bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethanol-Mediated Novel Survival Strategy against Drought Stress in Plants
Authors: Bashir Khurram , Todaka Daisuke , Rasheed Sultana , Matsui Akihiro , Ahmad Zarnab , Sako Kaori , Utsumi Yoshinori , Vu Anh Thu , Tanaka Maho , Takahashi Satoshi , Ishida Junko , Tsuboi Yuuri , Watanabe Shunsuke , Kanno Yuri , Ando Eigo , Shin Kwang-Chul , Seito Makoto , Motegi Hinata , Sato Muneo , Li Rui , Kikuchi Saya , Fujita Miki , Kusano Miyako , Kobayashi Makoto , Habu Yoshiki , Nagano Atsushi J , Kawaura Kanako , Kikuchi Jun , Saito Kazuki , Hirai Masami Yokota , Seo Mitsunori , Shinozaki Kazuo , Kinoshita Toshinori , Seki Motoaki
Published: August 2022

Water scarcity is a serious agricultural problem causing significant losses to crop yield and product quality. The development of technologies to mitigate the damage caused by drought stress is essential for ensuring a sustainable food supply for the increasing global population. We herein report that the exogenous application of ethanol, an inexpensive and environmentally friendly chemical, significantly enhances drought tolerance in Arabidopsis thaliana, rice and wheat. The transcriptomic analyses of ethanol-treated plants revealed the upregulation of genes related to sucrose and starch metabolism, phenylpropanoids and glucosinolate biosynthesis, while metabolomic analysis showed an increased accumulation of sugars, glucosinolates and drought-tolerance-related amino acids. The phenotyping analysis indicated that drought-induced water loss was delayed in the ethanol-treated plants. Furthermore, ethanol treatment induced stomatal closure, resulting in decreased transpiration rate and increased leaf water contents under drought stress conditions. The ethanol treatment did not enhance drought tolerance in the mutant of ABI1, a negative regulator of abscisic acid (ABA) signaling in Arabidopsis, indicating that ABA signaling contributes to ethanol-mediated drought tolerance. The nuclear magnetic resonance analysis using 13C-labeled ethanol indicated that gluconeogenesis is involved in the accumulation of sugars. The ethanol treatment did not enhance the drought tolerance in the aldehyde dehydrogenase (aldh) triple mutant (aldh2b4/aldh2b7/aldh2c4). These results show that ABA signaling and acetic acid biosynthesis are involved in ethanol-mediated drought tolerance and that chemical priming through ethanol application regulates sugar accumulation and gluconeogenesis, leading to enhanced drought tolerance and sustained plant growth. These findings highlight a new survival strategy for increasing crop production under water-limited conditions.
Data Medicine: ‘Broad’ or ‘Dynamic’ Consent?
Authors: Stoeklé Henri-Corto , Hulier-Ammar Elisabeth , Hervé Christian
Published: August 2022

The General Data Protection Regulation imposes, at European level, a need to seek express or explicit consent for the processing of health data. In the framework of biomedical research, some favor the use of express ‘broad’ consent, whereas other maintain, or wish to maintain the use of presumed or implicit consent, often referred to as ‘non-opposition’ in conditions in which such consent is still authorized. In our view, broad consent and presumed consent are likely to prove to be easy solutions in the short term but much less relevant in the long term, for both hospital and patients, if the bioethical objective remains the improvement of patient quality of life and/or survival, regardless of the disease considered. Dynamic consent could be the best way to achieve this objective because only this type of consent could improve hospital transparency and increase patient confidence by allaying certain fears.
Vascular endothelial growth factor from retinal pigment epithelium is essential in choriocapillaris and axial length maintenance
Authors: Zhang Yan , Jeong Heonuk , Mori Kiwako , Ikeda Shin-Ichi , Shoda Chiho , Miwa Yukihiro , Nakai Ayaka , Chen Junhan , Ma Ziyan , Jiang Xiaoyan , Torii Hidemasa , Kubota Yoshiaki , Negishi Kazuno , Kurihara Toshihide , Tsubota Kazuo
Published: August 2022

Myopia, which prevalence is rapidly increasing, causes visual impairment; however, the onset mechanism of pathological axial length (AL) elongation remains unclear. A highly vascularized choroid between the retinal pigment epithelium (RPE) and sclera not only maintains physiological activities, but also contributes to ocular development and growth regulation. Vascular endothelial growth factor (VEGF) secreted from the RPE to the choroid is essential for retinal function and maintenance of the choriocapillaris. Herein, we demonstrated that the loss of VEGF secreted from the RPE caused abnormal choriocapillaris development and AL elongation, with features similar to those of the lens-induced myopia (LIM) mouse model, whereas VEGF overexpression by knocking-out von Hippel–Lindau (VHL) specific to the RPE expands the choriocapillaris and shortens the AL. Additionally, LDL Receptor Related Protein 2 (LRP2) deletion in the RPE downregulated VEGF expression and leads to pathological AL elongation. Furthermore, high-myopia patients without choriocapillaris demonstrated longer ALs than did those with preserved choriocapillaris. These results suggest that physiological secretion of VEGF from the RPE is required for proper AL development by maintaining the choriocapillaris. The pinpoint application of VEGF to the choriocapillaris may become a potential intervention for the prevention and treatment of axial myopia progression.
Memory and Probability
Authors: Bordalo Pedro , Conlon John J , Gennaioli Nicola , Kwon Spencer Y , Shleifer Andrei
Published: August 2022

In many economic decisions, people estimate probabilities, such as the likelihood that a risk materializes or that a job applicant will be a productive employee, by retrieving experiences from memory. We model this process based on two established regularities of selective recall: similarity and interference. We show that the similarity structure of a hypothesis and the way it is described (not just its objective probability) shape the recall of experiences and thus probability assessments. The model accounts for and reconciles a variety of empirical findings, such as overestimation of unlikely events when these are cued versus neglect of noncued ones, the availability heuristic, the representativeness heuristic, conjunction and disjunction fallacies, and over- versus underreaction to information in different situations. The model yields several new predictions, for which we find strong experimental support.
Meso-scale method of asymptotic analysis of elastic vibrations in periodic and non-periodic multi-structures
Authors: Nieves M J , Movchan A B
Published: August 2022

The method of meso-scale asymptotic approximations has proved to be very effective for the analysis of models of solids containing large clusters of defects, such as small inclusions or voids. Here, we present a new avenue where the method is extended to elastic multi-structures. Geometrically, a multi-structure makes a step up in the context of overall dimensions, compared to the dimensions of its individual constituents. The main mathematical challenge comes from the analysis of the junction regions assigned to the multi-structure itself. Attention is given to problems of vibration and on the coupling of vibration modes corresponding to displacements of different orientations. The method is demonstrated through the dynamic analysis of infinite or finite multi-scale asymmetric flexural systems consisting of a heavy beam connected to a non-periodic array of massless flexural resonators within some interval. In modelling the interaction between the beam and the resonators, we derive a vectorial system of partial differential equations through which the axial and flexural motions of the heavy beam are coupled. The solution of these equations is written explicitly in terms of Green’s functions having intensities determined from a linear algebraic system. The influence of the resonators on the heavy beam is investigated within the framework of scattering and eigenvalue problems. For large collections of resonators, dynamic homogenization approximations for the medium within the location of the resonant array are derived, leading to (i) the classical Rayleigh beam for symmetric systems and (ii) a generalized Rayleigh beam for asymmetric structures that support flexural–longitudinal wave coupling. Independent numerical simulations are also presented that demonstrate the accuracy of the analytical results.
A Longitudinal Study of Semantic Networks in Schizophrenia and other Psychotic Disorders Using the Word Association Task
Authors: Pintos Andrea Stephanie , Hui Christy Lai-Ming , De Deyne Simon , Cheung Charlton , Ko Wai Tung , Nam Suen Yi , Chan Sherry Kit-Wa , Chang Wing-Chung , Lee Edwin Ho-Ming , Lo Alison Wai-Fan , Lo Tak-Lam , Elvevåg Brita , Chen Eric Yu-Hai
Published: August 2022

The underpinnings of language deviations in psychotic symptoms (eg, formal thought disorder, delusions) remain unclear. We examined whether the semantic networks underlying word associations are useful predictors of clinical outcomes in psychosis. Fifty-one patients with schizophrenia and other psychotic disorders and 51 matched healthy controls generated words in a Cantonese continued word association task. Patterns of word associations were examined using semantic similarity metrics derived from word embeddings (fastText) and the structure of individual semantic networks. A longitudinal design—baseline and 6 months later—enabled investigation of the relationship of changes in semantic associations in patients who were in an acute psychotic state at baseline compared to clinical stabilization 6 months later. The semantic similarity measure increased over time in patients, while it remained stable in controls. Moreover, the change in semantic similarity over time correlated with the changes in patients’ formal thought disorder symptoms. There were differences in individual semantic networks between the groups at both time points. Patients had less structured networks on average, as evidenced by a smaller network diameter and clustering coefficient, and smaller average shortest path lengths. The identification of several state-like semantic measures that change over time with patients’ mental states allows for nuanced comparison with clinical measures. Semantic measures are complex. Semantic similarity was a state-like measure that changed over time with mental state in psychotic disorders, whereas individual semantic network parameters were trait-like and stable over time.
The role of protectors: a UK perspective
Authors: Harney Patrick , McCallum Marie
Published: August 2022

Absent from English statute, trust protectors are notoriously ill-defined, and that term can take on vastly different meanings between jurisdictions, and between trust instruments. Protector problems are a more frequent feature in offshore trust litigation, in particular regarding the precise nature of protector powers, and whether these should be defined as fiduciary, personal or otherwise. In this article, we explore the UK perspective on the use and incorporation of trust protectors, in comparison to their use in the traditional offshore jurisdictions where they are particularly prevalent, and seemingly only increasing in stature and power, at times exercising genuinely discretionary review functions and sometimes holding powers that exceed those of their trustees. Different interpretations of the key protector power of veto are also explored, with reference to the recent alternate findings on this issue between the Jersey Courts in Piedmont and Riviera Trusts [2021] and the Supreme Court of Bermuda in Re the X Trusts [2021].
Evaluation of feeding ruminal-protected folate and cobalt pectinate on growth performance, carcass characteristics and plasma vitamin B12 and folate status in finishing beef steers
Authors: Word Alyssa B , Holland Ben P , Karr Kendall J , Socha Michael T , Kending Cory , Branine Mark E
Published: August 2022

A large pen feedlot study was conducted to evaluate the response of yearling steers fed novel sources of rumen-protected folate (RPFA) and cobalt (cobalt pectinate; Co-PECT) on plasma levels of vitamin B12 and folate, growth performance, and carcass characteristics. A total of 2,100 steers (initial BW = 381 ± 45.2 kg.) were enrolled in the study at the time of randomization with 2,091 steers started on treatment diets following the transition to the finishing diet. A generalized randomized block design with sampling error (GRBD) with two treatments and 15 pen replications per treatment (5 blocks × 6 pens/block; 30 pens total with 70 steers/pen) were evaluated with pen serving as the experimental unit. A control (CON) treatment consisted of the standard finishing diet while the test diet consisted of the standard finishing diet providing 3.0 mg ∙ kg−1 DM of RPFA and 1.0 mg ∙ kg−1 DM total supplemental cobalt with approximately half coming from Co-PECT (TEST). Blood samples were collected from 60 randomly selected steers at study initiation and prior to shipping for plasma B12 and folate measurement. Data were analyzed with the model including fixed effects of treatment, block, and treatment within block interaction. Live growth performance was not affected by treatment; however, carcass-adjusted performance and hot carcass weight were numerically improved by TEST in 3 of the 5 blocks (treatment × within block interaction, P ≤ 0.03) of cattle. Plasma levels for both folic acid and vitamin B12 were extremely low at study initiation and increased over the course of the feeding period. Feeding TEST increased (P < 0.01) plasma B12 levels compared to CON by the completion of the trial; however, mean levels would still be considered marginal. Plasma folate was lower (P < 0.05) in TEST steers at the beginning of the study, with no difference between treatments by the time cattle were shipped. Results suggested that cattle coming into the feedlot may be of low or marginal status in both plasma folate and vitamin B12. While the status of folate and B12 improved in both CON and TEST with days on feed, providing RPFA and Co-PECT further helped improve vitamin B12 status; although, overall levels remained low, which may have affected the overall response to RPFA. Additional research is required to better understand the role of B vitamin supplementation for growing-finishing feedlots and develop methods for assessing the status and improving potential responses.
A tale of two bellies: systematics of the oval frogs (Anura: Microhylidae:Elachistocleis)
Authors: Novaes-e-Fagundes Gabriel , Lyra Mariana L , Loredam Vinicius S A , Carvalho Thiago R , Haddad Célio F B , Rodrigues Miguel T , Baldo Diego , Barrasso Diego A , Loebmann Daniel , Ávila Robson W , Brusquetti Francisco , Prudente Ana L C , Wheeler Ward C , Goyannes Dill Orrico Victor , Peloso Pedro
Published: August 2022

Oval frogs (Elachistocleis) have a broad geographic distribution covering nearly all of South America and parts of Central America. They also have a large inter- and intraspecific variation of the few morphological characters commonly used as diagnostic traits among species of the genus. Based on molecular data, we provide the most complete phylogeny of Elachistocleis to date, and explore its genetic diversity using distance-based and tree-based methods for putative species delimitation. Our results show that at least two of the most relevant traditional characters used in the taxonomy of this group (belly pattern and dorsal median white line) carry less phylogenetic information than previously thought. Based on our results, we propose some synonymizations and some candidate new species. This study is a first major step in disentangling the current systematics of Elachistocleis. Yet, a comprehensive review of morphological data is needed before any new species descriptions can be properly made.
Phylogenetic analysis of the predatory plant bug subfamily Deraeocorinae (Hemiptera: Heteroptera: Miridae) based on molecular and morphological data
Authors: Kim Junggon , Cassis Gerasimos , Jung Sunghoon
Published: August 2022

The first comprehensive phylogenetic analyses of the plant bug subfamily Deraeocorinae is presented. A total of 86 morphological characters and 3899 base pairs of mitochondrial (16S, COI) and nuclear (18S, 28S) sequences were analysed separately for each partition and combined datasets, using parsimony, maximum likelihood and Bayesian inference. The fossil species Amberderaeous gigophthalmusKim, Taszakowski & Jung, 2020 was analysed in the morphological and combined datasets in order to assess its systematic position. The phylogenetic results revealed that Deraeocorinae as presently constituted is not monophyletic, with the tribe Termatophylini nested separately to the other deraeocorine supraspecific lineages analysed. The remaining Deraeocorinae was found to be monophyletic as well as Clivinemini, Hyaliodini and Saturniomirini. Clivinemini + Saturniomirini is the sister group of the remaining Deraeocorinae. Deraeocorini, which is the most diverse tribe in the subfamily, was found to be non-monophyletic, with Surinamellini nested within it. Based on the results, we proposed that the clade including the questionably placed taxa and a temporarily placed fossil taxon is synonymized from Surinamellini to Deraeocorini, and that Surinamellini is treated as paraphyletic. The nominate genus Deraeocoris s.l. was found to be non-monophyletic. Termatophylini was provisionally retained within Deraeocorinae, pending broader taxon sampling of Deraeocorinae and other mirid subfamilies.
Medication Initiation, Patient-directed Discharges, and Hospital Readmissions Before and After Implementing Guidelines for Opioid Withdrawal Management
Authors: Zavodnick Jillian , Heinsinger Nicolette M. , Lepore Angelo C. , Sterling Robert C.
Published: August 2022

Objectives

Rising rates of hospitalization for patients with opioid use disorder (OUD) result in high rates of patient-directed discharge (PDD, also called “discharge against medical advice”) and 30-day readmissions. Interdisciplinary addiction consult services are an emerging criterion standard to improve care for these patients, but these services are resource- and expertise-intensive. A set of withdrawal guidelines was developed to guide generalists in caring for patients with opioid withdrawal at a hospital without an addiction consult service.

Methods

Retrospective chart review was performed to determine PDD, 30-day readmission, and psychiatry consult rates for hospitalized patients with OUD during periods before (July 1, 2017, to March 31, 2018) and after (January 1, 2019, to July 31, 2019) the withdrawal guidelines were implemented. Information on the provision of opioid agonist therapy (OAT) was also obtained.

Results

Use of OAT in patients with OUD increased significantly after guideline introduction, from 23.3% to 64.8% (P < 0.001). Patient-directed discharge did not change, remaining at 14% before and after. Thirty-day readmissions increased 12.4% to 15.7% (P = 0.05065). Receiving any OAT was associated with increased PDD and readmission, but only within the postintervention cohort.

Conclusions

A guideline to facilitate generalist management of opioid withdrawal in hospitalized patients improved the process of care, increasing the use of OAT and decreasing workload on the psychiatry consult services. Although increased inpatient OAT has been previously shown to decrease PDD, in this study PDD and readmission rates did not improve. Guidelines may be insufficient to impact these outcomes.
Synthetic Cathinone–Induced Myocarditis and Psychosis: A Case Report
Authors: Lee Pei-Ying , Hsu Chun-Chi , Chan Chia-Hsiang
Published: August 2022

Psychoactive substances are a diverse group of chemical substances that are ever-evolving structurally. Novel psychoactive substances are being reported in and are becoming increasingly popular in East and Southeast Asia, with synthetic cathinones becoming the drugs of choice. The use of synthetic cathinones has increased significantly over the years. However, the easy accessibility of these substances and their potentially damaging health effects have raised many concerns. Herein, we present the case of a patient who ingested mixed synthetic cathinones and eventually developed acute myocarditis and subsequent psychotic symptoms. The delayed presentation of psychosis coupled with initial cardiovascular symptoms was a unique phenomenon, making differential diagnosis challenging. The association between the use of synthetic cathinones and psychosis and myocarditis should be explored in view of the lack of relevant clinical data and potentially dire outcomes.
Efficacy of Brief Interventions for Comorbid Substance Misuse in Patients on Opioid Agonist Treatment: A Systematic Review and Meta-analysis
Authors: Ghosh Abhishek , Kathiravan Sanjana , Singh Pranshu , Sharma Babita , Gupta Surabhi , Pillai Renjith R.
Published: August 2022

Background and Aims

Multiple substance use is a common but underrecognized problem in patients on opioid agonist treatment (OAT). Co-occurring substance misuse is associated with poor clinical and psychosocial outcomes. We aimed (a) to determine the effect of screening and brief intervention (SBI) for substance misuse in people on OAT and (b) to qualitatively summarize the implementation of SBI.

Methods

We performed a systematic review of clinical trials on the efficacy of SBI for alcohol and drug misuse in participants on OAT. We searched 5 electronic databases and included published studies and unpublished trials. We measured the standardized mean difference in substance risk scores before and after intervention. We also estimated the standardized mean difference in alcohol consumption per day before and after intervention.

Results

We included a total of 8 studies; 5 of these were included in the meta-analysis, and all were reviewed for narrative synthesis. We observed a significant change in the pre-post brief intervention substance risk scores with a medium effect size (Hedges g = 0.752, 95% confidence interval, 0.405–1.099). Sensitivity analyses with different pretest-posttest correlations did not change our result. Modest effects of SBI were found in reducing both alcohol and illicit drug risk scores, and among the population on methadone and buprenorphine treatment. We also observed a significant decrease in alcohol consumption per day 3 months after SBI. Studies showed a limited and incomplete screening for substance misuse and delivery of brief intervention in OAT settings.

Conclusions

Screening and brief intervention may be a potential treatment for co-occurring substance misuse among patients on OAT.
Identifying Barriers to Buprenorphine Treatment for Patients with Opioid Use Disorder Among Anesthesiologists and Pain Practitioners: A Survey Study
Authors: John Samuel , Boorman David W. , Potru Sudheer
Published: August 2022

Objective

The aim of the study is to investigate barriers to opioid use disorder (OUD) care among acute and chronic pain physicians and advanced practice providers, including hypothesized barriers of lack of interest in OUD care and stigma toward this patient population.

Methods

The study used an anonymous 16-item online survey through Google Forms. Respondents were 153 health practitioners across the United States and Canada, all of whom are registered in one of several pain or anesthesia professional societies. Data were analyzed with descriptive and categorical statistics.

Results

The most common barriers include “lack of appropriate clinical environment for prescribing by both acute and chronic pain practitioners” (48%) and “lack of administrative/departmental support” (46%). A total of 32% of respondents reported that OUD care was important but they were not interested in doing more, while 28% of practitioners believed that they treat patients with OUD differently than others in a negative way. More males reported “difficulty” in treating OUD as a barrier (45% vs 25%). Chronic pain practitioners reported poor payor mix as a barrier twice as often as their acute pain colleagues. In free response, lack of multidisciplinary OUD care was a notable barrier.

Conclusions

The top barriers to OUD treatment were clinical environment, departmental support, difficulty in treating the condition, and payor mix, supporting the hypotheses. Given an OUD patient scenario, 55% of acute pain physicians and 73% of chronic pain physicians expressed a willingness to prescribe buprenorphine.
Impact of Medicaid Expansion Under the Affordable Care Act on Receipt of Surgery for Breast Cancer
Authors: Elmore Leisha C. , Li Meng , Lin Heather , Shen Yu , Shaitelman Simona F. , Babiera Gildy , Tamirisa Nina , Bedrosian Isabelle
Published: August 2022

Objective:

To determine whether Medicaid expansion under the 2010 Affordable Care Act affected rates of breast cancer surgery.

Background:

Data regarding the impact of Medicaid expansion on access to surgical treatment of breast cancer are limited.

Methods:

Patients in the National Cancer Database diagnosed with non-metastatic breast cancer between January 1, 2010 and December 31, 2017 and residing in a state that expanded Medicaid in January 2014 or in a state that opted out of expansion were included. A quasi-experimental, difference-in-differences (DID) approach was used to assess rate of omission of surgical treatment.

Results:

Of 624,237 patients diagnosed with invasive breast cancer, 24,728 (4%) patients did not undergo surgical treatment. Overall, no significant differences in rates of omission of surgery over time were seen based on Medicaid expansion status. Significant findings were noted based on patient residential location. In rural areas, Medicaid expansion was associated with lower rates of omission of surgery (adjusted DID −2.47%, 95% confidence interval [CI] −4.01% to −0.94%; P = 0.002). In urban area, rates of omission of surgery increased over time for both groups, but the relative increase was lower in expansion states (adjusted DID −0.72%, 95% CI −1.25% to −0.20%; P = 0.007). In metro areas, changes in rates of surgery over time were comparable across expansion and non-expansion states (adjusted DID −0.08%, 95% CI −0.32% to 0.16%; P = 0.512).

Conclusions:

Medicaid expansion had no measurable effect on the receipt of surgery for breast cancer in the overall cohort. Medicaid expansion was associated with higher rates of surgery in rural areas, representing the minority of the population.
Risk of Acute Kidney Injury and Fracture-Related Infection After Antibiotic Prophylaxis With Piperacillin-Tazobactam in Open Fractures
Authors: McMurtrie Thompson , Cone Ryan J. , Mihas Alexander K. , Patch David A. , McGwin Gerald , Spitler Clay A.
Published: August 2022

Objectives:

To evaluate the effects of prophylactic piperacillin-tazobactam (PT) on inpatient acute kidney injury (AKI) and fracture-related infection (FRI) in patients with open fractures.

Setting:

The study was conducted at a Level 1 trauma center.

Patients:

We reviewed 358 Gustilo–Anderson type II and III open fractures at our institution from January 2013 to December 2017.

Intervention:

Administration of PT (the PT group) or antibiotics other than PT (the historical control group) during the first 48 hours of arrival for open fracture antibiotic prophylaxis.

Main Outcome Measurements:

The main outcome measurements were rates of inpatient AKI and FRI within six months after definitive fixation.

Results:

There were 176 patients in the PT group and 182 patients in the historical control group. The PT group had worse American Society of Anesthesiologists class (P = 0.004) and injury severity scores (P < 0.001), a higher average number of debridements before closure/coverage (P = 0.043), and higher rates of gross soil contamination (P = 0.049) and staged procedures (P = 0.008) compared with the historical control group.

There was no difference in the rate of AKI between the PT and historical control groups (5.7% vs. 2.7%, P = 0.166) nor when stratified by Gustilo–Anderson fracture classification (type II: 5.8% vs. 3.6%, P = 0.702; type III: 5.6% vs. 2.0%, P = 0.283). There was no significant difference in the rate of FRI between the PT and historical control groups (23.6% vs. 19.6%, P = 0.469).

Conclusion:

The use of PT in prophylactic antimicrobial treatment in patients with Gustilo–Anderson type II and III open fractures does not increase the rate of AKI or FRI. We believe PT can be used as an effective monotherapy in these patients without an increased risk of renal injury, but future investigations are necessary.

Level of Evidence:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Integrating new oral selective oestrogen receptor degraders in the breast cancer treatment
Authors: Garcia-Fructuoso Isabel , Gomez-Bravo Raquel , Schettini Francesco
Published: August 2022

Purpose of review

Oral SERDs are under extensive development to overcome fulvestrant main limitations, including intramuscular-only formulation and poor performance in early-stage hormone receptor-positive (HR+)/HER2-negative breast cancer. This review summarizes the most relevant evidence published so far and envisions the potential integration of oral SERDs in the therapeutic algorithm of HR+/HER2-negative metastatic breast cancer (MBC).

Recent findings

Amcenestrant and giredestrant, two of the most promising oral SERDs, recently failed to show a significant improvement in progression-free survival (PFS) in pivotal trials. Conversely, elacestrant demonstrated significant PFS superiority over standard-of-care endocrine therapy (aromatase inhibitors or fulvestrant) in MBC. Additionally, it did not show unusual side effects observed with other oral SERDs, like bradycardia, hematotoxicity and vision impairment, and proved to be effective also in case of ESR1-mutant endocrine-resistant breast cancer. Combination trials of oral SERDs with target agents, such as CDK4/6-inhibitors, are ongoing. Finally, some window-of-opportunity trials showed promising on-target activity in early-stage for this drug class.

Promising results from early-phase trials are not translating into sufficient clinical benefit in pivotal trials of main oral SERDs in monotherapy, except for elacestrant. Whether oral SERDs might become the backbone for combination strategies in MBC or the preferred (neo)adjuvant endocrine agents is under evaluation.
Circadian effect of time of anaesthesia on postoperative outcomes in major elective and urgent intervention: a secondary analysis of the Peri-interventional Outcome Study in the Elderly (POSE)
Authors: Hoogma Danny Feike , Al Tmimi Layth , Fieuws Steffen , Tournoy Jos , Kowark Ana , Rossaint Rolf , Coburn Mark , Rex Steffen
Published: August 2022

BACKGROUND

A recent prospective study reported a decrease in postoperative mortality when cardiac surgery was started in the afternoon instead of in the morning. In contrast, several large retrospective analyses have not confirmed this finding. Larger prospective studies are required to elucidate the effects of circadian rhythm on postoperative outcomes.

OBJECTIVE

To identify any relation between starting time of anaesthesia/surgery and postoperative outcomes in patients aged 80 years or older to aid in clinical decision making with regard to scheduling surgery.

DESIGN

A multivariable model with a priori defined confounders was constructed to evaluate the impact of anaesthesia starting time on hospital length of stay and postoperative complications.

SETTING

A European multicentre, observational study of outcomes after geriatric anaesthesia from October 2017 to December 2018.

PATIENTS

Patients aged 80 years or older having major elective or urgent intervention with anaesthesia starting time between 7 a.m. and 7 p.m.

MAIN OUTCOME MEASURE

Primary outcome measure was the difference in hospital length of stay after any major elective or urgent morning or afternoon intervention.

RESULTS

We included 3551 patients of whom 2592 had an intervention starting in the morning (7 a.m. to 1 p.m.). These patients, compared with those with interventions in the afternoon (1 p.m. to 7 p.m.), were slightly younger, were less frail but had a longer duration of the intervention. Hospital length of stay or postoperative complications were not different between morning or afternoon interventions. Multivariable analysis showed no impact of time of anaesthesia (morning vs. afternoon) on hospital length of stay or postoperative complications, hazard ratio of 1.03 (95% CI 0.94 to 1.12) and odds ratio of 1.13 (95% CI 0.92 to 1.39), respectively.

CONCLUSION

Our results do not support the hypothesis of circadian effects on postoperative outcomes for elective and urgent major interventions in patients at least 80 years of age.

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT03152734
Opioid deprescribing in patients with chronic noncancer pain: a systematic review of international guidelines
Authors: Hamilton Melanie , Kwok Wing S. , Hsu Arielle , Mathieson Stephanie , Gnjidic Danijela , Deyo Richard , Ballantyne Jane , Von Korff Michael , Blyth Fiona , Lin Chung-Wei Christine
Published: August 2022

In response to the overuse of prescription opioid analgesics, clinical practice guidelines encourage opioid deprescribing (ie, dose reduction or cessation) in patients with chronic noncancer pain. Therefore, this study evaluated and compared international clinical guideline recommendations on opioid deprescribing in patients with chronic noncancer pain. We searched PubMed, EMBASE, PEDro, National Institute for Health and Care Excellence (United Kingdom), and MAGICapp databases from inception to June 4, 2021, with no language or publication restrictions. In addition, we searched the National Guideline Clearinghouse and International Guideline Network databases from inception to December 2018. Two independent reviewers conducted the initial title and abstract screening. After discrepancies were resolved through discussion, 2 independent reviewers conducted the full-text screening of each potentially eligible reference. Four independent reviewers completed the prepiloted, standardized data extraction forms of each included guideline. Extracted information included bibliographical details; strength of recommendations; and the outcomes, such as when and how to deprescribe, managing withdrawal symptoms, additional support, outcome monitoring, and deprescribing with coprescription of sedatives. A narrative synthesis was used to present the results. This study found that clinical practice guidelines agree on when and how to deprescribe opioid analgesics but lack advice on managing a patient's withdrawal symptoms, outcome monitoring, and deprescribing with coprescription of sedatives. Quality assessment of the guidelines suggests that greater discussion on implementation and dissemination is needed.
The Beirut ammonium nitrate blast: A multicenter study to assess injury characteristics and outcomes
Authors: Al-Hajj Samar , Farran Sarah H. , Zgheib Hady , Tfaily Mohamad Ali , Halaoui Adham , Wehbe Sarah , Karam Stephanie , Fadlallah Yaser , Fahd Fares , Toufaili Lana , Arjinian Sebouh , AL-Zaghrini Elie , Al Hariri Moustafa , El Hussein Mahmoud , Souaiby Naji , Mowafi Hani , Mufarrij Afif Jean
Published: August 2022

BACKGROUND

Blasts incidents impose catastrophic aftermaths on populations regarding casualties, sustained injuries, and devastated infrastructure. Lebanon witnessed one of the largest nonnuclear chemical explosions in modern history—the August 2020 Beirut Port blast. This study assesses the mechanisms and characteristics of blast morbidity and mortality and examines severe injury predictors through the Injury Severity Score.

METHODS

A retrospective, multicenter cross-sectional study was conducted. Data of trauma patients presenting to five major acute-care hospitals in metropolitan Beirut up to 4 days following the blast were collected in a two-stage process from patient hospital chart review and follow-up phone calls.

RESULTS

A total of 791 patients with a mean age of 42 years were included. The mean distance from the blast was 2.4 km (SD, 1.9 km); 3.1% of victims were in the Beirut Port itself. The predominant mechanism of injury was being struck by an object (falling/projectile) (293 [37.0%]), and the most frequent site of injury was the head/face (209 [26.4%]). Injury severity was low for 548 patients (71.2%), moderate for 62 (8.1%), and severe/critical for 27 (3.5%). Twenty-one deaths (2.7%) were recorded. Significant serious injury predictors (Injury Severity Score, >15) were sustaining multiple injuries (odds ratio [OR], 2.62; p = 0.005); a fracture (OR, 5.78; p < 0.001); primary blast injuries, specifically a blast lung (OR, 18.82; p = 0.001), concussion (OR, 7.17; p < 0.001), and eye injury (OR, 8.51; p < 0.001); and secondary blast injuries, particularly penetrating injuries (OR, 9.93; p < 0.001) and traumatic amputations (OR, 13.49; p = 0.01). Twenty-five percent were admitted to the hospital, with 4.6% requiring the intensive care unit. At discharge, 25 patients (3.4%) had recorded neurologic disability.

CONCLUSION

Most injuries sustained by the blast victims were minor. Serious injuries were mostly linked to blast overpressure and projectile fragments. Understanding blast injuries characteristics, their severity, and management is vital to informing emergency services, disaster management strategies, hospital preparedness, and, consequently, improving patient outcomes.

LEVEL OF EVIDENCE

Prognostic and Epidemiologic; Level III.
Surgical stabilization of rib fractures versus nonoperative treatment in patients with multiple rib fractures following cardiopulmonary resuscitation: an international, retrospective matched case-control study (CWIS-CPR)
Authors: Prins Jonne T.H. , Van Lieshout Esther M.M. , Eriksson Evert A. , Barnes Matthew , Blokhuis Taco J. , Caragounis Eva-Corina , Benjamin Christie D. , De Loos Erik R. , DeVoe William B. , Formijne Jonkers Henk A. , Kiel Brandon , Ko Huan-Jang , Marasco Silvana F. , Spanjersberg Willem R. , Su Ying-Hao , Summerhayes Robyn G. , Van Huijstee Pieter J. , Vermeulen Jefrey , Vos Dagmar I. , Verhofstad Michael H.J. , Wijffels Mathieu M.E.
Published: August 2022

Background

The presence of six or more rib fractures or a displaced rib fracture due to cardiopulmonary resuscitation (CPR) has been associated with longer hospital and intensive care unit (ICU) length of stay. Evidence on the effect of surgical stabilization of rib fractures (SSRF) following CPR is limited. This study aimed to evaluate outcomes after SSRF versus nonoperative management in patients with multiple rib fractures after CPR.

Methods

An international, retrospective study was performed in patients who underwent SSRF or nonoperative management for multiple rib fractures following CPR between January 1, 2012 and July 31, 2020. Patients who underwent SSRF were matched to nonoperative controls by cardiac arrest location and cause, rib fracture pattern, and age. The primary outcome was ICU length of stay (LOS).

Results

Thirty-nine operatively treated patient were matched to 66 nonoperatively managed controls with comparable CPR-related characteristics. Patients who underwent SSRF more often had displaced rib fractures (n = 28, 72% vs. n = 31, 47%; p = 0.015) and a higher median number of displaced ribs (2, P25-P75 0-3 vs. 0, P25-P75 0-3; p = 0.014). SSRF was performed at a median of 5 days (P25-P75 3-8) after CPR. In the nonoperative group, a rib fixation specialist was consulted in 14 patients (21%). The ICU LOS was longer in the SSRF group (13 days, P25-P75 9-23 vs. 9 days, P25-P75 5-15; p = 0.004). Mechanical ventilator-free days, hospital LOS, thoracic complications, and mortality were similar.

Conclusion

Despite matching, those who underwent SSRF over nonoperative management for multiple rib fractures following CPR had more severe consequential chest wall injury and a longer ICU LOS. A benefit of SSRF on in-hospital outcomes could not be demonstrated.

A low consultation rate for rib fixation in the nonoperative group indicates that the consideration to perform SSRF in this population might be associated with other non-radiographic or injury-related variables.

Level of evidence

therapeutic study, level III
The role of wingbeat frequency and amplitude in flight power
Authors: Krishnan Krishnamoorthy , Garde Baptiste , Bennison Ashley , Cole Nik C. , Cole Emma-L. , Darby Jamie , Elliott Kyle H. , Fell Adam , Gómez-Laich Agustina , de Grissac Sophie , Jessopp Mark , Lempidakis Emmanouil , Mizutani Yuichi , Prudor Aurélien , Quetting Michael , Quintana Flavio , Robotka Hermina , Roulin Alexandre , Ryan Peter G. , Schalcher Kim , Schoombie Stefan , Tatayah Vikash , Tremblay Fred , Weimerskirch Henri , Whelan Shannon , Wikelski Martin , Yoda Ken , Hedenström Anders , Shepard Emily L. C.
Published: August 2022

Body-mounted accelerometers provide a new prospect for estimating power use in flying birds, as the signal varies with the two major kinematic determinants of aerodynamic power: wingbeat frequency and amplitude. Yet wingbeat frequency is sometimes used as a proxy for power output in isolation. There is, therefore, a need to understand which kinematic parameter birds vary and whether this is predicted by flight mode (e.g. accelerating, ascending/descending flight), speed or morphology. We investigate this using high-frequency acceleration data from (i) 14 species flying in the wild, (ii) two species flying in controlled conditions in a wind tunnel and (iii) a review of experimental and field studies. While wingbeat frequency and amplitude were positively correlated,
R
2
values were generally low, supporting the idea that parameters can vary independently. Indeed, birds were more likely to modulate wingbeat amplitude for more energy-demanding flight modes, including climbing and take-off. Nonetheless, the striking variability, even within species and flight types, highlights the complexity of describing the kinematic relationships, which appear sensitive to both the biological and physical context. Notwithstanding this, acceleration metrics that incorporate both kinematic parameters should be more robust proxies for power than wingbeat frequency alone.
Postural orthostatic tachycardia syndrome explained using a baroreflex response model
Authors: Geddes Justen R. , Ottesen Johnny T. , Mehlsen Jesper , Olufsen Mette S.
Published: August 2022

Patients with postural orthostatic tachycardia syndrome (POTS) experience an excessive increase in heart rate (HR) and low-frequency (∼0.1 Hz) blood pressure (BP) and HR oscillations upon head-up tilt (HUT). These responses are attributed to increased baroreflex (BR) responses modulating sympathetic and parasympathetic signalling. This study uses a closed-loop cardiovascular compartment model controlled by the BR to predict BP and HR dynamics in response to HUT. The cardiovascular model predicts these quantities in the left ventricle, upper and lower body arteries and veins. HUT is simulated by letting gravity shift blood volume (BV) from the upper to the lower body compartments, and the BR control is modelled using set-point functions modulating peripheral vascular resistance, compliance, and cardiac contractility in response to changes in mean carotid BP. We demonstrate that modulation of parameters characterizing BR sensitivity allows us to predict the persistent increase in HR and the low-frequency BP and HR oscillations observed in POTS patients. Moreover, by increasing BR sensitivity, inhibiting BR control of the lower body vasculature, and decreasing central BV, we demonstrate that it is possible to simulate patients with neuropathic and hyperadrenergic POTS.
Lymphoedema conditions disrupt endothelial barrier function
in vitro
Authors: Hall Joshua D. , Farzaneh Sina , Babakhani Galangashi Reza , Pujari Akshay , Sweet Daniel T. , Kahn Mark L. , Jiménez Juan M.
Published: August 2022

Lymphatic vessel contractions generate net antegrade pulsatile lymph flow. By contrast, impaired lymphatic vessels are often associated with lymphoedema and altered lymph flow. The effect of lymphoedema on the lymph flow field and endothelium is not completely known. Here, we characterized the lymphatic flow field of a platelet-specific receptor C-type lectin-like receptor 2 (CLEC2) deficient lymphoedema mouse model. In regions of lymphoedema, collecting vessels were significantly distended, vessel contractility was greatly diminished and pulsatile lymph flow was replaced by quasi-steady flow.
In vitro
exposure of human dermal lymphatic endothelial cells (LECs) to lymphoedema-like quasi-steady flow conditions increased intercellular gap formation and permeability in comparison to normal pulsatile lymph flow. In the absence of flow, LECs exposed to steady pressure (SP) increased intercellular gap formation in contrast with pulsatile pressure (PP). The absence of pulsatility in steady fluid flow and SP conditions without flow-induced upregulation of myosin light chain (MLCs) regulatory subunits 9 and 12B mRNA expression and phosphorylation of MLCs, in contrast with pulsatile flow and PP without flow. These studies reveal that the loss of pulsatility, which can occur with lymphoedema, causes LEC contraction and an increase in intercellular gap formation mediated by MLC phosphorylation.
Auditory sensory range of male mosquitoes for the detection of female flight sound
Authors: Nakata Toshiyuki , Simões Patrício , Walker Simon M. , Russell Ian J. , Bomphrey Richard J.
Published: August 2022

Male mosquitoes detect and localize conspecific females by their flight-tones using the Johnston's organ (JO), which detects antennal deflections under the influence of local particle motion. Acoustic behaviours of mosquitoes and their JO physiology have been investigated extensively within the frequency domain, yet the auditory sensory range and the behaviour of males at the initiation of phonotactic flights are not well known. In this study, we predict a maximum spatial sensory envelope for flying
Culex quinquefasciatus
by integrating the physiological tuning response of the male JO with female aeroacoustic signatures derived from numerical simulations. Our sensory envelope predictions were tested with a behavioural assay of free-flying males responding to a female-like artificial pure tone. The minimum detectable particle velocity observed during flight tests was in good agreement with our theoretical prediction formed by the peak JO sensitivity measured in previous studies. The iso-surface describing the minimal detectable particle velocity represents the quantitative auditory sensory range of males and is directional with respect to the female body orientation. Our results illuminate the intricacy of the mating behaviour and point to the importance of observing the body orientation of flying mosquitoes to understand fully the sensory ecology of conspecific communication.
Occam’s razor gets a new edge: the use of symmetries in model selection
Authors: Borgqvist Johannes G. , Palmer Sam
Published: August 2022

We demonstrate the power of using symmetries for model selection in the context of mechanistic modelling. We analyse two different models called the
power law model
(PLM) and the
immunological model
(IM) describing the increase in cancer risk with age, due to mutation accumulation or immunosenescence, respectively. The IM fits several cancer types better than the PLM implying that it would be selected based on minimizing residuals. However, recently a symmetry-based method for model selection has been developed, which has been successfully used in an
in silico
setting to find the correct model when traditional model fitting has failed. Here, we apply this method in a real-world setting to investigate the mechanisms of carcinogenesis. First, we derive distinct symmetry transformations of the two models and then we select the model which not only fits the original data but is also invariant under transformations by its symmetry. Contrary to the initial conclusion, we conclude that the PLM realistically describes the mechanism underlying the colon cancer dataset. These conclusions agree with experimental knowledge, and this work demonstrates how a model selection criterion based on biological properties can be implemented using symmetries.