bluuebunny/crossref_metadata_2025 huggingface dataset:
Why we should rethink the third-person effect: disentangling bias and earned confidence using behavioral data
Authors: Lyons Benjamin A
Published: August 2022

Although positioned as a cognitive bias, third-person effect research has relied on self-reported difference scores that fail to capture bias appropriately. I use pre-registered and exploratory analyses of three nationally representative surveys (N = 10,004) to examine perceptions of susceptibility to false news and behavioral measures of actual susceptibility. Americans consistently exhibit third-person perception. However, some of this perceptual gap may be “earned.” I show that 62–68% of those exhibiting TPP are in fact less susceptible than average. Accordingly, I construct a performance-derived measure of true overconfidence. I find domain-involvement correlates of TPP tend not to hold for actual overconfidence. I also find significant differences in potential behavioral outcomes suggesting the traditional measure may often reflect genuine differences in self and others’ susceptibility to media, rather than a self-serving bias of presumed invulnerability. These results have important implications for our understanding and measurement of perceptual biases in communication research.
Bilateral correction of asphyxiating thoracic dystrophy
Authors: Wang Wenlin , Long Weiguang , Liu Yang , Cai Bin
Published: August 2022

Several operations for asphyxiating thoracic dystrophy (ATD) have been used previously, but they all have disadvantages. We report a 25-year-old male ATD patient who had significant depressions on both sides of thorax. We designed a special operation for him, which had not only eliminated the depression, but also increased the volume of the thorax. The results show that this operation is a reasonable choice for this kinds of patient.
Rare case of papillary fibroelastoma resection with concomitant cox-maze IV procedure
Authors: Hooda Zamaan , Ramaprasad Ganesh , Cerda Luis , Zuberi Jamshed , Connolly Mark
Published: August 2022

Primary cardiac tumors represent 0.1% of all cardiac tumors, making them a rare pathologic phenomenon. The second most common cardiac tumors are papillary fibroelastomas, which also represent the most common valvular tumors. This report examines a rare case of a patient that underwent resection of papillary fibroelastoma with simultaneous Cox-Maze IV procedure for treatment of atrial fibrillation. This 67-year-old male patient was initially scheduled for transcatheter ablation for treatment of rate-controlled atrial fibrillation. During a pre-procedural trans-thoracic echocardiogram, it was discovered that the patient had a moderately sized pedunculated mass on the aortic valve, suspicious of papillary fibroelastoma. Despite the patient having no history of embolic events or aortic insufficiency from the papillary fibroelastoma, the transcatheter ablation procedure was canceled. He was referred to cardiothoracic surgery for further evaluation, and it was determined that this patient was a candidate for papillary fibroelastoma resection along with Cox-Maze IV procedure for atrial fibrillation.
The development of natural gas in Asia—the results of the forecast scenarios of the POLES model
Authors: Le Minh Thong
Published: August 2022

Many studies have shown the important role of natural gas in worldwide energy transition to gradually reduce the impacts on climate change. Asia is considered the centre of future gas demand growth. With a view to demonstrating the role of natural gas in the energy transition in Asia, this article will analyse the results from the scenarios forecasting the development of natural gas based on the Prospective Outlook on Long-term Energy Systems energy forecasting model.
The effect of magnetic field on the inner Galactic rotation curve
Authors: Chan Man Ho , Del Popolo Antonino
Published: August 2022

In the past few decades, some studies pointed out that magnetic field might affect the rotation curves in galaxies. However, the impact is relatively small compared with the effects of dark matter and the baryonic components. In this letter, we revisit the impact of magnetic field on the rotation curve of our Galaxy. We show that the inner Galactic rotation curve could be affected significantly by the magnetic field. The addition of the inner bulge component, which has been proposed previously to account for the inner rotation curve data, is not necessary. The magnetic field contribution can fully account for the excess of the inner rotation velocity between 5 to 50 pc from the Galactic Centre. Our analysis can also constrain the azimuthal component of the central regular magnetic field strength to $B_0 \sim 50-60\, \mu$G, which is consistent with the observed range.
Fertility Preservation in Young Adult Patients with Rectal Cancer: A Few Things to Consider
Authors: Zhou Haiyang
Published: August 2022

This article evaluates the toxicity and feasibility of gemcitabine/nab-paclitaxel/S-1 chemotherapy on a 21-day cycle in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma, reporting dose-limiting toxicity and maximum tolerated dose of S-1 in this regimen.
Concordance Between Genomic Alterations Detected by Tumor and Germline Sequencing: Results from a Tertiary Care Academic Center Molecular Tumor Board
Authors: Green Michelle F , Watson Catherine H , Tait Sarah , He Jie , Pavlick Dean C , Frampton Garrett , Riedel Jinny , Plichta Jennifer K , Armstrong Andrew J , Previs Rebecca A , Kauff Noah , Strickler John H , Datto Michael B , Berchuck Andrew , Menendez Carolyn S
Published: August 2022

Objective

The majority of tumor sequencing currently performed on cancer patients does not include a matched normal control, and in cases where germline testing is performed, it is usually run independently of tumor testing. The rates of concordance between variants identified via germline and tumor testing in this context are poorly understood. We compared tumor and germline sequencing results in patients with breast, ovarian, pancreatic, and prostate cancer who were found to harbor alterations in genes associated with homologous recombination deficiency (HRD) and increased hereditary cancer risk. We then evaluated the potential for a computational somatic-germline-zygosity (SGZ) modeling algorithm to predict germline status based on tumor-only comprehensive genomic profiling (CGP) results.

Methods

A retrospective chart review was performed using an academic cancer center’s databases of somatic and germline sequencing tests, and concordance between tumor and germline results was assessed. SGZ modeling from tumor-only CGP was compared to germline results to assess this method’s accuracy in determining germline mutation status.

Results

A total of 115 patients with 146 total alterations were identified. Concordance rates between somatic and germline alterations ranged from 0% to 85.7% depending on the gene and variant classification. After correcting for differences in variant classification and filtering practices, SGZ modeling was found to have 97.2% sensitivity and 90.3% specificity for the prediction of somatic versus germline origin.

Conclusions

Mutations in HRD genes identified by tumor-only sequencing are frequently germline. Providers should be aware that technical differences related to assay design, variant filtering, and variant classification can contribute to discordance between tumor-only and germline sequencing test results. In addition, SGZ modeling had high predictive power to distinguish between mutations of somatic and germline origin without the need for a matched normal control, and could potentially be considered to inform clinical decision-making.
Supporting Patients with Cancer after Dobbs v. Jackson Women’s Health Organization
Authors: Shuman Andrew G , Aapro Matti S , Anderson Benjamin , Arbour Katherine , Barata Pedro C , Bardia Aditya , Bruera Eduardo , Chabner Bruce A , Chen Herbert , Choy Edwin , Conte Pierfranco , Curigliano Giuseppe , Dizon Don , O’Reilly Eileen , Tito Fojo Antonio , Gelderblom Hans , Graubert Timothy A , Gurtler Jayne S , Hall Evan , Hirsch Fred R , Idbaih Ahmed , Ilson David H , Kelley Michael , La Vecchia Carlo , Ludwig Heinz , Moy Beverly , Muss Hyman , Opdam Frans , Pentz Rebecca D , Posner Marshall R , Ross Jeffrey S , Sacher Adrian , Senan Suresh , Soto-Perez-de-Celis Enrique , Tanabe Kenneth K , Vermorken Jan B , Wehrenberg-Klee Eric , Bates Susan E
Published: August 2022

In the context of cancer, whether or not to choose pregnancy termination represents a difficult and multifaceted decision. In this editorial, members of The Oncologist editorial team attempt to contextualize the potential implications of the recent Supreme Court decision in Dobbs v. Jackson Women’s Health Organizationfor patients with cancer.
Meconium-Stained Amniotic Fluid: Impact on Prognosis of Neonatal Bacterial Meningitis
Authors: Li Ya-Ting , Li Cai-Xia , Huang Chu-Jun , Wen Qian-Yu , Deng Shu-Min , Zhu Ling-Ping , Liu Zi-Feng , Chen Zhuang-Gui
Published: August 2022

Objectives

Clinical data with respect to the impact of meconium on the prognosis of neonatal bacterial meningitis are scarce. Therefore, in this study, we aimed to determine whether meconium-stained amniotic fluid (MSAF) represents a risk factor for poor prognosis of neonatal bacterial meningitis in a confirmed case population.

Methods

This was a retrospective cohort study of 256 neonates diagnosed with bacterial meningitis hospitalized at one of three hospitals in Shantou, China, between October 2013 and September 2018. Clinical manifestation, laboratory test results and treatment were compared between the two groups, with outcomes dichotomized into ‘good’ or ‘poor’ prognosis. Multivariate analysis and follow-up logistic regression analysis were used to identify predictive factors of a poor outcome.

Results

Of the 256 neonates with BM, 95 (37.1%) had a good prognosis at discharge and 161 (62.9%) had a poor prognosis. In the poor prognosis group, 131/161 (79.4%) neonates had a permanent neurological sequelae and 19 (11.8%) had ≥2 sequelae. Of note, 11 neonates died. The rate of poor prognosis of BM was significantly higher among neonates with than without MSAF (26.1% vs. 12.6%, respectively; p < 0.05). A logistic multivariate analysis to evaluate the prognostic effect of MSAF to BM showed that neonatal with MSAF is more likely to have a worse prognosis of BM [unadjusted odds ratio (OR), 2.44, 95% confidence interval (CI), 1.24–5.10; adjusted OR, 2.31; 95% CI, 1.09–5.17].

Conclusion

MSAF is significantly associated with poor prognosis of neonatal bacterial meningitis. Therefore, in case of MSAF, more attention should be paid to neonatal bacterial meningitis.
XIIIThe Victorian Period
Authors: Garza Ana Alicia , Burke Lois , Snailham Fiona , Blackburn-Daniels Sally , Hind Heather , Baker William
Published: August 2022

This chapter has six sections: 1. General and Prose, including Dickens; 2. The Novel; 3. Poetry; 4. Periodicals, Publishing History; 5. Miscellaneous; 6. Drama. Section 1 is by Ana Alicia Garza; section 2 is by Lois Burke and Fiona Snailham; section 3 is by Sally Blackburn-Daniels; section 4 is by Heather Hind; sections 5 and 6 are by William Baker.
PREVALENCE, CHARACTERISTICS, AND OUTCOMES OF RHEGMATOGENOUS RETINAL DETACHMENT IN EYES WITH TRABECULECTOMY OR GLAUCOMA DRAINAGE DEVICES
Authors: Starr Matthew R. , Huang Denis , Wong Jae-Chiang , Patel Luv G. , Ammar Michael , Hsu Jason , Sivalingam Arunan , Mehta Sonia , Ho Allen C. , Kuriyan Ajay E. , Khan M. Ali , Cohen Michael N. , Xu David , Lee Daniel , Moster Marlene R. , Yonekawa Yoshihiro
Published: August 2022

Purpose:

To describe the prevalence, management, and outcomes of rhegmatogenous retinal detachment (RRD) after incisional glaucoma filtering surgery.

Methods:

All patients with a history of trabeculectomy or glaucoma drainage device surgery who were subsequently diagnosed with an RRD from January 1, 2016, to January 1, 2021, at the Wills Eye Hospital were identified.

Results:

Forty-six eyes met the inclusion criteria. The mean age was 60.7 ± 19.6 years, and 15 patients (32.6%) were female. Of all eyes, 34 (73.9%) were diagnosed with primary open-angle glaucoma. The mean time from most recent incisional glaucoma surgery to RRD diagnosis was 1,133 ± 1,644 days. There were 19 eyes (41.3%) with preoperative proliferative vitreoretinopathy (9 eyes [19.6%] with Grade C proliferative vitreoretinopathy) and 35 eyes (76.1%) had macula-off RRD at the time of presentation. At RRD presentation, 4 eyes (8.7%) had concomitant endophthalmitis, 5 (10.9%) had concurrent choroidal detachment, and 2 (4.7%) had concurrent vitreous hemorrhage. Primary vitrectomy was performed in most (91.3%) cases. Silicone oil tamponade was often required (71.1%). The single surgery success rate was 65.2% (30 of 46). The mean preoperative logarithm of the minimum angle of resolution visual acuity was 1.72 ± 0.78 (Snellen acuity 20/1,050), and the mean final postoperative logarithm of the minimum angle of resolution was 1.59 ± 0.89 (20/778, P = 0.2853). Of glaucoma surgeries performed, the 5-year prevalence of RRD was 0.71% (26 of 3,664, 95% Poisson confidence interval 0.48%–1.04%).

Conclusion:

The 5-year prevalence of RRDs after trabeculectomy or glaucoma drainage device was 0.71%. Most patients presented with macula-involving detachments, often with proliferative vitreoretinopathy. Anatomical and visual outcomes were poor.
LONG-TERM EFFECTS OF ANTI-VEGF MONOTHERAPY FOR RETINOPATHY OF PREMATURITY ON THE RETINAL AND REFRACTIVE DEVELOPMENT OF EYE
Authors: Sukgen Emine Alyamaç , Atalay Hatice Tuba , Özdek Şengül
Published: August 2022

Purpose:

To evaluate vascular maturation of retina, axial, refractive, and foveal development after anti-VEGF treatment including bevacizumab, ranibizumab, and aflibercept in infants with treatment requiring retinopathy of prematurity (ROP) in long term.

Methods:

This retrospective chart review study included children with a history of any anti-VEGF monotherapy for ROP in Zone 1 or posterior Zone 2 who have reached at least 24 months of corrected age. The records of ophthalmologic examination including strabismus evaluation, visual acuity measurement, refractive and axial measurements, optical coherence tomography, and fundus fluorescein angiography examinations with RetCam III were reviewed.

Results:

A total of 36 eyes of 18 children met the inclusion criteria. The mean gestational age at birth was 27.8

2.13 (23–30) weeks, and ocular assessments were performed between 33 and 61.5 (mean: 42.58

8.6) months of corrected age. Treatment was with bevacizumab in 10 eyes, with ranibizumab in 14 eyes, and with aflibercept in 12 eyes. The mean spherical equivalent was −0.25

1.82; axial length was 20.81

0.62 mm. There was no significant difference among three anti-VEGF groups regarding the abnormal vascular retinal development (P = 0.183) or leakage (P = 0.842) on fluorescein angiography.

Conclusion:

All the anti-VEGF agents provided similar adequate axial and refractive development as well as similar abnormal vascular development in the peripheral retina. The long-term impact of this abnormally vascularized peripheral retina is a curiosity issue. From this point of view, it is an important need to determine the follow-up period and method after the anti-VEGF treatment for ROP.
Neurofibromatosis Type 2
Authors: Filizoglu Nuh , Ozguven Salih
Published: August 2022

Neurofibromatosis type 2 (NF2) is an autosomal-dominant tumor predisposing syndrome that results from mutations in the NF2 tumor suppressor gene on chromosome 22. The development of bilateral vestibular schwannomas is the characteristic feature of the disease. However, other nervous system tumors, including meningiomas, ependymomas, and schwannomas, can be seen frequently. Herein, we present 68Ga-DOTATATE PET/CT findings of 2 siblings with NF2.
18F-Fluciclovine PET Detected Early Tumor Recurrence in Prostatectomy Bed With Low PSA of 0.3 ng/mL But Negative on 18F-PSMA PET Scan
Authors: Nguyen Trinh T. , Bhosale Priya R. , Lu Yang
Published: August 2022

A 58-year-old man with metastatic prostate cancer was treated with prostatectomy, radiation therapy to bone metastasis, and androgen deprivation therapy plus abiraterone. He had posttreatment nadir PSA of 0.1 ng/mL. A follow-up 18F-fluciclovine PET performed with PSA of 0.3 ng/mL showed a focal tracer-avid lesion in the left prostatectomy bed. This lesion was negative on 18F-DCFPyL PET/CT, but with typical MRI features for disease recurrence. Minimal urinary activity of fluciclovine helped detection of local disease recurrence in the prostatectomy bed.
Characterizations of Resilience in Poststroke Aphasia
Authors: Hunting Pompon Rebecca , Mach Helen
Published: August 2022

The definitions and features of resilience, the process and outcome of successfully responding to adversity, are variable across the disability and rehabilitation literatures, and its influence on aphasia treatment and outcomes is as of yet unknown. This scoping review identified and thematically categorized characterizations and descriptions of resilience and the similarly used terms adaptation, adjustment, and coping in the aphasia research literature. Frequently noted features of resilience included internal/cognitive emotional responses, such as positive self-concept, attitude/outlook, and psychological function, as well as external/behavioral responses, such as engaging in new activities and opportunities for social connection. These general features align with a definition of resilience recently developed for individuals with chronic impairment. And, although little information about the influence of resilience on treatment engagement and outcomes emerged from the reviewed literature, a number of clinical considerations and research directions are suggested.
Treatment of acute upper gastrointestinal bleeding occurred after percutaneous coronary intervention for acute myocardial infarction in patients with acute renal impairment: a case report
Authors: Wu Rong , Li Jinhua , Guo Yuhuang
Published: August 2022

Upper gastrointestinal (UGI) bleeding after percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) in ordinary patients is a common complication and poses a dilemma for clinical doctors to treat. In patients with renal impairment, that is more difficult and has rarely been reported. This case report involves an 82-year-old man who received regular hemodialysis and underwent PCI for acute inferior wall ST-segment elevation myocardial infarction. On the third day after PCI, the patient developed acute UGI bleeding, and gastroscopy confirmed that he had developed compound gastroduodenal ulcers (active stage) with hyperemia of the surrounding mucosa. After fasting, blood transfusion, acid inhibition, gastric protection and symptomatic support treatment, the patient’s UGI bleeding remained uncontrolled. Finally, upper gastrointestinal bleeding was stopped by empiric transcatheter arterial embolization (TAE). The patient’s condition was controlled through active treatment, and he was eventually discharged from the hospital. Bleeding complications after coronary stenting often present a dilemma, particularly in patients with renal impairment. Therefore, patients such as this should be thoroughly evaluated before any treatment. In the case of no obvious hemorrhagic spots found on endoscopic examination and failure of conservative medical treatment, empiric transcatheter arterial embolization TAE is a well-tolerated and effective treatment for UGI bleeding.
Melon pan-genome and multi-parental framework for high-resolution trait dissection
Authors: Oren Elad , Dafna Asaf , Tzuri Galil , Halperin Ilan , Isaacson Tal , Elkabetz Meital , Meir Ayala , Saar Uzi , Ohali Shachar , La Thuy , Romay Cinta , Tadmor Yaakov , Schaffer Arthur A , Buckler Edward S , Cohen Roni , Burger Joseph , Gur Amit
Published: August 2022

Linking between genotype and phenotype is a fundamental goal in biology and requires robust data for both layers. The prominent increase in plant genome sequencing and comparisons of multiple related individuals, exposed the abundance of structural genomic variation and suggest that a single reference genome cannot represent the complete sequence diversity of a crop species, leading to the expansion of the pan-genome concept. For high-resolution forward genetics, this unprecedented access to genomic variation should be paralleled by availability and phenotypic characterization of genetic diversity, and effective integration between these layers. Here, we describe a multi-parental framework for trait dissection in melon, leveraging a novel pan-genome constructed for this crop. Melon (Cucumis melo L.) is an important crop from the Cucurbitaceae family, which display extensive phenotypic variation available for breeding. A diverse core set of 25 founder lines (MelonCore25) was sequenced using a combination of short and long-read technologies and their genomes were assembled de novo. The construction of a melon pan-genome exposed substantial variation in genome size and structure, including detection of ~300,000 structural variants and ~9 million SNPs. A half-diallel derived set of 300 F2 populations representing all possible MelonCore25 parental combinations was constructed as framework for trait dissection through integration with the pan-genome. We demonstrate the potential of this unified framework for genetic analysis of various melon traits, including rind color and mottling pattern, fruit sugar content and resistance to fungal diseases. We anticipate that utilization of this integrated resource will enhance genetic dissection of important traits and accelerate melon breeding.

Significance statement

Pan-genomes aim to address the abundance of genome structural variation within species for improved genomic analyses. New pan-genome, constructed from de novo genome assemblies of 25 diverse melon (Cucumis melo L.) accessions is integrated with a half-diallel derived set of 300 F2 populations representing all possible parental combinations. The potential of this unified multi-parental trait dissection framework for melon genetics and breeding is presented.
Platelet-derived transcription factors license human monocyte inflammation
Authors: Hawwari Ibrahim , Rossnagel Lukas , Reyes Nathalia Sofia Rosero , Maasewerd Salie , Jentzsch Marius , Demczuk Agnieszka , Teichmann Lino L , Meffert Lisa , Ribeiro Lucas S. , Kallabis Sebastian , Meissner Felix , Rivas Magali Noval , Arditi Moshe , Bertheloot Damien , Franklin Bernardo S.
Published: August 2022

CD14+monocytes, the predominant population in human blood, are primarily engaged in host defense and pro-inflammatory cytokine responses. Aberrant monocyte activity causes life-threatening cytokine storms, while dysfunctional monocytes lead to ’immunoparalysis.’ Understanding the mechanisms controlling monocyte functions is therefore paramount. Here, we reveal platelets’ vital role in human monocytes’ pro-inflammatory responses. Low platelet counts in immune thrombocytopenia (ITP) patients, or platelet depletion in healthy monocytes result in monocyte immunoparalysis, characterized by reduced pro-inflammatory gene expression and weakened cytokine responses to immune challenge. Remarkably, adding fresh platelets reverses monocyte immunoparalysis. In mice, thrombocytopenia results in down-regulation of myeloid innate immune genes, and compromised host defense transcriptional programs in monocytes despite normal responses to LPS. Platelets control monocyte cytokines independently of traditional cross-talk pathways, acting as reservoirs of transcription factors like NFκB and MAPK p38. We pinpointed megakaryocyte-derived NFκB2 transfer to human monocytes by mass spectrometry-based proteomics. Functionally, platelets proportionally restored impaired cytokine secretion in human monocytes lacking p38a and NFκB. We unveil the intercellular transfer of inflammatory regulators, positioning platelets as central checkpoints in monocyte-mediated inflammation.

Key Points

Platelets are essential to TLR and NLR cytokine responses of human monocytes,

Immune thrombocytopenia leads to monocyte immunoparalysis;

Platelet supplementation reverses monocyte immunoparalysis;

Platelets transfer NFκB that reactivates cytokine production in genetically deficient monocytes.
The dissemination of Rift Valley fever virus to the eye and sensory neurons of zebrafish larvae is stat1 dependent
Authors: ter Horst S. , Siekierska A. , De Meulemeester AS. , Cuvry A. , Cools L. , Neyts J. , de Witte P. , Rocha-Pereira J.
Published: August 2022

The Rift Valley fever virus (RVFV) is listed by the WHO as priority disease and causes haemorrhagic fever, encephalitis, and permanent blindness. To study RVFV pathogenesis and identify small-molecule antivirals, we established a novel in vivo model using zebrafish larvae. Pericardial injection of RVFV resulted in ~4 log10 viral RNA copies/larva, which was inhibited by antiviral 2′-fluoro-2′-deoxycytidine. The optical transparency of the larvae allowed detection of RVFVeGFP in the liver and sensory nervous system, including the optic tectum and retina, but not the brain or spinal cord. Thus, RVFV-induced blindness likely occurs due to direct damage to the eye and peripheral neurons, rather than the brain. Treatment with JAK-inhibitor ruxolitinib, as well as knockout of stat1a but not stat1b, enhanced RVFV replication to ~6 log10 viral RNA copies/larva and ultra-bright livers, although without dissemination to sensory neurons or the eye, hereby confirming the critical role of stat1 in RVFV pathogenesis.
Neisseria gonorrhoeae diagnostic escape from a gyrA-based test for ciprofloxacin susceptibility can lead to increased zoliflodacin resistance
Authors: Rubin Daniel H. F. , Mortimer Tatum D. , Grad Yonatan H.
Published: August 2022

The etiologic agent of gonorrhea, Neisseria gonorrhoeae, has become resistant to each of the first line antibiotics used to treat it. However, most isolates in the US remain susceptible to ciprofloxacin, leading to the hypothesis that a diagnostic that accurately reports susceptibility to ciprofloxacin may allow its reintroduction into clinical use. One diagnostic approach is to identify codon 91 in gyrA, where coding for the wildtype serine is associated with ciprofloxacin susceptibility and phenylalanine with resistance. Here, we found that escape from this diagnostic method can occur through gyrA F91S reversion and expansion of pre-existing ciprofloxacin non-susceptible N. gonorrhoeae lineages with gyrA 91S. Furthermore, we found that mutations conferring ciprofloxacin resistance in gyrA 91S isolates led to cross-resistance with zoliflodacin, an antibiotic in phase 3 trial for treatment of gonorrhea. These findings define N. gonorrhoeae mutations that should be monitored via surveillance systems, particularly in populations and regions deploying gyrA 91-based diagnostics, and demonstrate how diagnostics that guide antibiotic therapy can have unintended consequences.
A lone spike in blood glucose can enhance the thrombo-inflammatory response in cortical vessels
Authors: Shaked Iftach , Foo Conrad , Liu Rui , Cui Yingying , Ji Xiang , Broggini Thomas , Mächler Philipp , Sundd Prithu , Devor Anna , Friedman Beth , Kleinfeld David
Published: August 2022

How transient hyperglycemia contributes to cerebro-vascular disease has been a challenge to study under controlled conditions. We present an approach to model luminal vessel thrombo-inflammation using amplified, ultrashort laser-pulses to physically disrupt brain-venule endothelium. Vessel disruption in conjunction with transient hyperglycemia from a single injection of metabolically activeD-glucose results in real-time responses to venule damage that include rapid serum extravasation, platelet aggregation, and neutrophil recruitment, in normal mice. In contrast, vessel thrombo-inflammation following laser-induced vessel disruption is significantly reduced in mice injected with metabolically inert L-glucose. Thrombo-inflammation is pharmacologically ameliorated by a platelet inhibitor, by a scavenger of reactive oxygen species, or by a nitric oxide donor. For comparison, in diabetic mice injured vessel thrombo-inflammatory responses are also reduced by restoration of normo-glycemia. Our approach provides a controlled method to probe synergies of transient metabolic and physical vascular perturbations and reveals new aspects of brain pathophysiology.
Microstimulation of human somatosensory cortex evokes task-dependent, spatially patterned responses in motor cortex
Authors: Shelchkova Natalya D. , Downey John E. , Greenspon Charles M. , Okorokova Elizaveta V. , Sobinov Anton R. , Verbaarschot Ceci , He Qinpu , Sponheim Caleb , Tortolani Ariana F. , Moore Dalton D. , Kaufman Matthew T. , Lee Ray C. , Satzer David , Gonzalez-Martinez Jorge , Warnke Peter C. , Miller Lee E. , Boninger Michael L. , Gaunt Robert A. , Collinger Jennifer L. , Hatsopoulos Nicholas G. , Bensmaia Sliman J.
Published: August 2022

Abstract

Motor (M1) and somatosensory (S1) cortex play a critical role in motor control but the nature of the signaling between these structures is not known. To fill this gap, we recorded – in three human participants whose hands were paralyzed as a result of a spinal cord injury – the responses evoked in the hand and arm representations of primary motor cortex (M1) while we delivered ICMS to the somatosensory cortex (S1). We found that ICMS of S1 activated some M1 neurons at short, fixed latencies, locked to each pulse in a manner consistent with monosynaptic activation. However, most of the changes in M1 firing rates were much more variable in time, suggesting a more indirect effect of the stimulation. The spatial pattern of M1 activation varied systematically depending on the stimulating electrode: S1 electrodes that elicited percepts at a given hand location tended to activate M1 neurons with movement fields at the same location. However, the indirect effects of S1 ICMS on M1 were strongly context dependent, such that the magnitude and even sign relative to baseline varied across tasks. We tested the implications of these effects for brain-control of a virtual hand, in which ICMS was used to convey tactile feedback about object interactions. While ICMS-evoked activation of M1 disrupted decoder performance, this disruption could be minimized with biomimetic stimulation, which emphasizes contact transients at the onset and offset of grasp, reduces sustained stimulation, and has been shown to convey useful contact-related information.

Significance

Motor (M1) and somatosensory (S1) cortex play a critical role in motor control but the nature of the signaling between these structures is not known. To fill this gap, we recorded from M1 while delivering intracortical microstimulation (ICMS) to S1 of three human participants, whose hands were paralyzed by spinal cord injury. We found that ICMS activates M1 and that the motor fields of activated M1 neurons match the sensory fields of the stimulated S1 electrodes. These findings have important implications for using ICMS to convey tactile feedback for brain-controlled bionic hands. Indeed, the ICMS-evoked M1 activity worsens control of the hand. Fortunately, this effect is minimized by using biomimetic tactile feedback, which emphasizes contact transients and reduces sustained ICMS.
Cryo-EM structure of the Type IV pilus extension ATPase from enteropathogenic Escherichia coli
Authors: Nayak Ashok R. , Singh Pradip K. , Zhao Jinlei , Samsó Montserrat , Donnenberg Michael S.
Published: August 2022

Type 4 pili (T4P) are retractable surface appendages found on numerous bacteria and archaea that play essential roles in various microbial functions, including host colonization by pathogens. An ATPase is required for T4P extension, but the mechanism by which chemical energy is transduced to mechanical energy for pilus extension has not been elucidated. Here we report the cryo-electron microscopy (cryo-EM) structure of the BfpD ATPase from enteropathogenic Escherichia coli (EPEC) in the presence of either ADP or a mixture of ADP and AMP-PNP. Both structures, solved at 3 Å resolution, reveal the typical toroid shape of AAA+ ATPases and unambiguous six-fold symmetry. This six-fold symmetry contrasts with the two-fold symmetry previously reported for other T4P extension ATPase structures, all of which were from thermophiles and solved by crystallography. In the presence of the nucleotide mixture, BfpD bound exclusively AMP-PNP and this binding resulted in a modest outward expansion in comparison to the structure in the presence of ADP, suggesting a concerted model for hydrolysis. De novo molecular models reveal a partially open configuration of all subunits where the nucleotide binding site may not be optimally positioned for catalysis. ATPase functional studies reveal modest activity similar to that of other extension ATPases, while calculations indicate that this activity is insufficient to power pilus extension. Our results reveal that, despite similarities in primary sequence and tertiary structure, T4P extension ATPases exhibit divergent quaternary configurations. Our data raise new possibilities regarding the mechanism by which T4P extension ATPases power pilus formation.
Pimavanserin for the Treatment of Alzheimer’s Disease Psychosis: An Evaluation of the Clinical Importance of Efficacy Results
Authors: Ballard Clive , Cummings Jeffrey , Tariot Pierre N , Pathak Sanjeev , Coate Bruce , Stankovic Srdjan
Published: August 2022

Alzheimer’s disease psychosis (ADP) is a common and serious condition with substantial unmet need for safe and effective treatments. Pimavanserin is approved in the US to treat Parkinson’s disease hallucinations and delusions. This post-hoc analysis of randomized, double-blind, placebo-controlled, phase 2 trial of nursing-home-residents with ADP evaluated the efficacy of pimavanserin by improvements (least squares mean change) in the Neuropsychiatric Inventory–Nursing Home Version Psychosis Score (NPI-NH PS). The clinical significance of the primary endpoint was assessed using responder analyses (≥ 30% and ≥ 50%); numbers needed to treat (NNT); cumulative response (0-100% improvement); All Patients and Severe Psychosis (NPI-NH PS ≥ 12) subgroups were evaluated; improvements in hallucinations and delusions by NPI-NH-PS frequency (3 or 4 points) and severity (2 or 3 points); and ≥ 50% responder analysis at earlier timepoints (weeks 2 and 4). Among 345 patients screened, 181 patients were randomized to pimavanserin (n = 90) and placebo (n = 91). Patients were elderly (mean age: 86 years) and frail (baseline mean NPI-NH PS scores of 9.5 and 10 for pimavanserin and placebo, respectively). Pimavanserin significantly improved NPI-NH PS relative to placebo (−3.76 versus −1.93, respectively; p = 0.0451). In responder analyses, pimavanserin demonstrated a significantly greater reduction in NPI-NH PS versus placebo at both the ≥ 30% (p = 0.0159) and ≥ 50% (p = 0.0240) thresholds with NNTs of 6 and 7, respectively. Furthermore, pimavanserin demonstrated significantly earlier reductions in NPI-NH PS compared with placebo for the ≥ 30% (p = 0.0336) and ≥ 50% (p = 0.0044) thresholds. The cumulative response analysis demonstrated significantly greater efficacy of pimavanserin for All Patients (p = 0.052) and Severe Psychosis (p = 0.004), and Severe Patients versus All Patients demonstrated a greater reduction in NPI-NH PS (p = 0.011; effect size = 0.73). Pimavanserin also demonstrated numerically greater improvements for the frequency and severity of delusions and hallucinations. Responder analyses at earlier timepoints demonstrated significantly greater response rates with pimavanserin versus placebo at week 2 (p = 0.016) but not 4 (p = 0.051). These findings support pimavanserin as safe and effective in a population of nursing-home-resident patients with ADP.
Rare and common variant analyses of amyotrophic lateral sclerosis in the French-Canadian genome
Authors: Ross Jay P. , Akçimen Fulya , Liao Calwing , Kwan Karina , Phillips Daniel E. , Schmilovich Zoe , Spiegelman Dan , Genge Angela , Dupré Nicolas , Dion Patrick A. , Farhan Sali M.K. , Rouleau Guy A.
Published: August 2022

The genetic etiology of ALS includes few rare, large-effect variants and potentially many common, small-effect variants per case. The genetic risk liability for ALS might require a threshold comprised of a certain amount of variants. Here, we tested the degree to which risk for ALS was affected by rare variants in ALS genes, polygenic risk score, or both. 335 ALS cases and 356 controls from Québec, Canada were concurrently tested by SNP-chip genotyping and targeted sequencing of known ALS genes. ALS GWAS summary statistics were used to estimate an ALS PRS. Cases and controls were subdivided into rare variant carriers and non-carriers. Risk for ALS was significantly associated with PRS and rare variants independently, but the interaction was not significant. ALS PRS affected risk only in those not carrying a rare variant, suggesting that rare variants in ALS genes are generally sufficient for disease risk. Rather than modifying the penetrance of rare variants, ALS PRS is most informative in the absence of these variants.
Estimating the future global dose demand for Measles-Rubella microarray patches
Authors: Ko Melissa , Malvoti Stefano , Cherian Thomas , Mantel Carsten , Biellik Robin , Jarrahian Courtney , Menozzi-Arnaud Marion , Amorij Jean-Pierre , Christiansen Hans , Papania Mark , Meltzer Martin I. , Masresha Balcha Girma , Pastor Desiree , Durrheim David N. , Giersing Birgitte , Hasso-Agopsowicz Mateusz
Published: August 2022

Background

Progress towards measles and rubella (MR) elimination has stagnated as countries are unable to reach the required 95% vaccine coverage. Microarray patches (MAPs) are anticipated to offer significant programmatic advantages to needle and syringe (N/S) presentation and increase MR vaccination coverage. A demand forecast analysis of the programmatic doses required (PDR) could accelerate MR-MAP development by informing the size and return of the investment required to manufacture MAPs.

Methods

Unconstrained global MR-MAP demand for 2030-2040 was estimated for three scenarios, for groups of countries with similar characteristics (archetypes), and four types of uses of MR-MAPs (use cases). The base scenario 1 assumed that MR-MAPs would replace a share of MR doses delivered by N/S, and that MAPs can reach a proportion of previously unimmunised populations. Scenario 2 assumed that MR-MAPs would be piloted in selected countries in each region of the World Health Organization (WHO); and scenario 3 explored introduction of MR-MAPs earlier in countries with the lowest measles vaccine coverage and highest MR disease burden.

Results

For the base scenario (1), the estimated global PDR for MR-MAPs was forecasted at 30 million doses in 2030 and increased to 220 million doses by 2040. Compared to scenario 1, scenario 2 resulted in an overall decrease in PDR of 18%, and scenario 3 resulted in a 21% increase in PDR between 2030-2040.

Conclusions

Significant demand is expected for MR-MAPs between 2030-2040, however, efforts are required to address remaining data quality, uncertainties and gaps that underpin the assumptions in this analysis.

Key points

the delivery of measles and rubella vaccines with microarray patches (MR-MAPs) could disrupt the immunization landscape. We estimated the demand for MR-MAPs between 2030-2040 at 4.05 billion doses. This analysis will inform the size of investment required to manufacture MR-MAPs.
Melanonychia and use of nail biopsy to screen for subungual melanoma in a large ethnically diverse pediatric cohort: A cross-sectional study
Authors: Park Helen H. , Lieu Alexander , Conic Rosalynn R.Z. , Metterle Lauren , Zhang Sijia , Toledo Isabella , Hightower George K.
Published: August 2022

Background

There are no widely accepted pediatric guidelines on who should undergo biopsy of the nail apparatus to screen for subungual melanoma (SUM). Reported cases of pre-adolescent children diagnosed with SUM presenting as melanonychia remain controversial. Further, observed age differences in the incidence of acral lentiginous melanoma are complicated by reported ethnic differences in adult prevalence and survival rates.

Methods

We conducted a retrospective chart review of Rady Children’s Hospital San Diego, a tertiary hospital system, with over 2 million patients in its electronic health records to identify patients diagnosed with melanonychia younger than 12 years and biopsies in these children, between January 1, 2010, and July 31, 2021.

Results

There were 623,805 patients younger than 12 years of age seen in the outpatient setting. Average age was 7.2 years for melanonychia diagnosis, and 5.1 years for those biopsied. Nail apparatus biopsies were performed in 22 different individuals and involved the hand 17/22 (77%) and the foot 5/22 (23%). The presence of Hutchinson’s sign was documented in 9/22 (41%) patients. Males were diagnosed with melanonychia and underwent biopsy more often than females. Many of the biopsies were performed in Hispanic/Latino 11/22 (50%) and Asian/Pacific Islander 3/22 (14%) patients.

Discussion

Regardless of reported ethnicity, biopsy of nail apparatus is highly unlikely to uncover invasive ALM in children younger than 12 years. Prospective studies are needed to understand how incidence of melanonychia, age, gender, and ethnicity/race influence parental and clinicians’ perceptions of melanoma risk.
Thriving in the heat – Lysine acetylation stabilizes the quaternary structure of a Mega-Dalton hyperthermoactive PEP-synthase
Authors: Albanese Pascal , Song Wenfei , van Keulen Siri , Koendjbiharie Jeroen , Koh Fujiet , Steigenberger Barbara , Vincent Tomoko , Konijnenberg Albert , Heck Albert J.R. , Kengen Servé W.M. , Bonvin Alexandre M.J.J. , Förster Friedrich , Scheltema Richard A.
Published: August 2022

Over time structural adaptations enabled proteins and enzymes to have sufficient stability and flexibility to perform the basic functions of life under various environmental conditions. The catalytic cores of key metabolic enzymes of hyperthermophilic archaea work at a temperature range of 80-120 °C, similar to the conditions wher the earliest life forms may have thrived. Here we characterize a key enzyme of the central carbon metabolism of Pyrococcus furious, through an integrative approach combining structural mass spectrometry, cryo-electron microscopy, mass photometry and molecular modelling with molecular dynamics simulations. From our investigation, we unveil the structural organization of phosphoenolpyruvate synthase (PPSA). Its 24-meric assembly - weighing over 2 MDa - harbors flexible distal domains, whose proper functioning and coordination depends on widespread chemical acetylation of lysine residues. This non-enzymatic post-translational modification, along with other types of lysine modifications, also occurs on most other major protein complexes of P. furiosus. These modifications likely originated in the chemically favorable primordial conditions and gradually became highly specialized and enzyme-driven in more distantly related mesophiles and Eukaryotes.
Imaging increased metabolism in the spinal cord in mice after middle cerebral artery occlusion
Authors: Ni Ruiqing , Straumann Nadja , Fazio Serana , Dean-Ben Xose Luis , Louloudis Georgios , Keller Claudia , Razansky Daniel , Ametamey Simon , Mu Linjing , Nombela-Arrieta César , Klohs Jan
Published: August 2022

Emerging evidence indicates crosstalk between the brain and the hematopoietic system following cerebral ischemia. Here, we investigated metabolism and oxygenation in the spleen and spinal cord in a transient middle cerebral artery occlusion (tMCAO) mouse model that is widely used in focal cerebral ischemia research. Naïve, sham and tMCAO mice underwent positron emission tomography (PET) using [18F]fluorodeoxyglucose (FDG) for assessing glucose metabolism and multispectral optoacoustic tomography (MSOT) assisted with quantitative model-based reconstruction and unmixing algorithms for accurate mapping of oxygenation patterns in the peripheral tissues at 24 h after reperfusion. We found increased levels of [18F]FDG uptake and reduced MSOT oxygen saturation, indicating hypoxia in the thoracic spinal cord of tMCAO mice compared with sham-operated mice but not in the spleen. A positive correlation was observed between splenic and ipsilateral striatal [18F]FDG uptake. Reduced spleen size was observed in tMCAO mice compared with sham-operated miceex vivo. tMCAO led to a significant increase in the numbers of mature T cells (CD4 and CD8) in femoral bone marrow tissues, concomitant with a stark reduction in these cell subsets in the spleen and their decrease in peripheral blood. The numbers of mature granulocytes (determined as CD11b+Gr1hicells) decreased in bone marrow tissues and blood but increased in the spleen. The combination of quantitative PET and MSOT thus enabled the observation of hypoxia and increased metabolic activity in the spinal cord of tMCAO mice at 24 h after occlusion compared to sham-operated mice.
IL-12/18/21 pre-activation enhances the anti-tumor efficacy of expanded γδT cells and overcomes resistance to anti-PD-L1 treatment
Authors: Teo Huey Yee , Song Yuan , Yong Kylie Su Mei , Liu Yonghao , Mei Yu , Hanafi Zuhairah Binte , Zhu Ying , Gascoigne Nicholas R. J. , Chen Qingfeng , Liu Haiyan
Published: August 2022

γδT cells are promising candidates for cellular immunotherapy due to their immune regulation through cytokine production and MHC-independent direct cytotoxicity against a broad spectrum of tumors. However, current γδT cell-based cancer immunotherapy has limited efficacies and novel strategies are needed to improve its clinical outcomes. Here, we report that cytokine pre-treatment with IL-12/18, IL-12/15/18, IL-12/18/21 and IL-12/15/18/21 could effectively enhance the activation and cytotoxicity ofin vitroexpanded murine and human γδT cells. However, only adoptive transfer of IL-12/18/21 pre-activated γδT cells significantly inhibited tumor growth in a murine melanoma model and a hepatocellular carcinoma model. Both IL-12/18/21 pre-activated antibody-expanded and zoledronate-expanded human γδT cells effectively controlled tumor growth in a humanized mouse model. IL-12/18/21 pre-activation promoted γδT cell proliferation and cytokine productionin vivoand enhanced IFN-γ and TNF-α production, as well as granzyme B expression by endogenous CD8+T cells in a cell-cell contact dependent manner. Furthermore, the adoptive transfer of IL-12/18/21 pre-activated γδT cells could overcome the resistance to anti-PD-L1 therapy, and the combination therapy had a synergistic effect on the therapeutic outcomes. Moreover, the enhanced anti-tumor function of adoptively transferred IL-12/18/21 pre-activated γδT cells was largely diminished in the absent of endogenous CD8+T cells when administered alone or in combination with anti-PD-L1, suggesting a CD8+T cell-dependent mechanism. Taken together, IL-12/18/21 pre-activation could promote γδT cell anti-tumor function and overcome the resistance to checkpoint blockade therapy, indicating an effective combinational cancer immunotherapeutic strategy.

Synopsis

IL-12/18/21 pre-activation enhances the anti-tumor efficacy of adoptively transferred γδT cells by promoting its proliferation, activation, and cytotoxicity, as well as activating endogenous CD8+T cells.

Adoptive transfer of IL-12/18/21 pre-activated γδT cells could overcome the resistance to anti-PD-L1 therapy, indicating an effective combinational cancer immunotherapeutic strategy.