bluuebunny/crossref_metadata_2025 huggingface dataset:
Carbon/nitrogen metabolism and stress response networks – calcium-dependent protein kinases as the missing link?
Authors: Alves Hugo L S , Matiolli Cleverson C , Soares Rafael C , Almadanim M Cecília , Oliveira M Margarida , Abreu Isabel A
Published: March 2021

Calcium-dependent protein kinases (CDPKs) play essential roles in plant development and stress responses. CDPKs have a conserved kinase domain, followed by an auto-inhibitory junction connected to the calmodulin-like domain that binds Ca2+. These structural features allow CDPKs to decode the dynamic changes in cytoplasmic Ca2+ concentrations triggered by hormones and by biotic and abiotic stresses. In response to these signals, CDPKs phosphorylate downstream protein targets to regulate growth and stress responses according to the environmental and developmental circumstances. The latest advances in our understanding of the metabolic, transcriptional, and protein–protein interaction networks involving CDPKs suggest that they have a direct influence on plant carbon/nitrogen (C/N) balance. In this review, we discuss how CDPKs could be key signaling nodes connecting stress responses with metabolic homeostasis, and acting together with the sugar and nutrient signaling hubs SnRK1, HXK1, and TOR to improve plant fitness.
Generalized Convulsive Status Epilepticus
Authors: LaHue Sara C. , Levin Morris
Published: March 2021

The longer seizure activity continues, the higher the chance of irreversible brain injury, so time is of the essence. An update of generalized convulsive status epilepticus management is discussed.
Myelopathy
Authors: LaHue Sara C. , Levin Morris
Published: March 2021

Myelopathy is an important localization with a broad differential. This case walks through an approach to compressive and noncompressive causes of myelopathy.
Neurologic Complications of Immune Checkpoint Inhibitors
Authors: LaHue Sara C. , Levin Morris
Published: March 2021

Immune checkpoint inhibitors are a revolutionary new category of medication for many people with cancer, but they carry with them unique side effects that are reviewed in this case.
Functional Hemiparesis
Authors: LaHue Sara C. , Levin Morris
Published: March 2021

The classic conversion disorder is difficult to diagnose with certainty. This chapter attempts to provide a way to sort out this presentation.
Cardioembolic Stroke with Contraindications to Anticoagulation
Authors: LaHue Sara C. , Levin Morris
Published: March 2021

Identification of atrial fibrillation can provide the explanation for a stroke, but it is not always clear when to start anticoagulation in order to prevent another stroke. This chapter breaks down stroke risk and anticoagulation timing in patients with atrial fibrillation as a cause for stroke.
Intracerebral Hemorrhage on Anticoagulation
Authors: LaHue Sara C. , Levin Morris
Published: March 2021

Patients can quickly decompensate with intracerebral hemorrhage. Emergent treatment of secondary increases in intracranial pressure, and the methods for reversing anticoagulation, are discussed.
First Seizure
Authors: LaHue Sara C. , Levin Morris
Published: March 2021

The first seizure is a perennial enigma. This case discussion should provide a paradigm for evaluation and treatment.
Encephalopathy and Seizure After Transplant
Authors: LaHue Sara C. , Levin Morris
Published: March 2021

Transplant patients are at increased risk for many medical hurdles, including posterior reversible encephalopathy syndrome (PRES). This case reviews the diagnosis, workup, and management of PRES as well as recommendations for anticipating secondary complications.
Nonepileptic Spells
Authors: LaHue Sara C. , Levin Morris
Published: March 2021

There are several misconceptions about nonepileptic spells, which this case discussion attempts to clarify.
Febrile Seizure
Authors: LaHue Sara C. , Levin Morris
Published: March 2021

This case takes us through a diagnostic and treatment paradigm that should serve clinicians who encounter patients with suspected febrile seizures.
Joining a Collaborative
Authors: Meddings Jennifer , Chopra Vineet , Saint Sanjay
Published: March 2021

When hospitals join in a collaborative infection prevention project, they agree to work within the requirements and discipline of the sponsors. That includes providing baseline and monthly infection rate data to the collaborative leaders and committing some staff members to intense weekly phone talks with the collaborative experts and other coaching sessions. Ideally, a community emerges, both online and in-person. The community members exchange experiences and ideas related to the initiative, socialize, and establish a behavioral norm within each hospital that can help convince resisters, particularly physicians, to change their ways. To make up for the limited attention paid to the problems individual hospitals may encounter, some collaboratives provide a troubleshooting group of expert advisors. The collaborative approach has strong support from federal and state agencies, but some studies have questioned its effectiveness.
Haunted by Pain, Fatigue, and Insomnia
Authors: Doleys Daniel M. , Doleys Nicholas D.
Published: March 2021

The impact of an accident or injury, even if the physical consequences seem relatively minor in nature, can have a prolonged effect on an individual’s psychological well-being. Emotionally traumatic, early-life experiences, have been linked to certain chronic pain problems. Some patients are embarrassed by the effect and feel they should be mentally strong enough to overcome it. Others submit to it and become immobilized. It can significantly magnify the experience of pain. Recognition and treatment of posttraumatic stress disorder need not be overly complicated. Some cases may require referral to a specialist. Nightmares, flash backs, hypervigilance, and avoidance are common.
Something Doesn’t Seem Right
Authors: Doleys Daniel M. , Doleys Nicholas D.
Published: March 2021

This case depicts a situation wherein the facts do not seem to fit. In a hurried and busy clinical practice, one is glad to encounter what seems to be a pleasant patient. Patients with personality disorders, especially those with a borderline personality disorder (BPD), can be very deceptive. Their overall manner is often very congenial, until their expectations or requests are not met. Their presentation may be very different to the staff versus the clinician. Self-destructive (mutilation) behavior can be seen in the more severe cases. Female patients can be very disarming. Their objective, in the chronic pain setting, relates more to issues of control and manipulation than to receiving effective pain management. Treatment can be intensive and involve residential placement. Use of controlled substances can be very dangerous. Patient with BPD are best referred to a specialist.
How Can Someone Do This to Themselves?
Authors: Doleys Daniel M. , Doleys Nicholas D.
Published: March 2021

It is not uncommon to encounter patients who appear to exaggerate their pain complaints for one reason or another. However, these are to be differentiated form those diagnosed with malingering or factitious disorders (FD). Both can be difficult to identify. Malingerers engage in a willfully and deliberately attempt to misrepresent their situation for some type of gain. FD represents a group of patients with significant psychiatric problems. Their behavior often includes self-inflicted wounds, which need to be differentiated from actions that may reflect a suicide attempt, depression, or the self-injurious behavior related to dissociative disorder. The FD patient may well have an altered sensitivity to pain. Their treatment is complex and requires an experienced professional.
The “What If” and “Yes But” Syndrome
Authors: Doleys Daniel M. , Doleys Nicholas D.
Published: March 2021

Repeated requests for a definitive diagnosis, prognosis, and reassurance as to the positive outcome of a therapy made by some patients with chronic pain can be very exhausting to both patient and clinician—especially when it is clear that no amount of information will be satisfactory. The practitioner can easily feel like be asked to be a psychic or fortune teller. Pain catastrophizing (PC) has emerged as critical area of study. PC has been linked pain intensity, decreased function, and treatment outcomes, including the effect of pain medications such as opioids. It is most effectively addressed by the use of cognitive-behavioral therapy procedures. Learning how to apply these strategies in the context of the typical office visit can reduce the frustration level of the clinician and patient. In more severe cases, referral to behavioral specialist may to advisable.
The Abandoned Patient
Authors: Doleys Daniel M. , Doleys Nicholas D.
Published: March 2021

The bane of existence for the clinician who treat patients with chronic pain, especially from a pharmacological perspective, is the “abandoned” patient. The incidence of this has significantly increased according to a 2016 Centers for Disease Control and Prevention report. Indented or not, this report has been used as the foundation for creating, if not imposing, restrictions on the prescribing of opioids The emphasis on total morphine equivalent dosing leaves little room for arguing quality of life issues. Clinicians are encouraged not to fear disciplinary action or prosecution when acting in the usual course of medical practice and offering appropriate documentation. The abandoned patient ranges along a continuum form the person informed that a medication will no longer be prescribed to those from a practice that has been discontinued to those who have committed some egregious violation of the medical agreement. In any case, it is important not to side-step your usual assessment process; prescribe only when you feel comfortable doing so. Under extreme circumstances, a short-term prescription at a low dose to safeguard against catastrophic events may be justified. As always, “trust, but verify.”
Fungal asthma among Ugandan adult asthmatics
Authors: Kwizera Richard , Bongomin Felix , Olum Ronald , Meya David B , Worodria William , Bwanga Freddie , Fowler Stephen J , Gore Robin , Denning David W , Kirenga Bruce J
Published: March 2021

Fungal sensitization is associated with poor asthma control. We aimed to determine the prevalence and factors associated with fungal asthma among Ugandan adults. Individuals aged ≥18 years with a new diagnosis of asthma in the last 12 months participating in the African Severe Asthma Program constituted the study population. Skin prick test results, clinical and demographic data were retrieved from the database, and serum Aspergillus fumigatus specific antibodies and total IgE were measured in stored blood. We enrolled 374 patients, median (IQR) age 34 (25–45) years, 286 (76.5%) females and 286 (76.5%) with severe asthma. Prevalence of Aspergillus fumigatus sensitization was 42.0% (95% CI: 37.1–47.0%), allergic bronchopulmonary aspergillosis (ABPA) 3.2% (1.8–5.5%), severe asthma with fungal sensitization (SAFS) 16% (12.7–20.1%) and allergic bronchopulmonary mycosis (ABPM) 2.9% (1.7–5.2%). Older age (55–64 years) (crude odds ratio (cOR) = 2.6), sensitization to at least one allergen (cOR = 9.38) and hypertension (cOR = 1.99) were significantly associated with Aspergillus sensitization, whereas tertiary education level (cOR = 0.29), severe depression (cOR = 0.15) and strong emotions (cOR = 0.47) were not. High occupational exposure to Aspergillus (cOR = 4.26) and contact with moulds (cOR = 14.28) were significantly associated with ABPA. Palpitations (cOR = 5.54), uncontrolled asthma (cOR = 3.54), eczema/dermatitis (cOR = 3.07), poor lung function (cOR = 2.11) and frequent exacerbations (cOR = 1.01) were significantly associated with SAFS. Eczema/dermatitis (cOR = 1.55) was significantly associated with ABPM, but cold weather trigger (cOR = 0.24) was not. Fungal asthma is a significant problem among Ugandans with asthma and should be particularly considered in individuals who remain uncontrolled despite optimal standard of care for asthma, as it is responsive to available and affordable oral antifungal therapy.

Lay Summary

This study showed that fungal asthma is a significant problem among Ugandans with asthma with a high prevalence. Fungal asthma should be considered in patients with uncontrolled asthma despite receiving optimal standard of care. This is the first modern attempt to define these endotypes of asthma in Africa.
New constraints on the 12CO(2–1)/(1–0) line ratio across nearby disc galaxies
Authors: den Brok J S , Chatzigiannakis D , Bigiel F , Puschnig J , Barnes A T , Leroy A K , Jiménez-Donaire M J , Usero A , Schinnerer E , Rosolowsky E , Faesi C M , Grasha K , Hughes A , Kruijssen J M D , Liu D , Neumann L , Pety J , Querejeta M , Saito T , Schruba A , Stuber S
Published: March 2021

Both the CO(2–1) and CO(1–0) lines are used to trace the mass of molecular gas in galaxies. Translating the molecular gas mass estimates between studies using different lines requires a good understanding of the behaviour of the CO(2–1)-to-CO(1–0) ratio, R21. We compare new, high-quality CO(1–0) data from the IRAM 30-m EMIR MultiLine Probe of the ISM Regulating Galaxy Evolution survey to the latest available CO(2–1) maps from HERA CO-Line Extragalactic Survey, Physics at High Angular resolution in Nearby Galaxies-ALMA, and a new IRAM 30-m M51 Large Program. This allows us to measure R21 across the full star-forming disc of nine nearby, massive, star-forming spiral galaxies at 27 arcsec (∼1–2 kpc) resolution. We find an average R21 = 0.64 ± 0.09 when we take the luminosity-weighted mean of all individual galaxies. This result is consistent with the mean ratio for disc galaxies that we derive from single-pointing measurements in the literature, $R_{\rm 21, lit}~=~0.59^{+0.18}_{-0.09}$. The ratio shows weak radial variations compared to the point-to-point scatter in the data. In six out of nine targets, the central enhancement in R21 with respect to the galaxy-wide mean is of order of ${\sim}10{-}20{{\ \rm per\ cent}}$. We estimate an azimuthal scatter of ∼20 per cent in R21 at fixed galactocentric radius but this measurement is limited by our comparatively coarse resolution of 1.5 kpc. We find mild correlations between R21 and carbon monoxide (CO) brightness temperature, infrared (IR) intensity, 70–160 µm ratio, and IR-to-CO ratio. All correlations indicate that R21 increases with gas surface density, star formation rate surface density, and the interstellar radiation field.
Monoceros OB4: a new association in Gaia DR2
Authors: Teixeira P S , Alves J , Sicilia-Aguilar A , Hacar A , Scholz A
Published: March 2021

We use Gaia DR2 data to survey the classic Monoceros OB1 region and look for the existence of a dispersed young population, co-moving with the cloud complex. An analysis of the distribution of proper motions reveals a 20–30 Myr association of young stars, about 300–400 pc away from the far side of the Mon OB1 complex, along the same general line of sight. We characterize the new association, Monoceros OB4, and estimate it contains between 1400 and 2500 stars, assuming a standard initial mass function, putting it on par in size with NGC 2264. We find from the internal proper motions that Mon OB4 is unbound and expanding. Our results seem to unveil a larger and more complex Monoceros star formation region, suggesting an elongated arrangement that seems to be at least 300 × 60 pc.
Novelty and Convergence in Adaptation to Whole Genome Duplication
Authors: Bohutínská Magdalena , Alston Mark , Monnahan Patrick , Mandáková Terezie , Bray Sian , Paajanen Pirita , Kolář Filip , Yant Levi
Published: March 2021

Whole genome duplication (WGD) can promote adaptation but is disruptive to conserved processes, especially meiosis. Studies in Arabidopsis arenosa revealed a coordinated evolutionary response to WGD involving interacting proteins controlling meiotic crossovers, which are minimized in an autotetraploid (within-species polyploid) to avoid missegregation. Here, we test whether this surprising flexibility of a conserved essential process, meiosis, is recapitulated in an independent WGD system, Cardamine amara, 17 My diverged from A. arenosa. We assess meiotic stability and perform population-based scans for positive selection, contrasting the genomic response to WGD in C. amara with that of A. arenosa. We found in C. amara the strongest selection signals at genes with predicted functions thought important to adaptation to WGD: meiosis, chromosome remodeling, cell cycle, and ion transport. However, genomic responses to WGD in the two species differ: minimal ortholog-level convergence emerged, with none of the meiosis genes found in A. arenosa exhibiting strong signal in C. amara. This is consistent with our observations of lower meiotic stability and occasional clonal spreading in diploid C. amara, suggesting that nascent C. amara autotetraploid lineages were preadapted by their diploid lifestyle to survive while enduring reduced meiotic fidelity. However, in contrast to a lack of ortholog convergence, we see process-level and network convergence in DNA management, chromosome organization, stress signaling, and ion homeostasis processes. This gives the first insight into the salient adaptations required to meet the challenges of a WGD state and shows that autopolyploids can utilize multiple evolutionary trajectories to adapt to WGD.
5-Fluorouracil blocks quorum-sensing of biofilm-embedded methicillin-resistantStaphylococcus aureusin mice
Authors: Sedlmayer Ferdinand , Woischnig Anne-Kathrin , Unterreiner Vincent , Fuchs Florian , Baeschlin Daniel , Khanna Nina , Fussenegger Martin
Published: March 2021

Antibiotic-resistant pathogens often escape antimicrobial treatment by forming protective biofilms in response to quorum-sensing communication via diffusible autoinducers. Biofilm formation by the nosocomial pathogen methicillin-resistant Staphylococcus aureus (MRSA) is triggered by the quorum-sensor autoinducer-2 (AI-2), whose biosynthesis is mediated by methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) and S-ribosylhomocysteine lyase (LuxS). Here, we present a high-throughput screening platform for small-molecular inhibitors of either enzyme. This platform employs a cell-based assay to report non-toxic, bioavailable and cell-penetrating inhibitors of AI-2 production, utilizing engineered human cells programmed to constitutively secrete AI-2 by tapping into the endogenous methylation cycle via ectopic expression of codon-optimized MTAN and LuxS. Screening of a library of over 5000 commercial compounds yielded 66 hits, including the FDA-licensed cytostatic anti-cancer drug 5-fluorouracil (5-FU). Secondary screening and validation studies showed that 5-FU is a potent quorum-quencher, inhibiting AI-2 production and release by MRSA, Staphylococcus epidermidis, Escherichia coli and Vibrio harveyi. 5-FU efficiently reduced adherence and blocked biofilm formation of MRSA in vitro at an order-of-magnitude-lower concentration than that clinically relevant for anti-cancer therapy. Furthermore, 5-FU reestablished antibiotic susceptibility and enabled daptomycin-mediated prevention and clearance of MRSA infection in a mouse model of human implant-associated infection.
Setting up and discontinuance of a local or regional division
Authors: Tochtermann Peter
Published: March 2021

A CMS wishing to set up a local division or a number of CMSs wishing to set up a regional division have to forward their request to the Chairman of the Administrative Committee and indicate the seat of such division (see also Art 7(3) and (5) UPCA).
Trade Sanctions
Authors: Lodge Hugo D
Published: March 2021

In the UK, trade sanctions should be distinguished from arms embargoes. The latter comprise a ban on the export of military arms and related material, e.g. ammunition, weapons, and other military goods. Thus, embargoes relate to all goods and technologies on a ‘UK military list’. Certain similar goods though not listed may also require a licence either under ‘military end-use controls’ or ‘weapons of mass destruction’ end-use controls.
Partial melting of granodiorite: insights from ediacaran granulite-facies metamorphism in Southern Brazil
Authors: Pavan M , Sawyer E W , Moraes R , Faleiros F M
Published: March 2021

In the Southern Ribeira Belt (Brazil), the Itatins Complex, composed of ortho- and para-derived migmatites record granulite facies metamorphism. Our work focuses on the ortho-derived migmatite, which displays features indicative of partial melting ranging from in-situ melting (cm-thick lenses and veins) to accumulations of melt as leucosomes and patches of diatexite. The unit comprises a biotite felsic granulite (metagranodiorite) with a residual neosome and a leucocratic neosome, generally referred to as leucosome. Phase equilibria modelling using a modified bulk composition from the geochemical standard JG-1 (granodiorite) was carried out to evaluate whether a protolith of granodiorite bulk composition could produce the mineral assemblages observed in the residual neosome and the compositions of melt and residue produced by the partial melting. Isopleth thermobarometry of plagioclase, biotite and orthopyroxene points to P-T conditions of 0.7–1.0 GPa and 845–872 ºC. The modified granodiorite bulk composition generated just 10 mol % melt at these conditions, far lower than the amount estimated from outcrops (around 32 %). A T-XH2O pseudosection shows that increasing H2O content enhances the fertility of the bulk composition and it can become capable of producing melt volumes similar to that observed in outcrop. The melt compositions determined for partial melting of the modified granodiorite bulk composition in open- and closed-systems using THERMOCALC are granitic, and peraluminous. The melts have SiO2 contents between 52.02 mol % and 77.27 mol. % and show XFe values of 0.68 and 0.86. In K2O vs. Na2O+CaO, K2O vs. XFe and K2O-(FeO+MgO)-(Na2O+CaO) space natural samples (5 from the residual neosome and 2 from leucosome) from the Itatins Complex plot in the direction of the trends for melt and residue compositions obtained from modelling of the modified granodiorite bulk composition. The differences between modeled compositions and real rocks are interpreted to result from the interaction of melt with its residual counterpart. Chondrite normalized REE patterns from the residual neosome shows considerably greater depletion of HREE than geochemical standard JG-1 (granodiorite), and the two analyzed leucosomes show lower HREE contents. Zircon rims have REE patterns interpreted to indicate metamorphic recrystallization. U-Pb zircon Concordia ages indicate that the protolith formed during the Paleoproterozoic (2137 Ma) but that metamorphic recrystallization is Neoproterozoic (between 632 and 601 Ma). The metamorphic age pre-dates the intense granitic magmatism that affected the Southern Ribeira Belt between 600 and 570 Ma.
Molecular dissection of haustorium development in Orobanchaceae parasitic plants
Authors: Furuta Kaori Miyashima , Xiang Lei , Cui Songkui , Yoshida Satoko
Published: March 2021

Characterizing molecular aspects of haustorium development by parasitic plants in the Orobanchaceae family has identified hormone signaling/transport and specific genes as major players.
Indonesian Autonomies: Explaining Divergent Self-Government Outcomes in Aceh and Papua
Authors: Barter Shane Joshua , Wangge Hipolitus Ringgi
Published: March 2021

A form of power-sharing, territorial autonomy is essential for managing separatism. Indonesia provides two non-Western cases to illuminate what makes autonomy work. In Aceh, autonomy helped to overcome conflict and can be regarded as successful, while in Papua, autonomy has failed, evident in continued unrest. Within the same country, the same institutional response to violent separatism has generated divergent self-government outcomes. Why has autonomy succeeded in Aceh, but failed in Papua? Utilizing within-case and temporal comparisons, we suggest that the content of autonomy may be less important than the process through which it unfolds. The powers granted to Aceh and Papua are similar, although how self-government was negotiated and whom it empowered varied. Early in Aceh and in Papua, autonomy was essentially imposed, empowering corrupt leaders, and sidelining dissidents. Aceh’s ultimately successful autonomy was negotiated and saw popular former rebels take the reins of self-government.
Institutionalized insecurity: post-war employment restructuring and the symbolic power of the local business climate
Authors: Hanley Caroline
Published: March 2021

This article investigates an early case of the institutionalization of insecurity by examining labor-management struggles over capital mobility at the General Electric Company (GE) in Schenectady, NY during the 1950s and 1960s. During this period, GE expanded production in the US South and Southwest, reducing employment in Northern plant communities. In the union stronghold of Schenectady, GE’s strategic use of the emergent ‘business climate’ concept undermined union power to resist employment restructuring by reshaping the local politics of employment security: it mobilized community actors against labor’s framing of the problem and enhanced the Company’s ability to present its position as non-political or disinterested, which aided its operation of symbolic power. This article advances our understanding of the sources of legitimacy in claims-making and shows how cultural processes can contribute to change in the distribution of workplace rewards.
Viromics of extant insect orders unveil the evolution of the flavi-like superfamily
Authors: Paraskevopoulou Sofia , Käfer Simon , Zirkel Florian , Donath Alexander , Petersen Malte , Liu Shanlin , Zhou Xin , Drosten Christian , Misof Bernhard , Junglen Sandra
Published: March 2021

Insects are the most diversified and species-rich group of animals and harbor an immense diversity of viruses. Several taxa in the flavi-like superfamily, such as the genus Flavivirus, are associated with insects; however, systematic studies on insect virus genetic diversity are lacking, limiting our understanding of the evolution of the flavi-like superfamily. Here, we examined the diversity of flavi-like viruses within the most complete and up-to-date insect transcriptome collection comprising 1,243 insect species by employing a Flaviviridae RdRp profile hidden Markov model search. We identified seventy-six viral sequences in sixty-one species belonging to seventeen insect, one entognathan, and one arachnidan orders. Phylogenetic analyses revealed that twenty-seven sequences fell within the Flaviviridae phylogeny but did not group with established genera. Despite the large diversity of insect hosts studied, we only detected one virus in a blood-feeding insect, which branched within the genus Flavivirus, indicating that this genus likely diversified only in hematophagous arthropods. Nine new jingmenviruses with novel host associations were identified. One of the jingmenviruses established a deep rooting lineage additional to the insect- and tick-associated clades. Segment co-segregation phylogenies support the separation of tick- and insect-associated groups within jingmenviruses, with evidence for segment reassortment. In addition, fourteen viruses grouped with unclassified flaviviruses encompassing genome length of up to 20 kb. Species-specific clades for Hymenopteran- and Orthopteran-associated viruses were identified. Forty-nine viruses populated three highly diversified clades in distant relationship to Tombusviridae, a plant-infecting virus family, suggesting the detection of three previously unknown insect-associated families that contributed to tombusvirus evolution.
ONT-Based Draft Genome Assembly and Annotation of Alternaria atra
Authors: Bonthala Bhawna , Small Corinn S. , Lutz Maximilian A. , Graf Alexander , Krebs Stefan , Sepúlveda German , Stam Remco
Published: March 2021

Species of Alternaria (phylum Ascomycota, family Pleosporaceae) are known as serious plant pathogens, causing major losses on a wide range of crops. Alternaria atra (previously known as Ulocladium atrum) can grow as a saprophyte on many hosts and causes Ulocladium blight on potato. It has been reported that it can also be used as a biocontrol agent against Botrytis cinerea. Here, we present a scaffold-level reference genome assembly for A. atra. The assembly contains 43 scaffolds with a total length of 39.62 Mbp, with scaffold N50 of 3,893,166 bp, L50 of 4, and the longest 10 scaffolds containing 89.9% of the assembled data. RNA-sequencing-guided gene prediction using BRAKER resulted in 12,173 protein-coding genes with their functional annotation. This first high-quality reference genome assembly and annotation for A. atra can be used as a resource for studying evolution in the highly complicated Alternaria genus and might help in understanding the mechanisms defining its role as pathogen or biocontrol agent.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
Dose-Dependent Inhibition of CYP2D6 by Bupropion in Patients With Depression
Authors: Hole Kristine , Arnestad Marianne , Molden Espen , Haslemo Tore
Published: March 2021

Purpose

The aim of this study was to investigate the potential dose-dependent CYP2D6 inhibition by bupropion (BUP) in patients with depression.

Methods

Patients combining BUP with venlafaxine were included from a therapeutic drug monitoring (TDM) database at the Diakonhjemmet Hospital (Oslo, Norway). The O/N-desmethylvenlafaxine metabolic ratio measured in TDM samples was used as a biomarker for CYP2D6 phenotype and was compared between patients treated with BUP 150 mg/d and 300 mg/d or greater. In addition, reference groups of venlafaxine-treated patients genotyped as CYP2D6 poor metabolizers (PMs, no CYP2D6 activity) and normal metabolizers (NMs, fully functional CYP2D6 activity) were included.

Findings

A total of 221 patients were included in the study. The median O/N-desmethylvenlafaxine metabolic ratio was significantly higher in patients treated with BUP 150 mg/d (n = 59) versus 300 mg/d or greater (n = 34, 1.77 vs 0.96, P < 0.001). In CYP2D6 NMs (n = 62) and PMs (n = 66), the median metabolic ratios were 40.55 and 0.48, respectively. For patients treated with BUP 150 mg/d, 11 (19%) of the 59 patients were phenoconverted to PMs, whereas this was the case for 17 (50%) of the 34 patients treated with BUP 300 mg/d or greater.

Conclusions

Bupropion exhibits a clear dose-dependent CYP2D6 inhibitory effect during treatment of patients with depression. This finding is of clinical relevance when adjusting dosing of CYP2D6 substrates during comedication with BUP. Half of the patients treated with high-dose BUP are converted to CYP2D6 PM phenotype. Because of the variability in CYP2D6 inhibition, TDM of CYP2D6 substrates should be considered to provide individualized dose adjustments during comedication with BUP.
Recognition, Evaluation, and Management of Pediatric Hereditary Angioedema
Authors: Krack Andrew T. , Bernstein Jonathan A. , Ruddy Richard M.
Published: March 2021

Hereditary angioedema (HAE) is a rare, often underrecognized genetic disorder caused by either a C1 esterase inhibitor deficiency (type 1) or mutation (type 2). This leads to overproduction of bradykinin resulting in vasodilation, vascular leakage, and transient nonpitting angioedema occurring most frequently in the face, neck, upper airway, abdomen, and/or extremities. Involvement of the tongue and laryngopharynx has been associated with asphyxiation and death. Hereditary angioedema is an autosomal-dominant condition; therefore, there is a 50% chance an offspring will inherit this disorder. Any patient presenting with isolated angioedema should be screened with a C4 measurement, as 25% of cases have no family history of HAE. All patients with HAE will have a functional deficiency of C1 esterase inhibitor. Contributors that delay the diagnosis of HAE include recognition delay by clinicians who confuse this condition with histaminergic angioedema, the disease's varied presentations, and limitations to timely testing. Pediatric emergency clinicians should be knowledgeable about how to distinguish between bradykinin- and histamine-mediated angioedema, as there are significant differences in the diagnostic testing, treatment, and clinical response between these 2 different conditions. Evidence indicates that early diagnosis and treatment of HAE reduces morbidity and mortality. Clinician recognition of the mechanistically different problems will ensure patients are appropriately referred to an expert for outpatient management.
Decline in Pediatric Emergency Department Behavioral Team Activations After Institution of an Agitation Protocol
Authors: Pavlov Hannah , Santillanes Genevieve , Claudius Ilene
Published: March 2021

Objective

Aggressive behavior among pediatric patients with psychiatric complaints in emergency departments is a growing problem. An agitation protocol was instituted in 1 pediatric emergency department to provide scaled recommendations for differing levels of aggression. The study objective was to determine if the frequency of activation of an emergency behavioral response team changed after protocol initiation.

Methods

A protocol for escalating management of agitation in pediatric patients was introduced in February 2016. The electronic medical record was queried for subsequent behavioral response team activations over the next 16 months. Patient demographics and specific features surrounding the activation were retrospectively recorded from the medical record, including length of stay, medications administered, and documented deescalation techniques. Frequency and features of behavioral team activations were compared with activations from a period before the planning and implementation of the protocol (May 2014 to May 2015).

Results

Twenty-one patient visits were found to require behavioral response team activation over 16 months, compared with 31 for the 13-month preprotocol period. Attempts at verbal/ environmental redirection were seen in 77% and deescalation by medication administration before the activation occurred in 14% of patients. During the behavioral team activation, 81% of the patients were given psychiatric medications and 81% were placed in physical restraints.

Conclusions

A decrease from a baseline of 2.4 to 1.3 behavioral response team activations per month, or a 46% decline, was noted following the institution of a clinical protocol for pediatric agitation.
A National Survey to Assess the Population’s Perception of Breast Implant-Associated Anaplastic Large Cell Lymphoma and Breast Implant Illness
Authors: Azzi Alain J. , Almadani Yasser , Davison Peter
Published: March 2021

Background:

The goal of this study was to gauge the public’s general perception of breast implants, levels of concern, spontaneous word associations, and misperceptions that might need to be addressed by plastic surgeons regarding breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) and breast implant illness (BII).

Methods:

An anonymous survey was completed by a total of 979 female participants in the United States by means of Amazon Mechanical Turk.

Results:

Over 91 percent of participants indicated that they had never heard the term BIA-ALCL. Of the respondents who were aware of the term, 37.21 percent reported being moderately or extremely concerned about BIA-ALCL and 85.4 percent were less likely to recommend breast implants to a friend. Awareness of BII was significantly higher at 50.9 percent, whereas almost 40 percent of participants reported being either moderately or extremely concerned about BII. Over 78 percent of participants were less likely to recommend breast implants to a friend because of BII. The most common word association with BII was “pain,” followed by “cancer.” The terms “cancer” and “scary” were the two most common word associations with BIA-ALCL. A significant overlap in word associations was observed between BIA-ALCL and BII, potentially representing a lack of distinction between the two terms. The survey demonstrated a paucity of important knowledge within the general population; notably, 71 percent of respondents who were not aware that, to date, only textured implants/expanders were associated with BIA-ALCL.

Conclusion:

These findings support the need for further targeted awareness to remedy existing misperceptions and fill the knowledge gaps relating to BII and BIA-ALCL.
Intraoperative Fluid Management Implies Insignificant Influence to Surgical Outcomes in Head and Neck Microvascular Reconstruction Cases
Authors: Zheng Gang , Liu Jun , Yu Peirong
Published: March 2021

Background:

Deliberate fluid administration has been used to maintain a hyperdynamic systemic circulation in free tissue transfer operations. The effects of intraoperative volume loading on postoperative complications have been controversial. The authors hypothesized that increasing intraoperative fluid administration was associated with increased postoperative surgical complications.

Methods:

Free flap operations for head and neck reconstruction between 2004 and 2014 were reviewed. A generalized estimating equation model was used to estimate the effect of intraoperative fluid administration on surgical outcomes. The optimized thresholds of anesthetic time were tested by the Youden index for flap compromise and major complications.

Results:

A total of 2983 consecutive cases were included in the study. The incidences of flap compromise and total loss were 1.5 and 3.3 percent, respectively. Intraoperative fluid administration was not associated with surgical complications (p = 0.195). However, a 1-hour increase in anesthesia time was associated with a 19 percent increased risk of flap compromise (adjusted OR, 1.19; 95 percent CI, 1.10 to 1.29; p < 0.001).

Conclusion:

Prolonged anesthetic time, but not fluid administration, was associated with adverse surgical outcomes.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
IL-6 and D-Dimer at Admission Predicts Cardiac Injury and Early Mortality during SARS-CoV-2 Infection
Authors: Si Daoyuan , Du Beibei , Yang Bo , Jin Lina , Ni Lujia , Zhang Qian , Zhang Zhongfan , Azam Mohammed Ali , Lai Patrick F.H. , Massé Stéphane , Sun Huan , Wang Xingtong , Epelman Slava , Lawler Patrick R. , Yang Ping , Nanthakumar Kumaraswamy
Published: March 2021

BACKGROUND

We recently described mortality of cardiac injury in COVID-19 patients. Admission activation of immune, thrombotic biomarkers and their ability to predict cardiacinjury and mortality patterns in COVID-19 is unknown.

METHODS

This retrospective cohort study included 170 COVID-19 patients with cardiac injury at admission to Tongji Hospital in Wuhan from January 29–March 8, 2020. Temporal evolution of inflammatory cytokines, coagulation markers, clinical, treatment and mortality were analyzed.

RESULTS

Of 170 patients, 60 (35.3%) died early (<21d) and 61 (35.9%) died after prolonged stay. Admission lab work that correlated with early death were elevate levels of interleukin 6 (IL-6) (p<0.0001), Tumor Necrosis Factor-a (TNF-a) (p=0.0025), and C-reactive protein (CRP) (p<0.0001). We observed the trajectory of biomarker changes after admission, and determined that early mortality had a rapidly increasing D-dimer, gradually decreasing platelet and lymphocyte counts. Multivariate and simple linear regression models showed that death risk was determined by immune and thrombotic pathway activation. Increasing cTnI levels were associated with those of increasing IL-6 (p=0.03) and D-dimer (p=0.0021). Exploratory analyses suggested that patients that received heparin has lower early mortality compared to those who did not (p =0.07), despite similar risk profile.

CONCLUSIONS

In COVID-19 patients with cardiac injury, admission IL-6 and D-dimer predicted subsequent elevation of cTnI and early death, highlighting the need for early inflammatory cytokine-based risk stratification in patients with cardiac injury.

Condensed Abstract

COVID-19 with cardiac injury is associated with worse survival. Admission activation of immune, thrombotic biomarkers and their ability to predict cardiac injury and mortality patterns in COVID-19 is unknown. This study proved that cardiac injury in these patients is closely related to the activation of immunological and thrombotic pathways and can be predicted by admission biomarkers of these pathways. This study supports the strategy of biomarker-guided, point-of-care therapy that warrants further studies in a randomized manner to develop anti-immune and anti-thrombotic treatment regimens in severe COVID-19 patients with cardiac injury.
Transcriptomic Profiling on Localized Gastric Cancer Identified CPLX1 as a Gene Promoting Malignant Phenotype of Gastric Cancer and a Predictor of Recurrence after Surgery and Subsequent Chemotherapy
Authors: Tanaka Haruyoshi , Kanda Mitsuro , Shimizu Dai , Tanaka Chie , Hattori Norifumi , Inokawa Yoshikuni , Hayashi Masamichi , Nakayama Goro , Kodera Yasuhiro
Published: March 2021

Localized gastric cancer (GC) becomes fatal once recurring. We still have room for improving their prognoses. Firstly, a transcriptomic analysis was done on surgically resected specimens of 16 patients with UICC stage III GC who underwent curative gastrectomy and adjuvant oral fluoropyrimidine monotherapy. Four of them were free from disease for longer than 5 years, and the others experienced 15 metachronous metastasis at either liver, peritoneum, or distant lymph nodes (n = 4 each) within 2 years after surgery. CPLX1 was identified as a novel oncogene candidate for recurrence among 57,749 genes. Secondary, we tested alteration of malignant phenotypes including drug resistance of gastric cancer cell lines by small interfering RNA-mediated CPLX1 knockdown. Inhibiting CPLX1 expression decreased the proliferation, motility, and invasiveness of GC cells, and increased apoptosis and sensitivity to fluorouracil. Thirdly, we validated the clinical significance of CPLX1 expression in GC by quantitative RT-PCR on 180 primary gastric cancer tissues of which patients underwent gastric resection for stage II and III GC without preoperative treatment between 2001 and 2014. Increased expression of CPLX1 mRNA in gastric cancer tissues correlated with worse prognoses and was an independent risk factor for peritoneal recurrence in subgroups receiving adjuvant chemotherapy. CPLX1 may represent a biomarker for recurrence of gastric cancer and a target for therapy.

Brief description

Transcriptomic analysis identified CPLX1 gene as a novel oncogene candidate for gastric cancer. CPLX1 may promote epithelial-mesenchymal transition and evading apoptosis of gastric cancer cells even under a cytotoxic agent, and also be a predictor for recurrence after surgery for UICC Stage II-III gastric cancer.
Neurophysiological biomarkers of post-concussion syndrome: a scoping review
Authors: Mortaheb Sepehr , Filippini Maria Maddalena , Kaux Jean-François , Annen Jitka , Lejeune Nicolas , Martens Géraldine , Calderón Maria Antonia Fuentes , Laureys Steven , Thibaut Aurore
Published: March 2021

Background and objectives

Post-concussion syndrome (PCS) consists of neurologic and psychological complaints persisting after a mild traumatic brain injury (mTBI). It affects up to 50% of mTBI patients, causes long-term disability and reduces quality of life. The aim of this scoping review was to examine possible uses of different neuroimaging modalities in PCS.

Methods

Articles from Pubmed database were screened to extract studies that investigated the relationship between any neuroimaging features and symptoms of PCS. Descriptive statistics were applied to report results.

Results

88 out of 939 papers were included in the final review. 12 examined conventional MRI (42% specificity), 27 diffusion weighted imaging (56% specificity), 25 functional MRI (84% specificity), 10 electro(magneto)encephalography (80% specificity), and 14 examined other techniques (71% specificity).

Conclusion

MRI was the most widely used technique, while functional techniques seem to be the most sensitive tools to evaluate PCS. Common patterns associated with symptoms of PCS were a decreased anticorrelation between the default mode network and the task positive network and reduced brain activity in specific areas (most often prefrontal cortex).

Significance

Our findings highlight the importance to use functional approaches which demonstrated a functional alternation in brain connectivity and activity in most studies assessing PCS.

Highlights

post-concussion syndrome causes long term problems for up to 50% of patients after concussion.

Among different neuroimaging techniques, fMRI and EEG show to be the most sensitive tools for PCS assessment.

Heterogeneity of axonal injury, symptoms, and populations limits having a specific prognostic criteria for the PCS patients.
iTaxoTools 0.1: Kickstarting a specimen-based software toolkit for taxonomists
Authors: Vences Miguel , Miralles Aurélien , Brouillet Sophie , Ducasse Jacques , Fedosov Alexander , Kharchev Vladimir , Kostadinov Ivaylo , Kumari Sangeeta , Patmanidis Stefanos , Scherz Mark D. , Puillandre Nicolas , Renner Susanne S.
Published: March 2021

While powerful and user-friendly software suites exist for phylogenetics, and an impressive cybertaxomic infrastructure of online species databases has been set up in the past two decades, software specifically targeted at facilitating alpha-taxonomic work, i.e., delimiting and diagnosing species, is still in its infancy. Here we present a project to develop a bioinformatic toolkit for taxonomy, based on open-source Python code, including tools focusing on species delimitation and diagnosis and centered around specimen identifiers. At the core of iTaxoTools is user-friendliness, with numerous autocorrect options for data files and with intuitive graphical user interfaces. Assembled standalone executables for all tools or a suite of tools with a launcher window will be distributed for Windows, Linux, and Mac OS systems, and in the future also implemented on a web server. The alpha version (iTaxoTools 0.1) distributed with this paper contains GUI versions of six species delimitation programs (ABGD, ASAP, DELINEATE, GMYC, PTP, tr2) and a simple threshold-clustering delimitation tool. There are also new Python implementations of existing algorithms, including tools to compute pairwise DNA distances, ultrametric time trees based on non-parametric rate smoothing, species-diagnostic nucleotide positions, and standard morphometric analyses. Other utilities convert among different formats of molecular sequences, geographical coordinates, and units; merge, split and prune sequence files and tables; and perform simple statistical tests. As a future perspective, we envisage iTaxoTools to become part of a bioinformatic pipeline for next-generation taxonomy that accelerates the inventory of life while maintaining high-quality species hypotheses.