bluuebunny/crossref_metadata_2025 huggingface dataset:
Focused NPIs in Statements and Questions
Authors: Jeong Sunwoo , Roelofsen Floris
Published: March 2023

Negative Polarity Items (NPIs) with emphatic prosody such as ANY or EVER, and minimizers such as lift a finger or sleep a wink are known to generate particular contextual inferences that are absent in the case of non-emphatic NPIs such as unstressed any or ever. It remains an open question, however, what the exact status of these inferences is and how they come about. In this paper, we analyze these cases as NPIs bearing focus, and examine the interaction between focus semantics and the lexical semantics of NPIs across statements and questions. In the process, we refine and expand the empirical landscape by demonstrating that focused NPIs give rise to a variety of apparently heterogeneous contextual inferences, including domain widening in statements and inferences of negative bias in questions. These inferences are further shown to be modulated in subtle ways depending on the specific clause-type in which the NPI occurs (e.g., polar questions vs. wh-questions) and the type of emphatic NPI involved (e.g., ANY vs. lift a finger). Building on these empirical observations, we propose a unified account of NPIs which posits a single core semantic operator, even, across both focused and unfocused NPIs. What plays a central role in our account is the additive component of even, which we formulate in such a way that it applies uniformly across statements and questions. This additive component of even, intuitively paraphrased as the implication that all salient focus alternatives of the prejacent of the operator must be settled in the doxastic state of the speaker, is selectively activated depending on the presence of focus alternatives, and is shown to be able to derive all the observed contextual inferences stemming from focused NPIs, both in statements and in questions.
A tell tail sign: a conserved C-terminal tail-anchor domain targets a subset of pathogen effectors to the plant endoplasmic reticulum
Authors: Breeze Emily , Vale Victoria , McLellan Hazel , Pecrix Yann , Godiard Laurence , Grant Murray , Frigerio Lorenzo
Published: March 2023

The endoplasmic reticulum (ER) is the entry point to the secretory pathway and, as such, is critical for adaptive responses to biotic stress, when the demand for de novo synthesis of immunity-related proteins and signalling components increases significantly. Successful phytopathogens have evolved an arsenal of small effector proteins which collectively reconfigure multiple host components and signalling pathways to promote virulence; a small, but important, subset of which are targeted to the endomembrane system including the ER. We identified and validated a conserved C-terminal tail-anchor motif in a set of pathogen effectors known to localize to the ER from the oomycetes Hyaloperonospora arabidopsidis and Plasmopara halstedii (downy mildew of Arabidopsis and sunflower, respectively) and used this protein topology to develop a bioinformatic pipeline to identify putative ER-localized effectors within the effectorome of the related oomycete, Phytophthora infestans, the causal agent of potato late blight. Many of the identified P. infestans tail-anchor effectors converged on ER-localized NAC transcription factors, indicating that this family is a critical host target for multiple pathogens.
Evidence for a bottom-light initial mass function in massive star clusters
Authors: Baumgardt H , Hénault-Brunet V , Dickson N , Sollima A
Published: March 2023

We have determined stellar mass functions of 120 Milky Way globular clusters and massive Large Magellanic Cloud/Small Magellanic Cloud star clusters based on a comparison of archival Hubble Space Telescope photometry with a large grid of direct N-body simulations. We find a strong correlation of the global mass function slopes of star clusters with both their internal relaxation times and their lifetimes. Once dynamical effects are being accounted for, the mass functions of most star clusters are compatible with an initial mass function described by a broken power-law distribution N(m) ∼ mα with break masses at 0.4 and 1.0 M⊙ and mass function slopes of αLow = −0.3 for stars with masses m < 0.4 M⊙, αHigh = −2.30 for stars with m > 1.0 M⊙, and αMed = −1.65 for intermediate-mass stars. Alternatively, a lognormal mass function with a characteristic mass log MC = −0.36 and width σC = 0.28 for low-mass stars and a power-law mass function for stars with m > 1 M⊙ also fit our data. We do not find a significant environmental dependence of the initial mass function on cluster mass, density, global velocity dispersion, or metallicity. Our results lead to a larger fraction of high-mass stars in globular clusters compared to canonical Kroupa/Chabrier mass functions, increasing the efficiency of self-enrichment in clusters and helping to alleviate the mass budget problem of multiple stellar populations in globular clusters. By comparing our results with direct N-body simulations, we finally find that only simulations in which most black holes are ejected by natal birth kicks correctly reproduce the observed correlations.
Probing the global dust properties and cluster formation potential of the giant molecular cloud G148.24+00.41
Authors: Rawat Vineet , Samal M R , Walker D L , Zavagno A , Tej A , Marton G , Ojha D K , Elia Davide , Chen W P , Jose J , Eswaraiah C
Published: March 2023

Clouds more massive than about 105 M⊙ are potential sites of massive cluster formation. Studying the properties of such clouds in the early stages of their evolution offers an opportunity to test various cluster formation processes. We make use of CO, Herschel, and UKIDSS observations to study one such cloud, G148.24+00.41. Our results show the cloud to be of high mass ($\sim \, 1.1\times 10^5$ M⊙), low dust temperature (∼ 14.5 K), nearly circular (projected radius ∼ 26 pc), and gravitationally bound with a dense gas fraction of ∼18 per cent and a density profile with a power-law index of ∼−1.5. Comparing its properties with those of nearby molecular clouds, we find that G148.24+00.41 is comparable to the Orion-A molecular cloud in terms of mass, size, and dense gas fraction. From our analyses, we find that the central area of the cloud is actively forming protostars and is moderately fractal with a Q-value of ∼ 0.66. We also find evidence of global mass-segregation with a degree of mass-segregation (ΛMSR) ≈ 3.2. We discuss these results along with the structure and compactness of the cloud, the spatial and temporal distribution of embedded stellar population and their correlation with the cold dust distribution, in the context of high-mass cluster formation. We compare our results with models of star cluster formation, and conclude that the cloud has the potential to form a cluster in the mass range ∼ 2000–3000 M⊙ through dynamical hierarchical collapse and assembly of both gas and stars.
Single-molecule analysis of DNA-binding proteins from nuclear extracts (SMADNE)
Authors: Schaich Matthew A , Schnable Brittani L , Kumar Namrata , Roginskaya Vera , Jakielski Rachel C , Urban Roman , Zhong Zhou , Kad Neil M , Van Houten Bennett
Published: March 2023

Single-molecule characterization of protein–DNA dynamics provides unprecedented mechanistic details about numerous nuclear processes. Here, we describe a new method that rapidly generates single-molecule information with fluorescently tagged proteins isolated from nuclear extracts of human cells. We demonstrated the wide applicability of this novel technique on undamaged DNA and three forms of DNA damage using seven native DNA repair proteins and two structural variants, including: poly(ADP-ribose) polymerase (PARP1), heterodimeric ultraviolet-damaged DNA-binding protein (UV-DDB), and 8-oxoguanine glycosylase 1 (OGG1). We found that PARP1 binding to DNA nicks is altered by tension, and that UV-DDB did not act as an obligate heterodimer of DDB1 and DDB2 on UV-irradiated DNA. UV-DDB bound to UV photoproducts with an average lifetime of 39 seconds (corrected for photobleaching, τc), whereas binding lifetimes to 8-oxoG adducts were < 1 second. Catalytically inactive OGG1 variant K249Q bound oxidative damage 23-fold longer than WT OGG1, at 47 and 2.0 s, respectively. By measuring three fluorescent colors simultaneously, we also characterized the assembly and disassembly kinetics of UV-DDB and OGG1 complexes on DNA. Hence, the SMADNE technique represents a novel, scalable, and universal method to obtain single-molecule mechanistic insights into key protein–DNA interactions in an environment containing physiologically-relevant nuclear proteins.
Hyponatraemia and fluid overload are associated with higher risk of mortality in dialysis patients
Authors: Pinter Jule , Genser Bernd , Moissl Ulrich , Stuard Stefano , Kooman Jeroen , Canaud Bernard , Wanner Christoph
Published: March 2023

Background

The 5-year mortality rate for haemodialysis patients is over 50%. Acute and chronic disturbances in salt and fluid homeostasis contribute to poor survival and are established as individual mortality risk factors. However, their interaction in relation to mortality is unclear.

Methods

We used the European Clinical Database 5 to investigate in a retrospective cohort analysis the relationship between transient hypo- and hypernatremia, fluid status and mortality risk of 72 163 haemodialysis patients from 25 countries. Incident haemodialysis patients with at least one valid measurement of bioimpedance spectroscopy were followed until death or administrative censoring from 1 January 2010 to 4 December 2019. Fluid overload and depletion were defined as >2.5 L above, and −1.1 L below normal fluid status, respectively. N = 2 272 041 recorded plasma sodium and fluid status measurements were available over a monthly time grid and analysed in a Cox regression model for time-to-death.

Results

Mortality risk of hyponatremia (plasma sodium <135 mmol/L) was slightly increased when fluid status was normal [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.18–1.35], increased by half when patients were fluid depleted (HR 1.56, 95% CI 1.27–1.93) and accelerated during fluid overload (HR 1.97, 95% CI 1.82–2.12).

Conclusions

Plasma sodium and fluid status act independently as risk factors on mortality. Patient surveillance of fluid status is especially important in the high-risk subpopulation of patients with hyponatremia. Prospective patient-level studies should examine the effects of chronic hypo- and hypernatremia, risk determinants, and their outcome risk.
The impact of food restriction on liver enzyme levels: a systematic review and meta-analysis
Authors: Huang Hang , Qiu Yunmei , Tang Anyang , Li Wanzhi , Yao Wanyi , Zhong Mei , Yang Ting , Zou Tangbin
Published: March 2023

Context

The relationship between food restriction (FR) and liver enzyme levels, such as alanine transferase (ALT), aspartate transferase (AST), and γ-glutamyl transferase (GGT), has not yet been confirmed.

Objective

A meta-analysis of research articles was conducted to investigate the association of FR and liver enzyme levels.

Data sources

The PubMed, Web of Science, Embase, and Cochrane Library databases were screened for articles published up to April 30, 2022.

Data extraction

Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement methodology was used to search for research articles. Publication bias was detected using Begg’s test. Finally, 17 trials involving 1982 participants and that reported mean value, mean difference, and standard deviation were identified.

Data analysis

Data were described as the weighted mean difference of body mass index, body weight, and standardized mean difference (SMD) of ALT, AST, and GGT. A reduction in ALT level was observed after a FR intervention (total SMD, –0.36, 95% confidence interval [CI], –0.68 to –0.05). GGT levels also were decreased in 4 studies (total SMD, –0.23; 95%CI, –0.33 to –0.14). According to subgroup analysis, serum AST levels decreased in the medium-term (between 5 wk and 6 mo) group (subtotal SMD, –0.48; 95%CI, –0.69 to –0.28).

Conclusion

Existing evidence suggests that dietary restriction improves adult liver enzyme levels. The long-term maintenance of healthy liver enzyme levels, particularly in real-world applications, necessitates additional consideration.
Rice HEAT SHOCK PROTEIN60-3B maintains male fertility under high temperature by starch granule biogenesis
Authors: Lin Sen , Liu Ze , Sun Shiyu , Xue Feiyang , Li Huanjun , Tursun Askar , Cao Lichun , Zhang Long , Wilson Zoe A , Zhang Dabing , Liang Wanqi
Published: March 2023

Heat stress has a deleterious effect on male fertility in rice (Oryza sativa), but mechanisms to protect against heat stress in rice male gametophytes are poorly understood. Here, we have isolated and characterized a heat-sensitive male-sterile rice mutant, heat shock protein60-3b (oshsp60-3b), that shows normal fertility at optimal temperatures but decreasing fertility as temperatures increase. High temperatures interfered with pollen starch granule formation and reactive oxygen species (ROS) scavenging in oshsp60-3b anthers, leading to cell death and pollen abortion. In line with the mutant phenotypes, OsHSP60-3B was rapidly upregulated in response to heat shock and its protein products were localized to the plastid. Critically, overexpression of OsHSP60-3B enhanced the heat tolerance of pollen in transgenic plants. We demonstrated that OsHSP60-3B interacted with FLOURY ENDOSPERM6(FLO6) in plastids, a key component involved in the starch granule formation in the rice pollen. Western blot results showed that FLO6 level was substantially decreased in oshsp60-3b anthers at high temperature, indicating that OsHSP60-3B is required to stabilize FLO6 when temperatures exceed optimal conditions. We suggest that in response to high temperature, OsHSP60-3B interacts with FLO6 to regulate starch granule biogenesis in rice pollen and attenuates ROS levels in anthers to ensure normal male gametophyte development in rice.
Implementing a deterministic search algorithm with a single qubit
Authors: Peng Chen-Hui , Bin Liang , He Xin , Sun Yong-Nan , Su Qi-Ping , Yang Chui-Ping
Published: March 2023

Quantum search algorithms have important applications in quantum information, which have been experimentally demonstrated in several quantum systems with database sizes up to 16. We first propose an efficient quantum search scheme based on an optimized Grover’s algorithm and a novel encoding method. With this scheme, a target element can be deterministically searched in a large database using only a single qubit. Then we implement this search scheme in linear optics with database sizes up to 40. Experimental results fit well with the theoretical results, with all fidelities greater than 99.7%. The limitation of the number of elements encoded in a single qubit is also investigated in the experiment. The experimental results indicate that a target state can be successfully searched from a database of size 36 using a single qubit in our laboratory. Since only one qubit and one-qubit gates are required, this search scheme is quite efficient and general, and can be adopted to implement the same task in most quantum systems.
Identification of new candidate drugs for primary Sjögren’s syndrome using a drug repurposing transcriptomic approach
Authors: Felten Renaud , Ye Tao , Schleiss Cedric , Schwikowski Benno , Sibilia Jean , Monneaux Fanny , Dumortier Hélène , Jonsson Roland , Lessard Christopher , Ng Fai , Takeuchi Tsutomu , Mariette Xavier , Gottenberg Jacques-Eric
Published: March 2023

Objectives

To date, no immunomodulatory drug has demonstrated its efficacy in primary SS (pSS). We sought to analyse potential commonalities between pSS transcriptomic signatures and signatures of various drugs or specific knock-in or knock-down genes.

Methods

Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in two cohorts and three public databases. In each of the five datasets, we analysed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on nine cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database.

Results

We analysed 1008 peripheral blood transcriptomes from five independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated.

Conclusion

This first drug repositioning transcriptomic approach in SS confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets.
When it looks like Behçet’s syndrome but is something else: differential diagnosis of Behçet’s syndrome: a two-centre retrospective analysis
Authors: Lötscher Fabian , Kerstens Floor , Krusche Martin , Ruffer Nikolas , Kötter Ina , Turkstra Franktien
Published: March 2023

Objective

To investigate the differential diagnostic spectrum in patients with suspected Behçet’s syndrome (BS) in low prevalence regions. In addition, the number of patients fulfilling the ICBD criteria despite not having BS was evaluated.

Methods

This retrospective analysis was performed in two referral centres for BS. Patients with confirmed BS (clinical diagnosis with fulfilment of ISG criteria or a score of ≥5 points in the ICBD criteria) were excluded. The remaining patients were divided into 11 differential diagnosis categories. If no definitive alternative diagnosis could be established, patients were termed ‘probable BS’ in case of (i) relapsing orogenital aphthosis in the absence of other causes and either HLA-B51 positivity, or origin from an endemic area or presence of an additional typical BS symptom that is not part of the classification criteria, or (ii) with 3–4 points scored in the ICBD criteria.

Results

In total 202 patients were included and categorized as follows: 58 patients (28.7%) as ‘probable BS’, 57 (28.2%) skin disease, 26 (12.9%) chronic pain syndrome, 14 (6.9%) eye disease, 11 (5.4%) spondyloarthropathy, 9 (4.5%) gastrointestinal disease, 7 (3.5%) neurological disease, 4 (2%) arthritis, 3 (1.5%) auto-inflammation, 3 (1.5%) connective tissue disease and 10 (5.0%) miscellaneous disease. HLA-B51 was positive in 55/132 (41.7%); 75/202 (37.1%) of the patients fulfilled the ICBD criteria.

Conclusion

In a low disease prevalence setting, the straightforward application of the ICBD criteria may lead to overdiagnosis of BS. The differential diagnosis of BS is enormously broad. Clinicians should be aware that HLA-B51 positivity is still not considered as a diagnostic feature in BS.
Effect of the new 75-mg orodispersible film of sildenafil on erection and sexual quality of life: insights from an observational study
Authors: Sansone Andrea , Frangione Valeria , Lanzarotti Arturo , Cocci Andrea , Ceruti Carlo , De Sio Marco , Imbimbo Ciro , Mirone Vincenzo , Schips Luigi , Terrone Carlo , Jannini Emmanuele A
Published: March 2023

Background

The newly devised orodispersible film (ODF) of sildenafil is the first phosphodiesterase type 5 inhibitor (PDE5i) available in a 75-mg dose. This intermediate dose and the particular properties of the ODF formulation can improve the clinical management of erectile dysfunction (ED) patients.

Aim

We investigated the effects of the sildenafil ODF 75-mg dose on both sexual quality of life and erectile function based on the results from an observational study in daily practice in Italy.

Methods

This study was a post hoc analysis of results from an observational, real-life study carried out in ED patients at 6 treatment centers in Italy. All subjects were asked to take the prescribed dose of sildenafil ODF at inclusion (visit 1) and to return for a control visit (visit 2) to confirm or adapt the prescribed dose after a minimum of 4 weeks. An end of study control visit (visit 3) was performed after additional 4 weeks.

Outcomes

Erectile function, assessed by the International Index of Erectile Function–Erectile Function (IIEF-EF) domain; sexual quality of life, measured using the sexual quality of life instrument for men (SQoL-M).

Results

Among the 36 subjects initially recruited for the 75-mg dose, 5 patients dropped out of the study (2 at visit 2 and 3 at visit 3), none of whom due to treatment inefficacy or serious adverse events. At visit 2, the mean (SD) IIEF-EF scores significantly increased (∆ = 7.97 [4.71], P < 0.0001) as SQoL-M scores also did (∆ = 10.76 [10.46], P < 0.0001). At visit 3, IIEF-EF and SQoL-M scores were still significantly improved compared to baseline (∆ = 10.64 [7.01], P < 0.0001, and ∆ = 18.15 [12.32], P < 0.0001, respectively). By ANCOVA, we found no significant effects for age, BMI, previous use of PDE5i, presence of metabolic comorbidities, or smoking habits on study outcomes at both visits 2 and 3.

Clinical implication

The new 75-mg ODF sildenafil formulation is a safe and effective treatment for ED, significantly improving both erectile function and sexual quality of life in patients undergoing treatment.

Strengths and limitations

This is the first study assessing the efficacy of the sildenafil ODF 75-mg dose in a real-life setting. However, the small sample size, possible underlying cultural factors, and limited availability of clinically relevant data may have affected the reliability of our results.

Conclusion

The use of the 75 mg ODF formulation for sildenafil represents an effective and safe novel treatment option for ED patients.
Sleep and mental health in recruit paramedics: a 6-month longitudinal study
Authors: Nguyen Elle , Meadley Ben , Harris Rachael , Rajaratnam Shantha M W , Williams Brett , Smith Karen , Bowles Kelly-Ann , Dobbie Megan L , Drummond Sean P A , Wolkow Alexander P
Published: March 2023

Study Objectives

To explore potential relationships and longitudinal changes in sleep and mental health in recruit paramedics over the first 6 months of work, and whether sleep disturbances pre-emergency work predict future mental health outcomes.

Methods

Participants (N = 101, 52% female, Mage = 26 years) completed questionnaires prior to (baseline), and after 6 months of emergency work to assess for symptoms of insomnia, obstructive sleep apnea, post-traumatic stress disorder (PTSD), depression, anxiety, and trauma exposure. At each timepoint, participants also completed a sleep diary and wore an actigraph for 14 days to assess sleep patterns. Correlations between baseline sleep and mental health were conducted and changes in these variables across timepoints were examined using linear mixed models. Hierarchical regressions assessed whether sleep at baseline predicted mental health at follow-up.

Results

Insomnia and depression symptoms, and total sleep time increased while sleep onset latency decreased across the first 6 months of emergency work. Participants experienced an average of 1 potentially traumatic event during the 6-month period. Baseline insomnia predicted increased depression symptoms at the 6-month follow-up, while baseline wake after sleep onset predicted follow-up PTSD symptoms.

Conclusion

Results highlight an increase in insomnia and depression across the initial months of emergency work, while sleep disturbances before emergency work were identified as potential risk factors for the development of depression and PTSD among paramedics in their early career. Screening and early interventions targeting poor sleep at the beginning of emergency employment may assist in reducing the risk of future mental health outcomes in this high-risk occupation.
Manipulation of Signal Gradient and Transcription Factors Recapitulates: Multiple Hypothalamic Identities
Authors: Yamamoto Maho , Ong Agnes Lee Chen , Shinozuka Takuma , Shirai Manabu , Sasai Noriaki
Published: March 2023

During development, the hypothalamus emerges from the ventral diencephalon and is regionalized into several distinct functional domains. Each domain is characterized by a different combination of transcription factors, including Nkx2.1, Nkx2.2, Pax6, and Rx, which are expressed in the presumptive hypothalamus and its surrounding regions, and play critical roles in defining each area.

Here, we recapitulated the molecular networks formed by the gradient of Sonic Hedgehog (Shh) and the aforementioned transcription factors. Using combinatorial experimental systems of directed neural differentiation of mouse embryonic stem (ES) cells, as well as a reporter mouse line and gene overexpression in chick embryos, we deciphered the regulation of transcription factors by different Shh signal intensities. We then used CRISPR/Cas9 mutagenesis to demonstrate the mutual repression between Nkx2.1 and Nkx2.2 in a cell-autonomous manner; however, they induce each other in a non-cell-autonomous manner. Moreover, Rx resides upstream of all these transcription factors and determines the location of the hypothalamic region. Our findings suggest that Shh signaling and its downstream transcription network are required for hypothalamic regionalization and establishment.
Utility of Inter-Frequency Amplitude Ratio of Vestibular-Evoked Myogenic Potentials in Identifying Meniere’s Disease: A Systematic Review and Meta-Analysis
Authors: Singh Niraj Kumar , Kumar Prawin , Jagadish Nirmala , Mendhakar Akshay , Mahajan Yatin
Published: March 2023

Objectives:

A recently devised parameter of vestibular-evoked myogenic potential (VEMP) based on the principles of frequency tuning is the inter-frequency amplitude ratio (IFAR). It refers to the ratio of the amplitude of 1000 Hz tone burst evoked VEMP to 500 Hz evoked tone burst. A pathology like Meniere’s disease changes the frequency response and alters the frequency tuning of the otolith organs. Because IFAR is based on the principle of frequency tuning of VEMP, it is likely to help identify Meniere’s disease. Few studies in the last decade have investigated the utility of IFAR in identifying Meniere’s disease. However, a systematic review and a meta-analysis on IFAR in Meniere’s disease are lacking. The present study investigates whether the IFAR of VEMP helps identify Meniere’s disease and differentiates it from healthy ears and other vestibular pathologies.

Design:

The present study is a systematic review and a meta-analysis. The studies investigating the IFAR of cervical and ocular VEMPs in Meniere’s disease, healthy controls, and other vestibular pathologies were searched across research databases such as PubMed, Science Direct, and Scopus. The search strategy was developed using the PICO (population, intervention, comparison, and outcomes) format, and Medical Subject Headings (MeSH) terms and Boolean operators were employed. The systematic review was performed using the Rayyan software, whereas the Review Manager software was used to carry out the meta-analysis. A total of 16,605 articles were retrieved from the databases. After the duplicate removal, 2472 articles remained. These were eliminated using title screening, abstract screening, and full-length inspections. A total of nine articles were found eligible for quality assessment and meta-analysis, and the New Castle-Ottawa Scale was used for quality assessment. After the data extraction, 24 six articles were found to have the desired data format for the meta-analysis.

Results:

The results showed significantly higher IFAR in the affected ears of individuals in the Meniere’s disease group than in the control group’s unaffected ears. There was no significant difference between the unaffected ears of individuals in the Meniere’s disease group and the ears of the control group. The only study on Meniere’s disease and benign paroxysmal positional vertigo found significantly larger ocular VEMP IFAR in ears with Meniere’s disease than in benign paroxysmal positional vertigo.

Conclusions:

This systematic review and meta-analysis found IFAR efficient in differentiating Meniere’s disease from healthy controls. We also found an enhanced IFAR as a potential marker for Meniere’s disease. However, more investigations are needed to confirm the utility of an enhanced IFAR value in the exclusive identification of Meniere’s disease.
Effect of Implant Linkage on Axial and Rotational Stiffness of Nail–Plate Constructs for Comminuted Distal Femoral Fractures
Authors: Lin Charles C. , Parody Nicholas , Anil Utkarsh , Egol Kenneth A.
Published: March 2023

Objectives:

To determine the effect of linking the intramedullary nail and the laterally applied locking plate to treat comminuted distal femur fractures and allow for immediate weight bearing.

Methods:

Comminuted extra-articular distal femur fractures were created in 16 synthetic osteoporotic femurs and split into 2 groups: linked versus unlinked. In the linked construct, in addition to standard plate fixation and proximal locking of the nail, 2 nonthreaded locking bolts (prototypes) were placed through both the plate and the nail. In the unlinked construct, the same number of screws affixed the plate to the bone but were directed around the nail, and separate distal interlocking screws were placed for nail fixation. Each specimen underwent sequential axial and torsional loading, and axial and torsional stiffness were calculated and compared.

Results:

On average, the unlinked constructs demonstrated a greater axial stiffness at all levels of axial loading, and linked constructs demonstrated greater average rotational stiffness. However, there were no statistically significant differences (P > 0.189) between the linked and unlinked groups at any axial or torsional load.

Conclusion:

In distal femur fractures with metaphyseal comminution, there were no significant differences in axial or torsional stiffness when linking the plate to the nail. Linking the construct seems to provide no significant mechanical advantage compared with the unlinked environment, but it may be a useful strategy to reduce nail “traffic” in the distal segment with no significant disadvantage.
Serial Urinary C-C Motif Chemokine Ligand 14 and Risk of Persistent Severe Acute Kidney Injury
Authors: Prowle John R. , Artigas Antonio , Bagshaw Sean M. , Forni Lui G. , Heung Michael , Hoste Eric , Marlies Ostermann , Koyner Jay L. , Chawla Lakmir , Kampf J. Patrick , Kwan Thomas , McPherson Paul , Kellum John A. ,   for the Sapphire and Ruby Investigators
Published: March 2023

OBJECTIVES:

To assess the added prognostic value of serial monitoring of urinary C-C motif chemokine ligand 14 (uCCL14) over that of single measurements, which have been shown to be prognostic for development of persistent severe acute kidney injury (AKI) in critically ill patients.

DESIGN:

Retrospective observational study.

SETTING:

Data derived from two multinational ICU studies (Ruby and Sapphire).

PATIENTS:

Critically ill patients with early stage 2–3 AKI.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We analyzed three consecutive uCCL14 measurements at 12-hour intervals after diagnosis of stage 2–3 AKI by Kidney Disease Improving Global Outcomes criteria. Primary outcome was persistent severe AKI, defined as 72 consecutive hours of stage 3 AKI, death, or receipt of dialysis prior to 72 hours. uCCL14 was measured using the NEPHROCLEAR uCCL14 Test on the Astute 140 Meter (Astute Medical, San Diego, CA). Based on predefined, validated cutoffs, we categorized uCCL14 as: low (≤ 1.3 ng/mL), medium (> 1.3 to ≤ 13 ng/mL), or high (> 13 ng/mL). Seventy-five of 417 patients with three consecutive uCCL14 measurements developed persistent severe AKI. Initial uCCL14 category strongly correlated with primary endpoint and, in most cases (66%), uCCL14 category was unchanged over the first 24 hours. Compared with no change and accounting for baseline category, decrease in category was associated with decreased odds of persistent severe AKI (odds ratio [OR], 0.20; 95% CI, 0.08–0.45; p < 0.001) and an increase in category with increased odds (OR, 4.04; 95% CI, 1.75–9.46; p = 0.001).

CONCLUSIONS:

In one-third of patients with moderate to severe AKI uCCL14 risk category altered over three serial measurements and such changes were associated with altered risk for persistent severe AKI. Serial CCL-14 measurement may detect progression or resolution of underlying kidney pathology and help refine AKI prognosis.
Hemorrhage, Disseminated Intravascular Coagulopathy, and Thrombosis Complications Among Critically Ill Patients with COVID-19: An International COVID-19 Critical Care Consortium Study*
Authors: Fanning Jonathon P. , Weaver Natasha , Fanning Robert B. , Griffee Matthew J. , Cho Sung-Min , Panigada Mauro , Obonyo Nchafatso G. , Zaaqoq Akram M. , Rando Hannah , Chia Yew Woon , Fan Bingwen Eugene , Sela Declan , Chiumello Davide , Coppola Silvia , Labib Ahmed , Whitman Glenn J. R. , Arora Rakesh C. , Kim Bo S. , Motos Anna , Torres Antoni , Barbé Ferran , Grasselli Giacomo , Zanella Alberto , Etchill Eric , Usman Asad Ali , Feth Maximilian , White Nicole M. , Suen Jacky Y. , Li Bassi Gianluigi , Peek Giles J. , Fraser John F. , Dalton Heidi ,   on behalf of the COVID-19 Critical Care Consortium
Published: March 2023

OBJECTIVES:

To determine the prevalence and outcomes associated with hemorrhage, disseminated intravascular coagulopathy, and thrombosis (HECTOR) complications in ICU patients with COVID-19.

DESIGN:

Prospective, observational study.

SETTING:

Two hundred twenty-nine ICUs across 32 countries.

PATIENTS:

Adult patients (≥ 16 yr) admitted to participating ICUs for severe COVID-19 from January 1, 2020, to December 31, 2021.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

HECTOR complications occurred in 1,732 of 11,969 study eligible patients (14%). Acute thrombosis occurred in 1,249 patients (10%), including 712 (57%) with pulmonary embolism, 413 (33%) with myocardial ischemia, 93 (7.4%) with deep vein thrombosis, and 49 (3.9%) with ischemic strokes. Hemorrhagic complications were reported in 579 patients (4.8%), including 276 (48%) with gastrointestinal hemorrhage, 83 (14%) with hemorrhagic stroke, 77 (13%) with pulmonary hemorrhage, and 68 (12%) with hemorrhage associated with extracorporeal membrane oxygenation (ECMO) cannula site. Disseminated intravascular coagulation occurred in 11 patients (0.09%). Univariate analysis showed that diabetes, cardiac and kidney diseases, and ECMO use were risk factors for HECTOR. Among survivors, ICU stay was longer (median days 19 vs 12;p< 0.001) for patients with versus without HECTOR, but the hazard of ICU mortality was similar (hazard ratio [HR] 1.01; 95% CI 0.92–1.12;p= 0.784) overall, although this hazard was identified when non-ECMO patients were considered (HR 1.13; 95% CI 1.02–1.25;p= 0.015). Hemorrhagic complications were associated with an increased hazard of ICU mortality compared to patients without HECTOR complications (HR 1.26; 95% CI 1.09–1.45;p= 0.002), whereas thrombosis complications were associated with reduced hazard (HR 0.88; 95% CI 0.79–0.99,p= 0.03).

CONCLUSIONS:

HECTOR events are frequent complications of severe COVID-19 in ICU patients. Patients receiving ECMO are at particular risk of hemorrhagic complications. Hemorrhagic, but not thrombotic complications, are associated with increased ICU mortality.
Real-Time Ultrasound Guidance as Compared With Landmark Technique for Subclavian Central Venous Cannulation: A Systematic Review and Meta-Analysis With Trial Sequential Analysis*
Authors: Zawadka Mateusz , La Via Luigi , Wong Adrian , Olusanya Olusegun , Muscarà Liliana , Continella Carlotta , Andruszkiewicz Pawel , Sanfilippo Filippo
Published: March 2023

OBJECTIVES:

We conducted a systematic review and meta-analysis to assess the effectiveness of real-time dynamic ultrasound-guided subclavian vein cannulation as compared to landmark technique in adult patients.

DATA SOURCES:

PubMed and EMBASE until June 1, 2022, with the EMBASE search restricted to the last 5 years.

STUDY SELECTION:

We included randomized controlled trials (RCTs) comparing the two techniques (real-time ultrasound-guided vs landmark) for subclavian vein cannulation. The primary outcomes were overall success rate and complication rate, whereas secondary outcomes included success at first attempt, number of attempts, and access time.

DATA EXTRACTION:

Independent extraction by two authors according to prespecified criteria.

DATA SYNTHESIS:

After screening, six RCTs were included. Two further RCTs using a static ultrasound-guided approach and one prospective study were included in the sensitivity analyses. The results are presented in the form of risk ratio (RR) or mean difference (MD) with 95% CI. Real-time ultrasound guidance increased the overall success rate for subclavian vein cannulation as compared to landmark technique (RR = 1.14; [95% CI 1.06–1.23]; p = 0.0007; I
2 = 55%; low certainty) and complication rates (RR = 0.32; [95% CI 0.22–0.47]; p < 0.00001; I
2 = 0%; low certainty). Furthermore, ultrasound guidance increased the success rate at first attempt (RR = 1.32; [95% CI 1.14–1.54]; p = 0.0003; I
2 = 0%; low certainty), reduced the total number of attempts (MD = –0.45 [95% CI –0.57 to –0.34]; p < 0.00001; I
2 = 0%; low certainty), and access time (MD = –10.14 s; [95% CI –17.34 to –2.94]; p = 0.006; I
2 = 77%; low certainty). The Trial Sequential Analyses on the investigated outcomes showed that the results were robust. The evidence for all outcomes was considered to be of low certainty.

CONCLUSIONS:

Real-time ultrasound-guided subclavian vein cannulation is safer and more efficient than a landmark approach. The findings seem robust although the evidence of low certainty.
Surgical resection for a huge right ventricular hemangioma
Authors: Yang Jen Chen , Chen I Chen , Chang Chung Yi , Wei Jeng
Published: March 2023

Cardiac hemangiomas are particularly rare entities, are often asymptomatic, and are often merely observed because of its slow growth and benign nature. We report a 52-year-old male patient who presented with exercise intolerance and chest discomfort due to the mass effect of a large 14 × 10 × 6-cm epicardial hemangioma. The tumor arose from the recess between the aorta and main pulmonary artery and featured a prominent feeding artery from the right coronary artery. The tumor was successfully resected, and pathology confirmed the diagnosis of cavernous hemangioma. We review the clinical features, imaging characteristics, pathological findings, and prognosis of cardiac hemangiomas.
Cognitive Behavioral Therapy Enhances Survival in Cardiac Patients Aged Under 60
Authors: Murphy Barbara M. , Navaratnam Hema S. , Le Grande Michael R. , Higgins Rosemary O. , Rogerson Michelle C. , Elliott Peter , Worcester Marian U. C. , Jackson Alun C.
Published: March 2023

Purpose:

To optimize recovery and improve prognosis, people who have had an acute cardiac event (ACE) need support to manage their cardiac risk. In 2008, we conducted a randomized controlled trial (RCT) of Beating Heart Problems (BHP), an 8-wk group program based on cognitive behavioral therapy (CBT) and motivational interviewing (MI), designed to improve behavioral and mental health. This study investigated 14-yr mortality status for RCT participants in order to evaluate the survival impact of the BHP program.

Methods:

In 2021, mortality data on 275 participants from the earlier RCT were obtained from the Australian National Death Index. Survival analysis was undertaken to investigate differences in survival for participants in the treatment and control groups.

Results:

Over the 14-yr follow-up period, there were 52 deaths (18.9%). For those aged <60 yr, there was a significant survival benefit to program participation, with 3% deaths in the treatment group and 13% deaths in the control group (P = .022). For those aged ≥60 yr, the death rate was identical in both groups (30%). Other significant predictors of mortality included older age, higher 2-yr risk score, lower functional capacity, lower self-rated health, and having no private health insurance.

Conclusions:

Participation in the BHP conferred a survival benefit for patients aged <60 yr but not for participants overall. The findings highlight the long-term benefit of behavioral and psychosocial management of cardiac risk through CBT and MI for those who are younger at the time of their first ACE.
Oxygen Uptake Efficiency Slope in South American Healthy Adults
Authors: Milani Juliana Goulart Prata Oliveira , Milani Mauricio , Cipriano Graziella França Bernardelli , de Castro Isac , Hansen Dominique , Cipriano Junior Gerson
Published: March 2023

Purpose:

The purpose of this study is to provide comprehensive reference values for oxygen uptake efficiency slope (OUES) in healthy adults. International heterogeneity was also explored through published databases.

Methods:

A cross-sectional study was conducted with treadmill cardiopulmonary exercise testing (CPX) from a Brazilian healthy adult sample, in which absolute OUES and values normalized by weight and body surface area (BSA) were calculated. Data were stratified by sex and age group. Prediction equations were calculated using age and anthropometric variables. International data were pooled and differences were explored using factorial analysis of variance or thettest, as appropriate. The OUES age-related patterns were calculated using regression analysis.

Results:

A total of 3544 CPX were included (1970 males and 1574 females) and the age ranged from 20-80 yr. Males had higher values than females for OUES, OUES/kg, and OUES/BSA. Lower values were found with aging and the data followed a quadratic regression curve. Reference value tables and predictive equations were provided for absolute and normalized OUES in both sexes. International comparisons of absolute OUES values among Brazilian, European, and Japanese data revealed substantial heterogeneity. The OUES/BSA measure minimized the discrepancies between Brazilian and European data.

Conclusions:

Our study provided comprehensive OUES reference values in a large healthy adult sample from South America with a wide age range and included absolute and normalized values. Differences observed between Brazilian and European data were reduced in the BSA-normalized OUES.
Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation
Authors: de Carvalho Ribeiro Marcelle , Iracheta-Vellve Arvin , Babuta Mrigya , Calenda Charles D. , Copeland Christopher , Zhuang Yuan , Lowe Patrick P. , Hawryluk Danielle , Catalano Donna , Cho Yeonhee , Barton Bruce , Dasarathy Srinivasan , McClain Craig , McCullough Arthur J. , Mitchell Mack C. , Nagy Laura E. , Radaeva Svetlana , Lien Egil , Golenbock Douglas T. , Szabo Gyongyi
Published: March 2023

Background & Aims:

Prolonged systemic inflammation contributes to poor clinical outcomes in severe alcohol-associated hepatitis (AH) even after the cessation of alcohol use. However, mechanisms leading to this persistent inflammation remain to be understood.

Approach & Results:

We show that while chronic alcohol induces nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in the liver, alcohol binge results not only in NLRP3 inflammasome activation but also in increased circulating extracellular apoptosis-associated speck-like protein containing a caspase recruitment domain (ex-ASC) specks and hepatic ASC aggregates both in patients with AH and in mouse models of AH. These ex-ASC specks persist in circulation even after the cessation of alcohol use. Administration of alcohol-induced–ex-ASC specks in vivo in alcohol-naive mice results in sustained inflammation in the liver and circulation and causes liver damage. Consistent with the key role of ex-ASC specks in mediating liver injury and inflammation, alcohol binge failed to induce liver damage or IL-1β release in ASC-deficient mice. Our data show that alcohol induces ex-ASC specks in liver macrophages and hepatocytes, and these ex-ASC specks can trigger IL-1β release in alcohol-naive monocytes, a process that can be prevented by the NLRP3 inhibitor, MCC950. In vivo administration of MCC950 reduced hepatic and ex-ASC specks, caspase-1 activation, IL-1β production, and steatohepatitis in a murine model of AH.

Conclusions:

Our study demonstrates the central role of NLRP3 and ASC in alcohol-induced liver inflammation and unravels the critical role of ex-ASC specks in the propagation of systemic and liver inflammation in AH. Our data also identify NLRP3 as a potential therapeutic target in AH.
Influence of Personal and Injury-Related Factors Predicting Deficits in Quality of Life Domains Among Pediatric Athletes: Findings From the Sport Concussion Outcomes in Pediatrics Study
Authors: Valovich McLeod Tamara C. , Snedden Traci , Halstead Mark , Wilson Julie , Master Christina , Grady Matthew , Fazekas Matthew , Santana Jonathan , Zaslow Tracy , Miller Shane , Coel Rachel , Howell David R. ,   The PRiSM Concussion Research Interest Group
Published: March 2023

Objective:

To examine patient and injury factors that may predict quality of life (QoL) and symptom duration after concussion.

Design:

Prospective, longitudinal.

Settings:

Six children's hospital-based medical centers and 9 secondary school athletic training facilities.

Patients:

Pediatric patients (8-18 years) were enrolled as part of the Sport Concussion Outcomes in Pediatrics (SCOPE) study during their initial visit for a diagnosis of sport-related concussion.

Interventions:

Patients completed a medical history, the Postconcussion Symptom Inventory (PCSI), and Patient-Reported Outcomes Measurement Information System Pediatric Profile-25 (PROMIS-PP).

Main Outcome Measures:

Eight predictor variables [age, sex, assessment time, loss of consciousness, amnesia and history of concussion, migraines, or attention-deficit hyperactivity disorder or (ADHD)] were assessed using regression models constructed for each dependent variable.

Results:

A total of 244 patients (15.1 ± 2.1 years, 41% female) were enrolled (mean = 5 ± 3 days after concussion; range = 1-14 days). Female sex, later initial assessment, and presence of amnesia were associated with lower QoL scores on several domains, whereas loss of consciousness was associated with higher QoL for fatigue. A history of migraines was associated with lower peer relationship QoL. Patients who subsequently developed persisting symptoms had lower mobility scores and higher anxiety, depressive symptom, fatigue, and pain interference scores.

Conclusions:

Female sex, later clinic presentation, and amnesia were associated with a lower QoL related to mobility, anxiety, depressive symptoms, fatigue, and pain interference. Interestingly, previous concussion and preinjury ADHD diagnosis did not negatively impact postinjury QoL at the initial visit. Future studies should assess the influence of these factors on QoL at later postinjury time points using a concussion-specific outcomes instrument.