bluuebunny/crossref_metadata_2025 huggingface dataset:
FLINO: a new method for immunofluorescence bioimage normalization
Authors: Graf John , Cho Sanghee , McDonough Elizabeth , Corwin Alex , Sood Anup , Lindner Andreas , Salvucci Manuela , Stachtea Xanthi , Van Schaeybroeck Sandra , Dunne Philip D , Laurent-Puig Pierre , Longley Daniel , Prehn Jochen H M , Ginty Fiona
Published: September 2021

Motivation

Multiplexed immunofluorescence bioimaging of single-cells and their spatial organization in tissue holds great promise to the development of future precision diagnostics and therapeutics. Current multiplexing pipelines typically involve multiple rounds of immunofluorescence staining across multiple tissue slides. This introduces experimental batch effects that can hide underlying biological signal. It is important to have robust algorithms that can correct for the batch effects while not introducing biases into the data. Performance of data normalization methods can vary among different assay pipelines. To evaluate differences, it is critical to have a ground truth dataset that is representative of the assay.

Results

A new immunoFLuorescence Image NOrmalization method is presented and evaluated against alternative methods and workflows. Multiround immunofluorescence staining of the same tissue with the nuclear dye DAPI was used to represent virtual slides and a ground truth. DAPI was restained on a given tissue slide producing multiple images of the same underlying structure but undergoing multiple representative tissue handling steps. This ground truth dataset was used to evaluate and compare multiple normalization methods including median, quantile, smooth quantile, median ratio normalization and trimmed mean of the M-values. These methods were applied in both an unbiased grid object and segmented cell object workflow to 24 multiplexed biomarkers. An upper quartile normalization of grid objects in log space was found to obtain almost equivalent performance to directly normalizing segmented cell objects by the middle quantile. The developed grid-based technique was then applied with on-slide controls for evaluation. Using five or fewer controls per slide can introduce biases into the data. Ten or more on-slide controls were able to robustly correct for batch effects.

Availability and implementation

The data underlying this article along with the FLINO R-scripts used to perform the evaluation of image normalizations methods and workflows can be downloaded from https://github.com/GE-Bio/FLINO.

Supplementary information

Supplementary data are available at Bioinformatics online.
A first-generation haplotype map (HapMap-1) of tea (Camellia sinensis L. O. Kuntz)
Authors: Singh Nisha , Rawal Hukam C , Angadi Ulavappa B , Sharma Tilak Raj , Singh Nagendra Kumar , Mondal Tapan Kumar
Published: September 2021

Motivation

Tea is a cross-pollinated woody perennial plant, which is why, application of conventional breeding is limited for its genetic improvement. However, lack of the genome-wide high-density SNP markers and genome-wide haplotype information has greatly hampered the utilization of tea genetic resources toward fast-track tea breeding programs. To address this challenge, we have generated a first-generation haplotype map of tea (Tea HapMap-1). Out-crossing and highly heterozygous nature of tea plants, make them more complicated for DNA-level variant discovery.

Results

In this study, whole genome re-sequencing data of 369 tea genotypes were used to generate 2,334,564 biallelic SNPs and 1,447,985 InDels. Around 2928.04 million paired-end reads were used with an average mapping depth of ∼0.31× per accession. Identified polymorphic sites in this study will be useful in mapping the genomic regions responsible for important traits of tea. These resources lay the foundation for future research to understand the genetic diversity within tea germplasm and utilize genes that determine tea quality. This will further facilitate the understanding of tea genome evolution and tea metabolite pathways thus, offers an effective germplasm utilization for breeding the tea varieties.

Supplementary information

Supplementary data are available at Bioinformatics online.
An Outcome-Oriented, Social–Ecological Framework for Assessing Protected Area Effectiveness
Authors: Ghoddousi Arash , Loos Jacqueline , Kuemmerle Tobias
Published: September 2021

Both the number and the extent of protected areas have grown considerably in recent years, but evaluations of their effectiveness remain partial and are hard to compare across cases. To overcome this situation, first, we suggest reserving the term effectiveness solely for assessing protected area outcomes, to clearly distinguish this from management assessments (e.g., sound planning). Second, we propose a multidimensional conceptual framework, rooted in social–ecological theory, to assess effectiveness along three complementary dimensions: ecological outcomes (e.g., biodiversity), social outcomes (e.g., well-being), and social–ecological interactions (e.g., reduced human pressures). Effectiveness indicators can subsequently be evaluated against contextual and management elements (e.g., design and planning) to shed light on management performance (e.g., cost-effectiveness). We summarize steps to operationalize our framework to foster more holistic effectiveness assessments while improving comparability across protected areas. All of this can ensure that protected areas make real contributions toward conservation and sustainability goals.
The yin and yang of intracellular reactive oxygen species following T-cell activation
Authors: Mousa Hani S , Jones Joanne L
Published: September 2021

This scientific commentary refers to ‘Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity’ by Liebmann et al. (doi:10.1093/brain/awab307).
Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy
Authors: Marafi Dana , Fatih Jawid M , Kaiyrzhanov Rauan , Ferla Matteo P , Gijavanekar Charul , Al-Maraghi Aljazi , Liu Ning , Sites Emily , Alsaif Hessa S , Al-Owain Mohammad , Zakkariah Mohamed , El-Anany Ehab , Guliyeva Ulviyya , Guliyeva Sughra , Gaba Colette , Haseeb Ateeq , Alhashem Amal M , Danish Enam , Karageorgou Vasiliki , Beetz Christian , Subhi Alaa A , Mullegama Sureni V , Torti Erin , Sebastin Monisha , Breilyn Margo Sheck , Duberstein Susan , Abdel-Hamid Mohamed S , Mitani Tadahiro , Du Haowei , Rosenfeld Jill A , Jhangiani Shalini N , Coban Akdemir Zeynep , Gibbs Richard A , Taylor Jenny C , Fakhro Khalid A , Hunter Jill V , Pehlivan Davut , Zaki Maha S , Gleeson Joseph G , Maroofian Reza , Houlden Henry , Posey Jennifer E , Sutton V Reid , Alkuraya Fowzan S , Elsea Sarah H , Lupski James R
Published: September 2021

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders.

Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers.

Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease.

Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.
Cholinergic white matter pathways in dementia with Lewy bodies and Alzheimer’s disease
Authors: Schumacher Julia , Ray Nicola J , Hamilton Calum A , Donaghy Paul C , Firbank Michael , Roberts Gemma , Allan Louise , Durcan Rory , Barnett Nicola , O’Brien John T , Taylor John-Paul , Thomas Alan J
Published: September 2021

Patients who have dementia with Lewy bodies and Alzheimer’s disease show early degeneration of the cholinergic nucleus basalis of Meynert. However, how white matter projections between the nucleus basalis of Meynert and the cortex are altered in neurodegenerative disease is unknown.

Tractography of white matter pathways originating from the nucleus basalis of Meynert was performed using diffusion-weighted imaging in 46 patients with Alzheimer’s disease dementia, 48 with dementia with Lewy bodies, 35 with mild cognitive impairment with Alzheimer’s disease, 38 with mild cognitive impairment with Lewy bodies and 71 control participants. Mean diffusivity of the resulting pathways was compared between groups and related to cognition, attention, functional EEG changes and dementia conversion in the mild cognitive impairment groups.

We successfully tracked a medial and a lateral pathway from the nucleus basalis of Meynert. Mean diffusivity of the lateral pathway was higher in both dementia and mild cognitive impairment groups than controls (all P < 0.03). In the patient groups, increased mean diffusivity of this pathway was related to more impaired global cognition (β = −0.22, P = 0.06) and worse performance on an attention task (β = 0.30, P = 0.03). In patients with mild cognitive impairment, loss of integrity of both nucleus basalis of Meynert pathways was associated with increased risk of dementia progression [hazard ratio (95% confidence interval), medial pathway: 2.51 (1.24–5.09); lateral pathway: 2.54 (1.24–5.19)]. Nucleus basalis of Meynert volume was reduced in all clinical groups compared to controls (all P < 0.001), but contributed less strongly to cognitive impairment and was not associated with attention or dementia conversion. EEG slowing in the patient groups as assessed by a decrease in dominant frequency was associated with smaller nucleus basalis of Meynert volumes (β = 0.22, P = 0.02) and increased mean diffusivity of the lateral pathway (β = −0.47, P = 0.003).

We show that degeneration of the cholinergic nucleus basalis of Meynert in Alzheimer’s disease and dementia with Lewy bodies is accompanied by an early reduction in integrity of white matter projections that originate from this structure. This is more strongly associated with cognition and attention than the volume of the nucleus basalis of Meynert itself and might be an early indicator of increased risk of dementia conversion in people with mild cognitive impairment.
Dopamine neurons exhibit emergent glutamatergic identity in Parkinson’s disease
Authors: Steinkellner Thomas , Conrad William S , Kovacs Imre , Rissman Robert A , Lee Edward B , Trojanowski John Q , Freyberg Zachary , Roy Subhojit , Luk Kelvin C , Lee Virginia M , Hnasko Thomas S
Published: September 2021

Loss of midbrain dopamine neurons causes the cardinal symptoms of Parkinson’s disease. However, not all dopamine neurons are equally vulnerable and a better understanding of the cell-type specific properties relating to selective dopamine neuron degeneration is needed. Most midbrain dopamine neurons express the vesicular glutamate transporter VGLUT2 during development and a subset continue to express low levels of VGLUT2 in adulthood, enabling the co-release of glutamate. Moreover, VGLUT2 expression in dopamine neurons can be neuroprotective since its genetic disruption was shown to sensitize dopamine neurons to neurotoxins. Here, we show that in response to toxic insult, and in two distinct models of alpha-synuclein stress, VGLUT2 dopamine neurons were resilient to degeneration. Dopamine neurons expressing VGLUT2 were enriched whether or not insult induced dopamine neuron loss, suggesting that while VGLUT2 dopamine neurons are more resilient, VGLUT2 expression can also be transcriptionally upregulated by injury. Finally, we observed that VGLUT2 expression was enhanced in surviving dopamine neurons from post-mortem Parkinson’s disease individuals. These data indicate that emergence of a glutamatergic identity in dopamine neurons may be part of a neuroprotective response in Parkinson’s disease.
Neurological complications induced by immune checkpoint inhibitors: a comprehensive descriptive case-series unravelling high risk of long-term sequelae
Authors: Plaçais Léo , Michot Jean-Marie , Champiat Stéphane , Romano-Martin Patricia , Baldini Capucine , Joao Maria Silva , Marabelle Aurélien , Voisin Anne-Laure , Not Adeline , Labeyrie Céline , Beaudonnet Guillemette , Laparra Ariane , Maria Alexandre T J , Masseau Agathe , Dehette Stéphanie , Deleporte Amélie , Echaniz-Laguna Andoni , Denier Christian , Adams David , Lambotte Olivier , Noel Nicolas , Cauquil Cécile
Published: September 2021

Neurological immune-related adverse events are complications of programmed-cell death 1 or programmed-cell death 1 ligand immunotherapies that can be life threatening and often lead to anticancer immunotherapy withdrawal. Scant clinical data are available that integrate the clinical presentation, therapeutic management and long-term outcome. All consecutive adult patients treated by programmed-cell death 1 or programmed-cell death 1 ligand immunotherapies, given alone or in combination with other treatment, who experienced a neurological immune-related adverse event with a severity grade ≥2 in Paris Saclay-University hospitals were investigated from June 2014 to February 2019. The frequency of neurological immune-related adverse events was calculated from the prospective Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie cohort. Forty patients presenting with 51 distinct neurological immune-related adverse events were included. The prevalence of grade ≥2 neurological immune-related adverse events was estimated to be 1.22% in the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie cohort. Among 40 patients with neurological immune-related adverse events, 65% received programmed-cell death 1 or programmed-cell death 1 ligand monotherapy and 35% received a combination of programmed-cell death 1 plus anti-CTLA4 (Common Terminology Criteria for Adverse Events). Clinical neurological presentations were peripheral (48%), central (35%), or mixed (18%). The severity of neurological immune-related adverse events was grade 2 for 14 (35%) and ≥grade 3 for 26 patients (65%). The mortality rate related to neurological immune-related adverse events was 8%. Corticosteroid treatment led to neurological recovery in 74%. Long-term follow-up highlighted that 53% of patients experienced long-term neurological sequelae. Five patients were rechallenged by programmed-cell death 1 monotherapy without recurrence of their neurological immune-related adverse event(s). Neurological immune-related adverse events induced by programmed-cell death 1 or programmed-cell death 1 ligand are rare but are severe with a mortality rate of 8% and long-term sequelae for 53% of patients. Corticosteroids should be started when neurological immunological complications are identified to avoid long-term sequelae.
Overexpression of miR-101 suppresses collagen synthesis by targeting EZH2 in hypertrophic scar fibroblasts
Authors: Li Jie , Li Yan , Wang Yunchuan , He Xiang , Wang Jing , Cai Weixia , Jia Yanhui , Xiao Dan , Zhang Jian , Zhao Ming , Shen Kuo , Li Zichao , Jia Wenbin , Wang Kejia , Zhang Yue , Su Linlin , Zhu Huayu , Hu Dahai
Published: September 2021

Background

MicroRNA-101 (miR-101) is a tumor suppressor microRNA (miRNA) and its loss is associated with the occurrence and progression of various diseases. However, the biological function and target of miR-101 in the pathogenesis of hypertrophic scars (HS) remains unknown.

Methods

We harvested HS and paired normal skin (NS) tissue samples from patients and cultured their fibroblasts (HSF and NSF, respectively). We used quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), fluorescence in situ hybridization (FISH), enzyme-linked immunosorbent assays (ELISA) and Western blot analyses to measure mRNA levels and protein expression of miR-101, enhancer of zeste homolog 2 (EZH2), collagen 1 and 3 (Col1 and Col3) and α-smooth muscle actin (α-SMA) in different in vitro conditions. We also used RNA sequencing to evaluate the relevant signaling pathways and bioinformatics analysis and dual-luciferase reporter assays to predict miR-101 targets. We utilized a bleomycin-induced fibrosis mouse model in which we injected miR-101 mimics to evaluate collagen deposition in vivo.

Results

We found low expression of miR-101 in HS and HSF compared to NS and NSF. Overexpressing miR-101 decreased Col1, Col3 and α-SMA expression in HSF. We detected high expression of EZH2 in HS and HSF. Knockdown of EZH2 decreased Col1, Col3 and α-SMA in HSF. Mechanistically, miR-101 targeted the 3′-untranslated region (3′UTR) of EZH2, as indicated by the decreased expression of EZH2. Overexpressing EZH2 rescued miR-101-induced collagen repression. MiR-101 mimics effectively suppressed collagen deposition in the bleomycin-induced fibrosis mouse model.

Conclusions

Our data reveal that miR-101 targets EZH2 in HS collagen production, providing new insight into the pathological mechanisms underlying HS formation.
Prognostic impact of tumor-specific insulin-like growth factor binding protein 7 (IGFBP7) levels in breast cancer: a prospective cohort study
Authors: Godina Christopher , Khazaei Somayeh , Tryggvadottir Helga , Visse Edward , Nodin Björn , Jirström Karin , Borgquist Signe , Bosch Ana , Isaksson Karolin , Jernström Helena
Published: September 2021

The prognostic impact of insulin-like growth factor binding protein 7 (IGFBP7) in breast cancer is unclear. Host factors, including lifestyle, anthropometry and metabolic profile, might influence tumor-specific IGFBP7. This study aimed to investigate whether IGFBP7 levels and messenger ribonucleic acid (mRNA) expression are associated with the patient and tumor characteristics and prognosis in breast cancer. Patients with primary breast cancer in Lund, Sweden, were included preoperatively in the study between 2002 and 2012 (n = 1018). Tumor-specific IGFBP7 protein levels were evaluated with immunohistochemistry using tissue microarrays in tumors from 878 patients. IGFBP7 mRNA expression and its corresponding clinical data were obtained from The Cancer Genome Atlas and analyzed for 809 patients. Tumor-specific IGFBP7 protein levels were categorized based on Histo 300 scores into IGFBP7low (6.2%), IGFBP7intermediate (75.7%) and IGFBP7high (18.1%). Both low IGFBP7 protein levels and mRNA expression were associated with less aggressive tumor characteristics. Overall, IGFBP7low conferred low recurrence risk. The prognostic impact of IGFBP7high varied according to any alcohol consumption and tamoxifen treatment. IGFBP7high was associated with low recurrence risk in alcohol consumers but high recurrence risk in alcohol abstainers (Pinteraction= 0.039). Moreover, the combination of IGFBP7high and estrogen receptor-positive tumors was associated with low recurrence risk only in tamoxifen-treated patients (Pinteraction= 0.029). To conclude, IGFBP7low might be a good, independent prognosticator in breast cancer. The prognostic impact of IGFBP7high depends on host factors and treatment. IGFBP7 merits further investigation to confirm whether it could be a suitable biomarker for treatment selection.
Scaling Principles of White Matter Connectivity in the Human and Nonhuman Primate Brain
Authors: Ardesch Dirk Jan , Scholtens Lianne H , de Lange Siemon C , Roumazeilles Lea , Khrapitchev Alexandre A , Preuss Todd M , Rilling James K , Mars Rogier B , van den Heuvel Martijn P
Published: September 2021

Brains come in many shapes and sizes. Nature has endowed big-brained primate species like humans with a proportionally large cerebral cortex. Comparative studies have suggested, however, that the total volume allocated to white matter connectivity—the brain’s infrastructure for long-range interregional communication—does not keep pace with the cortex. We investigated the consequences of this allometric scaling on brain connectivity and network organization. We collated structural and diffusion magnetic resonance imaging data across 14 primate species, describing a comprehensive 350-fold range in brain size across species. We show volumetric scaling relationships that indeed point toward a restriction of macroscale connectivity in bigger brains. We report cortical surface area to outpace white matter volume, with larger brains showing lower levels of overall connectedness particularly through sparser long-range connectivity. We show that these constraints on white matter connectivity are associated with longer communication paths, higher local network clustering, and higher levels of asymmetry in connectivity patterns between homologous areas across the left and right hemispheres. Our findings reveal conserved scaling relationships of major brain components and show consequences for macroscale brain circuitry, providing insights into the connectome architecture that could be expected in larger brains such as the human brain.
Minimally Invasive Tissue Sampling: A Tool to Guide Efforts to Reduce AIDS-Related Mortality in Resource-Limited Settings
Authors: Letang Emilio , Rakislova Natalia , Martinez Miguel J , Carlos Hurtado Juan , Carrilho Carla , Bene Rosa , Mandomando Inacio , Quintó Llorenç , Nhampossa Tacilta , Chicamba Valéria , Luis Elvira , Ismail Mamudo R , Fernandes Fabiola , Lorenzoni Cesaltina , Ferreira Luiz , Freire Monique , Teresa Rodrigo-Calvo Maria , Guerrero José , Munguambe Khátia , Maixenchs Maria , Navarro Mireia , Casas Isaac , Marimon Lorena , Ferrando Melania , Macete Eusebio , Lacerda Marcus , Bassat Quique , Menéndez Clara , Ordi Jaume
Published: September 2021

Background

Available information on the causes of death among people living with human immunodeficiency virus (PLHIV) in low- and middle-income countries (LMICs) remains scarce. We aimed to provide data on causes of death in PLHIV from two LMICs, Brazil and Mozambique, to assess the impact of clinical misdiagnosis on mortality rates and to evaluate the accuracy of minimally invasive tissue sampling (MITS) in determining the cause of death in PLHIV.

Methods

We performed coupled MITS and complete autopsy on 164 deceased PLHIV (18 children, 36 maternal deaths, and 110 adults). HIV antibody levels and HIV RNA viral loads were determined from postmortem serum samples.

Results

Tuberculosis (22.7%), toxoplasmosis (13.9%), bacterial infections (13.9%), and cryptococcosis (10.9%) were the leading causes of death in adults. In maternal deaths, tuberculosis (13.9%), bacterial infections (13.9%), cryptococcosis (11.1%), and cerebral malaria (8.3%) were the most frequent infections, whereas viral infections, particularly cytomegalovirus (38.9%), bacterial infections (27.8%), pneumocystosis (11.1%), and HIV-associated malignant neoplasms (11.1%) were the leading cause among children. Agreement between the MITS and the complete autopsy was 100% in children, 91% in adults, and 78% in maternal deaths. The MITS correctly identified the microorganism causing death in 89% of cases.

Conclusions

Postmortem studies provide highly granular data on the causes of death in PLHIV. The inaccuracy of clinical diagnosis may play a significant role in the high mortality rates observed among PLHIV in LMICs. MITS might be helpful in monitoring the causes of death in PLHIV and in highlighting the gaps in the management of the infections.
Implementing Whole-Genome Sequencing for Ongoing Surveillance of Antimicrobial Resistance: Exemplifying Insights IntoKlebsiella pneumoniae
Authors: Aanensen David M , Carlos Celia C , Donado-Godoy Pilar , Okeke Iruka N , Ravikumar K L ,   NIHR Global Health Research Unit on Genomic Surveillance of Antimicrobial Resistance, Abudahab Khalil , Abrudan Monica , Argimón Silvia , Harste Harry , Kekre Mihir , Muddyman Dawn , Taylor Ben , Underwood Anthony , Wheeler Nicole , David Sophia , Fabian Bernal Johan , Arevalo Alejandra , Fernanda Valencia Maria , Osma Castro Erik C D , Nagaraj Geetha , Shamanna Varun , Govindan Vandana , Prabhu Akshata , Sravani D , Shincy M R , Rose Steffimole , Ravishankar K N , Oaikhena Anderson O , Afolayan Ayorinde O , Ajiboye Jolaade J , Ewomazino Odih Erkison , Lagrada Marietta L , Macaranas Polle Krystle V , Olorosa Agnettah M , Gayeta June M , Herrera Elmer M , Molloy Ali , Vegvari Carolin
Published: September 2021

In this Supplement, we detail outputs of the National Institute for Health Research Global Health Research Unit on Genomic Surveillance of Antimicrobial Resistance project, covering practical implementation of whole-genome sequencing across our consortium, which consists of laboratories in Colombia, India, Nigeria, and the Philippines.
Three-year Efficacy and Safety of Takeda’s Dengue Vaccine Candidate (TAK-003)
Authors: Rivera Luis , Biswal Shibadas , Sáez-Llorens Xavier , Reynales Humberto , López-Medina Eduardo , Borja-Tabora Charissa , Bravo Lulu , Sirivichayakul Chukiat , Kosalaraksa Pope , Martinez Vargas Luis , Yu Delia , Watanaveeradej Veerachai , Espinoza Felix , Dietze Reynaldo , Fernando LakKumar , Wickramasinghe Pujitha , Duarte MoreiraJr Edson , Fernando Asvini D , Gunasekera Dulanie , Luz Kleber , Venâncioda Cunha Rivaldo , Rauscher Martina , Zent Olaf , Liu Mengya , Hoffman Elaine , LeFevre Inge , Tricou Vianney , Wallace Derek , Alera MariaTheresa , Borkowski Astrid
Published: September 2021

Background

Takeda’s live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across 8 dengue-endemic countries. Previously, we have reported its efficacy and safety in both seronegative and seropositive participants and that its performance varies by serotype, with some decline in efficacy from first to second year postvaccination. This exploratory analysis provides an update with cumulative and third-year data.

Methods

Healthy 4–16 year olds (n = 20099) were randomized 2:1 to receive TAK-003 or placebo (0, 3 month schedule). The protocol included baseline serostatus testing of all participants and detection of all symptomatic dengue throughout the trial with a serotype specific reverse transcriptase-polymerase chain reaction.

Results

Cumulative efficacy after 3 years was 62.0% (95% confidence interval, 56.6–66.7) against virologically confirmed dengue (VCD) and 83.6% (76.8–88.4) against hospitalized VCD. Efficacy was 54.3% (41.9–64.1) against VCD and 77.1% (58.6–87.3) against hospitalized VCD in baseline seronegatives, and 65.0% (58.9–70.1) against VCD and 86.0% (78.4–91.0) against hospitalized VCD in baseline seropositives. Efficacy against VCD during the third year declined to 44.7% (32.5–54.7), whereas efficacy against hospitalized VCD was sustained at 70.8% (49.6–83.0). Rates of serious adverse events were 2.9% in TAK-003 group and 3.5% in placebo group during the ongoing long-term follow-up (ie, second half of the 3 years following vaccination), but none were related. No important safety risks were identified.

Conclusions

TAK-003 was efficacious against symptomatic dengue over 3 years. Efficacy declined over time but remained robust against hospitalized dengue. A booster dose evaluation is planned.
Administration of a β-Lactam Prior to Vancomycin as the First Dose of Antibiotic Therapy Improves Survival in Patients With Bloodstream Infections
Authors: Amoah Joe , Klein Eili Y , Chiotos Kathleen , Cosgrove Sara E , Tamma Pranita D
Published: September 2021

Background

Prompt initiation of antibiotic therapy improves the survival of patients with bloodstream infections (BSIs). We sought to determine if the sequence of administration of the first dose of antibiotic therapy (ie, β-lactam or vancomycin, if both are deemed necessary and cannot be administered simultaneously) impacts early mortality for patients with BSI.

Methods

We conducted a multicenter, observational study of patients ≥13 years with BSIs to evaluate the association of the sequence of antibiotic administration with 7-day mortality using inverse probability of treatment weighting (IPTW) incorporating propensity scores. Propensity scores were generated based on demographics, Pitt bacteremia score, intensive care unit status, highest lactate, highest white blood cell count, Charlson comorbidity index, severe immunocompromise, administration of active empiric therapy, combination therapy, and time from emergency department arrival to first antibiotic dose.

Results

Of 3376 eligible patients, 2685 (79.5%) received a β-lactam and 691 (20.5%) received vancomycin as their initial antibiotic. In the IPTW cohort, exposed and unexposed patients were similar on all baseline variables. Administration of a β-lactam agent prior to vancomycin protected against 7-day mortality (adjusted odds ratio [aOR], 0.48 [95% confidence interval {CI}, .33–.69]). Similar results were observed when evaluating 48-hour mortality (aOR, 0.45 [95% CI, .24–.83]). Administration of vancomycin prior to a β-lactam was not associated with improved survival in the subgroup of 524 patients with methicillin-resistant Staphylococcus aureus BSI (aOR, 0.93 [95% CI, .33–2.63]).

Conclusions

For ill-appearing patients likely to be experiencing a BSI, prioritizing administration of a β-lactam over vancomycin may reduce early mortality, underscoring the significant impact of a relatively simple practice change on improving patient survival.
Defining Antibiotic Inertia: Application of a Focused Clinical Scenario Survey to Illuminate A New Target for Antimicrobial Stewardship During Transitions of Care
Authors: Kooda Kirstin , Bellolio Fernanda , Dierkhising Ross , Tande Aaron J
Published: September 2021

In clinical scenario surveys, inpatient providers were more likely to report continuing inappropriate (odds ratio, 2.02 [95% confidence interval, 1.35–3.03]; P<.001) or broad-spectrum (1.8 [1.27–2.56]; P=.001) antibiotic therapy when initiated by emergency department providers, than to change to appropriate or narrow-spectrum therapy, respectively. Antibiotic inertia could represent a significant antibiotic stewardship target.
Remdesivir Treatment in Hospitalized Patients With Coronavirus Disease 2019 (COVID-19): A Comparative Analysis of In-hospital All-cause Mortality in a Large Multicenter Observational Cohort
Authors: Mozaffari Essy , Chandak Aastha , Zhang Zhiji , Liang Shuting , Thrun Mark , Gottlieb Robert L , Kuritzkes Daniel R , Sax Paul E , Wohl David A , Casciano Roman , Hodgkins Paul , Haubrich Richard
Published: September 2021

Background

Remdesivir (RDV) improved clinical outcomes among hospitalized patients with coronavirus disease 2019 (COVID-19) in randomized trials, but data from clinical practice are limited.

Methods

We examined survival outcomes for US patients hospitalized with COVID-19 between August and November 2020 and treated with RDV within 2 days of hospitalization vs those not receiving RDV during their hospitalization using the Premier Healthcare Database. Preferential within-hospital propensity score matching with replacement was used. Additionally, patients were also matched on baseline oxygenation level (no supplemental oxygen charges [NSO], low-flow oxygen [LFO], high-flow oxygen/noninvasive ventilation [HFO/NIV], and invasive mechanical ventilation/extracorporeal membrane oxygenation [IMV/ECMO]) and 2-month admission window and excluded if discharged within 3 days of admission (to exclude anticipated discharges/transfers within 72 hours, consistent with the Adaptive COVID-19 Treatment Trial [ACTT-1] study). Cox proportional hazards models were used to assess time to 14-/28-day mortality overall and for patients on NSO, LFO, HFO/NIV, and IMV/ECMO.

Results

A total of 28855 RDV patients were matched to 16687 unique non-RDV patients. Overall, 10.6% and 15.4% RDV patients died within 14 and 28 days, respectively, compared with 15.4% and 19.1% non-RDV patients. Overall, RDV was associated with a reduction in mortality at 14 days (hazard ratio [95% confidence interval]: 0.76 [0.70–0.83]) and 28 days (0.89 [0.82–0.96]). This mortality benefit was also seen for NSO, LFO, and IMV/ECMO at 14 days (NSO: 0.69 [0.57–0.83], LFO: 0.68 [0.80–0.77], IMV/ECMO: 0.70 [0.58–0.84]) and 28 days (NSO: 0.80 [0.68–0.94], LFO: 0.77 [0.68–0.86], IMV/ECMO: 0.81 [0.69–0.94]). Additionally, HFO/NIV RDV group had a lower risk of mortality at 14 days (0.81 [0.70–0.93]) but no statistical significance at 28 days.

Conclusions

RDV initiated upon hospital admission was associated with improved survival among patients with COVID-19. Our findings complement ACTT-1 and support RDV as a foundational treatment for hospitalized COVID-19 patients.
Pathogen-Specific Effects of Probiotics in Children With Acute Gastroenteritis Seeking Emergency Care: A Randomized Trial
Authors: Freedman Stephen B , Finkelstein Yaron , Pang Xiao Li , Chui Linda , Tarr Phillip I , VanBuren John M , Olsen Cody , Lee Bonita E , Hall-Moore Carla A , Sapien Robert , O’Connell Karen , Levine Adam C , Poonai Naveen , Roskind Cindy , Schuh Suzanne , Rogers Alexander , Bhatt Seema , Gouin Serge , Mahajan Prashant , Vance Cheryl , Hurley Katrina , Powell Elizabeth C , Farion Ken J , Schnadower David
Published: September 2021

Background

It is unknown if probiotics exert pathogen-specific effects in children with diarrhea secondary to acute gastroenteritis.

Methods

Analysis of patient-level data from 2 multicenter randomized, placebo controlled trials conducted in pediatric emergency departments in Canada and the United States. Participants were 3–48 months with >3 diarrheal episodes in the preceding 24 hours and were symptomatic for <72 hours and <7 days in the Canadian and US studies, respectively. Participants received either placebo or a probiotic preparation (Canada-Lactobacillus rhamnosus R0011/Lactobacillus helveticus R0052; US-L. rhamnosus GG). The primary outcome was post-intervention moderate-to-severe disease (ie, ≥9 on the Modified Vesikari Scale [MVS] score).

Results

Pathogens were identified in specimens from 59.3% of children (928/1565). No pathogen groups were less likely to experience an MVS score ≥9 based on treatment allocation (test for interaction = 0.35). No differences between groups were identified for adenovirus (adjusted relative risk [aRR]: 1.42; 95% confidence interval [CI]: .62, 3.23), norovirus (aRR: 0.98; 95% CI: .56, 1.74), rotavirus (aRR: 0.86; 95% CI: .43, 1.71) or bacteria (aRR: 1.19; 95% CI: .41, 3.43). At pathogen-group and among individual pathogens there were no differences in diarrhea duration or the total number of diarrheal stools between treatment groups, regardless of intervention allocation or among probiotic sub-groups. Among adenovirus-infected children, those administered the L. rhamnosus R0011/L. helveticus R0052 product experienced fewer diarrheal episodes (aRR: 0.65; 95% CI: .47, .90).

Conclusions

Neither probiotic product resulted in less severe disease compared to placebo across a range of the most common etiologic pathogens. The preponderance of evidence does not support the notion that there are pathogen specific benefits associated with probiotic use in children with acute gastroenteritis.

Clinical Trials Registration

NCT01773967 and NCT01853124.
One-Year Sustained Cellular and Humoral Immunities in Coronavirus Disease 2019 (COVID-19) Convalescents
Authors: Zhang Jie , Lin Hao , Ye Beiwei , Zhao Min , Zhan Jianbo , Dong Shaobo , Guo Yaxin , Zhao Yingze , Li Min , Liu Sai , Zhang Hangjie , Xiao Wenling , Guo Yuanyuan , Yue Can , Zhang Danni , Yang Mengjie , Zhang Jing , Quan Chuansong , Shi Weifeng , Liu Xinxue , Liu Peipei , Jiang Yongzhong , Wu Guizhen , Gao George F , Liu William J
Published: September 2021

Background

The longitudinal antigen-specific immunity in COVID-19 convalescents is crucial for long-term protection upon individual re-exposure to SARS-CoV-2, and even more pivotal for ultimately achieving population-level immunity. We conducted this cohort study to better understand the features of immune memory in individuals with different disease severities at 1 year post–disease onset.

Methods

We conducted a systematic antigen-specific immune evaluation in 101 COVID-19 convalescents, who had asymptomatic, mild, moderate, or severe disease, through 2 visits at months 6 and 12 after disease onset. The SARS-CoV-2–specific antibodies, comprising neutralizing antibody (NAb), immunoglobulin (Ig) G, and IgM, were assessed by mutually corroborated assays (ie, neutralization, enzyme-linked immunosorbent assay [ELISA], and microparticle chemiluminescence immunoassay [MCLIA]). Meanwhile, T-cell memory against SARS-CoV-2 spike, membrane, and nucleocapsid proteins was tested through enzyme-linked immunospot assay (ELISpot), intracellular cytokine staining, and tetramer staining-based flow cytometry, respectively.

Results

SARS-CoV-2–specific IgG antibodies, and NAb, can persist among >95% of COVID-19 convalescents from 6 to 12 months after disease onset. At least 19/71 (26%) of COVID-19 convalescents (double positive in ELISA and MCLIA) had detectable circulating IgM antibody against SARS-CoV-2 at 12 months post–disease onset. Notably, numbers of convalescents with positive SARS-CoV-2–specific T-cell responses (≥1 of the SARS-CoV-2 antigen S1, S2, M, and N proteins) were 71/76 (93%) and 67/73 (92%) at 6 and 12 months, respectively. Furthermore, both antibody and T-cell memory levels in the convalescents were positively associated with disease severity.

Conclusions

SARS-CoV-2–specific cellular and humoral immunities are durable at least until 1 year after disease onset.
Uneven development: convergence, divergence and politics
Authors: Cox Kevin R
Published: September 2021

The paper positions itself in contrast to some themes in work on local and regional development. These have included an emphasis on policy rather than politics, tendencies to over-generalize across countries, and to abstract from the more global context. The empirical context for the discussion is the shifting character of geographically uneven development since the Second World War: first a convergence and then, after the mid-1970s, a divergence. Convergence is held to be the result of what some have called spatial Keynesianism. The conditions for this and for its demise, resulting in divergence, are traced out with particular reference to how the shifting pressures and opportunities were refracted by the specificities of countries. State form emerges as particularly important in understanding different trajectories, along with a neo-liberal globalisation that has been in contrast to the monetary and trading regime inaugurated by the Bretton Woods agreements.
Flummoxed by flux: the indeterminate principles of haemodialysis
Authors: Bowry Sudhir K , Kircelli Fatih , Misra Madhukar
Published: September 2021

In haemodialysis (HD), unwanted substances (uraemic retention solutes or ‘uraemic toxins’) that accumulate in uraemia are removed from blood by transport across the semipermeable membrane. Like all membrane separation processes, the transport requires driving forces to facilitate the transfer of molecules across the membrane. The magnitude of the transport is quantified by the phenomenon of ‘flux’, a finite parameter defined as the volume of fluid (or permeate) transferred per unit area of membrane surface per unit time. In HD, as transmembrane pressure is applied to facilitate fluid flow or flux across the membrane to enhance solute removal, flux is defined by the ultrafiltration coefficient (KUF; mL/h/mmHg) reflecting the hydraulic permeability of the membrane. However, in HD, the designation of flux has come to be used in a much broader sense and the term is commonly used interchangeably and erroneously with other measures of membrane separation processes, resulting in considerable confusion. Increased flux is perceived to reflect more ‘porous’ membranes having ‘larger’ pores, even though other membrane and therapy attributes determine the magnitude of flux achieved during HD. Adjectival designations of flux (low-, mid-, high-, super-, ultra-) have found indiscriminate usage in the scientific literature to qualify a parameter that influences clinical decision making and prescription of therapy modalities (low-flux or high-flux HD). Over the years the concept and definition of flux has undergone arbitrary and periodic adjustment and redefinition by authors in publications, regulatory bodies (US Food and Drug Administration) and professional association guidelines (European Renal Association, Kidney Disease Outcomes Quality Initiative), with little consensus. Industry has stretched the boundaries of flux to derive marketing advantages, justify increased reimbursement or contrive new classes of therapy modalities when in fact flux is just one of several specifications that determine membrane or dialyser performance. Membranes considered as high-flux previously are today at the lower end of the flux spectrum. Further, additional parameters unrelated to the rate of diffusive or convective transport (flux) are used in conjunction with or in place of KUF to allude to flux: clearance (mL/min, e.g. of β2-microglobulin) or sieving coefficients (dimensionless). Considering that clinical trials in nephrology, designed to make therapy recommendations and guide policy with economic repercussions, are based on the parameter flux they merit clarification—by regulatory authorities and scientists alike—to avoid further misappropriation.
Blood-incompatibility in haemodialysis: alleviating inflammation and effects of coagulation
Authors: Bowry Sudhir K , Kircelli Fatih , Himmele Rainer , Nigwekar Sagar U
Published: September 2021

Blood-incompatibility is an inevitability of all blood-contacting device applications and therapies, including haemodialysis (HD). Blood leaving the environment of blood vessels and the protection of the endothelium is confronted with several stimuli of the extracorporeal circuit (ECC), triggering the activation of blood cells and various biochemical pathways of plasma. Prevention of blood coagulation, a major obstacle that needed to be overcome to make HD possible, remains an issue to contend with. While anticoagulation (mainly with heparin) successfully prevents clotting within the ECC to allow removal of uraemic toxins across the dialysis membrane wall, it is far from ideal, triggering heparin-induced thrombocytopenia in some instances. Soluble fibrin can form even in the presence of heparin and depending on the constitution of the patient and activation of platelets, could result in physical clots within the ECC (e.g. bubble trap chamber) and, together with other plasma and coagulation proteins, result in increased adsorption of proteins on the membrane surface. The buildup of this secondary membrane layer impairs the transport properties of the membrane to reduce the clearance of uraemic toxins. Activation of complement system-dependent immune response pathways leads to leukopenia, formation of platelet–neutrophil complexes and expression of tissue factor contributing to thrombotic processes and a procoagulant state, respectively. Complement activation also promotes recruitment and activation of leukocytes resulting in oxidative burst and release of pro-inflammatory cytokines and chemokines, thereby worsening the elevated underlying inflammation and oxidative stress condition of chronic kidney disease patients. Restricting all forms of blood-incompatibility, including potential contamination of dialysis fluid with endotoxins leading to inflammation, during HD therapies is thus still a major target towards more blood-compatible and safer dialysis to improve patient outcomes. We describe the mechanisms of various activation pathways during the interaction between blood and components of the ECC and describe approaches to mitigate the effects of these adverse interactions. The opportunities to develop improved dialysis membranes as well as implementation strategies with less potential for undesired biological reactions are discussed.
Subtyping hospitalized patients with hypokalemia by machine learning consensus clustering and associated mortality risks
Authors: Thongprayoon Charat , Mao Michael A , Kattah Andrea G , Keddis Mira T , Pattharanitima Pattharawin , Erickson Stephen B , Dillon John J , Garovic Vesna D , Cheungpasitporn Wisit
Published: September 2021

Background

Hospitalized patients with hypokalemia are heterogeneous and cluster analysis, an unsupervised machine learning methodology, may discover more precise and specific homogeneous groups within this population of interest. Our study aimed to cluster patients with hypokalemia at hospital admission using an unsupervised machine learning approach and assess the mortality risk among these distinct clusters.

Methods

We performed consensus clustering analysis based on demographic information, principal diagnoses, comorbidities and laboratory data among 4763 hospitalized adult patients with admission serum potassium ≤3.5 mEq/L. We calculated the standardized mean difference of each variable and used the cutoff of ±0.3 to identify each cluster's key features. We assessed the association of the hypokalemia cluster with hospital and 1-year mortality.

Results

Consensus cluster analysis identified three distinct clusters that best represented patients’ baseline characteristics. Cluster 1 had 1150 (32%) patients, cluster 2 had 1344 (28%) patients and cluster 3 had 1909 (40%) patients. Based on the standardized difference, patients in cluster 1 were younger, had less comorbidity burden but higher estimated glomerular filtration rate (eGFR) and higher hemoglobin; patients in cluster 2 were older, more likely to be admitted for cardiovascular disease and had higher serum sodium and chloride levels but lower eGFR, serum bicarbonate, strong ion difference (SID) and hemoglobin, while patients in cluster 3 were older, had a greater comorbidity burden, higher serum bicarbonate and SID but lower serum sodium, chloride and eGFR. Compared with cluster 1, cluster 2 had both higher hospital and 1-year mortality, whereas cluster 3 had higher 1-year mortality but comparable hospital mortality.

Conclusion

Our study demonstrated the use of consensus clustering analysis in the heterogeneous cohort of hospitalized hypokalemic patients to characterize their patterns of baseline clinical and laboratory data into three clinically distinct clusters with different mortality risks.