bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scoping future outbreaks: a scoping review on the outbreak prediction of the WHO Blueprint list of priority diseases
Authors: Jonkmans Nils , D’Acremont Valérie , Flahault Antoine 
Published: September 2021

BackgroundThe WHO’s Research and Development Blueprint priority list designates emerging diseases with the potential to generate public health emergencies for which insufficient preventive solutions exist. The list aims to reduce the time to the availability of resources that can avert public health crises. The current SARS-CoV-2 pandemic illustrates that an effective method of mitigating such crises is the pre-emptive prediction of outbreaks. This scoping review thus aimed to map and identify the evidence available to predict future outbreaks of the Blueprint diseases.MethodsWe conducted a scoping review of PubMed, Embase and Web of Science related to the evidence predicting future outbreaks of Ebola and Marburg virus, Zika virus, Lassa fever, Nipah and Henipaviral disease, Rift Valley fever, Crimean-Congo haemorrhagic fever, Severe acute respiratory syndrome, Middle East respiratory syndrome and Disease X. Prediction methods, outbreak features predicted and implementation of predictions were evaluated. We conducted a narrative and quantitative evidence synthesis to highlight prediction methods that could be further investigated for the prevention of Blueprint diseases and COVID-19 outbreaks.ResultsOut of 3959 articles identified, we included 58 articles based on inclusion criteria. 5 major prediction methods emerged; the most frequent being spatio-temporal risk maps predicting outbreak risk periods and locations through vector and climate data. Stochastic models were predominant. Rift Valley fever was the most predicted disease. Diseases with complex sociocultural factors such as Ebola were often predicted through multifactorial risk-based estimations. 10% of models were implemented by health authorities. No article predicted Disease X outbreaks.ConclusionsSpatiotemporal models for diseases with strong climatic and vectorial components, as in River Valley fever prediction, may currently best reduce the time to the availability of resources. A wide literature gap exists in the prediction of zoonoses with complex sociocultural and ecological dynamics such as Ebola, COVID-19 and especially Disease X.
Safety, feasibility and efficacy of metformin and sitagliptin in patients with a TIA or minor ischaemic stroke and impaired glucose tolerance
Authors: Osei Elizabeth , Zandbergen Adrienne , Brouwers Paul J A M , Mulder Laus J M M , Koudstaal Peter , Lingsma Hester , Dippel Diederik W J , den Hertog Heleen 
Published: September 2021

IntroductionImpaired glucose tolerance (IGT) is highly prevalent after stroke and is associated with recurrent stroke and unfavourable outcome.ObjectivesWe aimed to assess the feasibility, safety and effects on glucose metabolism of metformin or sitagliptin in patients with transient ischaemic attack (TIA) or minor ischaemic stroke and IGT.DesignWe performed a multicentre, randomised, controlled, open-label phase II trial with blinded outcome assessment.InterventionsPatients were randomised in a 2:1:1 ratio to ‘no medication’, sitagliptin or metformin.Primary and secondary outcome measuresPrimary outcome measures were baseline adjusted differences of 2-hour postload glucose; secondary outcome measures fasting glucose, glycosylated haemoglobin 1c (HbA1c) levels, tolerability and safety of metformin and sitagliptin at 6 months. Patients on metformin or sitagliptin were contacted by telephone for recording of possible adverse events and to support continuation of treatment at 2 weeks, 6 weeks and 3 months after inclusion. These events were not analysed as outcome measures.ResultsFifty-three patients were randomised to control group, 26 to metformin and 22 to sitagliptin. We found no significant differences in 2-hour postload glucose between patients on antidiabetic drugs and controls ((−0.04 mmol/L (95% CI −0.53 to 0.45)). Patients in the treatment arms had reduced fasting glucose: ((−0.21 mmol/L (95% CI −0.36 to −0.06)) and HbA1c levels ((−1.16 mmol/mol (95% CI −1.84 to −0.49)). Thirteen patients (50%) on metformin and 7 (32%) on sitagliptin experienced side effects. Sixteen patients (61%) in the metformin and 13 (59%) in the sitagliptin group were still on treatment after 6 months.ConclusionsMetformin and sitagliptin were both effective in reducing fasting glucose and HbA1c levels in patients with recent TIA or minor ischaemic stroke and IGT. However, the reduction of glucose levels and sample size was relatively small. The clinical relevance, therefore, needs to be tempered. A phase III trial is needed to investigate whether medical treatment, compared with lifestyle intervention or a combination of both, not only improves glucose metabolism in IGT, but also leads to reduction of recurrent TIA or ischaemic stroke in these patients.Trial registration numberNL3048.
Comparing lung ultrasound: extensive versus short in COVID-19 (CLUES): a multicentre, observational study at the emergency department
Authors: Kok Bram , Schuit Frederik , Lieveld Arthur , Azijli Kaoutar , Nanayakkara Prabath WB , Bosch Frank 
Published: September 2021

BackgroundBedside lung ultrasound (LUS) is an affordable diagnostic tool that could contribute to identifying COVID-19 pneumonia. Different LUS protocols are currently used at the emergency department (ED) and there is a need to know their diagnostic accuracy.DesignA multicentre, prospective, observational study, to compare the diagnostic accuracy of three commonly used LUS protocols in identifying COVID-19 pneumonia at the ED.Setting/patientsAdult patients with suspected COVID-19 at the ED, in whom we prospectively performed 12-zone LUS and SARS-CoV-2 reverse transcription PCR.MeasurementsWe assessed diagnostic accuracy for three different ultrasound protocols using both PCR and final diagnosis as a reference standard.ResultsBetween 19 March 2020 and 4 May 2020, 202 patients were included. Sensitivity, specificity and negative predictive value compared with PCR for 12-zone LUS were 91.4% (95% CI 84.4 to 96.0), 83.5% (95% CI 74.6 to 90.3) and 90.0% (95% CI 82.7 to 94.4). For 8-zone and 6-zone protocols, these results were 79.7 (95% CI 69.9 to 87.6), 69.0% (95% CI 59.6 to 77.4) and 81.3% (95% CI 73.8 to 87.0) versus 89.9% (95% CI 81.7 to 95.3), 57.5% (95% CI 47.9 to 66.8) and 87.8% (95% CI 79.2 to 93.2). Negative likelihood ratios for 12, 8 and 6 zones were 0.1, 0.3 and 0.2, respectively. Compared with the final diagnosis specificity increased to 83.5% (95% CI 74.6 to 90.3), 78.4% (95% CI 68.8 to 86.1) and 65.0% (95% CI 54.6 to 74.4), respectively, while the negative likelihood ratios were 0.1, 0.2 and 0.16.ConclusionIdentifying COVID-19 pneumonia at the ED can be aided by bedside LUS. The more efficient 6-zone protocol is an excellent screening tool, while the 12-zone protocol is more specific and gives a general impression on lung involvement.Trial registration numberNL8497.
Association between facility-level adherence to phosphorus management guidelines and mortality in haemodialysis patients: a prospective cohort study
Authors: Itaya Takahiro , Shimizu Sayaka , Hara Takashi , Matsuoka Yoshinori , Fukuhara Shunichi , Yamamoto Yosuke 
Published: September 2021

ObjectivesTo examine the association between facility-level adherence to phosphorus management guidelines and mortality among patients with haemodialysis, and to explore the facility-related factors associated with facility-level guideline adherence.DesignProspective cohort study.SettingThe Dialysis Outcomes and Practice Pattern Study, which included 57 representative dialysis facilities in Japan between 2012 and 2015.ParticipantsA total of 2054 adult patients who received maintenance haemodialysis were included. We defined exposure according to the following four categories, depending on whether facility-level target ranges of serum phosphorus concentration adhered to the Japanese clinical practice guidelines: adherence group (lower limit ≥3.5 mg/dL and upper limit ≤6.0 mg/dL), low-target group (lower limit <3.5 and upper limit ≤6.0), wide-target group (lower limit <3.5 and upper limit >6.0) and high-target group (lower limit ≥3.5 and upper limit >6.0).Primary outcome measureThe primary outcome was the patient all-cause mortality rate.ResultsThe mortality rate among the patients was 7.3 per 100 person-years; 27 facilities (47%) set targets according to the guidelines. HRs for mortality with reference to the adherence group were 1.04 (95% CI 0.76 to 1.43) in the low-target group, 1.11 (95% CI 0.68 to 1.81) in the wide-target group and 1.95 (95% CI 1.12 to 3.38) in the high-target group. Involvement of dieticians in dialysis treatment was associated with facility-level guideline adherence (OR 4.51; 95% CI 1.15 to 17.7).ConclusionsA higher facility-level target range for phosphorus was associated with increased patient mortality. Among facilities that set the target according to the guidelines, dieticians tended to be involved in dialysis care. These findings suggest the importance of reviewing facilities’ treatment policies in relation to updated guidelines and the need to work with relevant professionals.
Towards a global framework for assessing male involvement in maternal health: results of an international Delphi study
Authors: Galle Anna , Griffin Sally , Osman Nafissa , Roelens Kristien , Degomme Olivier 
Published: September 2021

PurposeCurrently, no standard instrument exists for assessing the concept of male involvement in maternal health, hampering comparison of results and interpretation of the literature. The aim of this study was to construct the key elements of a global multidimensional male involvement framework, based on the latest evidence and input of experts in the field.MethodsFor this purpose, a Delphi study, including an international panel of 26 experts, was carried out. The study consisted of three rounds, with 92% of respondents completing all three surveys. Experts were asked to rate indicators within six categories in terms of validity, feasibility, sensitivity, specificity and context robustness. Furthermore, they were encouraged to clarify their rating with open text responses. Indicators were excluded or adapted according to experts’ feedback before inclusion. A 85% agreement was used as threshold for consensus.ResultsA general consensus was reached for a global framework for assessing male involvement in maternal health, consisting of five categories: involvement in communication, involvement in decision-making, practical involvement, physical involvement and emotional involvement.ConclusionsUsing the male involvement framework as a tool to assess the concept of male involvement in maternal health at local, national, and international levels could allow improved assessment and comparison of study findings. Further research is needed for refining the indicators according to context and exploring how shared decision-making, gender equality and women’s empowerment can be assessed and facilitated within male involvement programmes.
Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates
Authors: Liao John B , Gwin William R , Urban Renata R , Hitchcock-Bernhardt Katie M , Coveler Andrew L , Higgins Doreen M , Childs Jennifer S , Shakalia Hania N , Swensen Ron E , Stanton Sasha E , Tinker Anna V , Wahl Tanya A , Ancheta Richard G , McGonigle Kathryn F , Dai James Y , Disis Mary L , Goff Barbara A 
Published: September 2021

BackgroundAnti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer.Patients and methodsThis phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67.ResultsThe most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53).ConclusionsPembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy.Trial registration numberNCT03029598.
Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design
Authors: Qin Haiying , Yang Lila , Chukinas John A , Shah Nirali N , Tarun Samiksha , Pouzolles Marie , Chien Christopher D , Niswander Lisa M , Welch Anthony R , Taylor Naomi A , Tasian Sarah K , Fry Terry J 
Published: September 2021

BackgroundSuccessful development of chimeric antigen receptor (CAR) T cell immunotherapy for children and adults with relapsed/refractory acute myeloid leukemia (AML) is highly desired given their poor clinical prognosis and frequent inability to achieve cure with conventional chemotherapy. Initial experiences with CD19 CAR T cell immunotherapy for patients with B-cell malignancies highlighted the critical impact of intracellular costimulatory domain selection (CD28 vs 4-1BB (CD137)) on CAR T cell expansion and in vivo persistence that may impact clinical outcomes. However, the impact of costimulatory domains on the efficacy of myeloid antigen-directed CAR T cell immunotherapy remains unknown.MethodsIn this preclinical study, we developed six CAR constructs targeting CD33, a highly expressed and validated AML target, comprised of one of three single-chain variable fragments with CD3ζ and either CD28 or 4-1BB costimulatory domains. We systematically compared the preclinical in vitro and in vivo efficacy of T cells lentivirally transduced with CD33 CAR constructs (CD33CARTs) against human AML.ResultsWe observed potent in vitro cytokine production and cytotoxicity of CD33CARTs incubated with human CD33+ AML cell lines, as well as robust in vivo antileukemia activity in cell line and childhood AML patient-derived xenograft (PDX) models. Gemtuzumab-based CD33CARTs were unexpectedly toxic in vivo in animal models despite observed in vitro anti-leukemia activity. CD28-based CD33CARTs consistently induced more robust inhibition of leukemia proliferation in AML cell line and PDX models than did 4-1BB-based CD33CARTs. A ‘best-in-class’ lintuzumab-CD28/CD3ζ CAR construct was thus selected for clinical translation.ConclusionsCD33 is a critical antigen for potential immunotherapeutic targeting in patients with AML. Based on this rigorous preclinical evaluation, our validated clinical grade lintuzumab-CD28/CD3ζ CD33CART immunotherapy is now under evaluation in a first-in-child/first-in-human phase 1 clinical trial for children and adolescents/young adults with relapsed/refractory AML.Trial registration numberclinicaltrials.gov;NCT03971799.
Thioflavin T fluorescence and NMR spectroscopy suggesting a non-G-quadruplex structure for a sodium binding aptamer embedded in DNAzymes
Authors: Saran Runjhun , Piccolo Kyle A. , He Yanping , Kang Yongqiang , Huang Po-Jung Jimmy , Wei Chunying , Chen Da , Dieckmann Thorsten , Liu Juewen 
Published: September 2021

Recently, a Na+-binding aptamer was reported to be embedded in a few RNA-cleaving DNAzymes, including NaA43, Ce13d, and NaH1. The Na+ aptamer consists of multiple GG stretches, which is a prerequisite for the formation of G-quadruplex (G4) structures. These DNAzymes require Na+ for activity but show no activity in the presence of K+ or other metal ions. Given that DNA can selectively bind K+ by forming a G4 structure, this work aims to answer whether this Na+ aptamer also uses a G4 to bind Na+. Through comparative ThT fluorescence spectrometry studies, while a control G4 DNA exhibited notable fluorescence enhancement up to 5 mM K+ with a Kd of 0.28 ± 0.06 mM, the Ce13d DNAzyme fluorescence was negligibly perturbed with similar concentrations of K+. Opposed to this, Ce13d displayed specific remarkable fluorescence decrease with low millimolar concentrations of Na+. NMR experiments at two different pH values suggest that Ce13d adopts a significantly different conformation or equilibrium of conformations in the presence of Na+ versus K+ and has a more stable structure in the presence of Na+. Additionally, absence of characteristic G4 peaks in one-dimensional 1H NMR suggest that G4 is not responsible for the Na+ binding. This hypothesis is confirmed by the absence of characteristic peaks in the CD spectra of this sequence. Therefore, we concluded that the aptamer must be selective for Na+ and that it binds Na+ using a structural element that does not contain G4.
SLC5A3-Dependent Myo-inositol Auxotrophy in Acute Myeloid Leukemia
Authors: Wei Yiliang , Huang Yu-Han , Skopelitis Damianos S. , Iyer Shruti V. , Costa Ana S.H. , Yang Zhaolin , Kramer Melissa , Adelman Emmalee R. , Klingbeil Olaf , Demerdash Osama E. , Polyanskaya Sofya A. , Chang Kenneth , Goodwin Sara , Hodges Emily , McCombie W. Richard , Figueroa Maria E. , Vakoc Christopher R. 
Published: September 2021

AbstractAn enhanced requirement for nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a dependency in this disease. We demonstrate that SLC5A3 is essential to support a myo-inositol auxotrophy in AML. The commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1, which encodes the rate-limiting enzyme for myo-inositol biosynthesis, inositol-3-phosphate synthase 1. We use gain- and loss-of-function experiments to reveal a synthetic lethal genetic interaction between ISYNA1 and SLC5A3 in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hypermethylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with IDH1/IDH2 and CEBPA mutations. Our findings reveal myo-inositol as a nutrient dependency in AML caused by the aberrant silencing of a biosynthetic enzyme.Significance:We show how epigenetic silencing can provoke a nutrient dependency in AML by exploiting a synthetic lethality relationship between biosynthesis and transport of myo-inositol. Blocking the function of this solute carrier may have therapeutic potential in an epigenetically defined subset of AML.This article is highlighted in the In This Issue feature, p. 275
NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity
Authors: Richards Rebecca M. , Zhao Feifei , Freitas Katherine A. , Parker Kevin R. , Xu Peng , Fan Amy , Sotillo Elena , Daugaard Mads , Oo Htoo Zarni , Liu Jie , Hong Wan-Jen , Sorensen Poul H. , Chang Howard Y. , Satpathy Ansuman T. , Majzner Robbie G. , Majeti Ravindra , Mackall Crystal L. 
Published: September 2021

Abstract

Chimeric antigen receptor (CAR) T cells hold promise for the treatment of acute myeloid leukemia (AML), but optimal targets remain to be defined. We demonstrate that CD93 CAR T cells engineered from a novel humanized CD93-specific binder potently kill AML in vitro and in vivo but spare hematopoietic stem and progenitor cells (HSPC). No toxicity is seen in murine models, but CD93 is expressed on human endothelial cells, and CD93 CAR T cells recognize and kill endothelial cell lines. We identify other AML CAR T-cell targets with overlapping expression on endothelial cells, especially in the context of proinflammatory cytokines. To address the challenge of endothelial-specific cross-reactivity, we provide proof of concept for NOT-gated CD93 CAR T cells that circumvent endothelial cell toxicity in a relevant model system. We also identify candidates for combinatorial targeting by profiling the transcriptome of AML and endothelial cells at baseline and after exposure to proinflammatory cytokines.

Significance:
CD93 CAR T cells eliminate AML and spare HSPCs but exert on-target, off-tumor toxicity to endothelial cells. We show coexpression of other AML targets on endothelial cells, introduce a novel NOT-gated strategy to mitigate endothelial toxicity, and demonstrate use of high-dimensional transcriptomic profiling for rational design of combinatorial immunotherapies.
See related commentary by Velasquez and Gottschalk, p. 559.
This article is highlighted in the In This Issue feature, p. 549
First record of Scinax centralis (Anura, Hylidae) in the Triângulo Mineiro region, state of Minas Gerais, southeastern Brazil, with further data on its vocalization
Authors: Bang Davi Lee , Pie Marcio , Giaretta Ariovaldo Antonio 
Published: September 2021

Scinax comprises more than 120 species which are split in two clades, the S. ruber and the S. catharinae clades. A few species within the S. catharinae clade occur in gallery forests of the Brazilian Cerrado. We here extend the distribution of S. centralis southwards based on new populations sampled in the banks of the Rio Paranaíba, in the borders of Minas Gerais (MG) and Goiás (GO) states, southeastern Brazil. We also provide further data on the species vocalization. Variation was seen among our population and topotypes regarding SVL and call dominant frequency, both likely representing a clinal variation. Our new population of S. centralis represents the first record of the species for the state of Minas Gerais.