility. Multiple morphological abnormalities of the flagellum (MMAF) syndrome is a heterogeneous genetic disease, with which more than 50 genes have been linked. Nevertheless, for 50% of patients with this condition, no genetic cause is identified. From a study of a cohort of 167 MMAF patients, pathogenic bi-allelic mutations were identified in theCCDC146gene in two patients. This gene encodes a poorly characterized centrosomal protein which we studied in detail here. First, protein localization was studied in two cell lines. We confirmed the centrosomal localization in somatic cells and showed that the protein also presents multiple microtubule-related localizations during mitotic division, suggesting that it is a microtubule-associated protein (MAP). To better understand the function of the protein at the sperm level, and the molecular pathogenesis of infertility associated withCCDC146mutations, two genetically modified mouse models were created: aCcdc146knock-out (KO) and a knock-in (KI) expressing a HA-tagged CCDC146 protein. KO male mice were completely infertile, and sperm exhibited a phenotype identical to our two MMAF patient’s phenotype withCCDC146mutations. No other pathology was observed, and the animals were viable. CCDC146 expression starts during late spermiogenesis, at the time of flagellum biogenesis. In the spermatozoon, the protein is conserved but is not localized to centrioles, unlike in somatic cells, rather it is present in the axoneme at the level of microtubule doublets. Expansion microscopy associated with the use of the detergent sarkosyl to solubilize microtubule doublets, suggest that the protein may be a microtubule inner protein (MIP). At the subcellular level, the absence of CCDC146 affected the formation, localization and morphology of all microtubule-based organelles such as the manchette, the head–tail coupling apparatus (HTCA), and the axoneme. Through this study, we have characterized a new genetic cause of infertility, identified a new factor in the formation and/or structure of the sperm axoneme, and demonstrated that the CCDC146 protein plays several cellular roles, depending on the cell type and the stages in the cell cycle.
Genetic Association Studies in Transgender Cohorts: A Systematic Review and Meta-Analysis
Authors: Ashley Blake , Harley Vincent
Published: March 2023

According to twin studies, there is a heritable contribution to gender incongruence, but the genetic mechanisms of this are unknown. Recent efforts to identify an aetiology of gender incongruence have focused on the hypothesis that sex hormones establish gender identity through influencing the development of neuroanatomy. Candidate gene studies that have sought to elucidate whether polymorphisms in sex steroidogenesis genes are overrepresented in transgender populations have been equivocal. A systematic search for case-control genetic association studies in transgender populations was conducted. Mean (+SD) or allele frequencies were extracted and combined quantitatively in random effects meta-analysis, summarised as standardised mean difference for continuous alleles or odds ratios for allele frequencies. Eight studies were included in the analysis. These studies spanned polymorphisms in five genes; the CAG repeat in androgen receptor (AR), the TA repeat in estrogen receptor 1 (ESR1), the CA repeat in estrogen receptor 2 (ESR2), the TTTA repeat in cytochrome P450 family 19 subfamily A member 1 (CYP19), and the T>C SNP in cytochrome P450 family 17 subfamily A member 1 (CYP17). Pooled estimates indicated that transgender women have a significant overrepresentation of shortESR1alleles compared to cisgender men (OR = 1.23, 95% CI: 1.06, 1.44, p = 0.0089). This may contribute an increased likelihood of developing gender incongruence amongst natal males. Future investigations into gender incongruence should use genome-wide methods.
Noise-induced synaptopathy impacts the long and short sensory hair cells differently in the mammalian cochlea
Authors: Lu Yan , Liu Jing , Li Bei , Wang Haoyu , Wang Shengxiong , Wang Fangfang , Wu Hao , Han Hua , Hua Yunfeng
Published: March 2023

In the mammalian cochlea, moderate acoustic overexposure leads to irreversible loss of ribbon-type synapse between sensory inner hair cell (IHC) and its postsynaptic auditory nerve fiber (ANF), causing a reduced dynamic range of hearing but not a permanently-elevated threshold. A prevailing view is that such ribbon loss (known as synaptopathy) selectively impacts those low-spontaneous-rate and high-threshold ANFs contacting predominantly the modiolar face of IHCs. However, the spatial pattern of synaptopathy remains scarce in the most sensitive mid-cochlear region, where long and short IHCs with distinct ribbon size gradients coexist. Here, we used volume electron microscopy to investigate noise exposure-related changes in the mouse IHCs with and without ribbon loss. Our quantifications reveal that the worst-hit areas of synaptopathy are the modiolar face of long IHCs and the pillar face of short IHCs. Moreover, we show relative enrichment of mitochondrial content in the survived ANF terminals, providing key experimental evidence for the long-proposed role of postsynaptic mitochondria in selective ribbon synapse degeneration following noise insult.
Methodological challenges and recommendations for identifying childhood immunisations using routine electronic health records in the United Kingdom
Authors: Suffel Anne M , Walker Jemma L , Campbell Colin , Carreira Helena , Warren-Gash Charlotte , McDonald Helen I
Published: March 2023

Routinely collected electronic health records (EHR) offer a valuable opportunity to carry out research on immunisation uptake, effectiveness and safety, using large and representative samples of the population. However, using EHR presents challenges for identifying vaccinated and unvaccinated cohorts. Some vaccinations are delivered in different care settings, so may not be fully recorded in primary care EHR. In contrast to other drugs, they do not require electronic prescription in many settings, which may lead to ambiguous coding of vaccination status and timing. Additionally, for childhood vaccination, there may be other challenges of identifying the study population eligible for vaccination due to changes in immunisation schedules over time, different vaccine indications depending on the context (e.g., tetanus vaccination after exposure) and the lack of full dates of birth in many databases of data confidentiality restrictions.

In this paper, we described our approach to tackling methodological issues related to identifying childhood immunisations in the Clinical Practice Research Datalink (CPRD) Aurum, a UK primary care dataset of EHR, as an example, and we introduce a comprehensive algorithm to support high-quality studies of childhood vaccination. We showed that a broad variety of considerations is important to identify vaccines in EHR and offer guidance on decisions to ascertain the vaccination status, such as considering data source and delivery systems (e.g., primary or secondary care), using a wide range of medical codes in combination to identify vaccination events, and using appropriate wash-out periods and quality checks to deal with issues of over-recording and back dating in EHR.

Our algorithm reproduced estimates of vaccination coverage which are comparable to official national estimates in England. This paper aims to improve transparency, quality, comparability and reproducibility of studies on immunisations.
A scalable, GMP-compatible, autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa
Authors: Neumayer Gernot , Torkelson Jessica L. , Li Shengdi , McCarthy Kelly , Zhen Hanson H. , Vangipuram Madhuri , Jackow Joanna , Rami Avina , Hansen Corey , Guo Zongyou , Gaddam Sadhana , Pappalardo Alberto , Li Lingjie , Cramer Amber , Roy Kevin R. , Nguyen Thuylinh Michelle , Tanabe Koji , McGrath Patrick S. , Bruckner Anna , Bilousova Ganna , Roop Dennis , Bailey Irene , Tang Jean Y. , Christiano Angela , Steinmetz Lars M. , Wernig Marius , Oro Anthony E.
Published: March 2023

Background

Gene editing in induced pluripotent stem (iPS) cells has been hailed to enable new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies.

Methods

We developed Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a new generation GMP-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a combined high-efficiency reprogramming and CRISPR-based genetic correction single step to generate genome scar- free,COL7A1corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off targets, and cancer-driver variants were evaluated by targeted and whole genome sequencing.

Findings

iPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT- treated mice.

Interpretation

DEBCT successfully overcomes previous roadblocks and represents a robust, scalable, and safe cGMP manufacturing platform for production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.
Unraveling Neuronal Identities Using SIMS: A Deep Learning Label Transfer Tool for Single-Cell RNA Sequencing Analysis
Authors: Gonzalez-Ferrer Jesus , Lehrer Julian , O’Farrell Ash , Paten Benedict , Teodorescu Mircea , Haussler David , Jonsson Vanessa D. , Mostajo-Radji Mohammed A.
Published: March 2023

Large single-cell RNA datasets have contributed to unprecedented biological insight. Often, these take the form of cell atlases and serve as a reference for automating cell labeling of newly sequenced samples. Yet, classification algorithms have lacked the capacity to accurately annotate cells, particularly in complex datasets. Here we present SIMS (Scalable, Interpretable Ma-chine Learning for Single-Cell), an end-to-end data-efficient machine learning pipeline for discrete classification of single-cell data that can be applied to new datasets with minimal coding. We benchmarked SIMS against common single-cell label transfer tools and demonstrated that it performs as well or better than state of the art algorithms. We then use SIMS to classify cells in one of the most complex tissues: the brain. We show that SIMS classifies cells of the adult cerebral cortex and hippocampus at a remarkably high accuracy. This accuracy is maintained in trans-sample label transfers of the adult hu-man cerebral cortex. We then apply SIMS to classify cells in the developing brain and demonstrate a high level of accuracy at predicting neuronal sub-types, even in periods of fate refinement, shedding light on genetic changes affecting specific cell types across development. Finally, we apply SIMS to single cell datasets of cortical organoids to predict cell identities and unveil genetic variations between cell lines. SIMS identifies cell-line differences and misannotated cell lineages in human cortical organoids derived from different pluripotent stem cell lines. When cell types are obscured by stress signals, label transfer from primary tissue improves the accuracy of cortical organoid annotations, serving as a reliable ground truth. Altogether, we show that SIMS is a versatile and robust tool for cell-type classification from single-cell datasets.
Structural Insights on Ionizable Dlin-MC3-DMA Lipids in DOPC Layers by Combining Accurate Atomistic Force Fields, Molecular Dynamics Simulations and Neutron Reflectivity
Authors: Ibrahim Mohd , Gilbert Jennifer , Heinz Marcel , Nylander Tommy , Schwierz Nadine
Published: March 2023

Ionizable lipids such as the promising Dlin-MC3-DMA (MC3) are essential for the successful design of lipid nanoparticles (LNPs) as drug delivery agents. Combining molecular dynamics simulations with experimental data such as neutron reflectivity experiments and other scattering techniques is essential to provide insights into the internal structure of LNPs, which is not fully understood to date. However, the accuracy of the simulations relies on the choice of force field parameters and high-quality experimental data is indispensable to verify the parametrization. For MC3, different parameterizations in combination with the CHARMM and the Slipids force field have recently emerged. Here, we complement the existing efforts by providing parameters for cationic and neutral MC3 compatible with the AMBER Lipid17 force field. Subsequently, we carefully assess the accuracy of the different force fields by providing a direct comparison to neutron reflectivity experiments of mixed lipid bilayers consisting of MC3 and DOPC at different pH. At low pH (cationic MC3) and at high pH (neutral MC3) the newly developed MC3 parameters in combination with AMBER Lipid17 for DOPC give good agreement with the experiments. Overall, the agreement is similar compared to the Park-Im parameters for MC3 in combination with the CHARMM36 force field for DOPC. The Ermilova-Swenson MC3 parameters in combination with the Slipids force field underestimate the bilayer thickness. While the distribution of cationic MC3 is very similar, the different force fields for neutral MC3 reveal distinct differences ranging from strong accumulation in the membrane center (current MC3/AMBER Lipid17 DOPC), over mild accumulation (Park-Im MC3/CHARMM36 DOPC) to surface accumulation (Ermilova-Swenson MC3/Slipids DOPC). These pronounced differences highlight the importance of accurate force field parameters and their experimental validation.
Lipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment
Authors: Stillman Jacob M. , Lopes Francisco M. , Lin Jing-Ping , Hu Kevin , Reich Daniel S. , Schafer Dorothy P.
Published: March 2023

Engulfment of cellular material and proteins is a key function for microglia, a resident macrophage of the central nervous system (CNS). Among the techniques used to measure microglial engulfment, confocal light microscopy has been used the most extensively. Here, we show that autofluorescence (AF), likely due to lipofuscin and typically associated with aging, can also be detected within microglial lysosomes in the young mouse brain by light microscopy. This lipofuscin-AF signal accumulates first within microglia and increases with age, but it is not exacerbated by amyloid beta-related neurodegeneration. We further show that this lipofuscin-AF signal within microglia can confound the interpretation of antibody-labeled synaptic material within microglia in young adult mice. Finally, we implement a robust strategy to quench AF in mouse, marmoset, and human brain tissue.
Olfactory and neuropeptide inputs to appetite neurons in the arcuate nucleus
Authors: Kuang Donghui , Hanchate Naresh K. , Lee Chia-Ying , Heck Ashley , Ye Xiaolan , Erdenebileg Michidsaran , Buck Linda B.
Published: March 2023

The sense of smell has potent effects on appetite, but the underlying neural mechanisms are largely a mystery. The hypothalamic arcuate nucleus contains two subsets of neurons linked to appetite: AgRP (agouti-related peptide) neurons, which enhance appetite, and POMC (pro-opiomelanocortin) neurons, which suppress appetite. Here, we find that AgRP and POMC neurons receive indirect inputs from partially overlapping areas of the olfactory cortex, thus identifying their sources of odor signals. We also find neurons directly upstream of AgRP or POMC neurons in numerous other areas, identifying potential relays between the olfactory cortex and AgRP or POMC neurons. Transcriptome profiling of individual AgRP neurons reveals differential expression of receptors for multiple neuromodulators. Notably, known ligands of the receptors define subsets of neurons directly upstream of AgRP neurons in specific brain areas. Together, these findings indicate that higher olfactory areas can differentially influence AgRP and POMC appetite neurons, that subsets of AgRP neurons can be regulated by different neuromodulators, and that subsets of neurons upstream of AgRP neurons in specific brain areas use different neuromodulators, together or in distinct combinations to modulate AgRP neurons and thus appetite.