bluuebunny/crossref_metadata_2025 huggingface dataset:
Tetraspanin CD81 promotes leukemia stem cell function and represents a new therapeutic vulnerability in acute myeloid leukemia
Authors: Gonzales Fanny , Peyrouze Pauline , Boyer Thomas , Guihard Soizic , Sevrin Francois , Laurent Djohana , Plesa Adriana , Barthelemy Adeline , Bongiovanni Antonino , Pottier Nicolas , Preudhomme Claude , Duployez Nicolas , Berthon Céline , Roumier Christophe , Cheok Meyling
Published: September 2023

Despite important progress over the last decade, acute myeloid leukemia (AML) is still associated with poor clinical outcome. Novel potent therapies ideally effective against AML stem cells (LSC), a major driver of leukemia initiation and progression, are urgently needed. In particular, targeting common AML-associated antigens at the stem and progenitor cell level represents an attractive therapeutic strategy to achieve deep long-term remissions and is currently the subject of intensive research efforts. In this study, we identified the tetraspanin CD81, a cell surface antigen frequently expressed on AML cells including LSC, as a new determinant of relapse and poor prognosis. CD81 expression was higher in AML cells compared to normal bone marrow cells, and more markedly expressed at relapse. We further showed that modulation of CD81 expression using gain- and loss-of-function approaches affected leukemia aggressiveness, tumor burden, LSC-homing and - xenoengraftment as well as mouse survival. Finally, anti-hCD81 monoclonal antibody-treatment combined with standard chemotherapy in mice with pre-established AML not only reduced leukemia burden but also prolonged relapse-free and overall survival. Collectively, these results identified a new efficacious and safe pharmacological strategy for targeting LSC, opening up novel therapeutic avenues to improve AML outcome.

Key points

CD81 expression in AML including LSC is a new determinant of aggressive disease and poor prognosis.

Anti-hCD81 monoclonal antibody-treatment of AML xenografts reduced leukemia burden and improved survival rates.
The Healthy Brain Initiative (HBI): A prospective cohort study protocol
Authors: Besser Lilah M. , Chrisphonte Stephanie , Kleiman Michael J. , O’Shea Deirdre , Rosenfeld Amie , Tolea Magdalena , Galvin James E.
Published: September 2023

Background

The Health Brain Initiative (HBI), established by University of Miami’s Comprehensive Center for Brain Health (CCBH), follows racially/ethnically diverse older adults without dementia living in South Florida. With dementia prevention and brain health promotion as an overarching goal, HBI will advance scientific knowledge by developing novel assessments and non-invasive biomarkers of Alzheimer’s disease and related dementias (ADRD), examining additive effects of sociodemographic, lifestyle, neurological and biobehavioral measures, and employing innovative, methodologically advanced modeling methods to characterize ADRD risk and resilience factors and transition of brain aging.

Methods

HBI is a longitudinal, observational cohort study that will follow 500 deeply-phenotyped participants annually to collect, analyze, and store clinical, cognitive, behavioral, functional, genetic, and neuroimaging data and biospecimens. Participants are ≥50 years old; have no, subjective, or mild cognitive impairment; have a study partner; and are eligible to undergo magnetic resonance imaging (MRI). Recruitment is community-based including advertisements, word-of-mouth, community events, and physician referrals. At baseline, following informed consent, participants complete detailed web-based surveys (e.g., demographics, health history, risk and resilience factors), followed by two half-day visits which include neurological exams, cognitive and functional assessments, an overnight sleep study, and biospecimen collection. Structural and functional MRI is completed by all participants and a subset also consent to amyloid PET imaging. Annual follow-up visits repeat the same data and biospecimen collection as baseline, except that MRIs are conducted every other year after baseline.

Ethics and expected impact

HBI has been approved by the University of Miami Miller School of Medicine Institutional Review Board. Participants provide informed consent at baseline and are re-consented as needed with protocol changes. Data collected by HBI will lead to breakthroughs in developing new diagnostics and therapeutics, create comprehensive diagnostic evaluations, and provide the evidence base for precision medicine approaches to dementia prevention with individualized treatment plans.
Outcomes Following Surgical Repair of Sinus Venosus Atrial Septal Defects: A Systematic Review
Authors: El-Andari Ryaan , Moolla Muhammad , John Kevin , Slingerland Ashley , Campbell Sandra , Nagendran Jeevan , Mathew Anoop
Published: September 2023

Background

Sinus venosus atrial septal defect (SVASD) is a rare congenital cardiac anomaly comprising 5- 10% of all atrial septal defects. Although surgical closure is the standard treatment, data on outcomes have been confined to small cohorts.

Methods

We conducted a systematic review and meta-analysis of studies reporting the outcomes of surgical repair of SVASD. The primary outcome was mortality. Secondary outcomes encompassed atrial fibrillation, sinus node dysfunction, pacemaker insertion, cerebrovascular accident (CVA), reoperation, residual septal defect, superior vena cava (SVC) obstruction, and reimplanted pulmonary vein obstruction, occurring after surgical repair of SVASD. Pooled incidences of outcomes were calculated using a random effects model.

Results

Forty studies involving 1,292 patients who underwent SVASD repair were included. The majority were male (59.4%), with 92.9% presenting with associated pulmonary anomalous venous connection. The weighted mean ages were 18.6 ± 12.5 years, and the overall weighted mean follow-up period was 8.6 ± 10.4 years. In-hospital mortality rate was 0.24%, with a 30-day mortality of 0.56% reported in 720 patients. Incidences of atrial fibrillation, sinus node dysfunction, pacemaker insertion, and CVA over the long-term follow-up were 2% (1-3%), 4% (2-6%), 2% (1-2%), respectively. Reoperation, residual septal defect, SVC obstruction, and reimplanted pulmonary vein obstruction occurred in 1% (0-2%), 2% (2-2%), 1% (1-1%), and 2% (2-2%) surgeries, respectively.

Conclusions

This is the first comprehensive analysis of outcomes following surgical repair of SVASD. The findings affirm the safety and effectiveness of surgery, establishing a reference point for evaluating emerging transcatheter therapies. Comparable safety and efficacy profiles to surgical repair are essential for widespread adoption of transcatheter treatments.
Effectiveness of Hyperbaric Oxygen Therapy Compared to Surgical Free Tissue Flap for Osteoradionecrosis of the Jaw: A Meta-Analysis
Authors: Sheth Megha K. , Collet Casey , Lin De-Chen , Sinha Uttam K.
Published: September 2023

Background

Osteoradionecrosis (ORN) of the jaw is an uncommon but potentially serious complication of radiation therapy for head and neck cancer, with many cases presenting months to years after completion of radiotherapy. ORN-related morbidity is high, making effective management of osteoradionecrosis essential. Current treatment options include hyperbaric oxygen therapy (HBOT), surgical management (free flap), and PENTOCLO, among others. Our goal is to analyze the reported efficacy of hyperbaric oxygen therapy versus microvascular free flap in ORN.

Methods

This review was conducted using the Preferred Reporting Items for Systematic Review & Meta-Analysis (PRISMA) guidelines. A systematic review search strategy was developed by a librarian (JED). The search was performed in the following databases on March 8, 2023: PubMed, EMBASE, andClinicalTrials.gov. Two reviewers independently assessed the titles, abstracts, and full-text manuscripts based on predetermined inclusion and exclusion criteria. The risk of bias of the final included studies was assessed using the Newcastle-Ottawa Scale. final included studies were assessed using the Newcastle-Ottawa risk of bias assessment, and analyses were performed using risk ratios.

Results

The initial search yielded 1,614 articles with 407 undergoing full-text review. Ultimately, nine studies met the eligibility criteria and were included in the review. In total, 339 patients were included across the nine studies. Each of the nine studies reported on resolution of ORN with HBOT versus surgical free flap, with six studies showing significant differences in outcomes, with surgical free flap yielding significantly higher complete resolution of ORN compared to HBOT (RR 0.42, 95% CI 0.2-0.85; RR 0.07, 95% CI 0-0.99; RR 0.04, 95% CI 0-0.57; RR 0.12, 95% CI 0.04-0.34; RR 0.21, 95% CI 0.08-0.54; RR 0.43, 95% CI 0.24-0.78). Three studies showed no significant differences in ORN resolution (RR 0.33, 95% CI 0.03-4.19; RR 0.33, 95% CI 0.03-4.19; RR 0.34, 95% CI 0.11-1.09). The summary outcome of ORN resolution found a significant difference between surgical free flap and HBOT (RR 0.28, 95% CI 0.17-0.45).

Conclusions

Despite the traditional practice of recommending HBOT for ORN treatment, our meta-analysis suggests that HBOT provides little benefit, especially for later stages of disease, and that surgical intervention via surgical free flap yields superior outcomes. However, there may be some benefit of HBOT in conservative management of early and intermediate cases of ORN. Surgical reconstruction with microvascular free flap may be a superior alternative to HBOT in the management of these patients.
Comparative performance of COVID-19 Test Methods in Healthcare Workers during the Omicron Wave
Authors: Tornberg Emma , Tomlinson Alexander , Oshiro Nicholas T.T. , Derfalie Esraa , Curlin Marcel E.
Published: September 2023

Introduction

The COVID-19 pandemic presents unique requirements for accessible, reliable testing, and many testing platforms and sampling techniques have been developed. However, not all test methods have been systematically compared to each other or a common gold standard, and the performance of tests developed in the early epidemic have not been consistently re-evaluated in the context of newly emerging SARS-CoV-2 variants.

Methods

We conducted a repeated measures study with adult healthcare workers presenting for SARS-CoV-2 testing. Participants were tested using seven test modalities: PCR with samples from the nasopharynx, oropharynx, and saliva; and BinaxNOW and iHealth antigen–based rapid detection tests (AgRDT) sampling the oropharynx and the nares. Test sensitivity was compared using any positive PCR test as the gold standard.

Results

325 individuals participated in the study. PCR tests were the most sensitive with saliva PCR at 0.957 ± 0.048, nasopharyngeal PCR at 0.877 ± 0.075, and oropharyngeal PCR at 0.849 ± 0.082. Standard nasal rapid antigen tests were less sensitive but roughly equivalent at 0.613 ± 0.110 for BinaxNOW brand and 0.627 ± 0.109 for iHealth. Oropharyngeal rapid antigen tests were the least sensitive with BinaxNOW and iHealth brands at 0.400 ± 0.111 and 0.311 ± 0.105 respectively.

Conclusion

PCR remains the most sensitive testing modality for COVID-19, with saliva PCR being significantly more sensitive than oropharyngeal PCR and equivalent to nasopharyngeal PCR. Saliva testing has patient comfort and financial benefits, making it a preferred testing modality. Nasal AgRDTs are less sensitive than PCR though more accessible and convenient.
Healthcare Costs and Healthcare Utilization Outcomes of Vitamin D3 Supplementation at 5000 IU Daily During a 10.9 month Observation Period within a Pragmatic Randomized Clinical Trial
Authors: LaRiccia Patrick J. , Cafaro Teresa , John Dibato , van Helmond Noud , Mitrev Ludmil V. , Bandomer Brigid , Brobyn Tracy L. , Hunter Krystal , Roy Satyajeet , Ng Kevin Q. , Goldstein Helen , Tsai Alan , Thwing Denise , Maag Mary Ann , Chung Myung K.
Published: September 2023

Vitamin D insufficiency has been linked to multiple conditions including bone disease, respiratory disease, cardiovascular disease, diabetes, and cancer. Observational studies indicate lower healthcare costs and healthcare utilization with sufficient vitamin D levels. The secondary aims of our previously published pragmatic clinical trial of vitamin D3 supplementation were comparisons of healthcare costs and healthcare utilization. Comparisons were made between the vitamin D3 at 5000 IU supplementation group and a non-supplemented control group. Costs of care between the groups were not statistically different. Vitamin D3 supplementation reduced healthcare utilization in four major categories: hospitalizations for any reason (rate difference: -0.19 per 1000 person-days, 95%-CI: -0.21 to -0.17 per 1000 person-days,p< 0.0001); ICU admissions for any reason (rate difference: -0.06 per 1000 person-days, 95%-CI: -0.08 to -0.04 per 1000 person-days,p< 0.0001); emergency room visits for any reason (rate difference: -0.26 per 1000 person-days, 95%-CI: -0.46 to -0.05 per 1000 person-days,p= 0.0131; and hospitalizations due to Covid-19 (rate difference: -8.47X10−3per 1000 person-days, 95%-CI: -0.02 to -1.05X10−3per 1000 person-days,p= 0.0253). Appropriately powered studies of longer duration are recommended for replication of these utilization findings and analysis of cost differences.
MODELING CYSTIC FIBROSIS PATIENT PROGNOSIS: NOMOGRAMS TO PREDICT LUNG TRANSPLANTATION AND SURVIVAL PRIOR TO HIGHLY EFFECTIVE MODULATOR THERAPY
Authors: Piccorelli Annalisa V. , Nick Jerry A.
Published: September 2023

Background

The duration of time a person with cystic fibrosis (pwCF) spends on the lung transplant waitlist is dependent on waitlist and post-transplant survival probabilities and can extend up to 2 years. Understanding the characteristics involved with lung transplant and survival prognoses may help guide decision making by the patient, the referring CF Center and the transplant team.

Methods

This study seeks to identify clinical predictors of lung transplant and survival of individuals with CF using 29,847 subjects from 2003-2014 entered in the Cystic Fibrosis Foundation Patient Registry (CFFPR).

Results

Predictors significant (p ≤ 0.05) in the final logistic regression model predicting probability of lung transplant/death were: FEV1(% predicted), BMI, age of diagnosis, age, number of pulmonary exacerbations, race, sex, CF-related diabetes (CFRD), corticosteroid use, infections withB. cepacia, P. aeruginosa, S. aureus, MRSA, pancreatic enzyme use, insurance status, and consecutive ibuprofen use for at least 4 years. The final Cox regression model predicting time to lung transplant identified these predictors as significant FEV1(% predicted), BMI, age of diagnosis, age, number of pulmonary exacerbations, race, sex, CF-related diabetes (CFRD), corticosteroid use, infections withB. cepacia, P. aeruginosa, S. aureus, MRSA, pancreatic enzyme use, and consecutive ibuprofen use for at least 4 years. The concordance indices were 0.89 and 0.92, respectively.

Conclusions

The models are translated into nomograms to simplify investigation of how various characteristics relate to lung transplant and survival prognosis individuals with CF not receiving highly effective CFTR modulator therapy.
Adverse childhood experiences across Multiracial and monoracial groups with and without Indigenous ancestry
Authors: Lam-Hine Tracy , Riddell Corinne A. , Bradshaw Patrick T. , Omi Michael , Allen Amani M.
Published: September 2023

Adverse childhood experiences (ACEs) are linked to increased risk of a host of health outcomes in adulthood. Descriptive ACEs prevalence studies have previously identified that Multiracial people have the highest mean ACE score of any racial group, but do not offer explanations for these disparities. However, Multiracial people form one of the fastest-growing populations in the US, and the largest subgroup of Multiracial people is those that claim American Indian/Native American (AI/NA) ancestry. Mean ACE counts (scores) are also high among the AI/NA population, which may reflect impacts of land occupation and structural racism. This descriptive study uses data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) to test the hypothesis that mean ACE scores and prevalence of ACE components are higher among Multiracial AI/NA participants than Multiracial non-AI/NA participants. Mean scores were highest among AI/NA (mean = 3.21, 95% CI: 2.54, 3.97), Multiracial AI/NA (2.95, 95% CI: 2.71, 3.18), Multiracial non-AI/NA (2.88, 95% CI: 2.57, 3.19), and Black (2.84, 95% CI: 2.65, 3.02) groups. Differences in mean ACE scores and prevalence of ACE components between the two Multiracial groups were all insignificant. Results from this study did not support our hypothesis, suggesting that the Multiracial population’s high ACE scores are not driven primarily by those with AI/NA ancestry. Future studies should repeat this analysis in larger datasets and explore other determinants of high mean ACE scores among the Multiracial population.
Near-term forecasting of Covid-19 cases and hospitalisations in Aotearoa New Zealand
Authors: Plank Michael J. , Watson Leighton , Maclaren Oliver J.
Published: September 2023

Near-term forecasting of infectious disease incidence and consequent demand for acute healthcare services can support capacity planning and public health responses. Despite well-developed scenario modelling to support the Covid-19 response, Aotearoa New Zealand lacks advanced infectious disease forecasting capacity. We develop a model using Aotearoa New Zealand’s unique Covid-19 data streams to predict reported Covid-19 cases, hospital admissions and hospital occupancy. The method combines a semi-mechanistic model for disease transmission to predict cases with Gaussian process regression models to predict the fraction of reported cases that will require hospital treatment. We evaluate forecast performance against out-of-sample data over the period from 2 October 2022 to 23 July 2023. Our results show that forecast performance is reasonably good over a 1-3 week time horizon, although generally deteriorates as the time horizon is lengthened. The model has been operationalised to provide weekly national and regional forecasts in real-time. This study is an important step towards development of more sophisticated situational awareness and infectious disease forecasting tools in Aotearoa New Zealand.

Author summary

The emergency phase of the Covid-19 pandemic has ended, but Covid-19 continues to put significant additional load on stretched healthcare systems. Forecasting the number of hospital cases caused an infectious disease like Covid-19 over the next few weeks can help with effective planning and response. The ability to forecast reliably requires timely, high-quality data and accurate mathematical models. We have developed a model for forecasting the number of Covid-19 cases and hospitalisations in Aotearoa New Zealand. The model works in two stages: firstly predicting the number of new cases and secondly estimating the proportion of those cases that will need hospital treatment. The model produces a range of likely values, which is important because is impossible to predict with 100% accuracy. We show that the model does a reasonably good job of predicting hospitalisations up to 3 weeks ahead. The model has been used by public health agencies in Aotearoa New Zealand to help with healthcare capacity planning.
Diagnostic Accuracy of Carotid Plaque Instability by Noninvasive Imaging: A Systematic Review and Meta-analysis
Authors: Pakizer David , Kozel Jiří , Taffé Patrick , Elmers Jolanda , Feber Janusz , Michel Patrik , Školoudík David , Sirimarco Gaia
Published: September 2023

Background

There is increasing evidence that plaque instability in the extracranial carotid artery may lead to an increased stroke risk independently of the degree of stenosis. We aimed to determine diagnostic accuracy of vulnerable and stable plaque using noninvasive imaging modalities when compared to histology in patients with symptomatic and asymptomatic carotid atherosclerosis.

Methods

Medline Ovid, Embase, Cochrane Library, and Web of Science were searched for diagnostic accuracy of noninvasive imaging modalities (CT, MRI, US) in the detection of 1) vulnerable/stable plaque, and 2) vulnerable/stable plaque characteristics, compared to histology. The quality of included studies was assessed by QUADAS-2 and univariate and bivariate random-effect meta-analyses were performed.

Results

We included 36 vulnerable and 5 stable plaque studies in the meta-analysis, and out of 211 plaque characteristics from remaining studies, we classified 169 as vulnerable and 42 as stable characteristics (28 CT, 120 MRI, 104 US characteristics). We found that MRI had high accuracy (90% [95% CI:82–95%]) in the detection of vulnerable plaque, similar to CT (86% [95% CI:76–92%]; p>0.05), whereas US showed less accuracy (80% [95% CI:75– 84%]; p=0.013). CT showed a high diagnostic accuracy to visualize characteristics of vulnerable or stable plaques (89% and 90%) similar to MRI (86% and 89%; p>0.05); however US had lower accuracy (77%, p<0.001 and 82%, p>0.05).

Conclusions

CT and MRI have a similar, high performance to detect vulnerable carotid plaques, whereas US showed significantly less diagnostic accuracy. Moreover, MRI visualized all vulnerable plaque characteristics allowing for a better stroke risk assessment.

Registration

PROSPERO ID CRD42022329690 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=329690)
Cryo-EM structures of human SID-1 transmembrane family proteins and implications for their low-pH-dependent RNA transport activity
Authors: Zheng Le , Yang Tingting , Guo Hangtian , Qi Chen , Lu Yuchi , Xiao Haonan , Gao Yan , Liu Yue , Yang Yixuan , Zhou Mengru , Nguyen Henry C. , Zhu Yun , Sun Fei , Zhang Chen-yu , Ji Xiaoyun
Published: September 2023

Human SIDT1 and SIDT2 are closely related members of the systemic RNA interference (RNAi)-defective (SID-1) transmembrane family. Both mediate RNA internalization and intracellular transport and are involved in various biological processes. However, the molecular basis of RNA uptake, especially for exogenous small RNAs, remains elusive. Here, we present the cryo-electron microscopy (cryo-EM) structures of human SIDT1 and SIDT2. Both structures reveal the overall architecture of a dimeric arrangement contributed by the β-strand-rich extracellular domain (ECD) and the transmembrane domain (TMD) with 11 passes, highlighting the remarkable structural congruence. Thein situassays confirm that SIDT1 and SIDT2 exist as dimers or higher-order oligomers. We demonstrate that for both SIDT1 and SIDT2, the ECD binds small RNAs, such as dietary plant-derived miRNA, only under acidic conditions. In addition, RNA binding under low pH can trigger higher-order assembly of the ECD dimer, suggesting the potential importance of oligomerization during RNA uptake. Our results illustrate the molecular features of the conserved SID-1 family proteins to elucidate the mechanism of the low pH-dependent activation of RNA uptake mediated by SIDT1 and SIDT2. This study provides a promising understanding of the molecular basis of the nucleic acid delivery platform, which may potentially open new avenues for the design and optimization of RNA-based therapies.
A dynamic Hedgehog gradient orients tracheal cartilage rings
Authors: Kingsley Evan P. , Mishkind Darcy , Hiscock Tom W. , Tabin Clifford J.
Published: September 2023

The patterning of periodic stripes during embryonic development generates similar structures that repeat at regular spatial intervals within a tissue. These patterns are often attributed to a Turing-like mechanism, which self-organizes characteristically spaced stripes, but these patterns are predicted to be disorganized. Conversely, well-oriented, parallel stripes are often observed in nature. We investigate this phenomenon during the formation of the cartilage rings that support the amniote airway. We find evidence that a Turing-like mechanism underpins the formation of the repeating cartilage elements. Additionally,SHHis transiently expressed in a thin dorsal domain along the length of the developing trachea, resulting in a dorsoventral gradient of Hedgehog activity that recedes over time. Using mathematical modelling, we predict that the spatiotemporal dynamics of the gradient are required to organize the stripes into parallel rings. Comparingin silicopredictions with experimental SHH manipulations shows that the Hedgehog gradient is essential for proper tracheal cartilage patterning.
Deep Learning based retinal layer segmentation in optical coherence tomography scans of patients with inherited retinal diseases
Authors: Eckardt Franziska , Mittas Robin , Horlava Nastassya , Schiefelbein Johannes , Asani Ben , Michalakis Stylianos , Gerhardt Maximilian , Priglinger Claudia , Keeser Daniel , Koutsouleris Nikolaos , Priglinger Siegfried , Theis Fabian , Peng Tingying , Schworm Benedikt
Published: September 2023

Background

On optical coherence tomography (OCT) scans of patients with inherited retinal diseases (IRDs), the outer nuclear layer (ONL) thickness measurement has been well established as a surrogate marker for photoreceptor preservation. Current automatic segmentation tools fail in OCT segmentation in IRDs, and manual segmentation is time consuming.

Methods and Material

Patients with IRD and the availability of an OCT scan were screened for the present study. Additionally, OCT scans of patients without retinal disease were included, to provide training data for the artificial intelligence (AI). We trained a U-net based model on healthy patients and applied a domain adaption technique to IRD patients’ scans.

Results

We established an AI-based image segmentation algorithm that reliably segments the ONL in OCT scans of IRD patients. In a test dataset, the dice-score of the algorithm was98.7%. Furthermore, we generated thickness maps of the full retinal thickness and the ONL layer for each patient.

Conclusion

Accurate segmentation of anatomical layers on OCT scans plays a crucial role for predictive models linking retinal structure to visual function. The here-presented OCT image segmentation algorithm could provide the basis for further studies on IRDs.
Mode of inheritance needs to be accounted for in interpreting genotype-phenotype links in monogenic disorders
Authors: Riera-Escamilla Antoni , Welt Corrine Kolka , Laan Maris
Published: September 2023

Introduction

A recently published study by Keet al. utilized whole exome sequencing (WES) to screen genetic variants contributing to premature ovarian insufficiency (POI) in a large cohort of 1,030 patients from China (doi: 10.1038/s41591-022-02194-3). The authors reported that 285 likely pathogenic (LP) and pathogenic (P) variants identified in 79 genes contributed to POI in 242 study subjects, representing 23.5% of the cohort. The majority, 191 patients (∼79%), carried monoallelic (heterozygous) variants.

Objective

We re-analyzed the contribution of reported genotypes considering the inheritance mode of POI and other inherited conditions linked to 79 genes with reported findings by Keet al.

Methods

The disease inheritance modes linked to targeted genes were retrieved from publicly available databases (OMIM, Genomic England PanelApp, PubMed, DOMINO, gnomAD). Genotypes of 242 cases reported by Keet al.were assessed in the context of known inheritance mode(s) of disorders linked to respective genes.

Results

Most, 48 of 79 genes were classified as recessive, whereas only 13 genes were dominant. Insufficient data was available for 18 genes to conclusively determine their inheritance mode. Nearly half of 242 cases reported by Keet al., 119 women (∼49%), carried heterozygous variants in known autosomal recessive genes and therefore these variants are not contributing to their POI phenotype. Only 68 of women (6.6%) carried biallelic variants in either recessive or dominant genes or monoallelic variants in dominant genes, hence contributing to the diagnostic yield. This is ∼3.5-fold lower than 23.5% claimed in Keet al. Additional 56 women (5.4%) were reported monoallelic variants in genes with insufficient data to determine the inheritance mode or multiple heterozygous variants in >1 recessive gene, whereby oligogenic contribution to POI cannot be excluded. But when even including these cases, the maximum estimated contributing yield is ∼12%, two times lower than claimed.

Conclusion

Using WES to screen monogenic causes of POI as part of the diagnostic pipeline will improve patient management strategies, but overestimated diagnostic yield in genetic research can create unrealistic expectations in the POI clinical community, typically non-specialist in genetics.
Development and validation of the Japanese version of the Lesbian, Gay, Bisexual, and Transgender Development of Clinical Skills Scale
Authors: Kanakubo Yusuke , Sugiyama Yoshifumi , Yoshida Eriko , Aoki Takuya , Mutai Rieko , Matsushima Masato , Okada Tadao
Published: September 2023

Introduction

The Lesbian, Gay, Bisexual, and Transgender Development of Clinical Skills Scale (LGBT-DOCSS) is a validated self-assessment tool for health and mental health professionals who provide care for sexual and gender minority patients. This study aimed to develop and validate a Japanese version of LGBT-DOCSS (LGBT-DOCSS-JP) and examine its psychometric properties.

Methods

LGBT-DOCSS was translated into Japanese and cross-culturally validated using cognitive debriefing. We then evaluated the structural validity, convergent and discriminant validity, internal consistency, and test–retest reliability of LGBT-DOCSS-JP using an online survey.

Results

Data were analyzed for 381 health and mental health professionals aged 20 years or older from three suburban medical institutions. The confirmatory factor analysis indicated that the original three-factor model did not fit well with LGBT-DOCSS-JP. Exploratory factor analysis revealed four new factors: Attitudinal Awareness, Basic Knowledge, Clinical Preparedness, and Clinical Training. Convergent and discriminant validity were supported using four established scales that measured attitudes toward lesbians and gay men, genderism and transphobia, authoritarianism and conventionalism, and social desirability. The internal consistency of LGBT-DOCSS-JP was supported by the Cronbach’s alpha values for the overall scale (0.84), as well for each of its subscales (Attitudinal Awareness and Basic Knowledge both 0.87, Clinical Preparedness 0.78, and Clinical Training 0.97). The test–retest reliability for the overall LGBT-DOCSS-JP was supported by an intraclass correlation coefficient score of 0.86.

Conclusions

LGBT-DOCSS-JP has the potential to serve as a valuable tool in the development and assessment of effective curricula for LGBT care education, as well as a means to promote self-reflection among trainees and professionals.
Evaluation ofHOTAIR,HOXD8,HOXD9,HOXD11Gene Expression Levels in Turkish Patients with Acute Myeloid Leukemia and Chronic Myeloid Leukemia: A Single Center Experience
Authors: Saraymen Esma , Erdem Yakut , Akalın Hilal , Taşçıoğlu Nazife , Saraymen Berkay , Çelik Serhat , Özdemir Yeşim , Kaynar Leylagül , Çetin Mustafa , Özkul Yusuf
Published: September 2023

BACKGRAUND

Homeobox (HOX) transcript antisense RNA (HOTAIR) andHOXgenes are reported to be more expressed in various cancers in humans in recent studies. The role ofHOTAIRandHOXDgenes in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) is not well known.

MATERIALS AND METHODS

In this study, expression levels ofHOXD8,HOXD9andHOXD11fromHOXDgene family andHOTAIRwere determined from peripheral blood samples of 30 AML and 30 CML patients and 20 healthy volunteers by quantitative Real Time PCR.

RESULTS

We determined that the expression levels ofHOXD9andHOXD11in the AML patients were significantly lower than the control group (p<0.001 and p=0.002, respectively). There was no significant difference in the expression levels ofHOTAIRandHOXD8when compared to the control group. In the CML patients there was a significant increase in the expression level ofHOTAIRwhen compared to the control group (p=0.002). The expression levels ofHOXD9andHOXD11were found to be significantly lower than the control group (p<0.001).

CONCLUSION

Our study showed thatHOTAIRmay not be a biomarker in the diagnosis and is not significantly correlated with the clinicopathological prognostic characteristics of AML. Additionally; it can be said thatHOTAIRis oncogenic by suppressing the expression ofHOXD9andHOXD11but notHOXD8in CML patients. The expression profiles ofHOTAIRmay be a potential biomarker in the diagnosis of CML patients in predicting and monitoring drug resistance.
Predicting survival and trial outcome in non-small cell lung cancer integrating tumor and blood markers kinetics with machine learning
Authors: Benzekry Sébastien , Karlsen Mélanie , Bigarré Célestin , Kaoutari Abdessamad El , Gomes Bruno , Stern Martin , Neubert Ales , Bruno Rene , Mercier François , Vatakuti Suresh , Curle Peter , Jamois Candice
Published: September 2023

Existing survival prediction models rely only on baseline or tumor kinetics data and lack machine learning integration. We introduce a novel kinetics-machine learning (kML) model that integrates baseline markers, tumor kinetics and four on-treatment simple blood markers (albumin, CRP, lactate dehydrogenase and neutrophils). Developed for immune-checkpoint inhibition (ICI) in non-small cell lung cancer on three phase 2 trials (533 patients), kML was validated on the two arms of a phase 3 trial (ICI and chemotherapy, 377 and 354 patients). It outperformed the current state-of-the-art for individual predictions with a test set c-index of 0.790, a 12-months survival accuracy of 78.7% and a hazard ratio of 25.2 (95% CI: 10.4 – 61.3,p< 0.0001) to identify long-term survivors. Critically, kML predicted the success of the phase 3 trial using only 25 weeks of on-study data (predicted HR = 0.814 (0.64 – 0.994) versus final study HR = 0.778 (0.65 – 0.931)). Our model constitutes a valuable approach to support personalized medicine and drug development.
Longitudinal analysis within one hospital in sub-Saharan Africa over 20 years reveals repeated replacements of dominant clones ofKlebsiella pneumoniaeand stresses the importance to include temporal patterns for vaccine design considerations
Authors: Heinz Eva , Pearse Oliver , Zuza Allan , Bilima Sithembile , Msefula Chisomo , Musicha Patrick , Siyabu Patriciah , Tewesa Edith , Graf Fabrice E , Lester Rebecca , Lissauer Samantha , Cornick Jennifer , Lewis Joseph M , Kawaza Kondwani , Thomson Nicholas R , Feasey Nicholas A
Published: September 2023

Infections caused by multidrug-resistant gram-negative bacteria present a severe threat to global public health. The WHO defines drug-resistantKlebsiella pneumoniaeas a priority pathogen for which alternative treatments are needed given the limited treatment options and the rapid acquisition of novel resistance mechanisms by this species. Longitudinal descriptions of genomic epidemiology ofKlebsiella pneumoniaecan inform management strategies but data from sub-Saharan Africa are lacking.

We present a longitudinal analysis of all invasiveK. pneumoniaeisolates from a single hospital in Blantyre, Malawi, southern Africa, from 1998-2020, combining clinical data with genome sequence analysis of the isolates. We show that after a dramatic increase in the number of infections from 2016K. pneumoniaebecomes hyperendemic, driven by an increase in neonatal infections. Genomic data show repeated waves of clonal expansion of different, often ward-restricted, lineages, suggestive of hospital associated transmission. We describe temporal trends in resistance and surface antigens, of relevance for vaccine development.

Our data highlight a clear need for new interventions to prevent rather than treatK. pneumoniaeinfections in our setting. Whilst one option may be a vaccine, the majority of cases could be avoided by an increased focus on and investment in infection prevention and control measures, which would reduce all healthcare associated infections and not just one.
Hematologic setpoints are a stable and patient-specific deep phenotype
Authors: Foy Brody H , Petherbridge Rachel , Roth Maxwell , Mow Christopher , Patel Hasmukh R , Patel Chhaya H , Ho Samantha N , Lam Evie , Karczewski Konrad J , Tozzo Veronica , Higgins John M
Published: September 2023

The complete blood count is an important screening tool for healthy adults and is the most commonly ordered test at periodic physical exams. However, results are usually interpreted relative to one-size-fits-all reference intervals, undermining the goal of precision medicine to tailor medical care to the needs of individual patients based on their unique characteristics. Here we show that standard complete blood count indices in healthy adults have robust homeostatic setpoints that are patient-specific and stable, with the typical healthy adult’s set of 9 blood count setpoints distinguishable from 98% of others, and with these differences persisting for decades. These setpoints reflect a deep physiologic phenotype, enabling improved detection of both acquired and genetic determinants of hematologic regulation, including discovery of multiple novel loci via GWAS analyses. Patient-specific reference intervals derived from setpoints enable more accurate personalized risk assessment, and the setpoints themselves are significantly correlated with mortality risk, providing new opportunities to enhance patient-specific screening and early intervention. This study shows complete blood count setpoints are sufficiently stable and patient-specific to help realize the promise of precision medicine for healthy adults.
Real World Experience and Clinical Utility of EsoGuard® - Interim Data from the Lucid Registry
Authors: Englehardt Richard , Samarasena Jason B. , Bildzukewicz Nikolai A. , Hamblin Rachelle , Lee Victoria T. , Verma Suman , deGuzman Brian J. , Aklog Lishan
Published: September 2023

Background

Barrett’s Esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), and guidelines exist for screening, surveillance, and treatment. However, historically most high-risk individuals have not been reliably screened, likely due to a combination of factors associated with patient/physician awareness and use of upper endoscopy (UE) as the traditional screening test. EsoGuard® (EG) is a DNA biomarker assay, and EsoCheck® (EC) is a non-invasive, swallowable capsule device designed to collect cells from a targeted region of the esophagus. EG and EC in combination offers a well-tolerated, accessible, in-office triage test to improve detection of BE in patients with multiple risk factors. The Lucid Registry captures real-world data from the commercial use of EC with EG, and we present an interim review of clinical utility data from the first 517 enrolled subjects.

Methods

Multicenter, prospective, registry designed to capture data from patients undergoing EC cell collection and EG testing in the commercial setting. Data collection consists of demographics, risk factors, test results, provider management, and early clinical outcomes (through a maximum of four months post-EG). This data snapshot includes subjects enrolled from the start of the registry (April 14, 2023), through August 16, 2023. The primary assessment of clinical utility was agreement between EG assay results and physicians’ decision on whether to refer the patient for subsequent UE. The relationship between BE/EAC risk factors and EG positivity rates was assessed.

Results

Among 517 subjects enrolled, average age was 47.9±14.3 years, 47.2% had history of gastroesophageal reflux disease (GERD), and 63.8% had a minimum of 3 established BE risk factors (i.e., met American Gastroenterological Association (AGA) criteria for screening). 58.8% of subjects were firefighters; when firefighting i.e., occupational exposure to smoke and carcinogens is treated as an additional BE/EAC risk factor (+) those of the AGA, 81.2% of the study population had ≥3 risks, making up the “AGA(+)” cohort. EG positivity was 14.1%. 437 subjects contributed data for the clinical utility endpoint: agreement between positive EG results and subsequent referral for UE was 100%; agreement between negative EG results and non-referral for UE was 99.4%; concordance between EG results and UE referral decisions was 97.9%. These findings were comparable between the AGA and AGA(+) cohorts.

Conclusions

Experience from the Lucid Registry demonstrates that physicians who have adopted EC/EG in the commercial setting are reliably utilizing EG as a triage test to inform decision making on which patients to refer for further endoscopic evaluation of BE.
Assessing Folic Acid Supplementation Adherence Among Pregnant Women in LMICs and its Impact on Neural Tube Defect Incidence: A Systematic Review Protocol
Authors: Daniel Jeremiah Oluwatomi Itodo , Sulaiman Abdulmuizz Oluwatomi , Isiakpona Chiwendu , Igoli Joanne , Chukwumaeze Chukwunonso Emmanuel , Morgan Eghosa , Olukoya Olatomiwa
Published: September 2023

Introduction

Neural tube defects (NTDs) are treatable but incurable birth defects, causing permanent disability and potential mortality if neglected. Despite its global significance, there has not been any systematic review exploring the link between folic acid adherence and NTD incidence in low-and-middle-income countries (LMICs), where its impact is disproportionately felt. This systematic review primarily aims to analyze the impact of folic acid supplementation adherence among expectant mothers on the incidence of NTDs in LMICs.

Methods and Analysis

Following the PRISMA guidelines, we will conduct a comprehensive search of original research articles and observational studies using the electronic databases of PubMed, Scopus, Medline, and Embase from inception till date. Our search comprises keywords related to our PICO framework and objectives. We will analyze data using tables and diagrams for qualitative presentation and conduct a random-effect Bayesian meta-analysis when applicable.

Two reviewers will screen titles and abstracts independently, conduct full-text reviews, and extract study data. In case of disagreements, a third reviewer will resolve them. We will present study details and assess bias risk. We will also assess the overall certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation framework.

Ethics and Dissemination

Ethical approval is unnecessary as this study involves a systematic review of published studies. We aim to publish our findings in a peer-reviewed journal.
Molecular principles of CRISPR-Cas13 mismatch intolerance enable selective silencing of point-mutated oncogenic RNA with single-base precision
Authors: Shembrey Carolyn , Yang Ray , Casan Joshua , Hu Wenxin , Sadras Teresa , Prasad Krishneel , Shortt Jake , Johnstone Ricky W , Trapani Joseph A , Ekert Paul G , Fareh Mohamed
Published: September 2023

Single nucleotide variants (SNVs) are extremely prevalent in human cancers. For instance, KRAS mutations occur in over 90% of pancreatic cancers and ∼40% of colorectal cancers. Virtually all KRAS mutations are SNVs, most of which remain clinically unactionable. The programmable RNA nuclease CRISPR-Cas13 has been deployed to specifically target RNAs such as overexpressed oncogenes and fusion transcripts. However, silencing oncogenic SNVs with single-base precision remains extremely challenging due to the intrinsic mismatch tolerance of Cas13. Here, we developed a comprehensive mutagenesis analysis of target-spacer interactions at single-nucleotide resolution, which revealed key spacer nucleotide positions intolerant to mismatches. We show that introducing synthetic mismatches at these precise positions enablesde novadesign of CRISPR RNA (crRNA) with strong preferential silencing of SNV transcripts. We demonstrate that our top-performing crRNAs possess prominent SNV-selectivity with dose-dependent silencing activity against all KRAS G12 variants at both the RNA and protein levels with minimal off-target silencing of wildtype KRAS. We applied these design principles to effectively silence oncogenic NRAS G12D and BRAF V600E transcripts, underscoring the adaptability of this platform to silence various SNVs. These findings demonstrate that the CRISPR Cas13 system can be reprogrammed to target mutant transcripts with single-base precision, showcasing the tremendous potential of this tool in personalized transcriptome editing.

Abstract Figure
Virulence and transmission biology of the widespread, ecologically important pathogen of zooplankton,Spirobacillus cienkowskii
Authors: Wale Nina , Freimark Claire B. , Ramirez Justin , Dziuba Marcin K. , Kafri Ahmad Y. , Bilich Rebecca , Duffy Meghan A.
Published: September 2023

Spirobacillus cienkowskii(Spirobacillus,hereafter) is a widely distributed bacterial pathogen that has significant impacts on the population dynamics of zooplankton (Daphnia spp.), particularly in months whenDaphniaare asexually reproducing. Yet little is known aboutSpirobacillus’virulence, transmission mode and dynamics. As a result, we cannot explain the dynamics ofSpirobacillusepidemics in nature or useSpirobacillusas a model pathogen, despiteDaphnia’stractability as a model-host. Here, we work to fill these knowledge gaps experimentally. We found thatSpirobacillusis among the most virulent ofDaphniapathogens, killing its host within a week and reducing host fecundity. We further found thatSpirobacillusdid not transmit horizontally among hosts unless the host died or was destroyed (i.e., it is an “obligate killer”). In experiments aimed at quantifying the dynamics of horizontal transmission among asexually reproducingDaphnia, we demonstrated thatSpirobacillustransmits poorly in the laboratory. In mesocosms,Spirobacillusfailed to generate epidemics; in experiments wherein individualDaphniawere exposed,Spirobacillus’transmission success was low. In the (limited) set of conditions we considered,Spirobacillus’transmission success did not change with host density or pathogen dose and declined following environmental incubation. Lastly, we conducted a field survey ofSpirobacillus’prevalence within egg-cases (ephippia) made by sexually reproducingDaphnia. We foundSpirobacillusDNA in ∼40% of ephippia, suggesting that, in addition to transmitting horizontally among asexually reproducingDaphnia,Spirobacillusmay transmit vertically from sexually reproducingDaphnia. Our work fills critical gaps in the biology ofSpirobacillusand illuminates new hypotheses vis-à-vis its life-history.

Importance

Spirobacillus cienkowskiiis a bacterial pathogen of zooplankton, first described in the 19thCentury and recently placed in a new family of bacteria, theSilvanigrellaceae.Spirobacilluscauses epidemics in lake zooplankton populations and increases the probability that zooplankton will be eaten by predators. However, little is known about howSpirobacillustransmits among hosts, its impact on host survival and reproduction (i.e., how virulent it is) in laboratory conditions and what role virulence plays inSpirobacillus’life cycle. Here, we experimentally quantifiedSpirobacillus’ virulence and showed thatSpirobacillusmust kill its host to transmit horizontally. We also found evidence thatSpirobacillusmay transmit vertically viaDaphnia’s seed-like egg cases. Our work will help scientists to (i) understandSpirobacillusepidemics, (ii) useSpirobacillusas a model pathogen for the study of host-parasite interactions and (iii) better understand the unusual group of bacteria to whichSpirobacillusbelongs.