bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Developments in the Design of Vertical Borehole Ground Heat Exchangers for Cost Reduction and Thermal Energy Storage
Authors: Liu Xiaobing , Spitler Jeffrey D. , Qu Ming , Shi Liang
Published: March 2021

Ground source (geothermal) heat pumps (GSHPs) can meet the thermal demands of buildings in an energy-efficient manner. The current high installation costs and long payback period limit the attractiveness of GSHP installation in the United States. Vertical borehole ground heat exchangers (VBGHEs), which are commonly used in GSHP systems, contribute most to the cost premium of GSHPs. Reducing the cost of VBGHEs could help increase market penetration of GSHP systems. This paper reviews recent developments for VBGHEs, including improvements in borehole heat transfer and borehole field layout, integration with thermal energy storage, and new design tools. Improvements in the borehole design and materials are more likely to be justified when the ground has high thermal conductivity. Integrating thermal energy storage can provide additional value to the GSHP system, especially when flexible electric demand at buildings becomes more valuable. Advanced design tools for VBGHEs that account for the thermal response of irregularly shaped borehole fields and that are more closely integrated with whole-building energy simulation programs may facilitate more innovations and optimization of GSHP system designs.
Numerical Investigation on Motion Responses of a Floating Hemisphere Over a Sloping Bottom
Authors: Liu Xiaolei , Wang Yiting , Wang Xuefeng , Wang Lei , Miao Quanming
Published: March 2021

In the last several decades, some numerical approaches have been proposed to deal with three-dimensional wave-body interaction problems in sloping bottom environment. Most of them either adopt the finite depth Green function or add numerical damping terms into the free surface condition to treat far field radiation condition, which certainly give rise to numerical errors. The hybrid model (Belibassakis, “A Boundary Element Method for the Hydrodynamic Analysis of Floating Bodies in Variable Bathymetry Regions,” Eng. Anal. Boundary Elements 32, pp. 796–810) adopting the consistent coupled-mode system for incident wave propagation problem combining with the three-dimensional bottom-dependent Green function to treat the diffraction and radiation problem is a complete formulation, as the latter function appropriately characterize the far field radiation wave pattern over a smoothly sloping bottom. However, this model has not been validated after its publication. In this connection, comparisons with computational fluid dynamic (CFD) results are presented to verify its accuracy. Application of this hybrid model is also performed to investigate the effects on the floating hemisphere by the sloping bottom.
Tilting Pad Bearing Pivot Friction and Design Effects on Thermal Bow-Induced Rotor Vibration
Authors: Shin Dongil , Palazzolo Alan B.
Published: March 2021

The Morton effect (ME) is a thermally induced vibration problem observed in a rotor supported by hydrodynamic bearings. The journal’s synchronous orbiting induces nonuniform viscous heating on its circumference, and the ensuing thermal bow often causes unacceptable vibration levels in the rotor. This paper investigates the influence of the tilting pad journal bearing (TPJB)’s pivot design on the severity and instability speed range of ME vibration. Simulations are conducted with two different types of pivots: cylindrical (CYL) and spherical (SPH), which produce different pad degrees-of-freedom and nonlinear pivot stiffness due to their geometries. The friction between pad and pivot, which only exists with the spherical pivot, is modeled, and its impact on the ME is evaluated. The example rotor model, as obtained from the literature, is single overhung, with experimentally measured excessive vibration and large journal temperature differentials, near 8000 rpm. The bearing and journal are modeled with three-dimensional (3D) finite elements, and the shaft with flexible beam elements for ME simulation. Nonlinear transient simulations are carried out for a wide operating speed range with varying pivot design parameters. Simulation results indicate that the predicted ME instability is sensitive to the pivot shape, pivot flexibility, and pad-pivot friction.
Delta-doped β-(AlxGa1−x)2O3/Ga2O3 heterostructure field-effect transistors by ozone molecular beam epitaxy
Authors: Tadjer Marko J. , Sasaki Kohei , Wakimoto Daiki , Anderson Travis J. , Mastro Michael A. , Gallagher James C. , Jacobs Alan G. , Mock Alyssa L. , Koehler Andrew D. , Ebrish Mona , Hobart Karl D. , Kuramata Akito
Published: March 2021

Heterojunction field-effect transistors based on the β-(AlxGa1−x)2O3/Ga2O3 heterostructure grown by ozone-assisted molecular beam epitaxy were demonstrated for the first time. Al composition ratios in the 14%–23% range were validated using x-ray diffraction on the three samples grown for this study. Electrochemical capacitance-voltage (ECV) measurements showed the presence of a charge sheet in the delta-doped (AlxGa1−x)2O3 barrier layer. Secondary ion mass spectroscopy and ECV measurements also revealed an unintentional Si peak at the (AlxGa1−x)2O3/Ga2O3 interface. Direct current (IDS-VGS) and transconductance (Gm-VGS) measurements demonstrated depletion-mode transistor operation as well as the presence of a parallel conduction channel. A one-dimensional Poisson model suggested that dopant redistribution in the delta-doped region could cause a secondary channel to form in the barrier in addition to the primary channel near the (AlxGa1−x)2O3/Ga2O3 interface under certain conditions met in these samples. Fabricated devices on sample A did not exhibit breakdown up to the measurement limit of 1100 V, with stability after ten cycles. A maximum output drain current density of 22 mA/mm was measured on sample B. Room temperature Hall measurements yielded a sheet carrier density of 1.12 × 1013 cm−2 with corresponding Hall mobility of 95 cm2/V s in sample C.
Recovery from forward masking in cochlear implant listeners: Effects of age and the electrode-neuron interface
Authors: Jahn Kelly N. , DeVries Lindsay , Arenberg Julie G.
Published: March 2021

Older adults exhibit deficits in auditory temporal processing relative to younger listeners. These age-related temporal processing difficulties may be further exacerbated in older adults with cochlear implant (CIs) when CI electrodes poorly interface with their target auditory neurons. The aim of this study was to evaluate the potential interaction between chronological age and the estimated quality of the electrode-neuron interface (ENI) on psychophysical forward masking recovery, a measure that reflects single-channel temporal processing abilities. Fourteen CI listeners (age 15 to 88 years) with Advanced Bionics devices participated. Forward masking recovery was assessed on two channels in each ear (i.e., the channels with the lowest and highest signal detection thresholds). Results indicated that the rate of forward masking recovery declined with advancing age, and that the effect of age was more pronounced on channels estimated to interface poorly with the auditory nerve. These findings indicate that the quality of the ENI can influence the time course of forward masking recovery for older CI listeners. Channel-to-channel variability in the ENI likely interacts with central temporal processing deficits secondary to auditory aging, warranting further study of programming and rehabilitative approaches tailored to older listeners.
Body Composition, Energy Availability, Training, and Menstrual Status in Female Runners
Authors: Ihalainen Johanna K. , Kettunen Oona , McGawley Kerry , Solli Guro Strøm , Hackney Anthony C. , Mero Antti A. , Kyröläinen Heikki
Published: March 2021

Purpose: To determine body composition, energy availability, training load, and menstrual status in young elite endurance running athletes (ATH) over 1 year, and in a secondary analysis, to investigate how these factors differ between nonrunning controls (CON), and amenorrheic (AME) and eumenorrheic (EUM) ATH. Correlations to injury, illness, and performance were also examined. Methods: Altogether 13 ATH and 8 CON completed the Low Energy Availability in Females Questionnaire. Anthropometric, energy intake, and peak oxygen uptake assessments were made at 4 time points throughout the year: at baseline post competition season, post general preparation, post specific preparation, and post competition season the following year. Logs of physical activity, menstrual cycle, illness, and injury were kept by all participants. Performance was defined using the highest International Association of Athletics Federations points prior to and after the study. Results: ATH had significantly lower body mass (P < .008), fat percentage (P < .001), and body mass index (P < .027) compared with CON, while energy availability did not differ between ATH and CON. The Low Energy Availability in Females Questionnaire score was higher in ATH than in CON (P < .028), and 8 ATH (vs zero CON) were AME. The AME had significantly more injury days (P < .041) and ran less (P < .046) than EUM, while total annual running distance was positively related to changes in performance in ATH (r < .62, P < .043, n < 11). Conclusions: More than half of this group of runners was AME, and they were injured more and ran less than their EUM counterparts. Furthermore, only the EUM runners increased their performance over the course of the year.
Lower Limb Movement Pattern Differences Between Males and Females in Squatting and Kneeling
Authors: Buchman-Pearle Jessa M. , Kingston David C. , Acker Stacey M.
Published: March 2021

Movement pattern differences may contribute to differential injury or disease prevalence between individuals. The purpose of this study was to identify lower limb movement patterns in high knee flexion, a risk factor for knee osteoarthritis, and to investigate kinematic differences between males and females, as females typically develop knee osteoarthritis more commonly and severely than males. Lower extremity kinematic data were recorded from 110 participants completing 4 variations of squatting and kneeling. Principal component analysis was used to identify principal movements associated with the largest variability in the sample. Across the tasks, similar principal movements emerged at maximal flexion and during transitions. At maximal flexion, females achieved greater knee flexion, facilitated by a wider base of support, which may alter posterior and lateral tibiofemoral stress. Principal movements also detected differences in movement temporality between males and females. When these temporal differences occur due to alterations in movement velocity and/or acceleration, they may elicit changes in muscle activation and knee joint stress. Movement variability identified in the current study provides a framework for potential modifiable factors in high knee flexion, such as foot position, and suggests that kinematic differences between the sexes may contribute to differences in knee osteoarthritis progression.
Vertical Ground Reaction Force Estimation From Benchmark Nonstationary Kinematic Data
Authors: Davis Daniel J. , Challis John H.
Published: March 2021

Time-differentiating kinematic signals from optical motion capture amplifies the inherent noise content of those signals. Commonly, biomechanists address this problem by applying a Butterworth filter with the same cutoff frequency to all noisy displacement signals prior to differentiation. Nonstationary signals, those with time-varying frequency content, are widespread in biomechanics (eg, those containing an impact) and may necessitate a different filtering approach. A recently introduced signal filtering approach wherein signals are divided into sections based on their energy content and then Butterworth filtered with section-specific cutoff frequencies improved second derivative estimates in a nonstationary kinematic signal. Utilizing this signal-section filtering approach for estimating running vertical ground reaction forces saw more of the signal’s high-frequency content surrounding heel strike maintained without allowing inappropriate amounts of noise contamination in the remainder of the signal. Thus, this signal-section filtering approach resulted in superior estimates of vertical ground reaction forces compared with approaches that either used the same filter cutoff frequency across the entirety of each signal or across the entirety of all signals. Filtering kinematic signals using this signal-section filtering approach is useful in processing data from tasks containing an impact when accurate signal second derivative estimation is of interest.
Changes in Intermuscular Coherence as a Function of Age and Phase of Speech Production During an Overt Reading Task
Authors: Reed Alesha , Cummine Jacqueline , Bhat Neesha , Jhala Shivraj , Bakhtiari Reyhaneh , Boliek Carol A.
Published: March 2021

Purpose: The authors evaluated changes in intermuscular coherence (IMC) of orofacial and speech breathing muscles across phase of speech production in healthy younger and older adults. Method: Sixty adults (30 younger = M: 26.97 year; 30 older = M: 66.37 year) read aloud a list of 40 words. IMC was evaluated across phase: preparation (300 ms before speech onset), initiation (300 ms after onset), and total execution (entire word). Results: Orofacial IMC was lowest in the initiation, higher in preparation, and highest for the total execution phase. Chest wall IMC was lowest for the preparation and initiation and highest for the total execution phase. Despite age-related differences in accuracy, neuromuscular modulation for phase was similar between groups. Conclusion: These results expand our knowledge of speech motor control by demonstrating that IMC is sensitive to phase of speech planning and production.
Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes
Authors: Saad-Roy Chadi M. , Morris Sinead E. , Metcalf C. Jessica E. , Mina Michael J. , Baker Rachel E. , Farrar Jeremy , Holmes Edward C. , Pybus Oliver G. , Graham Andrea L. , Levin Simon A. , Grenfell Bryan T. , Wagner Caroline E.
Published: March 2021

One dose or two?

For two-dose vaccines against severe acute respiratory syndrome coronavirus 2, some jurisdictions have decided to delay the second dose to rapidly get the vaccine into more people. The consequences of deviating from manufacturer-prescribed dosing regimens are unknown but will depend on the strength of immune responses to the vaccines. Saad-Roy
et al.
took a modeling approach to tackling the inevitable uncertainties facing vaccine rollout. The authors found that although one-dose strategies generally reduce infections in the short term, in the long term, the outcome depends on immune robustness. A one-dose strategy may increase the potential for antigenic evolution if immune responses are suboptimal and the virus continues to replicate in some vaccinated people, potentially leading to immune-escape mutations. It is critical to gather serological data from vaccinated people and, to avoid negative outcomes, to ramp up vaccination efforts worldwide.

Science
, this issue p.
363
The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps
Authors: Apel Falko , Andreeva Liudmila , Knackstedt Lorenz Sebastian , Streeck Robert , Frese Christian Karl , Goosmann Christian , Hopfner Karl-Peter , Zychlinsky Arturo
Published: March 2021

Upon phagocytosis by macrophages, components of neutrophil extracellular traps stimulate type I interferon production.
In Vitro
Activity of Rifamycin Derivatives against Nontuberculous Mycobacteria, Including Macrolide- and Amikacin-Resistant Clinical Isolates
Authors: Kim Dae Hun , Kim Su-Young , Huh Hee Jae , Lee Nam Yong , Koh Won-Jung , Jhun Byung Woo
Published: March 2021

We evaluated the
in vitro
activity of rifamycin derivatives, including rifampin, rifapentine, rifaximin, and rifabutin, against clinical nontuberculous mycobacteria (NTM) isolates. Of the rifamycin derivatives, rifabutin showed the lowest MICs against all NTM species, including
Mycobacterium avium
complex,
M. abscessus
, and
M. kansasii
.
Integrative and Conjugative Element-Mediated Azithromycin Resistance in Multidrug-Resistant Salmonella enterica Serovar Albany
Authors: Hong Yu-Ping , Chen Ying-Tsong , Wang You-Wun , Chen Bo-Han , Teng Ru-Hsiou , Chen Yi-Syong , Chiou Chien-Shun
Published: March 2021

We identified an
erm42
-carrying integrative and conjugative element, ICE_erm42, in 26.4% of multidrug-resistant
Salmonella enterica
serovar Albany isolates recovered from cases of human salmonellosis between 2014 and 2019 in Taiwan. ICE_erm42-carrying strains displayed high-level resistance to azithromycin, and the element could move into the phylogenetically distant species
Vibrio cholerae
via conjugation.
Stratigraphy, age, and provenance of the Eocene Chumstick basin, Washington Cascades; implications for paleogeography, regional tectonics, and development of strike-slip basins
Authors: Donaghy Erin E. , Umhoefer Paul J. , Eddy Michael P. , Miller Robert B. , LaCasse Taylor
Published: March 2021

Strike-slip faults form in a wide variety of tectonic settings and are a first-order control on the geometry and sediment accumulation patterns in adjacent sedimentary basins. Although the structural and depositional architecture of strike-slip basins is well documented, few studies of strike-slip basins have integrated depositional age, lithofacies, and provenance control within this context. The Chumstick basin formed in central Washington during a regional phase of dextral, strike-slip faulting and episodic magmatism associated with Paleogene ridge-trench interaction along the North America margin. The basin is bounded and subdivided by major strike-slip faults that were active during deposition of the intra-basinal, non-marine Chumstick Formation. We build on the existing stratigraphy and present new, detailed lithofacies mapping, conglomerate clast counts (N = 16; n = 1429), and sandstone detrital zircon analyses (N = 16; n = 1360) from the Chumstick Formation to document changes in sediment provenance, routing, and deposition. These data allow us to reconstruct regional Eocene paleo-drainage systems of Washington and Oregon and suggest that drainage within the Chumstick basin fed a regional river system that flowed to a forearc or marginal basin on the newly accreted Siletzia terrane. More generally, excellent age control from five interbedded tuffs and high sediment accumulation rates allow us to track the evolving sedimentary system over the Formation’s ca. 4−5 m.y. depositional history. This is the first time lithofacies and provenance variations can be constrained at high temporal resolution (0.5−1.5 m.y. scale) for an ancient strike-slip basin and permits a detailed reconstruction of sediment routing pathways and depositional environments. As a result, we can assess how varying sediment supply and accommodation space affects the depositional architecture during strike-slip basin evolution.
Randomised trial of epinephrine dose and flush volume in term newborn lambs
Authors: Sankaran Deepika , Chandrasekharan Praveen K , Gugino Sylvia F , Koenigsknecht Carmon , Helman Justin , Nair Jayasree , Mathew Bobby , Rawat Munmun , Vali Payam , Nielsen Lori , Tancredi Daniel J , Lakshminrusimha Satyan
Published: March 2021

Objectives

Neonatal resuscitation guidelines recommend 0.5–1 mL saline flush following 0.01–0.03 mg/kg of epinephrine via low umbilical venous catheter for persistent bradycardia despite effective positive pressure ventilation (PPV) and chest compressions (CC). We evaluated the effects of 1 mL vs 3 mL/kg flush volumes and 0.01 vs 0.03 mg/kg doses on return of spontaneous circulation (ROSC) and epinephrine pharmacokinetics in lambs with cardiac arrest.

Design

Forty term lambs in cardiac arrest were randomised to receive 0.01 or 0.03 mg/kg epinephrine followed by 1 mL or 3 mL/kg flush after effective PPV and CC. Epinephrine (with 1 mL flush) was repeated every 3 min until ROSC or until 20 min. Haemodynamics, blood gases and plasma epinephrine concentrations were monitored.

Results

Ten lambs had ROSC before epinephrine administration and 2 died during instrumentation. Among 28 lambs that received epinephrine, 2/6 in 0.01 mg/kg-1 mL flush, 3/6 in 0.01 mg/kg-3 mL/kg flush, 5/7 in 0.03 mg/kg-1 mL flush and 9/9 in 0.03 mg/kg-3 mL/kg flush achieved ROSC (p=0.02). ROSC was five times faster with 0.03 mg/kg epinephrine compared with 0.01 mg/kg (adjusted HR (95% CI) 5.08 (1.7 to 15.25)) and three times faster with 3 mL/kg flush compared with 1 mL flush (3.5 (1.27 to 9.71)). Plasma epinephrine concentrations were higher with 0.01 mg/kg-3 mL/kg flush (adjusted geometric mean ratio 6.0 (1.4 to 25.7)), 0.03 mg/kg-1 mL flush (11.3 (2.1 to 60.3)) and 0.03 mg/kg-3 mL/kg flush (11.0 (2.2 to 55.3)) compared with 0.01 mg/kg-1 mL flush.

Conclusions

0.03 mg/kg epinephrine dose with 3 mL/kg flush volume is associated with the highest ROSC rate, increases peak plasma epinephrine concentrations and hastens time to ROSC. Clinical trials evaluating optimal epinephrine dose and flush volume are warranted.
Gastric perforation mimicking ST-segment elevation myocardial infarction
Authors: Intan Ryan Enast , Hasibuan Fani Suslina , Gandi Parama , Alkaff Firas F
Published: March 2021

ST-elevation myocardial infarction (STEMI) is one of the medical emergencies in cardiology with high morbidity and mortality rate which requires rapid response. In elderly patients, its presenting symptoms may be atypical which may cause the diagnosis of MI to be delayed or missed. Therefore, ST-segment elevation on ECG has become the main instrument for initial diagnosis. However, there are a variety of conditions mimicking the ECG changes of STEMI. We report a case of 70-year-old patient with acute peritonitis and pneumoperitoneum secondary to gastric perforation with dynamic ECG changes mimicking anteroseptal STEMI. After the surgery, the ECG dynamically reverted to normal. He was then discharged after 4 days without any remaining symptoms. Misinterpretation of ECG findings may lead to unnecessary aggressive intervention, costly management strategies and delay in appropriate treatment.
Extramedullary relapse of multiple myeloma presenting as a breast lump
Authors: Seviar Dale , AlshiekhAli Zainab , Howlett David
Published: March 2021

Multiple myeloma (MM) involving the breast tissue is rare. We report the case of a 70-year-old woman with a background of previously treated MM in remission presenting with a breast lump. Histology showed a plasma cell neoplasm and subsequent staging investigations showed widespread extramedullary relapse of MM. Despite its rarity, this diagnosis should be considered within the differential diagnosis of breast masses as it can arise de novo or may be the first presenting feature of myeloma. The importance of the multidisciplinary team approach with triple assessment of the breast, as well as recent advances in knowledge regarding extramedullary disease in myeloma and novel treatment approaches in MM are discussed.
Hypertrophic cardiomyopathy in an extremely preterm infant
Authors: Aiyengar Apoorva , Howarth Claire , Pereira Sujith
Published: March 2021

We present a case of an extreme preterm infant (Baby X) born at 24-week gestation. The echocardiogram showed evidence of hypertrophic cardiomyopathy (HCM) and a patent ductus arteriosus (PDA). There are a number of well-known causes of neonatal HCM including genetic, metabolic and endocrine. PDA is commonly present in preterm infants, and this can contribute to cardiac remodelling and result in cardiac changes mimicking HCM. Furthermore, medications such as steroids can also cause HCM through various mechanisms. A careful consideration of all the different aetiologies for HCM is important for appropriate management of such cases. This report examines the evidence in the literature for the above differential diagnoses and highlights the challenges in diagnosing the underlying cause of HCM in a preterm infant.
MALT lymphoma and eosinophilic oesophagitis: incidental finding— review of possible factors influencing the aetiopathogenesis of eosinophilic oesophagitis
Authors: Fernandez Manso Beatriz , Barrio Torres Josefa , Martinez Escribano Beatriz , Perez Fernandez Cristina
Published: March 2021

An 11-year-old boy with a history of atopy and allergic rhinitis under treatment with sublingual immunotherapy was referred following several episodes of food impaction. Diagnosis of eosinophilic oesophagitis, chronic gastritis and gastric mucosa-associated lymphoid tissue (MALT) lymphoma associated toHelicobacter pyloriwere confirmed. Results of the extension study were negative and the lymphoma was resolved with eradicating treatment forH. pylori. No improvement was observed in the oesophagitis after the withdrawal of immunotherapy and treatment with high proton pump inhibitor doses or following the omission of several foods to which subclinical sensitisation was confirmed. Oesophagitis was finally resolved by removing cow's milk protein. After 10 years, neither eosinophilic oesophagitis nor MALT lymphoma was observed.

Gastric MALT lymphoma associated toH. pyloriis a rare disorder in children. Although coexistingH. pyloriinfection is common in patients with eosinophilic oesophagitis, the association of gastric MALT lymphoma with eosinophilic oesophagitis has not been reported before.
Subclavian artery aneurysm: a rare cause of massive haemoptysis
Authors: Nathani Alireza , Ghamande Shekhar , Sanchez Juan F , White Heath D
Published: March 2021

A 35-year-old man was admitted to the intensive care unit with massive haemoptysis. CT of the chest revealed a necrotic right upper lobe mass. Angiography of his thoracic vasculature revealed a pseudoaneurysm in the right subclavian artery with active contrast extravasation. This anatomic deformity was stented and coiled with the assistance of interventional radiology. Bronchoscopy with lavage and brushings of the right upper lobe mass revealed fungal hyphae and positive galactomannan, supporting that the patient developed invasive pulmonary aspergillosis leading to a mycotic pseudoaneurysm of the right subclavian artery followed by massive haemoptysis.
Real-world experience of using ciclosporin-A 0.1% in the management of ocular surface inflammatory diseases
Authors: Deshmukh Rashmi , Ting Darren Shu Jeng , Elsahn Ahmad , Mohammed Imran , Said Dalia G , Dua Harminder Singh
Published: March 2021

Purpose

To report the real-world experience of using topical ciclosporin, Ikervis, in the management of ocular surface inflammatory diseases (OSIDs).

Methods

This was a retrospective study of patients treated with Ikervis for OSIDs at the Queen’s Medical Centre, Nottingham, between 2016 and 2019. Relevant data, including demographics, indications, clinical parameters, outcomes and adverse events, were collected and analysed for patients who had completed at least 6 months follow-up. For analytic purpose, clinical outcome was categorised as ‘successful’ (resolved or stable disease), ‘active disease’ and ‘drug intolerance’.

Results

463 patients were included; mean age was 51.1±21.6 years, with a 59.0% female predominance. Mean follow-up was 14.6±9.2 months. The most common diagnosis was dry eye disease (DED; 322, 69.5%), followed by allergic eye disease (AED; 53, 11.4%) and ocular mucous membrane pemphigoid/Steven-Johnson syndrome (OMMP/SJS; 38, 8.2%). Successful treatment was achieved in 343 (74.1%) patients, with 44 (9.5%) requiring additional treatment and 76 (16.4%) reporting drug intolerance. The efficacy of Ikervis was highest in DED (264, 82.0%), followed by OMMP/SJS (25, 65.8%) and post-keratoplasty (7, 50.0%; p<0.001). Logistic regression analysis demonstrated age <70 years (p=0.007), AED (p=0.002) and OMMP/SJS (p=0.001) as significant predictive factors for Ikervis intolerance. AED and post-keratoplasty were 8.16 times (95% CI, 2.78 to 23.99) and 13.98 times (95% CI, 4.22 to 46.28), respectively, more likely to require additional treatment compared with DED.

Conclusions

Ikervis is a useful steroid-sparing topical treatment for managing OSIDs in the real-world setting. Preparations with improved tolerability are needed to benefit a larger number of patients.
Oxidized LDL, insulin sensitivity and beta-cell function in newborns
Authors: Fang Fang , Nuyt Anne Monique , Garofalo Carole , Zhang Jun , Julien Pierre , Fraser William , Levy Emile , Luo Zhong-Cheng
Published: March 2021

Introduction

Oxidized low-density lipoprotein (OxLDL), a biomarker of oxidative stress, itself possesses proatherogenic and proinflammatory effects. Elevated circulating OxLDL levels have been consistently associated with insulin resistance and diabetes in adults. We sought to assess whether OxLDL may be associated with insulin sensitivity and beta-cell function in early life.

Research design and methods

In a birth cohort study, we assessed cord plasma OxLDL concentration and OxLDL to total LDL ratio in relation to glucose to insulin ratio (an indicator of fetal insulin sensitivity), proinsulin to insulin ratio (an indicator of fetal beta-cell function), and leptin and adiponectin concentrations in 248 singleton newborns.

Results

Cord plasma OxLDL concentration was positively correlated with glucose to insulin ratio (r=0.24, p<0.001) and proinsulin to insulin ratio (r=0.20, p<0.001) and was not correlated with leptin or adiponectin. Adjusting for maternal and neonatal characteristics, each log unit increase in cord plasma OxLDL concentration was associated with a 25.8% (95% CI 12.8% to 40.3%) increase in glucose to insulin ratio and a 19.0% (95% CI 6.8% to 32.9%) increase in proinsulin to insulin ratio, respectively. Similar associations were observed for cord plasma OxLDL to LDL ratio in relation to cord plasma glucose to insulin ratio and proinsulin to insulin ratio.

Conclusions

Higher OxLDL levels were associated with lower fetal beta-cell function (higher proinsulin to insulin ratio) but higher insulin sensitivity (higher glucose to insulin ratio). The study is the first to demonstrate that OxLDL may affect glucose metabolic health in early life in humans.
Change in time spent visiting and experiences of green space following restrictions on movement during the COVID-19 pandemic: a nationally representative cross-sectional study of UK adults
Authors: Burnett Hannah , Olsen Jonathan R , Nicholls Natalie , Mitchell Richard
Published: March 2021

Objectives

Green space positively influences health and well-being; however, inequalities in use of green space are prevalent. Movement restrictions enforced due to the COVID-19 pandemic could have exacerbated existing inequalities regarding who visits green space. Therefore, this study aimed to explore how movement restrictions have changed the time spent visiting green space and experience of green space in the United Kingdom (UK) and how these differed by individual-level demographic characteristics.

Design and outcome measures

A nationally representative cross-sectional survey administered through YouGov between 30 April and 1 May 2020. Data were collected on the time spent visiting green space and change in the experience of green space, including missing social interaction, increased physical activity and feeling greater mental health benefits in green space. Demographic information was collected on sex, age, ethnicity, social grade and dog ownership. Associations between specific outcome variables and predictors were assessed using logistic regression.

Setting

UK, with population weights applied.

Participants

2252 adults aged 18 years and over.

Results

Overall, 63% of respondents reported a decrease in time spent visiting green space following movement restrictions. Lower social grade respondents were less likely to visit green space before and after restrictions were enforced (OR: 0.35 (95% CI 0.24 to 0.51); OR: 0.77 (95% CI 0.63 to 0.95)). Female respondents were more likely than male respondents to agree that green space benefited their mental health more following restrictions (PP: 0.70 vs 0.59). Older (65+ years) respondents were less likely than middle-aged (25–64 years) respondents to have visited green space following the restrictions (OR: 0.79 (95% CI 0.63 to 0.98)).

Conclusions

Inequalities in green space use were sustained, and possibly exacerbated, during movement restrictions. Our findings emphasise the importance of green spaces remaining open globally in any future ‘lockdowns’/pandemics. Further investigation is required to determine how visit patterns and experiences change through the different stages of the COVID-19 pandemic in the UK.
Suicide as an incident of severe patient harm: a retrospective cohort study of investigations after suicide in Swedish healthcare in a 13-year perspective
Authors: Fröding Elin , Gäre Boel Andersson , Westrin Åsa , Ros Axel
Published: March 2021

Objectives

To explore how mandatory reporting to the supervisory authority of suicides among recipients of healthcare services has influenced associated investigations conducted by the healthcare services, the lessons obtained and whether any suicide-prevention-related improvements in terms of patient safety had followed.

Design and settings

Retrospective study of reports from Swedish primary and secondary healthcare to the supervisory authority after suicide.

Participants

Cohort 1: the cases reported to the supervisory authority in 2006, from the time the reporting of suicides became mandatory, to 2007 (n=279). Cohort 2: the cases reported in 2015, a period of well-established reporting (n=436). Cohort 3: the cases reported from September 2017, which was the time the law regarding reporting was removed, to November 2019 (n=316).

Primary and secondary outcome measures

Demographic data and received treatment in the months preceding suicide were registered. Reported deficiencies in healthcare and actions were categorised by using a coding scheme, analysed per individual and aggregated per cohort. Separate notes were made when a deficiency or action was related to a healthcare-service routine.

Results

The investigations largely adopted a microsystem perspective, focusing on final patient contact, throughout the overall study period. Updating existing or developing new routines as well as educational actions were increasingly proposed over time, while sharing conclusions across departments rarely was recommended.

Conclusions

The mandatory reporting of suicides as potential cases of patient harm was shown to be restricted to information transfer between healthcare providers and the supervisory authority, rather than fostering participative improvement of patient safety for suicidal patients.

The similarity in outcomes across the cohorts, regardless of changes in legislation, suggests that the investigations were adapted to suit the structure of the authority’s reports rather than the specific incident type, and that no new service improvements or lessons are being identified.
Gut microbiota modulates COPD pathogenesis: role of anti-inflammatoryParabacteroides goldsteiniilipopolysaccharide
Authors: Lai Hsin-Chih , Lin Tzu-Lung , Chen Ting-Wen , Kuo Yu-Lun , Chang Chih-Jung , Wu Tsung-Ru , Shu Ching-Chung , Tsai Ying-Huang , Swift Simon , Lu Chia-Chen
Published: March 2021

Objective

Chronic obstructive pulmonary disease (COPD) is a global disease characterised by chronic obstruction of lung airflow interfering with normal breathing. Although the microbiota of respiratory tract is established to be associated with COPD, the causality of gut microbiota in COPD development is not yet established. We aimed to address the connection between gut microbiota composition and lung COPD development, and characterise bacteria and their derived active components for COPD amelioration.

Design

A murine cigarette smoking (CS)-based model of COPD and strategies evaluating causal effects of microbiota were performed. Gut microbiota structure was analysed, followed by isolation of target bacterium. Single cell RNA sequencing, together with sera metabolomics analyses were performed to identify host responsive molecules. Bacteria derived active component was isolated, followed by functional assays.

Results

Gut microbiota composition significantly affects CS-induced COPD development, and faecal microbiota transplantation restores COPD pathogenesis. A commensal bacteriumParabacteroides goldsteiniiwas isolated and shown to ameliorate COPD. Reduction of intestinal inflammation and enhancement of cellular mitochondrial and ribosomal activities in colon, systematic restoration of aberrant host amino acids metabolism in sera, and inhibition of lung inflammations act as the important COPD ameliorative mechanisms. Besides, the lipopolysaccharide derived fromP. goldsteiniiis anti-inflammatory, and significantly ameliorates COPD by acting as an antagonist of toll-like receptor 4 signalling pathway.

Conclusion

The gut microbiota–lung COPD axis was connected. A potentially benefial bacterial strain and its functional component may be developed and used as alternative agents for COPD prevention or treatment.
Racial differences in management and outcomes of acute myocardial infarction during COVID-19 pandemic
Authors: Rashid Muhammad , Timmis Adam , Kinnaird Tim , Curzen Nick , Zaman Azfar , Shoaib Ahmad , Mohamed Mohamed O , de Belder Mark A , Deanfield John , Martin Glen Philip , Wu Jianhua , Gale Chris P , Mamas Mamas
Published: March 2021

Objective

There are concerns that healthcare and outcomes of black, Asian and minority ethnic (BAME) communities are disproportionately impacted by the COVID-19 pandemic. We investigated admission rates, treatment and mortality of BAME with acute myocardial infarction (AMI) during COVID-19.

Methods

Using multisource national healthcare records, patients hospitalised with AMI in England during 1 February–27 May 2020 were included in the COVID-19 group, whereas patients admitted during the same period in the previous three consecutive years were included in a pre-COVID-19 group. Multilevel hierarchical regression analyses were used to quantify the changes in-hospital and 7-day mortality in BAME compared with whites.

Results

Of 73 746 patients, higher proportions of BAME patients (16.7% vs 10.1%) were hospitalised with AMI during the COVID-19 period compared with pre-COVID-19. BAME patients admitted during the COVID-19 period were younger, male and likely to present with ST-elevation acute myocardial infarction. COVID-19 BAME group admitted with non-ST-elevation acute myocardial infarction less frequently received coronary angiography (86.1% vs 90.0%, p<0.001) and had a longer median delay to reperfusion (4.1 hours vs 3.7 hours, p<0.001) compared with whites. BAME had higher in-hospital (OR 1.68, 95% CI 1.27 to 2.28) and 7-day mortality (OR 1.81 95% CI 1.31 to 2.19) during COVID-19 compared with pre-COVID-19 period.

Conclusion

In this multisource linked cohort study, compared with whites, BAME patients had proportionally higher hospitalisation rates with AMI, less frequently received guidelines indicated care and had higher early mortality during COVID-19 period compared with pre-COVID-19 period. There is a need to develop clinical pathways to achieve equity in the management of these vulnerable populations.
Association of state-level intoxicated driving laws with firearm homicide and suicide
Authors: Tessler Robert A , Haviland Miriam Joan , Bowen Andrew , Bowen Deidre , Rivara Frederick P , Rowhani-Rahbar Ali
Published: March 2021

Objectives

To determine if an association exists between the number of driving under the influence (DUI) convictions required to activate federal firearms prohibitions and annual firearm homicide and suicide rates by state.

Methods

Ecological cross-sectional study of all US states from 2013 to 2017. We collected DUI law data from Thomson Reuters Westlaw database and firearm mortality data from the Centers for Disease Control and Prevention Vital Statistics programme.

Results

Five states had laws such that one or two DUI convictions could result in prohibitions to firearms access according to federal law. Four states had no legal framework that would restrict firearms access because of DUI convictions; the remaining states could activate federal restrictions at three or more DUI convictions. Firearm-specific homicide (victimisations) rates were 19% lower among women in states where federal restrictions of firearms access occurred after one or two DUI offences (incidence rate ratio (IRR) 0.81; 95% CI 0.64 to 1.01) and 18% lower in states with firearm prohibitions after three or more offences (IRR 0.82; 95% CI 0.71 to 0.95) compared with the states with no legal framework for prohibiting firearms after DUI convictions. There was no association between number of DUI activations and overall, or firearm-specific, suicide among the entire population (men and women) or among only women, or only men.

Conclusions

DUI penalties that activate federal firearms prohibitions may be one pathway to reduce firearm homicide of female victims.
Releasing the brakes of tumor immunity with anti-PD-L1 and pushing its accelerator with L19–IL2 cures poorly immunogenic tumors when combined with radiotherapy
Authors: Olivo Pimentel Veronica , Marcus Damiënne , van der Wiel Alexander MA , Lieuwes Natasja G , Biemans Rianne , Lieverse Relinde IY , Neri Dario , Theys Jan , Yaromina Ala , Dubois Ludwig J , Lambin Philippe
Published: March 2021

Background

Poorly immunogenic tumors are hardly responsive to immunotherapies such as immune checkpoint blockade (ICB) and are, therefore, a therapeutic challenge. Combination with other immunotherapies and/or immunogenic therapies, such as radiotherapy (RT), could make these tumors more immune responsive. We have previously shown that the immunocytokine L19–IL2 combined with single-dose RT resulted in 75% tumor remission and a 20% curative abscopal effect in the T cell-inflamed C51 colon carcinoma model. This treatment schedule was associated with the upregulation of inhibitory immune checkpoint (IC) molecules on tumor-infiltrating T cells, leading to only tumor growth delay in the poorly immunogenic Lewis lung carcinoma (LLC) model.

Methods

We aimed to trigger curative therapeutic responses in three tumor models (LLC, C51 and CT26) by “pushing the accelerator” of tumor immunity with L19–IL2 and/or “releasing the brakes” with ICB, such as antibodies directed against cytotoxic T lymphocyte associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), combined with single-dose RT (10 Gy or 5 Gy). Primary tumor endpoint was defined as time to reach four times the size of tumor volume at start of treatment (4T×SV). Multivariate analysis of 4T×SV was performed using the Cox proportional hazards model comparing each treatment group with controls. Causal involvement of T and natural killer (NK) cells in the anti-tumor effect was assessed by in vivo depletion of T, NK or both cell populations. Immune profiling was performed using flow cytometry on single cell suspensions from spleens, bone marrow, tumors and blood.

Results

Combining RT, anti-PD-L1 and L19–IL2 cured 38% of LLC tumors, which was both CD8+ T and NK cell dependent. LLC tumors were resistant to RT +anti-PD-L1 likely explained by the upregulation of other IC molecules and increased T regulatory cell tumor infiltration. RT+L19–IL2 outperformed RT+ICB in C51 tumors; effects were comparable in CT26 tumors. Triple combinations were not superior to RT+L19–IL2 in both these models.

Conclusions

This study demonstrated that combinatorial strategies rationally designed on biological effects can turn immunotherapy-resistant tumors into immunologically responsive tumors. This hypothesis is currently being tested in the international multicentric randomized phase 2 trial: ImmunoSABR (NCT03705403).
Circulating cytokines associated with clinical response to systemic therapy in metastatic renal cell carcinoma
Authors: Chehrazi-Raffle Alexander , Meza Luis , Alcantara Marice , Dizman Nazli , Bergerot Paulo , Salgia Nicholas , Hsu JoAnn , Ruel Nora , Salgia Sabrina , Malhotra Jasnoor , Karczewska Ewa , Kortylewski Marcin , Pal Sumanta
Published: March 2021

Background

Circulating cytokines and angiogenic factors have been associated with clinical outcomes in patients with metastatic renal cell carcinoma (RCC) receiving systemic therapy. However, none have yet examined cytokine concentrations in parallel cohorts receiving either immunotherapy or targeted therapy.

Methods

In this prospective correlative study, we enrolled 56 patients who were planned for treatment with either a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or immune checkpoint inhibitor (ICI). Eligibility requirements permitted any RCC histologic subtype, International Metastatic Renal Cell Carcinoma risk classification, and line of therapy. Immunologic profile was assessed at baseline and after 1 month on treatment using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit was defined as complete response, partial response, or stable disease ≥6 months per RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria.

Results

Clinical benefit was similar between VEGF-TKI and ICI arms (65% vs 54%). Patients with clinical benefit from VEGF-TKIs had lower pretreatment levels of interleukin-6 (IL-6) (p=0.02), IL-1RA (p=0.03), and granulocyte colony-stimulating factor (CSF) (p=0.02). At 1 month, patients with clinical benefit from ICIs had higher levels of interferon-γ (IFN-γ) (p=0.04) and IL-12 (p=0.03). Among patients on VEGF-TKIs, those with clinical benefit had lower 1 month IL-13 (p=0.02) and granulocyte macrophage CSF (p=0.01) as well as higher 1 month VEGF (p=0.04) compared with patients with no clinical benefit.

Conclusion

For patients receiving VEGF-TKI or ICI therapy, distinct plasma cytokines were associated with clinical benefit. Our findings support additional investigation into plasma cytokines as biomarkers in metastatic RCC.
Early factors associated with later conversion to multiple sclerosis in patients presenting with isolated myelitis
Authors: Murphy Olwen C. , Mukharesh Loulwah , Salazar-Camelo Andrea , Pardo Carlos A. , Newsome Scott D.
Published: March 2021

Objective

To identify early clinical and paraclinical factors that may help predict later conversion to multiple sclerosis (MS) in patients presenting with isolated myelitis (ie, ‘transverse myelitis’ without clinical or radiological evidence of inflammation/demyelination elsewhere in the central nervous system).

Methods

In this retrospective cohort study, we included patients with isolated myelitis who were followed clinically and radiologically at our specialised myelopathy clinic. We excluded patients with MS at the onset, aquaporin-4-IgG seropositivity, myelin oligodendrocyte glycoprotein-IgG seropositivity or other identified aetiology. Logistic regression was used to identify factors predictive of conversion to MS (defined by the 2017 McDonald criteria).

Results

We included 100 patients, followed for a median of 4.3 years. Conversion to MS occurred in 25 of 77 patients (32%) with short-segment myelitis (longest lesion spanning <3 vertebral segments on MRI) as compared with 0 of 23 patients (0%) with longitudinally extensive myelitis (p=0.002). Among patients with short-segment myelitis, factors identified as highly predictive of conversion to MS using multivariate logistic regression included cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCB) (OR (OR) 9.2, 95% CI 2.1 to 41.0, p=0.004), younger age (OR 1.1 for each year younger, 95% CI 1.0 to 1.1, p=0.04) and longer follow-up (OR 1.3 for each year longer, 95% CI 1.0 to 1.6, p=0.04). Conversion to MS occurred at a median of 2.8 years after myelitis onset.

Conclusions

Short-segment MRI cord lesion(s), CSF-restricted OCB, younger age and longer follow-up are all factors predictive of conversion to MS in patients presenting with isolated myelitis.