bluuebunny/crossref_metadata_2025 huggingface dataset:
How to assess tissue oxygenation?
Authors: De Backer Daniel , Ospina-Tascón Gustavo A.
Published: April 2023

Purpose of review

To discuss the different techniques used to assess tissue oxygenation in critically ill patients.

Recent findings

While historically the analysis of oxygen consumption (VO2)/oxygen delivery (DO2) relationships has provided important information, methodological limitations prevent its use at bedside. PO2 measurements, while attractive, are unfortunately of limited value in the presence of microvascular blood flow heterogeneity which is observed in many critically ill conditions including sepsis. Surrogates of tissue oxygenation are hence used. Elevated lactate levels may suggest inadequate tissue oxygenation, but other sources than tissue hypoxia can also contribute to hyperlactatemia so that lactate measurements should be used in combination with other measurements of tissue oxygenation. Venous O2 saturation can be used to evaluate the adequacy of DO2 in respect to VO2, but it can be misleading normal or even high in sepsis. Measurements of Pv-aCO2 and computation of Pv-aCO2/CavO2 are very promising as physiologically sound, easy to measure, rapidly respond to therapy, and are associated with outcome. An elevated Pv-aCO2 reflects an impaired tissue perfusion while an increased Pv-aCO2/CavO2 ratio reflects tissue dysoxia.

Recent studies have highlighted the interest of surrogate measurements of tissue oxygenation and in particular PCO2 gradients.
Drainage Approach for Malignant Biliary Obstruction
Authors: Eisenberg Ian , Gaidhane Monica , Kahaleh Michel , Tyberg Amy
Published: April 2023

Endoscopic retrograde cholangiopancreatography (ERCP) is the standard of care in the management of unresectable malignant biliary obstruction. However, endoscopic ultrasound (EUS)-guided biliary drainage has become widely accepted over the past several years for complicated biliary drainage in cases when ERCP is unsuccessful or not feasible. Recent emerging evidence suggests EUS-guided hepaticogastrostomy and EUS-guided choledochoduodenostomy are noninferior, and possibly even superior to conventional ERCP for primary palliation of malignant biliary obstruction. This article reviews the procedural techniques and considerations of the different techniques as well as comparative literature on safety and efficacy between techniques.
The Natural History of Pancreatic Cystic Lesions in Liver Transplant Recipients
Authors: Canakis Andrew , Vittal Anusha , Deliwala Smit , Twery Benjamin , Canakis Justin , Patel Preet , Chahal Prabhleen
Published: April 2023

Objectives

The management of incidentally discovered pancreatic cystic lesions (PCLs) with surveillance or resection often requires shared decision-making. Patients with cirrhosis are more likely to have PCLs discovered due to increased imaging, and those undergoing liver transplantations (LTs) may be at increased risk of carcinogenesis due to immunosuppressive medications. Our study aimed to characterize the outcomes and risk of malignant progression of PCLs in post-LT patients.

Methods

Multiple databases were searched for studies looking at PCLs in post-LT patients from inception until February 2022. Primary outcomes were the incidence of PCLs in LT recipients and progression to malignancy. Secondary outcomes included development of worrisome features, outcomes of surgical resection for progression, and change in size.

Results

A total of 12 studies with 17,862 patients with 1411 PCLs were included. The pooled proportion of new PCL development in post-LT patients was 68% (95% confidence interval [CI], 42–86; I
2 = 94%) over the follow-up of 3.7 (standard deviation, 1.5) years. The pooled progression of malignancy and worrisome features was 1% (95% CI, 0–2; I
2 = 0%) and 4% (95% CI, 1–11; I
2 = 89%), respectively.

Conclusions

Compared with nontransplant patients, incidental PCLs do not carry a higher risk of malignancy.
Predictors of Delayed Diagnosis of Pediatric CNS Tumors in the Emergency Department
Authors: Young Ann L. , Monuteaux Michael C. , Cooney Tabitha M. , Michelson Kenneth A.
Published: April 2023

Objective

Central nervous system (CNS) tumor diagnoses are frequently delayed in children, which may lead to adverse outcomes and undue burdens on families. Examination of factors associated with delayed emergency department (ED) diagnosis could identify approaches to reduce delays.

Study Design

We performed a case-control study using data from 2014 to 2017 for 6 states. We included children aged 6 months to 17 years with a first diagnosis of CNS tumor in the ED. Cases had a delayed diagnosis, defined as 1 or more ED visits in the 140 days preceding tumor diagnosis (the mean prediagnostic symptomatic interval for pediatric CNS tumors in the United States). Controls had no such preceding visit.

Results

We included 2828 children (2139 controls, 76%; 689 cases, 24%). Among cases, 68% had 1 preceding ED visit, 21% had 2, and 11% had 3 or more. Significant predictors of delayed diagnosis included presence of a complex chronic condition (adjusted odds ratio [aOR], 9.73; 95% confidence interval [CI], 6.67–14.20), rural hospital location (aOR, 6.37; 95% CI, 1.80–22.54), nonteaching hospital status (aOR, 3.05, compared with teaching hospitals; 95% CI, 1.94–4.80), age younger than 5 years (aOR, 1.57; 95% CI, 1.16–2.12), public insurance (aOR, 1.49, compared with private; 95% CI, 1.16–1.92), and Black race (aOR, 1.42, compared with White; 95% CI, 1.01–1.98).

Conclusions

Delayed ED diagnosis of pediatric CNS tumors is common and frequently requires multiple ED encounters. Prevention of delays should focus on careful evaluation of young or chronically ill children, mitigating disparities for Black and publicly insured children, and improving pediatric readiness in rural and nonteaching EDs.
Evaluation of the Renal Angina Index to Predict the Development of Acute Kidney Injury in Children With Sepsis Who Live in Middle-Income Countries
Authors: Suárez María Del Pilar , Fernández-Sarmiento Jaime , González Luz Esthella , Rico Mayerly Prada , Barajas Juan Sebastián , Amaya Ricardo Gastelbondo
Published: April 2023

Objective

The renal angina index (RAI) provides a clinically feasible and applicable tool to identify critically ill children at risk of severe acute kidney injury (AKI) in high-income countries. Our objective was to evaluate the performance of the RAI as a predictor of the development of AKI in children with sepsis in a middle-income country and its association with unfavorable outcomes.

Methods

This is a retrospective cohort study in children with sepsis hospitalized in the pediatric intensive care unit (PICU) between January 2016 and January 2020. The RAI was calculated 12 hours after admission to predict the development of AKI and at 72 hours to explore its association with mortality, the need for renal support therapy, and PICU stay.

Results

We included 209 PICU patients with sepsis with a median age of 23 months (interquartile range, 7–60). We found that 41.1% of the cases (86/209) developed de novo AKI on the third day of admission (KDIGO 1, 24.9%; KDIGO 2, 12.9%; and KDIGO 3, 3.3%).

Overall mortality was 8.1% (17/209), higher in patients with AKI (7.7% vs 0.5%, P < 0.01). The RAI on admission was able to predict the presence of AKI on day 3 (area under the curve (AUC), 0.87; sensitivity, 94.2%; specificity, 100%; P < 0.01), with a negative predictive value greater than 95%. An RAI greater than 8 at 72 hours was associated with a greater risk of mortality (adjusted odds ratio [aOR], 2.6; 95% confidence interval [CI], 2.0–3.2; P < 0.01), a need for renal support therapy (aOR, 2.9; 95% CI, 2.3–3.6; P < 0.01), and a PICU stay of more than 10 days (aOR, 1.54; 95% CI, 1.1–2.1; P < 0.01).

Conclusions

The RAI on the day of admission is a reliable and accurate tool for predicting the risk of developing AKI on day 3, in critically ill children with sepsis in a limited resource context. A score greater than eight 72 hours after admission is associated with a higher risk of death, the need for renal support therapy, and PICU stay.
The Fidelity of a Pharmacy-Based Oral HIV Pre-Exposure Prophylaxis Delivery Model in Kenya
Authors: Omollo Victor , Asewe Magdaline , Mogere Peter , Maina Gakuo , Kuo Alexandra P. , Odoyo Josephine , Oware Kevin , Baeten Jared M. , Kohler Pamela , Owens Tamara , Bukusi Elizabeth A. , Ngure Kenneth , Ortblad Katrina F.
Published: April 2023

Background:

HIV pre-exposure prophylaxis (PrEP) delivery at private pharmacies is a promising new differentiated service delivery model that may address barriers to PrEP delivery at public health care facilities. We measured the fidelity of this model (ie, delivery as intended) in a pilot study in Kenya.

Setting:

Five private, retail pharmacies in Kisumu and Thika Counties.

Methods:

Trained pharmacy providers delivered PrEP services, including identifying eligible clients, counseling on HIV risk, assessing PrEP safety, testing for HIV, and dispensing PrEP. Pharmacy clients completed surveys that assessed the fidelity of the services received after each visit. Standardized client actors (ie, mystery shoppers) were trained on 4 different case scripts, then made unannounced pharmacy visits, and then completed a 40-item checklist that assessed the fidelity and quality of service delivery components.

Results:

From November 2020 to December 2021, 287 clients initiated and 159 (55%) refilled PrEP. At initiation, most clients were counseled on PrEP adherence (99%, 284 of 287) and potential side effects (97%, 279 of 287) and all received provider-assisted HIV self-testing before PrEP dispensing (findings consistent across refill visits). Nine standardized client actors completed 15 pharmacy visits. At each visit, most actors were asked about their behaviors associated with HIV risk (80%, 12/15) and all were counseled on PrEP safety and side effects. All actors reported that pharmacy providers treated them with respect.

Conclusions:

In this first pilot study of pharmacy-delivered PrEP services in Africa, the fidelity of service delivery was high, suggesting that trained providers at private pharmacies can deliver quality PrEP services.
Diagnosing viral encephalitis and emerging concepts
Authors: Yong Heather Y.F. , Pastula Daniel M. , Kapadia Ronak K.
Published: April 2023

Purpose of review

This review offers a contemporary clinical approach to the diagnosis of viral encephalitis and discusses recent advances in the field. The neurologic effects of coronaviruses, including COVID-19, as well as management of encephalitis are not covered in this review.

Recent findings

The diagnostic tools for evaluating patients with viral encephalitis are evolving quickly. Multiplex PCR panels are now in widespread use and allow for rapid pathogen detection and potentially reduce empiric antimicrobial exposure in certain patients, while metagenomic next-generation sequencing holds great promise in diagnosing challenging and rarer causes of viral encephalitis. We also review topical and emerging infections pertinent to neuroinfectious disease practice, including emerging arboviruses, monkeypox virus (mpox), and measles.

Although etiological diagnosis remains challenging in viral encephalitis, recent advances may soon provide the clinician with additional tools. Environmental changes, host factors (such as ubiquitous use of immunosuppression), and societal trends (re-emergence of vaccine preventable diseases) are likely to change the landscape of neurologic infections that are considered and treated in clinical practice.
Epidemiological and genomic investigation of chikungunya virus in Rio de Janeiro state, Brazil, between 2015 and 2018
Authors: Moreira Filipe Romero Rebello , de Menezes Mariane Talon , Salgado-Benvindo Clarisse , Whittaker Charles , Cox Victoria , Chandradeva Nilani , de Paula Hury Hellen Souza , Martins André Frederico , das Chagas Raphael Rangel , Brasil Rodrigo Decembrino Vargas , Cândido Darlan da Silva , Herlinger Alice Laschuk , Ribeiro Marisa de Oliveira , Arruda Monica Barcellos , Alvarez Patricia , Tôrres Marcelo Calado de Paula , Dorigatti Ilaria , Brady Oliver , Voloch Carolina Moreira , Tanuri Amilcar , Iani Felipe , de Souza William Marciel , Cardozo Sergian Vianna , Faria Nuno Rodrigues , de Aguiar Renato Santana
Published: April 2023

Since 2014, Brazil has experienced an unprecedented epidemic caused by chikungunya virus (CHIKV), with several waves of East-Central-South-African (ECSA) lineage transmission reported across the country. In 2018, Rio de Janeiro state, the third most populous state in Brazil, reported 41% of all chikungunya cases in the country. Here we use evolutionary and epidemiological analysis to estimate the timescale of CHIKV-ECSA-American lineage and its epidemiological patterns in Rio de Janeiro. We show that the CHIKV-ECSA outbreak in Rio de Janeiro derived from two distinct clades introduced from the Northeast region in mid-2015 (clade RJ1,n= 63/67 genomes from Rio de Janeiro) and mid-2017 (clade RJ2,n= 4/67). We detected evidence for positive selection in non-structural proteins linked with viral replication in the RJ1 clade (clade-defining: nsP4-A481D) and the RJ2 clade (nsP1-D351G). Finally, we estimate the CHIKV-ECSA’s basic reproduction number (R0) to be between 1.2 to 1.6 and show that its instantaneous reproduction number (Rt) displays a strong seasonal pattern with peaks in transmission coinciding with periods of highAedes aegyptitransmission potential. Our results highlight the need for continued genomic and epidemiological surveillance of CHIKV in Brazil, particularly during periods of high ecological suitability, and show that selective pressures underline the emergence and evolution of the large urban CHIKV-ECSA outbreak in Rio de Janeiro.
Long-Term Clinical Outcomes in Critically Ill Patients with Sepsis and Pre-existing Sarcopenia: A Retrospective Cohort Study
Authors: Darden Nola , Sharma Sonakshi , Wu Xue , Mancini Benjamin , Karamchandani Kunal , Bonavia Anthony S
Published: April 2023

Purpose

Critically ill patients with sepsis account for significant disease morbidity and healthcare costs. Sarcopenia has been proposed as an independent risk factor for poor short-term outcomes, although its effect on long-term outcomes remains unclear.

Methods

Retrospective cohort analysis of patients treated at a tertiary care medical center over 6 years (09/2014 - 12/2020). Critically ill patients meeting Sepsis-3 criteria were included, with sarcopenia defined by skeletal muscle index at the L3 lumbar area on abdominal Computed-Tomography scan. The prevalence of sarcopenia and its association with clinical outcomes was analyzed.

Results

Sarcopenia was present in 34 (23%) of 150 patients, with median skeletal muscle indices of 28.1 cm2/m2and 37.3 cm2/m2in sarcopenic females and males, respectively. In-hospital mortality was not associated with sarcopenia when adjusted for age and illness severity. One year mortality was increased in sarcopenic patients, after adjustment for illness severity (HR 1.9, p = 0.02) and age (HR 2.4, p = 0.001). However, it was not associated with increased likelihood for discharge to long-term rehabilitation or hospice care in adjusted analyses.

Conclusion

Sarcopenia independently predicts one year mortality but is not associated with unfavorable hospital discharge disposition in critically ill patients with sepsis.
Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Authors: Horby Peter W , Staplin Natalie , Peto Leon , Emberson Jonathan R , Campbell Mark , Pessoa-Amorim Guilherme , Basnyat Buddha , Thwaites Louise , Van Doorn Rogier , Hamers Raph L , Nel Jeremy , Amuasi John , Rawal Manisha , Ghosh Dipansu , Douse Jonathan , Hamilton Fergus , Kerry Anthony , Thu-Ta Pinky , Widdrington John , Green Chris , Desai Purav , Stewart Richard , Phong Nguyen Thanh , Baillie J Kenneth , Buch Maya H , Faust Saul N , Jaki Thomas , Jeffery Katie , Juszczak Edmund , Knight Marian , Lim Wei Shen , Montgomery Alan , Mukherjee Aparna , Mumford Andrew , Rowan Kathryn , Thwaites Guy , Mafham Marion , Haynes Richard , Landray Martin J ,   RECOVERY Collaborative Group
Published: April 2023

Background

Empagliflozin has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory, metabolic and haemodynamic effects.

Methods

In this randomised, controlled, open-label trial, several possible treatments are compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus empagliflozin 10mg once daily for 28 days or until discharge using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. On 3 March the independent data monitoring committee recommended that the investigators review the data and recruitment was consequently stopped on 7 March. The trial is registered with ISRCTN (50189673) andclinicaltrials.gov(NCT04381936).

Findings

Between 8 July 2021 and 6 March 2023, 4271 patients were randomly allocated to receive either empagliflozin (2113 patients) or usual care alone (2158 patients). Overall, 289 (14%) patients allocated to empagliflozin and 307 (14%) patients allocated to usual care died within 28 days (rate ratio 0.96; 95% confidence interval [CI] 0.82-1.13; p=0.64). There was no evidence of significant differences in duration of hospitalisation (median 8 days vs. 8 days) or the proportion of patients discharged from hospital alive within 28 days (79% vs. 78%; rate ratio 1.03; 95% CI 0.96-1.10; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no evidence of a significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (16% vs. 17%; risk ratio 0.95; 95% CI 0.84-1.08; p=0.44).

Interpretation

In adults hospitalised with COVID-19, empagliflozin was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.

Funding

UK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).

Trial registration

ClinicalTrials.govNCT04381936https://clinicaltrials.gov/ct2/show/NCT04381936

ISRCTN50189673http://www.isrctn.com/ISRCTN50189673
Genomic Analysis of Human Brain Metastases Treated with Stereotactic Radiosurgery Under the Phase-II Clinical Trial (NCT03398694) Reveals DNA Damage Repair at the Peripheral Tumor Edge
Authors: Shireman Jack M. , White Quinn , Agrawal Namita , Ni Zijian , Chen Grace , Zhao Lei , Gonugunta Nikita , Wang Xiaohu , Mccarthy Liam , Kasulabada Varshitha , Pattnaik Akshita , Ahmed Atique U. , Miller James , Kulwin Charles , Cohen-Gadol Aaron , Payner Troy , Lin Chih-Ta , Savage Jesse J. , Lane Brandon , Shiue Kevin , Kamer Aaron , Shah Mitesh , Iyer Gopal , Watson Gordon , Kendziorski Christina , Dey Mahua
Published: April 2023

Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.
COVID-19 testing avoidance among patients with cardiovascular disease
Authors: Matsumura Koichiro , Tabuchi Takahiro , Yagi Eijiro , Ijichi Takeshi , Hasegawa Misaki , Yamada Nobuhiro , Funauchi Yohei , Kakehi Kazuyoshi , Kawamura Takayuki , Nakazawa Gaku
Published: April 2023

Background

Rapid coronavirus 2019 (COVID-19) testing in symptomatic cases is extremely important for preventing the spread of COVID-19 infection and early therapeutic intervention. In contrast, whether symptomatic patients are tested depends largely on their health literacy, interpretation, and knowledge of COVID-19. We aimed to investigate the rate of COVID-19 testing avoidance despite having common cold symptoms in patients with cardiovascular disease and examine factors related to testing avoidance.

Methods

A large-scale epidemiological questionnaire survey, the Japan COVID-19 and Society Internet Survey 2022 (JACSIS), was conducted online from April to May 2022. The rate of COVID-19 testing avoidance was investigated in patients aged 20 to 80 years with cardiovascular risk factors (hypertension, dyslipidemia, or diabetes) or a history of cardiovascular disease (angina, myocardial infarction, or stroke), only those exhibiting common cold symptoms during the 2 months in the survey.

Results

Of the 1,565 eligible patients, 58% (909 patients) did not undergo COVID-19 testing. Multivariate analysis revealed that older age, obesity, non-walking regularly, long sedentary time, eating alone, frequent snacking, and having received 4 COVID-19 vaccinations were independently associated with testing avoidance.

Conclusions

In the chronic phase of the COVID-19 pandemic, prompt COVID-19 testing at the time of symptomatic disease is important, and strategies to reduce testing hesitancy should be considered.
Hemodynamic Response after Intra-Aortic Balloon Counter-Pulsation in Cardiac Amyloidosis and Cardiogenic Shock
Authors: Longinow Joshua , Il’Giovine Zachary J. , Martens Pieter , Higgins Andrew , Ives Lauren , Soltesz Edward G. , Tong Michael Z. , Estep Jerry D. , Starling Randall C. , Tang W.H. Wilson , Hanna Mazen , Lee Ran
Published: April 2023

Background

In those with heart failure-related cardiogenic shock, intra-aortic balloon pump may improve hemodynamics and be useful as a bridge to advanced therapies. We explore whether those with cardiac amyloidosis and heart failure-related cardiogenic shock might experience hemodynamic improvement and describe the hemodynamic response after intra-aortic balloon pump.

Methods

We retrospectively identified consecutive patients with a diagnosis of cardiac amyloid, either light-chain or transthyretin, who were admitted to our intensive care unit with heart failure-related cardiogenic shock. Patients were excluded if intra-aortic balloon pump was placed during heart transplant or for shock related to acute myocardial infarction. Invasive hemodynamics before and after intra-aortic balloon pump placement were assessed.

Results

We identified 23 patients with cardiac amyloid who had an intra-aortic balloon pump placed for heart failure-related cardiogenic shock. One-year survival was 74% and most (65%) were bridged to heart transplant while one was bridged to destination left ventricular assist device. Following intra-aortic balloon pump, mean arterial pressure, cardiac index, and cardiac power index were significantly increased, while mean right atrial pressure, mean pulmonary artery pressure, and pulmonary capillary wedge pressure were all significantly reduced. Smaller left ventricular end diastolic diameter (per cm) was associated with higher likelihood of a cardiac index of < 2.2 L/min/m2following intra-aortic balloon pump (OR 0.16, CI 0.01 – 0.93, P=0.04).

Conclusion

Intra-aortic balloon pump significantly improved cardiac index while reducing right atrial pressure, mean pulmonary artery pressure, and pulmonary capillary wedge pressure in CA patients with heart failure-related cardiogenic shock.
Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages
Authors: Marcotte Harold , Cao Yunlong , Zuo Fanglei , Simonelli Luca , Sammartino Josè Camilla , Pedotti Mattia , Sun Rui , Cassaniti Irene , Hagbom Marie , Piralla Antonio , Yang Jinxuan , Du Likun , Percivalle Elena , Bertoglio Federico , Schubert Maren , Abolhassani Hassan , Sherina Natalia , Guerra Concetta , Borte Stephan , Razaei Nima , Kumagai-Braesch Makiko , Xue Yintong , Grönwall Caroline , Klareskog Lars , Calzolai Luigi , Cavalli Andrea , Wang Qiao , Robbiani Davide F. , Hust Michael , Shi Zhengli , Feng Liqiang , Svensson Lennart , Chen Ling , Bao Linlin , Baldanti Fausto , Qin Chuan , Xiao Junyu , Hammarström Lennart , Yang Xing Lou , Varani Luca , Xie Xiaoliang Sunney , Pan-Hammarström Qiang
Published: April 2023

The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previously suggested that an insufficient mucosal IgA response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot sufficiently boost the mucosal sIgA response in uninfected individuals, particularly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric and secretory IgA1 antibodies derived from four neutralizing IgG monoclonal antibodies targeting the receptor-binding domain of the spike protein (01A05, rmAb23, DXP-604 and XG014). Compared to their parental IgG antibodies, dimeric and secretory IgA1 antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgA1 form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2 and BA.4/5 with a 50-150-fold increase in potency, reaching the level of the most potent monoclonal antibodies described till date. In hACE2 transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Conversion of IgA and dimerization further enhanced or restored the neutralizing ability against the emerging Omicron sub-variants (DXP-604 for BQ.1, BQ.1.1 and BA2.75; 01A05 for BA2.75, BA.2.75.2 and XBB.1). Thus, dimeric or secretory IgA delivered by nasal administration may potentially be exploited for the treatment and prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by subvariants and, potentially, future VOCs.

One Sentence Summary

Engineered dimeric and secretory IgA1 neutralized Omicron variant with higher potency than parental IgG.
Gut community structure as a risk factor for infection inKlebsiella-colonized patients
Authors: Vornhagen Jay , Rao Krishna , Bachman Michael A.
Published: April 2023

The primary risk factor for infection with members ofthe Klebsiella pneumoniaespecies complex is prior gut colonization, and infection is often caused by the colonizing strain. Despite the importance of the gut as a reservoir for infectiousKlebsiella, little is known about the association between the gut microbiome and infection. To explore this relationship, we undertook a case-control study comparing the gut community structure ofKlebsiella-colonized intensive care and hematology/oncology patients. Cases wereKlebsiella-colonized patients infected by their colonizing strain (N = 83). Controls wereKlebsiella-colonized patients that remained asymptomatic (N = 149). First, we characterized the gut community structure ofKlebsiella-colonized patients agnostic to case status. Next, we determined that gut community data is useful for classifying cases and controls using machine learning models and that the gut community structure differed between cases and controls.Klebsiellarelative abundance, a known risk factor for infection, had the greatest feature importance but other gut microbes were also informative. Finally, we show that integration of gut community structure with bacterial genotype or clinical variable data enhanced the ability of machine learning models to discriminate cases and controls. This study demonstrates that including gut community data with patient- andKlebsiella-derived biomarkers improves our ability to predict infection inKlebsiella-colonized patients.

Importance

Colonization is generally the first step in pathogenesis for bacteria with pathogenic potential. This step provides a unique window for intervention since a given potential pathogen has yet to cause damage to its host. Moreover, intervention during the colonization stage may help alleviate the burden of therapy failure as antimicrobial resistance rises. Yet, to understand the therapeutic potential of interventions that target colonization, we must first understand the biology of colonization and if biomarkers at the colonization stage can be used to stratify infection risk. The bacterial genusKlebsiellaincludes many species with varying degrees of pathogenic potential. Members of theK. pneumoniaespecies complex have the highest pathogenic potential. Patients colonized in their gut by these bacteria are at higher risk of subsequent infection with their colonizing strain. However, we do not understand if other members of the gut microbiota can be used as a biomarker to predict infection risk. In this study, we show that the gut microbiota differs between colonized patients that develop an infection versus those that do not. Additionally, we show that integrating gut microbiota data with patient and bacterial factors improves the ability to predict infections. As we continue to explore colonization as an intervention point to prevent infections in individuals colonized by potential pathogens, we must develop effective means for predicting and stratifying infection risk.
Widespread alterations of diffusion tensor imaging metrics in patients with schizophrenia without current auditory hallucinations
Authors: Nerland Stener , Slapø Nora Berz , Barth Claudia , Mørch-Johnsen Lynn , Jørgensen Kjetil Nordbø , Beck Dani , Wortinger Laura A. , Westlye Lars T. , Jönsson Erik G. , Andreassen Ole A. , Maximov Ivan I. , Geier Oliver M. , Agartz Ingrid
Published: April 2023

Background

Studies have linked auditory hallucinations (AH) in schizophrenia-spectrum disorders (SCZ) to altered cerebral white matter microstructure within the language and auditory processing circuitry (LAPC). However, the neuroanatomical distribution and specificity to the LAPC remains unclear. Here, we investigated the relationship between AH and DTI among patients with SCZ using diffusion tensor imaging (DTI).

Methods

We included patients with SCZ with (AH+; n=59) and without (AH-; n=81) current AH, and 140 age-and-sex-matched controls. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were extracted from 39 fibre tracts. We used principal component analysis (PCA) to identify general factors of variation across fibre tracts and DTI metrics. Regression models adjusted for sex, age, and age2were used to compare tract-wise DTI metrics and PCA factors between AH+, AH-, and healthy controls and to assess associations with clinical characteristics.

Results

Widespread differences relative to controls were observed for MD and RD in patients without current AH. Only limited differences in two fibre tracts were observed between AH+ and controls. Unimodal PCA factors based on MD, RD, and AD, as well as multimodal PCA factors, differed significantly relative to controls for AH-, but not AH+. We did not find any significant associations between PCA factors and clinical characteristics.

Conclusions

Contrary to previous studies, DTI metrics differed mainly in patientswithoutcurrent AH compared to controls, indicating a widespread neuroanatomical distribution. Our results challenge the notion that altered DTI metrics in the LAPC is a specific feature underlying AH.
CRISPR-Cas9 mediated endogenous utrophin upregulation improves Duchenne Muscular Dystrophy
Authors: Guiraud Simon , Dastidar Sumitava , Mazed Fetta , Amor Fatima , Ralu Maelle , de Cian Anne , Richard Isabelle , Ronzitti Giuseppe , Tedesco Francesco Saverio , Amendola Mario
Published: April 2023

Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disorder caused by loss of dystrophin. Upregulation of utrophin (UTRN), a dystrophin paralogue, is a promising therapeutic avenue. Here, we present a CRISPR-Cas9-mediated strategy to increase utrophin expression by disrupting microRNA (miR) binding sites (BS). Using a Cas9/gRNA ribonucleoprotein (RNP) complex we disrupted several miR BS in DMD myoblasts and selected the Let-7c BS has crucial for UTRN repression. Interestingly, Cas9/gRNA indels were as efficient as the complete removal of Let-7c BS in upregulating UTRN expression, without any major off-targets. In three-dimensional human DMD cultures, Cas9/gRNA-mediated editing resulted in significant utrophin upregulation and functional improvements of calcium dysregulation and muscle contraction. Finally, Let-7c BS disruption in mdx animals by systemic rAAVs mediated delivery of Cas9 and gRNA resulted in utrophin upregulation and amelioration of the muscle histopathological phenotype. These findings provide the foundations for a universal (mutation-independent) gene editing therapeutic strategy for DMD.

One Sentence Summary

CRISPR-Cas9 has the potential to upregulate utrophin to treat all DMD patients.
Allosteric coupling asymmetry mediates paradoxical activation of BRAF by type II inhibitors
Authors: Rasmussen Damien M. , Semonis Manny M. , Greene Joseph T. , Muretta Joseph M. , Thompson Andrew R. , Ramos Silvia Toledo , Thomas David D. , Pomerantz William C.K. , Freedman Tanya S. , Levinson Nicholas M.
Published: April 2023

The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction of BRAF dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking BRAF dimerization and conformation we built an allosteric model of inhibitor-induced dimerization that resolves the allosteric contributions of inhibitor binding to the two active sites of the dimer, revealing key differences between type I and type II RAF inhibitors. For type II inhibitors the allosteric coupling between inhibitor binding and BRAF dimerization is distributed asymmetrically across the two dimer binding sites, with binding to the first site dominating the allostery. This asymmetry results in efficient and selective induction of dimers with one inhibited and one catalytically active subunit. Our allosteric models quantitatively account for paradoxical activation data measured for 11 RAF inhibitors. Unlike type II inhibitors, type I inhibitors lack allosteric asymmetry and do not activate BRAF homodimers. Finally, NMR data reveal that BRAF homodimers are dynamically asymmetric with only one of the subunits locked in the active αC-in state. This provides a structural mechanism for how binding of only a single αC-in inhibitor molecule can induce potent BRAF dimerization and activation.
Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach
Authors: Kozawa Satoshi , Tejima Kengo , Takagi Shunki , Kuroda Masataka , Nogami-Itoh Mari , Kitamura Hideya , Niwa Takashi , Ogura Takashi , Natsume-Kitatani Yayoi , Sato Thomas N.
Published: April 2023

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around the lung itself. On the other hand, many human diseases are the products of complex multi-organ interactions. Hence, we postulate that a dysfunctional crosstalk of the lung with other organs plays a causative role in the onset, progression and/or complications of IPF. In this study, we employed a generative computational approach to identify such inter-organ mechanism of IPF. The approach works as follows: 1) To find unexpected relatedness of IPF to other diseases of non-lung organs and to identify molecular features that define such relatedness, 2) To identify differentially expressed genes between the lung tissues of IPF vs. those of non-IPF pulmonary disease patients, 3) To detect ligand-receptor relationships across multiple organs and their upstream and downstream signaling pathways in 1) and 2), 4) To generate a map of the inter-organ IPF mechanism with the molecular and cellular resolution. This approach found unexpected molecular relatedness of IPF to neoplasm, diabetes, Alzheimer’s disease, obesity, atherosclerosis, and arteriosclerosis. Furthermore, as a potential mechanism underlying this relatedness, we uncovered a putative molecular crosstalk system across the lung and the liver. In this inter-organ system, a secreted protein, kininogen 1, from hepatocytes in the liver interacts with its receptor, bradykinin receptor B1 in the lung. This ligand-receptor interaction across the liver and the lung leads to the activation of calmodulin pathways in the lung, leading to the activation of interleukin 6 and phosphoenolpyruvate carboxykinase 1 pathway across these organs. Furthermore, we retrospectively identified several pre-clinical and clinical evidence supporting this inter-organ mechanism of IPF. In conclusion, such feedforward and feedback system across the lung and the liver provides a unique opportunity for the development of the treatment and/or diagnosis of IPF. Furthermore, the result illustrates a generative computational framework for machine-mediated synthesis of mechanisms that facilitates and complements the traditional experimental approaches in biomedical sciences.
ER Stress Impedes Regulated Secretion by Governing Key Exocytotic and Granulogenic Molecular Switches
Authors: Mukherjee Mohima , Mukherjee Chandramouli , Ghosh Vinayak , Jain Aamna , Sadhukhan Souren , Dagar Sushma , Sahu Bhavani Shankar
Published: April 2023

Dense core vesicles (DCVs) and synaptic vesicles (SVs) are specialised secretory vesicles (SSVs) in neurons/neuroendocrine cells harbouring cargo whose abnormal release is associated with pathophysiology. Endoplasmic Reticulum (ER) stress and inter-organellar communication are also associated with disease biology. In pursuit of investigating the cell physiological consequences arising from the crosstalk of a stressed ER and DCVs, ER stress was modelled in PC12 neuroendocrine cells using Thapsigargin (Tg). DCV exocytosis was severely compromised in ER-stressed PC12 cells, reversed by Docosahexaenoic acid (DHA). Experiments with Tunicamycin(Tm), an independent ER stressor, yielded similar results. Concurrently, ER stress caused impaired DCV exocytosis also in INS-1 cells. Molecular analysis revealed blunted SNAP25 expression, potentially attributed to augmented levels of ATF4 (a well-known CREB inhibitor) and its transcriptional regulator CREB (also known to regulate key granulogenic players Chromogranin A, Secretogranin II). Our studies revealed severe defects in DCV exocytosis in ER-stressed cells for the first time, mediated by reduced levels of key ‘exocytotic’ and ‘granulogenic’ switches regulated via the CREB/ATF4/eIF2α axis.
The distribution, phenology, host range and pathogen prevalence ofIxodes ricinusin France: a systematic map and narrative review
Authors: Perez Grégoire , Bournez Laure , Boulanger Nathalie , Fite Johanna , Livoreil Barbara , McCoy Karen D. , Quillery Elsa , René-Martellet Magalie , Bonnet Sarah I.
Published: April 2023

The tickIxodes ricinusis the most important vector species of infectious diseases in European France. Understanding its distribution, phenology, and host species use, along with the distribution and prevalence of associated pathogens at national scales is essential for developing prevention strategies. The aim of this paper is to provide a systematic map and narrative review of the existing knowledge on the eco-epidemiology ofI.ricinusin France. Using literature published up to 2020, the present paper provides a distribution map for the species and a summary of environmental factors explaining observed geographical differences in phenology and temporal differences in abundance. The diversity of vertebrate host species used by this tick, along with their degree of infestation when available, are presented and discussed with respect to their potential contribution to the population dynamics ofI.ricinusand the circulation of tick-borne zoonotic pathogens. Prevalence data of detected pathogens are summarised in different maps. Results from 187 identified references show that the species is present in most departments, but scarce under Mediterranean climate and in coastal habitats. Its phenology is generally bimodal with variations depending on climate. Abundance seems positively influenced by forest cover and host abundance. Rodents and ruminants are the most studied species groups, but the diversity of sampling protocols (e.g., location, season, exhaustivity of inspection) precluded direct comparisons between species groups. Data on pathogens are patchy, with most studies conducted near research units. Among pathogens,Borrelia burgdorferisensu lato is the most searched for in ticks and seems more prevalent in north-eastern and central France. The review carried out here has made it possible to highlight the gaps in our knowledge of tick-host-pathogen interactions, their ecology and their distribution, and the need to address these gaps in order to optimize tick and tick-borne diseases prevention and control strategies.
The Sterile Insect Technique can efficiently reduce the reproduction of the spotted wing drosophila (Drosophila suzukii) in strawberry
Authors: Gard B. , Panel A. , Labbetoul A. , Bosshard N. , Xuereb A. , Cariou B. , Debelle A. , Oliva C. , Fellous S.
Published: April 2023

The spotted wing drosophila (SWD)Drosophila suzukii(Diptera: Drosophilidae) is a pest of soft fruit. Since its introduction in Europe in 2008 farmers struggle to protect their crops. The sterile insect technique (SIT) has proven efficient at controlling numerous fruit fly species and could be deployed to controlD. suzukii. In recent years, key elements of SIT applied toD. suzukiihave become available. However, field- and field-like experiments are scarce. In this experiment, we assayed the efficacy of a high-performance strain at reducing the reproduction ofD. suzukiiin complex, yet replicated and controlled conditions. Two ratios of sterile to fertile insects (5:1 and 1:1) using bisexual releases were compared to a control treatment with fertile, wild flies only. The presence of sterile individuals at a 5:1 ratio significantly reduced fly reproduction, measured after 5 days, by an approximate threefold factor. However, the proportion of infested fruits in the treated plots remained unaffected. The number of available berries in the cage appeared an unexpected determinant of fly infestation, suggesting undocumented density-dependent processes. The success of this assay opens the door to larger scales experiments, over several generations, and, in the near future, the field-evaluation of the efficacy of the SIT to controlD. suzukii.
GABA, glucose and insulin orchestrate CD4+T cells effector functions
Authors: Jin Z , Hammoud H , Bhandage AK , Korol SV , Trujeque-Ramos O , Koreli S. , Chowdhury AI , Sandbaumhüter FA , Jansson ET , Andrén PE , Bergsten P , Kamali-Moghaddam M , Birnir B
Published: April 2023

Metabolic programs of immune cells are closely linked to their effector functions. Physiological molecules including glucose, insulin and γ-aminobutyric acid (GABA) provide environmental cues and guidance, although how they coordinate to regulate the cells is still being unraveled. Here, we demonstrate that GABA-mediated reduction of metabolic activity and release of inflammatory molecules, including IFNγ and IL-10, was abolished in human CD4+T cells when the glucose concentration was elevated above normal levels. Insulin enhanced the GABAAreceptors-mediated currents and Ca2+influx. GABA decreased, whereas insulin sustained glycolysis but in a SGLT (Na+-glucose transporter)-dependent manner. In high glucose (16.7 mM), the SGLTs antagonist phlorizin alone or together with GABA restored the inhibition of IFNγ and IL-10 release. This study exposes concerted effects of GABA, glucose and insulin on CD4+T cells metabolic activity and release of inflammatory molecules, and identifies a role for SGLTs in CD4+T cells function.
WITHDRAWN: Purifying Selection and Persistent Polymorphism among Nuclei in the Multinucleate Arbuscular Mycorrhizal (AM) Fungi
Authors: Manyara David , Sánchez-García Marisol , Thorén Markus Hiltunen , Montoliu-Nerin Merce , Cheng George , Bever James D. , Johannesson Hanna , Rosling Anna
Published: April 2023

Withdrawal Statement

The authors have withdrawn this manuscript and do not wish it to be cited. As we have reviewed the quality of our datasets, we have discovered that our initial analyses do not confidently support our biological inferences well. We are recalibrating and intend to submit a new manuscript in the future. If you have any questions, please get in touch with the corresponding author.
A statistical learning method for simultaneous copy number estimation and subclone clustering with single cell sequencing data
Authors: Qin Fei , Cai Guoshuai , Xiao Feifei
Published: April 2023

The availability of single cell sequencing (SCS) enables us to assess intra-tumor heterogeneity and identify cellular subclones without the confounding effect of mixed cells. Copy number aberrations (CNAs) have been commonly used to identify subclones in SCS data using various clustering methods, since cells comprising a subpopulation are found to share genetic profile. However, currently available methods may generate spurious results (e.g., falsely identified CNAs) in the procedure of CNA detection, hence diminishing the accuracy of subclone identification from a large complex cell population. In this study, we developed a CNA detection method based on a fused lasso model, referred to as FLCNA, which can simultaneously identify subclones in single cell DNA sequencing (scDNA-seq) data. Spike-in simulations were conducted to evaluate the clustering and CNA detection performance of FLCNA benchmarking to existing copy number estimation methods (SCOPE, HMMcopy) in combination with the existing and commonly used clustering methods. Interestingly, application of FLCNA to a real scDNA-seq dataset of breast cancer revealed remarkably different genomic variation patterns in neoadjuvant chemotherapy treated samples and pre-treated samples. We show that FLCNA is a practical and powerful method in subclone identification and CNA detection with scDNA-seq data.