bluuebunny/crossref_metadata_2025 huggingface dataset:
Constant intensity acoustic propagation in the presence of non-uniform properties and impedance discontinuities: Hermitian and non-Hermitian solutions
Authors: Norris Andrew N.
Published: October 2022

Propagation of sound through a non-uniform medium without scattering is possible, in principle, if the density and acoustic compressibility assume complex values, requiring passive and active mechanisms, also known as Hermitian and non-Hermitian solutions, respectively. Two types of constant intensity wave conditions are identified: in the first, the propagating acoustic pressure has constant amplitude, while in the second, the energy flux remains constant. The fundamental problem of transmission across an impedance discontinuity without reflection or energy loss is solved using a combination of monopole and dipole resonators in parallel. The solution depends on an arbitrary phase angle that can be chosen to give a unique acoustic metamaterial with both resonators undamped and passive, requiring purely Hermitian acoustic elements. For other phase angles, one of the two elements must be active and the other passive, resulting in a gain/loss non-Hermitian system. These results prove that uni-directional and reciprocal transmission through a slab separating two half spaces is possible using passive Hermitian acoustic elements without the need to resort to active gain/loss energetic mechanisms.
A room impulse response database for multizone sound field reproduction (L)
Authors: Zhao Sipei , Zhu Qiaoxi , Cheng Eva , Burnett Ian S.
Published: October 2022

This letter introduces a database of Room Impulse Responses (RIRs) measured in seven different rooms for multizone sound field reproduction research in various acoustic environments. A circular array of 60 loudspeakers was installed in each room, with two microphone arrays placed sequentially in five different zones inside the loudspeaker array. A total of 260 400 RIRs were measured to establish the database. As a demonstration application of the database for multizone sound field reproduction, simulations were performed on the pressure matching and acoustic contrast control methods to investigate how a system optimized with the RIRs measured in one room would perform in other rooms.
Safety and Pharmacokinetics of LHF-535, a Potential Treatment for Lassa Fever, in Healthy Adults
Authors: Amberg Sean M. , Snyder Benjamin , Vliet-Gregg Portia A. , Tarcha Eric J. , Posakony Jeff , Bedard Kristin M. , Heald Alison E.
Published: October 2022

LHF-535 is a small-molecule antiviral currently under development as a therapeutic option to treat Lassa fever and other viral hemorrhagic fevers of arenavirus origin. The human safety and pharmacokinetics of LHF-535 were evaluated in two phase 1 trials in healthy volunteers.
Updated Review onNocardiaSpecies: 2006–2021
Authors: Traxler Rita M. , Bell Melissa E. , Lasker Brent , Headd Brendan , Shieh Wun-Ju , McQuiston John R.
Published: October 2022

This review serves as an update to the previousNocardiareview by Brown-Elliott et al. published in 2006 (B. A.
Weekly Flow: an Effective Organizational Tool for Structuring Biology Courses and Supporting Student Learning
Authors: Olins Heather Craig
Published: October 2022

Here, I describe a “Weekly Flow” strategy for structuring college biology courses and making organization transparent to students. Building a course around an established weekly schedule that consists of the same, or similar, elements (for example, assessments, readings, assignment types, and/or class activities) provides structure and predictability that helps students with time management and therefore enables them to engage more deeply with the course material.
eIF4A3 Promotes RNA Viruses’ Replication by Inhibiting Innate Immune Responses
Authors: Gao Qingxia , Jiang Meijun , Zhao Yaxin , Li Guoli , Yang Cha , Ren Caiyue , Jin Meilin , Chen Huanchun , Zhou Hongbo
Published: October 2022

Production of type I IFN is pivotal for the cellular antiviral immunity. Virus infection leads to the activation of transcription factor IRF3 and subsequent production of type I IFN to eliminate viral infection.
In through the Out Door: A Functional Virulence Factor Secretion System Is Necessary for Phage Infection in Ralstonia solanacearum
Authors: Xavier André da Silva , de Melo Alessandra G. , Hendrich Connor G. , Tremblay Denise M. , Rousseau Geneviève M. , Plante Pier-Luc , Forest Katrina T. , Alfenas-Zerbini Poliane , Allen Caitilyn , Moineau Sylvain
Published: October 2022

Ralstonia solanacearum
is a destructive plant pathogen that causes lethal bacterial wilt disease in hundreds of diverse plant hosts, including many economically important crops. Phages that kill
R. solanacearum
could offer effective and environmentally friendly wilt disease control, but only if the bacterium cannot easily evolve resistance.
Neuropilin-1 Mediates SARS-CoV-2 Infection of Astrocytes in Brain Organoids, Inducing Inflammation Leading to Dysfunction and Death of Neurons
Authors: Kong Weili , Montano Mauricio , Corley Michael J. , Helmy Ekram , Kobayashi Hirofumi , Kinisu Martin , Suryawanshi Rahul , Luo Xiaoyu , Royer Loic A. , Roan Nadia R. , Ott Melanie , Ndhlovu Lishomwa C. , Greene Warner C.
Published: October 2022

SARS-CoV-2 infection primarily targets the lung but may also damage other organs, including the brain, heart, kidney, and intestine. Central nervous system (CNS) pathologies include loss of smell and taste, headache, delirium, acute psychosis, seizures, and stroke.
Translating Marine Symbioses toward Drug Development
Authors: Schmidt Eric W. , Lin Zhenjian
Published: October 2022

Chemists have studied marine animals for the better part of a century because they contain a diverse array of bioactive compounds. Tens of thousands of compounds have been reported, many with elaborate structural motifs and biological mechanisms of action found nowhere else.
microshades
: An R Package for Improving Color Accessibility and Organization of Microbiome Data
Authors: Dahl Erin M. , Neer Emory , Bowie Kate R. , Leung Eric T. , Karstens Lisa
Published: October 2022

When creating figures, it is important to consider that individuals with color vision deficiency (CVD) may not perceive all colors. While there are several CVD-friendly color palettes, they are often insufficient for working with microbiome data. Here, we introduce
microshades
, an R package for creating CVD-accessible microbiome figures.
Understanding the Dynamic of POMS Infection and the Role of Microbiota Composition in the Survival of Pacific Oysters, Crassostrea gigas
Authors: Delisle Lizenn , Laroche Olivier , Hilton Zoë , Burguin Jean-François , Rolton Anne , Berry Jolene , Pochon Xavier , Boudry Pierre , Vignier Julien
Published: October 2022

For more than a decade, Pacific oyster mortality syndrome (POMS) has severely impacted the
Crassostrea gigas
aquaculture industry, at times killing up to 100% of young farmed Pacific oysters, a key commercial species that is cultivated globally. These disease outbreaks have caused major financial losses for the oyster aquaculture industry.
Structural and Functional Analysis of Peptides Derived from KEX2-Processed Repeat Proteins in Agaricomycetes Using Reverse Genetics and Peptidomics
Authors: Vogt Eva , Sonderegger Lukas , Chen Ying-Yu , Segessemann Tina , Künzler Markus
Published: October 2022

Two recent bioinformatics studies have demonstrated that KEX2-processed repeat proteins are widespread in the fungal kingdom. However, despite the prevalence of KEPs in fungal genomes, only few KEP-derived peptides have been detected and studied so far.
Detection of Diverse Sequence Types of Legionella pneumophila by Legiolert Enzymatic-Based Assay and the Development of a Long-Term Storage Protocol
Authors: Matthews Sara , Trigui Hana , Grimard-Conea Marianne , Vallarino Reyes Elliston , Villiard Gabriel , Charron Dominique , Bédard Emilie , Faucher Sébastien , Prevost Michèle
Published: October 2022

Legionnaires’ disease is caused by the bacterium
Legionella pneumophila
, which can be found in a variety of water systems. When outbreaks of Legionnaires’ disease occur, it is necessary to find the water systems transmitting the bacterium to humans.
A Nonclassical Mechanism of β-Lactam Resistance in Methicillin-Resistant Staphylococcus aureus and Its Effect on Virulence
Authors: Satishkumar Nidhi , Lai Li-Yin , Mukkayyan Nagaraja , Vogel Bruce E. , Chatterjee Som S.
Published: October 2022

Our study demonstrates the ability of PBP4 to be an important mediator of β-lactam resistance in not only methicillin-susceptible
Staphylococcus aureus
(MSSA) background strains as previously demonstrated but also in MRSA strains. When present together, PBP2a and PBP4 overexpression can produce increased levels of β-lactam resistance, causing complications in treatment.
Leveraging a Fluorescent Fatty Acid Probe to Discover Cell-Permeable Inhibitors of Plasmodium falciparum Glycerolipid Biosynthesis
Authors: Dapper Christie , Liu Jiapeng , Klemba Michael
Published: October 2022

The human malaria parasite
Plasmodium falciparum
relies on fatty acid scavenging to supply this essential precursor of lipid synthesis during its asexual replication cycle in human erythrocytes. This dependence on host fatty acids represents a potential vulnerability that can be exploited to develop new anti-malarial therapies.
In Vitro
Susceptibilities of Worldwide Isolates of Intrapulmonary
Aspergillus
Species and Important
Candida
Species in Sterile Body Sites against Important Antifungals: Data from the Antimicrobial Testing Leadership and Surveillance Program, 2017–2020
Authors: Jean Shio-Shin , Yang Hung-Jen , Hsieh Po-Chuen , Huang Yu-Tsung , Ko Wen-Chien , Hsueh Po-Ren
Published: October 2022

In addition to monitoring the antifungal susceptibilities of clinically important fungi, reviewing the PK/PD indices and the clinical therapy experience of antifungals under evaluation are important to guide an appropriate antifungal prescription. The efficacies of liposomal amphotericin B complex and anidulafungin for the treatment of pulmonary aspergillosis caused by different
Aspergillus
species need to be periodically evaluated in the future.
Cysteine Inhibits the Growth of Fusarium oxysporum and Promotes T-2 Toxin Synthesis through the Gtr/Tap42 Pathway
Authors: Qiu Mei , Deng Yijia , Deng Qi , Sun Lijun , Fang Zhijia , Wang Yaling , Huang Xiaoyue , Zhao Jian
Published: October 2022

F. oxysporum
and its T-2 contamination of food not only leads to food wastage but also poses a major food safety challenge to humans. The growth and T-2 production characteristics of
F. oxysporum
in high-protein substrates are considerably different from those in grains.
Recurrent chylous ascites in patient with previous retroperitoneal radiation treatment
Authors: Sharma Purva , Chakraborty Kanishka
Published: October 2022

Chylous ascites is the accumulation of lymphatic fluid in the peritoneal cavity due to disruption of lymphatic drainage caused due to obstruction or trauma. We report a man in his 60s who was previously treated for diffuse large B cell lymphoma with radiation to bulky abdominal/mesenteric lymphadenopathy. He was later found to have recurrent chylous ascites several years later, requiring multiple paracentesis. Recurrent lymphoma was ruled out with negative cytology of peritoneal fluid as well as lymph node biopsy with no evidence of malignancy. We believe that the patient had obstruction of lymphatic drainage due to previous radiation therapy causing fibrosis. The patient underwent lymphangiography which did not visualise the central lymphatic duct within the abdomen raising suspicion for obstruction of the ducts secondary to previous radiation.
Homozygous familial hypercholesterolaemia in a patient presenting with hypertensive encephalopathy
Authors: Maldar Shadab B , Pinto Christopher Jude
Published: October 2022

Homozygous familial hypercholesterolaemia (HoFH) is a disorder affecting low-density lipoprotein (LDL) receptor genes. Patients typically have a triad of elevated LDL-cholesterol (LDL-C), xanthomatosis and premature atherosclerotic cardiovascular disease. Our patient, a preteen boy, presented with signs of hypertensive encephalopathy. Physical examination showed arcus cornealis, planar xanthomas and tuberous xanthomas. After appropriate investigations, a direct aetiology of the hypertension could not be elucidated; however, our patient’s hypertension resolved with the reduction in serum lipid levels. β-hydroxy β-methylglutaryl coenzyme A reductase and cholesterol absorption inhibitors were administered as first-line treatment. A significant proportion of patients with HoFH continue to have elevated LDL-C levels, thereby requiring second-line agents, such as proprotein convertase subtilisin/kexin type inhibitors (evolocumab), microsomal triglyceride transfer protein inhibitors (lomitapide) and angiopoietin-like protein inhibitors (evinacumab). This case report aimed to raise awareness among paediatricians to consider HoFH as a possible aetiology in a child presenting with hypertension and suggestive physical findings.
Antegrade left ureterolithotripsy in a patient with previous psoas-hitch ureteral reimplantation
Authors: Colalillo Gaia , Annino Filippo , Khorrami Saba , Asimakopoulos Anastasios D
Published: October 2022

A standard surgical treatment of distal ureteric defects is represented by the ureteroneocystostomy-ureteric reimplantation. However, the procedure involves an anatomical alteration of the ureterovesical (neo)junction that often hinders the retrograde catheterisation of the reimplanted ureter.

We describe a case of antegrade ureterolithotripsy (AULT) in a psoas-hitch reimplanted ureter. A woman with severe left hydronephrosis supported by a subcentimetric proximal ureteral stone in a psoas-hitch reimplanted ureter was referred to our unit. Retrograde ureteroscopy was unsuccessful due to impossibility in incannulating the ureteral neo-orifice. Following the placement of a percutaneous nephrostomy, percutaneous AULT through ureteral sheath was successfully performed with complete treatment of the stone.

AULT may represent a viable alternative in the management of ureteral stones when the upper urinary tract is not amenable to retrograde ureteroscopy. In experienced hands, the procedure is straightforward and may avoid the adoption of transabdominal approaches.
Adolescent and young adult allergic asthma treatment challenges
Authors: Vukičević Lazarević Vesna , Marković Ivan , Šola Ana Marija
Published: October 2022

The transition from paediatric care to adult care is often difficult, especially in children with chronic diseases like asthma. A significant number of children reach remission throughout puberty; consequently, they are not tracked down for subsequent follow-ups and are not included in transition programmes to adult care. This case report focuses on a young adult with asthma that began in childhood and went into remission during adolescence, only to experience a recurrence when the patient was a young adult. Due to failing to complete the transition process into adult care services, she had poor adherence to therapy and asthma control.

Adherence and asthma control significantly improved after a multidisciplinary approach in an adult care setting. In conclusion, appropriate transition and a multidisciplinary approach are critical for the effective management of asthma in young adults.
Novel use of metallic stent to control post-debulking bleeding in a patient with central airway obstruction
Authors: Sivaramakrishnan Prakash , Mishra Mayank , Sindhwani Girish , Sharma Prakhar
Published: October 2022

Bronchoscopy-related bleeding is often encountered and is usually self-limiting or controllable by conservative measures. However, major bleeds can be life threatening for the patient as well as challenging for the physician to manage. There are several methods to achieve adequate haemostasis should a significant airway bleed occur. In this context, we describe a patient who had a post-bronchoscopic debulking bleed which persisted despite use of all available measures, and we deployed a self-expanding metallic stent in an attempt to control it. To the best of our knowledge, this is the first instance of a metallic airway stent being used to control bronchoscopy associated bleeding, though reports of its usage in management of intractable haemoptysis exist in the literature.
Development and implementation of the maternal and child health Handbook in Angola
Authors: Kuramata Michiru , Mochida Keiji , Fukushima Sachi , Sadamori Toru , Suzuki Miho , Francisco Ketha Rubuz , Freitas Helga Reis , Balogun Olukunmi Omobolanle , Takehara Kenji
Published: October 2022

Although the maternal and child health (MCH) Handbook is widely used in many countries, its development and implementation process has not been sufficiently documented in scientific publications. This is a report of how the Angola MCH Handbook was developed, what challenges we encountered during its implementation and how they were solved. Leading the process was the MCH Handbook Committee set up to develop the MCH Handbook and implement the programme in liaison with various stakeholders. We developed the MCH Handbook through participatory workshops with the objective of producing user-responsive content and designs, foster healthy interaction and build common understanding among stakeholders. After pilot use in select health facilities, the MCH Handbook programme, which included training, monitoring and supervision, mothers’ class and community awareness raising activities, was gradually implemented in three model provinces. Core members of the committee closely observed each step of the programme to identify challenges in each field, and revised the tool and programme throughout the process. As nationwide implementation of the MCH Handbook Programme progresses, it is important to continually identify challenges specific to different localities while taking measures to address them. In our experience, stakeholder involvement from the early planning and preparation stages was critical to ensure their continued commitment at later stages and for programme continuity. Our approach of tool development involving various stakeholders and flexible implementation strategies were key elements for user acceptance and programme sustainability that may be applicable for introduction of similar interventions in other settings.
Applying the Health Belief Model to predict preference for surgical intervention versus medical therapy among patients with open-angle glaucoma
Authors: Awad Khaled , Awad Ramy , Elkazaz Hager , Saleh Marwa , Mehanna Azza
Published: October 2022

Objective

To determine the factors influencing patient preference of surgical intervention versus medical therapy for open-angle glaucoma based on the Health Belief Model.

Methods and analysis

The study is a cross-sectional study. The study was conducted on 309 patients having open-angle glaucoma attending glaucoma clinic at Alexandria Ophthalmology Hospital, Alexandria, Egypt. The patients were subjected to an interview questionnaire comprising demographic data, patient knowledge and beliefs about glaucoma, glaucoma medications and treatment options, and patient preference of treatment modality, based on the Health Belief Model.

Results

About half of the patients (46%) were found to prefer surgical intervention. Patients were less knowledgeable about glaucoma, in general, but knowledge scores of patients preferring surgical intervention were significantly higher than those preferring medical therapy (Percentage Mean Score, PMS: 42.46%–37.37%, respectively). Male and female patients using more medications were significantly more likely to prefer surgical intervention (p=0.015 and p=0.003, respectively). Patients having preference for surgical intervention reported higher scores for perceived susceptibility and severity of long-term medical therapy (PMS=72.61% vs 54.62%–68.62% versus 52.83%, respectively), higher scores for perceived benefits of surgical intervention (PMS=92.90% vs 43.96%, respectively) and higher scores for self-efficacy (PMS=97.18% vs 50.37%, respectively). Meanwhile, they obtained lower scores for perceived barriers to surgical intervention (PMS=53.43% vs 86.07%, respectively).

Conclusions

Male gender, increased number of used eye-drops and more knowledge about glaucoma were significantly associated with patient preference for surgical intervention. Perceived benefits and barriers and self-efficacy were the significant predictors for patient surgical interference preference.
Validity and reliability of CVI Range assessment for Clinical Research (CVI Range-CR): a longitudinal cohort study
Authors: Chang Melinda , Roman-Lantzy Christine , O’Neil Sharon H , Reid Mark W , Borchert Mark S
Published: October 2022

Introduction

Cortical visual impairment (CVI) is the leading cause of paediatric visual impairment in developed countries. Children with CVI exhibit visual behaviours that differ from those with ocular causes of visual impairment. Currently, there is no standard method of assessing these visual characteristics. We have developed a modified version of the CVI Range, a functional vision assessment, suitable for use in clinical research (CVI Range–Clinical Research (CVI Range-CR)). The purpose of this study is to assess the reliability and validity of this instrument in children with CVI.

Methods and analysis

This is a prospective cohort study of 45 children with CVI. A neuro-ophthalmologist will grade visual acuity using the six-level Visual Behaviour Scale (VBS). A neuropsychologist will administer the CVI Range-CR, which will be recorded. The neuropsychologist and two external graders will review and score recorded assessments. These procedures will be performed at baseline and 12 months. We will calculate the intraclass correlation coefficient to assess inter-rater reliability at baseline and follow-up. Additionally, we will correlate CVI Range-CR scores to VBS scores.
Cervical spine movements during laryngoscopy and orotracheal intubation: a systematic review and meta-analysis
Authors: Correa Jaqueline Betina Broenstrup , Felice Vinicius Brenner , Sbruzzi Graciele , Friedman Gilberto
Published: October 2022

Background

Airway management is challenging in trauma patients because of the fear of worsening cervical spinal cord damage. Video-integrated and optic-integrated devices and intubation laryngeal mask airways have been proposed as alternatives to direct laryngoscopy with the Macintosh laryngoscope (MAC). We performed a meta-analysis to clarify which devices cause less cervical movement during airway management.

Methods

We searched MEDLINE, Cochrane Central, Embase and LILACS from inception to January 2022. We selected randomised controlled trials comparing alternative devices with the MAC for cervical movement from C0 to C5 in adult patients, evaluated by radiological examination. Additionally, cervical spine immobilisation (CSI) techniques were evaluated. We used the Cochrane Risk of Bias Tool to evaluate the risk of bias, and the principles of the Grading of Recommendations, Assessment, Development, and Evaluations system to assess the quality of the body of evidence.

Results

Twenty-one studies (530 patients) were included. Alternative devices caused statistically significantly less cervical movement than MAC during laryngoscopy with mean differences of −3.43 (95% CI −4.93 to –1.92) at C0–C1, −3.19 (–4.04 to –2.35) at C1–C2, −1.35 (−2.19 to −0.51) at C2–C3, and −2.61 (–3.62 to –1.60) at C3–C4; and during intubation: −3.60 (–5.08 to –2.12) at C0–C1, −2.38 (−3.17 to −1.58) at C1–C2, −1.20 (–2.09 to –0.31) at C2–C3. The Airtraq and the Intubation Laryngeal Mask Airway caused statistically significant less movement than MAC restricted to some cervical segments, as well as CSI. Heterogeneity was low to moderate in most results. The quality of the body of evidence was ‘low’ and ‘very low’.

Conclusions

Compared with the MAC, alternative devices caused less movement during laryngoscopy (C0–C4) and intubation (C0–C3). Due to the high risk of bias and the very low grade of evidence of the studies, further research is necessary to clarify the benefit of each device and to determine the efficacy of cervical immobilisation during airway management.
Development of a specialist ileoanal pouch surgery pathway: a multidisciplinary patient-centred approach
Authors: Celentano Valerio , Rafique Henna , Jerome Melanie , Lee Yu Jin , Kontovounisious Christos , Warren Oliver , MacDonald Alexander , Wahed Mahmood , Mills Sarah , Tekkis Paris
Published: October 2022

Background

Restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) is the gold standard procedure for ulcerative colitis refractory to medical treatment, as an alternative to permanent end ileostomy. Gaining experience in pouch surgery is difficult as the procedure is performed infrequently. This study presents an institutional initiative to promote standardisation of multidisciplinary care in IPAA surgery.

Methods

A dedicated pathway for patients who had an IPAA or are considering IPAA surgery was developed among colorectal surgeons, gastroenterologists, paediatric colorectal surgeons, inflammatory bowel disease (IBD) nurses, dietitians, stoma nurses, trainees in colorectal surgery. Pathway items were discussed and finalised via emails and videoconferences.

The pathway included triaging of patients referred for IPAA surgery, preoperative IBD multidisciplinary team discussion and management plan for surgery, surgical review prior to surgery, peer to peer counselling, surgical technique, postoperative short-term and long-term follow-up, audit, research and training in IPAA surgery.

Results

A multidisciplinary preoperative pathway was developed and a stepwise approach to minimally invasive ileoanal pouch surgery was formalised. A dedicated one-stop ileoanal pouch clinic was established integrating endoscopy and imaging on the same day of the consultation with the surgical and gastroenterology team. The clinic reviewed 72 patients over 24 months, and during the same time 36 patients underwent IPAA surgery at our institution.

Conclusions

We have described our initial experience in establishing a specialist IPAA surgery pathway and have proposed outcome measures that we hope will support a subspecialty IPAA service.
Outcomes and drivers of inappropriate dosing of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a systematic review and meta-analysis
Authors: Caso Valeria , de Groot Joris R , Sanmartin Fernandez Marcelo , Segura Tomás , Blomström-Lundqvist Carina , Hargroves David , Antoniou Sotiris , Williams Helen , Worsley Alice , Harris James , Caleyachetty Amrit , Vardar Burcu , Field Paul , Ruff Christian T
Published: October 2022

Objective

There has been limited systematic evaluation of outcomes and drivers of inappropriate non-vitamin K antagonist oral anticoagulants (NOACs) dosing among patients with atrial fibrillation (AF). This review identified and systematically evaluated literature on clinical and economic outcomes of inappropriate NOAC dosing and associated patient characteristics.

Methods

MEDLINE, Embase, Cochrane Library, International Pharmaceutical Abstracts, Econlit, PubMed and NHS EEDs databases were searched for English language observational studies from all geographies published between 2008 and 2020, examining outcomes of, or factors associated with, inappropriate NOAC dosing in adult patients with AF.

Results

One hundred and six studies were included in the analysis. Meta-analysis showed that compared with recommended NOAC dosing, off-label underdosing was associated with a null effect on stroke outcomes (ischaemic stroke and stroke/transient ischaemic attack (TIA), stroke/systemic embolism (SE) and stroke/SE/TIA). Meta-analysis of 15 studies examining clinical outcomes of inappropriate NOAC dosing found a null effect of underdosing on bleeding outcomes (major bleeding HR=1.04, 95% CI 0.90 to 1.19; p=0.625) but an increased risk of all-cause mortality (HR=1.28, 95% CI 1.10 to 1.49; p=0.006). Overdosing was associated with an increased risk of major bleeding (HR=1.41, 95% CI 1.07 to 1.85; p=0.013). No studies were found examining economic outcomes of inappropriate NOAC dosing. Narrative synthesis of 12 studies examining drivers of inappropriate NOAC dosing found that increased age, history of minor bleeds, hypertension, congestive heart failure and low creatine clearance (CrCl) were associated with an increased risk of underdosing. There was insufficient evidence to assess drivers of overdosing.

Conclusions

Our analysis suggests that off-label underdosing of NOACs does not reduce bleeding outcomes. Patients prescribed off-label NOAC doses are at an increased risk of all-cause mortality. These data underscore the importance of prescriber adherence to NOAC dosing guidelines to achieve optimal clinical outcomes for patients with AF.

PROSPERO registration number

CRD42020219844.
Transition to rilonacept monotherapy from oral therapies in patients with recurrent pericarditis
Authors: Brucato Antonio , Wheeler Alistair , Luis Sushil Allen , Abbate Antonio , Cremer Paul C , Zou Liangxing , Insalaco Antonella , Lewinter Martin , Lewis Basil S , Lin David , Nicholls Stephen , Pancrazi Massimo , Klein Allan L , Imazio Massimo , Paolini John F
Published: October 2022

Objective

Polypharmacy management of recurrent pericarditis (RP) often involves long-term therapies, often with negative effects. Slow tapering of oral therapies is often required to avoid recurrence. A post hoc analysis of the phase III trial Rilonacept inHibition of interleukin-1 Alpha and beta for recurrent Pericarditis: a pivotal Symptomatology and Outcomes Study (RHAPSODY) evaluated investigator approaches to transitioning to IL-1 blockade monotherapy with rilonacept, which was hypothesised to allow accelerated withdrawal of common multidrug pericarditis regimens.

Methods

RHAPSODY was a multicentre (Australia, Israel, Italy, USA), double-blind, placebo-controlled, randomised-withdrawal trial in adults and adolescents with RP. Investigators initiated rilonacept at the labelled dose level and discontinued oral pericarditis therapies during the 12-week run-in; randomised patients received study drug as monotherapy. Time to rilonacept monotherapy was quantified in patients receiving multidrug regimens at baseline who achieved rilonacept monotherapy during run-in.

Results

In 86 enrolled patients, mean time to rilonacept monotherapy was 7.9 weeks, with no recurrences. Of these, 64% (n=55) entered on multidrug regimens: non-steroidal anti-inflammatory drugs (NSAIDs) plus colchicine (44% (24/55)), colchicine plus glucocorticoids (24% (13/55)), or NSAIDs, colchicine, plus glucocorticoids (33% (18/55)). Investigators transitioned patients receiving colchicine and glucocorticoids at baseline to rilonacept monotherapy without recurrence regardless of taper approach: sequential (n=14; median, 7.7 weeks) or concurrent (n=17; median, 8.0 weeks). Median time to rilonacept monotherapy was similar regardless of glucocorticoid dose and duration: ≤15 mg/day (n=21): 7.3 weeks; >15 mg/day (n=18): 8.0 weeks; long-term (≥28 days): 7.6 weeks.

Conclusions

Rapid discontinuation of oral RP therapies while transitioning to rilonacept monotherapy was feasible without triggering pericarditis recurrence.

Trial registration number

NCT03737110.
Leisure-time and occupational physical activity and health outcomes in cardiovascular disease
Authors: Bonekamp Nadia E , Visseren Frank L J , Ruigrok Ynte , Cramer Maarten J M , de Borst Gert Jan , May Anne M , Koopal Charlotte
Published: October 2022

Objective

In healthy populations, leisure-time physical activity (LTPA) improves health outcomes, while, paradoxically, occupational physical activity (OPA) is associated with detrimental health effects. This study aimed to investigate the associations of LTPA and OPA with mortality, cardiovascular events and type 2 diabetes (T2D) in patients with cardiovascular disease (CVD).

Methods

In 7058 outpatients with CVD (age 61±10 years, 75% male) from the prospective Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease cohort, Cox models were used to quantify the associations between self-reported LTPA and OPA and all-cause mortality, cardiovascular events and T2D.

Results

Over 8.6 years (IQR: 4.6–12.5) of follow-up, 1088 vascular events, 1254 deaths and 447 incident T2D cases occurred. The top LTPA quarter had a lower risk of all-cause mortality (HR 0.63, 95% CI 0.54 to 0.74), recurrent cardiovascular events (HR 0.72, 95% CI 0.60 to 0.84) and incident T2D (HR 0.71, 95% CI 0.55 to 0.93), compared with the lowest quarter. The continuous LTPA associations were reverse J-shaped for all-cause mortality and vascular events and linear for T2D. OPA (heavy manual vs sedentary) showed a trend towards an increased risk of all-cause mortality (HR 1.08, 95% CI 0.86 to 1.35), cardiovascular events (HR 1.15, 95% CI 0.91 to 1.45) and T2D (HR 1.04, 95% CI 0.72 to 1.50). The detrimental effects of higher OPA were more pronounced in men, never-smokers, people with higher education and active employment.

Conclusions

In patients with CVD, LTPA was associated with lower risk of all-cause mortality, recurrent cardiovascular events and incident T2D. In contrast, OPA seemed to increase the risk of these outcomes. These findings support the existence of a physical activity paradox in patients with CVD.
Cardiovascular disease and mortality sequelae of COVID-19 in the UK Biobank
Authors: Raisi-Estabragh Zahra , Cooper Jackie , Salih Ahmed , Raman Betty , Lee Aaron Mark , Neubauer Stefan , Harvey Nicholas C. , Petersen Steffen E.
Published: October 2022

Objective

To examine association of COVID-19 with incident cardiovascular events in 17 871 UK Biobank cases between March 2020 and 2021.

Methods

COVID-19 cases were defined using health record linkage. Each case was propensity score-matched to two uninfected controls on age, sex, deprivation, body mass index, ethnicity, diabetes, prevalent ischaemic heart disease (IHD), smoking, hypertension and high cholesterol. We included the following incident outcomes: myocardial infarction, stroke, heart failure, atrial fibrillation, venous thromboembolism (VTE), pericarditis, all-cause death, cardiovascular death, IHD death. Cox proportional hazards regression was used to estimate associations of COVID-19 with each outcome over an average of 141 days (range 32–395) of prospective follow-up.

Results

Non-hospitalised cases (n=14 304) had increased risk of incident VTE (HR 2.74 (95% CI 1.38 to 5.45), p=0.004) and death (HR 10.23 (95% CI 7.63 to 13.70), p<0.0001). Individuals with primary COVID-19 hospitalisation (n=2701) had increased risk of all outcomes considered. The largest effect sizes were with VTE (HR 27.6 (95% CI 14.5 to 52.3); p<0.0001), heart failure (HR 21.6 (95% CI 10.9 to 42.9); p<0.0001) and stroke (HR 17.5 (95% CI 5.26 to 57.9); p<0.0001). Those hospitalised with COVID-19 as a secondary diagnosis (n=866) had similarly increased cardiovascular risk. The associated risks were greatest in the first 30 days after infection but remained higher than controls even after this period.

Conclusions

Individuals hospitalised with COVID-19 have increased risk of incident cardiovascular events across a range of disease and mortality outcomes. The risk of most events is highest in the early postinfection period. Individuals not requiring hospitalisation have increased risk of VTE, but not of other cardiovascular-specific outcomes.
Prognostic impact of left ventricular global longitudinal strain in atrial mitral regurgitation
Authors: Meucci Maria Chiara , Stassen Jan , Tomsic Anton , Palmen Meindert , Crea Filippo , Bax Jeroen J , Ajmone Marsan Nina , Delgado Victoria
Published: October 2022

Objective

Left atrial (LA) and left ventricular (LV) mechanics are impaired in patients with atrial functional mitral regurgitation (AFMR), but their prognostic value in this subset of patients remains unknown. The present study aimed to evaluate the association between LA and LV longitudinal strain and clinical outcomes in patients with AFMR.

Methods

A total of 197 patients (mean age 73±10 years, 44% men) with at least moderate AFMR were retrospectively identified. LV global longitudinal strain (GLS) and left atrial reservoir strain (LAS) were calculated by two-dimensional speckle tracking echocardiography. All-cause mortality was the primary endpoint of the study. The threshold value of LV GLS (≤16.3%) to identify impaired LV mechanics was defined based on the risk excess of the primary endpoint described with a spline curve analysis.

Results

Impaired LV GLS (≤16.3%) was found in 89 (45%) patients. During a median follow-up of 69 months, 45 (23%) subjects experienced the primary endpoint. Patients with impaired LV GLS (≤16.3%) had a significantly lower cumulative survival rate at 5 years, as compared with patients with LV GLS (>16.3%) (74% vs 93%, p<0.001). On multivariable Cox regression analysis, LV GLS expressed as continuous variable was independently associated with the occurrence of all-cause mortality (HR 0.856, 95% CI 0.763 to 0.960; p=0.008) after adjustment for age, LAS, pulmonary artery systolic pressure and severe tricuspid regurgitation. Conversely, LAS was not significantly associated with patients’ outcome.

Conclusions

In patients with significant AFMR, the impairment of LV GLS was independently associated with worse outcomes.
Preliminary evaluation of the impact of mandatory life jacket laws at declared high-risk rock platforms on unintentional rock fishing drowning deaths
Authors: Peden Amy E , Daw Shane , Lawes Jasmin C
Published: October 2022

Objectives

To explore the impact of mandatory lifejacket wear legislation on unintentional rock fishing-related drowning fatalities at declared high-risk rock platforms in New South Wales (NSW; Australia).

Methods

Rock fishing-related drownings for the five years pre-legislation enactment (23 November 2011 to 22 November 2016) and five years post-legislation enactment (23 November 2016 to 22 November 2021) were compared. Google Earth was used to assess if drowning deaths occurred at declared areas under legislation. Binary logistic regression was used to analyse change in the number of deaths in declared areas pre-legislation/post-legislation.

Results

Over the 10 years, 80 rock fishing drowning deaths occurred in New South Wales; 23 in declared areas pre-legislation and 13 post-legislation (−43.5%). The odds of a rock fishing drowning death occurring in a declared area pre-legislation was 2.3 times higher (95% CI 0.942 to 5.752; p=0.067).

Conclusion

Reductions in rock fishing deaths at declared areas were observed since the legislation’s introduction, but were not significant. Greater enforcement and extension to other high-risk platforms may reduce deaths further.
Arginase-2-specific cytotoxic T cells specifically recognize functional regulatory T cells
Authors: Weis-Banke Stine Emilie , Lisle Thomas Landkildehus , Perez-Penco Maria , Schina Aimilia , Hübbe Mie Linder , Siersbæk Majken , Holmström Morten Orebo , Jørgensen Mia Aaboe , Marie Svane Inge , Met Özcan , Ødum Niels , Madsen Daniel Hargbøl , Donia Marco , Grøntved Lars , Andersen Mads Hald
Published: October 2022

Background

High expression of the metabolic enzyme arginase-2 (ARG2) by cancer cells, regulatory immune cells, or cells of the tumor stroma can reduce the availability of arginine (L-Arg) in the tumor microenvironment (TME). Depletion of L-Arg has detrimental consequences for T cells and leads to T-cell dysfunction and suppression of anticancer immune responses. Previous work from our group has demonstrated the presence of proinflammatory ARG2-specific CD4 T cells that inhibited tumor growth in murine models on activation with ARG2-derived peptides. In this study, we investigated the natural occurrence of ARG2-specific CD8 T cells in both healthy donors (HDs) and patients with cancer, along with their immunomodulatory capabilities in the context of the TME.

Materials and methods

A library of 15 major histocompatibility complex (MHC) class I-restricted ARG2-derived peptides were screened in HD peripheral blood mononuclear cells using interferon gamma (IFN-γ) ELISPOT. ARG2-specific CD8 T-cell responses were identified using intracellular cytokine staining and ARG2-specific CD8 T-cell cultures were established by enrichment and rapid expansion following in vitro peptide stimulation. The reactivity of the cultures toward ARG2-expressing cells, including cancer cell lines and activated regulatory T cells (Tregs), was assessed using IFN-γ ELISPOT and a chromium release assay. The Treg signature was validated based on proliferation suppression assays, flow cytometry and quantitative reverse transcription PCR (RT-qPCR). In addition, vaccinations with ARG2-derived epitopes were performed in the murine Pan02 tumor model, and induction of ARG2-specific T-cell responses was evaluated with IFN-γ ELISPOT. RNAseq and subsequent GO-term and ImmuCC analysis was performed on the tumor tissue.

Results

We describe the existence of ARG2-specific CD8+T cells and demonstrate these CD8+T-cell responses in both HDs and patients with cancer. ARG2-specific T cells recognize and react to an ARG2-derived peptide presented in the context of HLA-B8 and exert their cytotoxic function against cancer cells with endogenous ARG2 expression. We demonstrate that ARG2-specific T cells can specifically recognize and react to activated Tregs with high ARG2 expression. Finally, we observe tumor growth suppression and antitumorigenic immunomodulation following ARG2 vaccination in an in vivo setting.

Conclusion

These findings highlight the ability of ARG2-specific T cells to modulate the immunosuppressive TME and suggest that ARG2-based immunomodulatory vaccines may be an interesting option for cancer immunotherapy.
Reproductive choices and intrafamilial communication in neurogenetic diseases with different self-estimated severities
Authors: Pierron Lucie , Tezenas du Montcel Sophie , Heinzmann Anna , Coarelli Giulia , Héron Delphine , Heide Solveig , Herson Ariane , Hennessy Juliette , Petit Elodie , Gargiulo Marcela , Durr Alexandra
Published: October 2022

Background

Low uptake of presymptomatic testing and medically assisted reproduction in families impacted by neurogenetic diseases prompted us to investigate how reproductive options are considered and whether there is a relationship with perceived severity of the disease. We hypothesised that self-estimated severity would influence opinion on reproductive options and that prenatal/preimplantation diagnosis would be a motivation to inform relatives about their risk.

Methods

We invited people impacted by neurogenetic diseases to evaluate the severity of their familial disease using analogic visual scales and to answer questionnaires about reproductive choices and intrafamilial communication. We compared answers between diseases and with the perceived severity of each disease.

Results

We analysed 562 questionnaires. Participants were impacted by Huntington disease (n=307), spinocerebellar ataxias (n=114), Steinert myotonic dystrophy (n=82) and amyotrophic lateral sclerosis/frontotemporal dementia (n=59). Self-estimated severity differed between pathologies (p<0.0001). Overall, participants considered prenatal diagnosis (78.0±34.4 out of 100) and preimplantation diagnosis (75.2±36.1 out of 100) justified more than termination of pregnancy (68.6±38.5 out of 100). They were less in favour of gamete donation (48.3±39.8 out of 100) or pregnancy abstention (43.3±40.3 out of 100). The greater the perceived severity of the disease, the more reproductive options were considered justified, except for gamete donation. Prenatal/preimplantation diagnosis was a motivation to inform relatives for only 55.3% of participants (p=0.01).

Conclusion

Self-estimated severity minimally impacts opinions towards reproductive options. Medically assisted reproduction procedures are rarely sought and do not motivate familial communication.
Intracranial hemorrhage in large vessel occlusion patients receiving endovascular thrombectomy with or without intravenous alteplase: a secondary analysis of the DIRECT-MT trial
Authors: Hu Xiaowei , Zhou Yu , Ospel Johanna , Yao Feirong , Liu Yizhi , Wang Hui , Li Bo , Hui Pinjing , Yang Pengfei , Zhang Yongwei , Zhang Lei , Li Zifu , Xing Pengfei , Shi Huaizhang , Han Hongxing , Wang Shouchun , Fang Qi , Liu Jianmin
Published: October 2022

Background

Alteplase before thrombectomy for patients with large vessel occlusion stroke raises concerns regarding an increased risk of intracranial hemorrhage (ICH), but the details of this relationship are not well understood.

Methods

This was a secondary analysis of the DIRECT-MT trial. ICH and its subtypes were independently reviewed and classified according to the Heidelberg Bleeding Classification. The effects of alteplase before thrombectomy on ICH and ICH subtypes occurrence were evaluated using logistic regression. Clinical and imaging characteristics that may modify these effects were exploratorily tested.

Results

Among 591 patients, any ICH occurred in 254 (43.0%), including hemorrhagic infarction type 1 in 12 (2.1%), hemorrhagic infarction type 2 in 127 (21.7%), parenchymal hematoma type 1 in 34 (5.8%), parenchymal hematoma type 2 in 50 (8.6%), and other hemorrhage types (3a-3c) in 24 (4.1%). Similar ICH frequencies were observed with combined alteplase and thrombectomy versus thrombectomy only (134/292 (45.9%) vs 120/299 (40.1%); OR 1.27, 95% CI 0.91 to 1.75, P=0.16), but patients treated with alteplase had a higher parenchymal hematoma rate (51/287 (17.8%) vs 33/297 (11.1%); OR 1.75, 95% CI 1.08 to 2.85, P=0.024). In the adjusted model, difference in parenchymal hematoma occurrence between groups remained significant (adjusted OR 1.71, 95% CI 1.00 to 2.92, P=0.049). Patients with history of diabetes (Pinteraction=0.048), hypertension (Pinteraction=0.02), antiplatelet therapy (Pinteraction=0.02), anticoagulation therapy (Pinteraction=0.04), and statin administration (Pinteraction=0.02) harbored a higher ICH rate when they received combination therapy.

Conclusions

Our data showed that in the DIRECT-MT trial, alteplase did not increase overall ICH for large vessel occlusion patients treated with thrombectomy, but it increased the parenchymal hematoma rate.
‘Why They Laugh At Us?’: the functions and ethics of humour in Singaporean theatrical depictions of stigmatised illness
Authors: Hyder Sophia
Published: October 2022

While humour in the context of illness might be perceived to be insensitive or inappropriate, it is used frequently in the medical setting and discussions of illness. This paper strives to answer why humour is used despite these feelings it might elicit, and attempts to outline conditions that inform the ethics of humour in an illness context.

This paper analyses two Singaporean theatrical depictions of chronic and stigmatised illnesses: Haresh Sharma’sOff Centre(1993), which is about schizophrenia and depression, and Paddy Chew’s monologueCompletely With/Out Character(1999), on HIV and AIDS. In these plays, humour functions to: first, dispense information on stigmatised illnesses through mediation; second, implicate audiences in stigma-making through defamiliarisation; and third, to exert discursive control for feelings of empowerment. Furthermore, analysing these plays within their contexts demonstrate that humour is crucial for providing a more nuanced understanding of the stigmatised illness experience, since humour can illuminate culturally held notions of sickness and health.

While humour is necessary for patients who are routinely misunderstood and alienated, it must be used with discretion to prevent abuse. As this paper demonstrates, the ethics of humour is more nuanced than simply possessing certain identity markers that provide the illusion of exoneration or inclusion. It is also affected by multiple axes of privilege and discrimination. In my conclusion, I argue that the ethics of humour in the illness context is contingent on whether imbalanced power relations and systems of oppression were employed and/or reproduced under the guise of non-seriousness.