bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced Quaternary exhumation in the Namche Barwa syntaxis, eastern Himalaya
Authors: Yang Rong , Herman Frédéric , Liu Ting , Biswas Rabiul Haque , Fellin Maria Giuditta , Tian Yuntao , Gong Junfeng , Jiao Ruohong , Maden Colin , Chen Hanlin
Published: April 2021

The Namche Barwa syntaxis in the eastern Himalaya is rapidly evolving in terms of its tectonics and topography. Here we constrain the exhumation history of the Yigong River to the immediate north of the syntaxis across different time scales using a multidisciplinary approach. Our new thermochronometric data reveal an acceleration of exhumation rates since 2 Ma in the downstream of the Yigong. Cosmogenic nuclides and thermoluminescence thermochronometry analyses confirm persistent rapid exhumation in the lower Yigong over the Quaternary with further increased exhumation in the last 100 ka. Together with the analysis of the morphology of the Yigong River profile, we interpret that northward expansion of the syntaxis together with capture of the Yigong by the Yarlung Tsangpo River during this expansion is responsible for the exhumation history of the Yigong River in the Quaternary.
Diapiric relamination of the Orocopia Schist (southwestern U.S.) during low-angle subduction
Authors: Chapman James B.
Published: April 2021

The Orocopia Schist and related schists are sediments subducted during the Laramide orogeny and are thought to have been underplated as a laterally extensive layer at the base of the crust in the southwestern United States Cordillera. This concept is hard to reconcile with the existence of continental mantle lithosphere in southeastern California and western Arizona. Analytical solutions and numerical modeling suggest that the Orocopia Schist may have ascended through the mantle lithosphere as sediment diapirs or subsolidus crustal plumes to become emplaced in the middle to lower crust. Modeled time-temperature cooling paths are consistent with the exhumation history of the Orocopia Schist and explain an initial period of rapid cooling shortly after peak metamorphism. The Orocopia Schist represents a potential example of relaminated sediment observable at the surface.
The spatial and temporal evolution of the Portland and Tualatin forearc basins, Oregon, USA
Authors: Scanlon Darby P. , Bershaw John , Wells Ray E. , Streig Ashley R.
Published: April 2021

The Portland and Tualatin basins are part of the Salish-Puget-Willamette Lowland, a 900-km-long, forearc depression lying between the volcanic arc and the Coast Ranges of the Cascadia convergent margin. Such inland seaways are characteristic of warm, young slab subduction. We analyzed the basins to better understand their evolution and relation to Coast Range history and to provide an improved tectonic framework for the Portland metropolitan area. We model three key horizons in the basins: (1) the top of the Columbia River Basalt Group (CRBG), (2) the bottom of the CRBG, and (3) the top of Eocene basement. Isochore maps constrain basin depocenters during (1) Pleistocene to mid-Miocene time (0–15 Ma), (2) CRBG (15.5–16.5 Ma), and (3) early Miocene to late Eocene (ca. 17–35 Ma) time. Results show that the Portland and Tualatin basins have distinct mid-Miocene to Quaternary depocenters but were one continuous basin from the Eocene until mid-Miocene time. A NW-striking gravity low coincident with the NW-striking, fault-bounded Portland Hills anticline is interpreted as an older graben coincident with observed thickening of CRBG flows and underlying sedimentary rocks. Neogene transpression in the forearc structurally inverted the Sylvan-Oatfield and Portland Hills normal faults as high-angle dextral-reverse faults, separating the Portland and Tualatin basins. An eastward shift of the forearc basin depocenter and ten-fold decrease in accommodation space provide temporal constraints on the emergence of the Coast Range to the west. Clockwise rotation and northward transport of the forearc is deforming the basins and producing local earthquakes beneath the metropolitan area.
Secular variations of magma source compositions in the North Patagonian batholith from the Jurassic to Tertiary: Was mélange melting involved?
Authors: Castro Antonio , Rodriguez Carmen , Fernández Carlos , Aragón Eugenio , Pereira Manuel Francisco , Molina José Francisco
Published: April 2021

This study of Sr-Nd initial isotopic ratios of plutons from the North Patagonian batholith (Argentina and Chile) revealed that a secular evolution spanning 180 m.y., from the Jurassic to Neogene, can be established in terms of magma sources, which in turn are correlated with changes in the tectonic regime. The provenance and composition of end-member components in the source of magmas are represented by the Sr-Nd initial isotopic ratios (87Sr/86Sr and 143Nd/144Nd) of the plutonic rocks. Our results support the interpretation that source composition was determined by incorporation of varied crustal materials and trench sediments via subduction erosion and sediment subduction into a subduction channel mélange. Subsequent melting of subducted mélanges at mantle depths and eventual reaction with the ultramafic mantle are proposed as the main causes of batholith magma generation, which was favored during periods of fast convergence and high obliquity between the involved plates. We propose that a parental diorite (= andesite) precursor arrived at the lower arc crust, where it underwent fractionation to yield the silicic melts (granodiorites and granites) that formed the batholiths. The diorite precursor could have been in turn fractionated from a more mafic melt of basaltic andesite composition, which was formed within the mantle by complete reaction of the bulk mélanges and the peridotite. Our proposal follows model predictions on the formation of mélange diapirs that carry fertile subducted materials into hot regions of the suprasubduction mantle wedge, where mafic parental magmas of batholiths originate. This model not only accounts for the secular geochemical variations of Andean batholiths, but it also avoids a fundamental paradox of the classical basalt model: the absence of ultramafic cumulates in the lower arc crust and in the continental crust in general.
Intracranial thrombosis associated with MSSA bacteraemia in the setting of influenza A
Authors: Raghavan Sairam , Gonakoti Sriram , Parra-Rodriguez Luis
Published: April 2021

The authors present a case of a 42-year-old previously healthy man who presented in sepsis, with right lateral gaze palsy. He was found to have bilateral cavernous sinus thrombosis (CST) and bilateral internal jugular thrombosis in the setting ofStaphylococcus aureusbacteraemia. The patient was successfully treated and recovered from his illness after a protracted stay in the medical intensive care unit. We go over the treatment course and follow-up of this patient and discuss the need to have a high degree of clinical suspicion for CST and suppurative thrombophlebitis of the internal jugular veins. We also discuss the possible role of the Panton-Valentine leukocidin in causing thrombotic complications ofS. aureusbacteraemia.
Protein-losing enteropathy in an infant with severe atopic dermatitis
Authors: Fujita Yuji , Nomura Kohei , Yoshihara Shigemi
Published: April 2021

Severe atopic dermatitis (AD) may lead to various complications such as hypoproteinaemia. We describe the case of a 7-month-old male infant with severe AD complicated with protein-losing enteropathy (PLE). He was diagnosed with AD at 2 months of age; however, because of familial steroid phobia, topical corticosteroids were not administered. At 7 months of age, he was admitted to our hospital for decreased feeding, diarrhoea, reduced urine volume and recurrent vomiting. Class 3 topical corticosteroid treatment was initiated. On day 3, eczema had almost resolved. However, serum protein levels had not improved; oliguria persisted and oedema worsened. Serum albumin scintigraphy revealed radioisotopes in the distal duodenum, leading to PLE diagnosis. Systemic prednisolone and albumin were administered, with no PLE relapse after discontinuation. To our knowledge, only two infant PLE cases associated with AD were reported to date. PLE should be considered in patients with severe AD and persistent hypoproteinaemia.
Aeromonas hydrophilaendogenous endophthalmitis in a patient with underlying adenocarcinoma of the colon
Authors: Sharpless Michael , Sharma Richa
Published: April 2021

An 83-year-old man presented with a red right eye, rapidly deteriorating vision and no history of ocular trauma or surgery. The patient had no vitritis on presentation, which confounded a diagnosis. Vitreous tap and injection of intravitreal antibiotics was performed day 2, however, the eye could not be saved and was surgically removed. Tissue culture reportedAeromonashydrophila as the infective organism. Investigation into the source of infection revealed mural thickening of the caecum with CT of the abdomen. On completion of antibiotic treatment, the patient was referred for a colonoscopy, which revealed low grade adenocarcinoma of the colon, and subsequently underwent laparoscopic hemicolectomy. While the source of infection was unable to be identified, it is possible the infection seeded from the patients underlying malignancy. This case demonstrates the importance of thoroughly investigating patients withA. hydrophilaendogenous endophthalmitis, as it can be an indication of underlying malignancy.
Neonatal amygdala microstructure mediates the relationship between gestational glycemia and offspring adiposity
Authors: Cai Shirong , Aris Izzuddin M , Yuan Wen Lun , Tan Kok Hian , Godfrey Keith M , Gluckman Peter D , Shek Lynette Pei-Chi , Chong Yap-Seng , Yap Fabian , Fortier Marielle V , Meaney Michael J , Lee Yung Seng , Qiu Anqi
Published: April 2021

Introduction

To determine if variations in the neonatal amygdala mediate the association between maternal antenatal glycemia and offspring adiposity in early childhood.

Research design and methods

123 non-obese pregnant women with no pregnancy complications aside from gestational diabetes underwent a 75 g 2-hour oral glucose tolerance test at 26–28 weeks’ gestation. Volume and fractional anisotropy (FA) of the neonatal amygdala (5–17 days old) were measured by MRI. The Body Mass Index (BMI) z-scores and sum of skinfold thickness (subscapular and triceps) of these children were tracked up to 60 months of age (18, 24, 36, 48, 54 and 60 months).

Results

Maternal fasting glucose levels were positively associated with the offspring’s sum of skinfold thickness at age 48 months (β=3.12, 95% CI 0.18 to 6.06 mm) and 60 months (β=4.14, 95% CI 0.46 to 7.82 mm) and BMI z-scores at 48 months (β=0.94, 95% CI 0.03 to 1.85), 54 months (β=0.74, 95% CI 0.12 to 1.36) and 60 months (β=0.74, 95% CI 0.08 to 1.39). Maternal fasting glucose was negatively associated with the offspring’s FA of the right amygdala (β=−0.019, 95% CI −0.036 to −0.003). Right amygdala FA was negatively associated with the sum of skinfold thickness in the offspring at age 48 months (β=−56.95, 95% CI −98.43 to −15.47 mm), 54 months (β=−46.18, 95% CI −88.57 to −3.78 mm), and 60 months (β=−53.69, 95% CI −105.74 to −1.64 mm). The effect sizes mediated by right amygdala FA between fasting glucose and sum of skinfolds were estimated at β=5.14 (95% CI 0.74 to 9.53) mm (p=0.022), β=4.40 (95% CI 0.08 to 8.72) (p=0.049) mm and β=4.56 (95% CI −0.17 to 9.29) mm (p=0.059) at 48, 54 and 60 months, respectively.

Conclusions

In the offspring of non-obese mothers, gestational fasting glucose concentration is negatively associated with neonatal right amygdala FA and positively associated with childhood adiposity. Neonatal right amygdala FA may be a potential mediator between maternal glycemia and childhood adiposity.
Variation in hypoglycemia ascertainment and report in type 2 diabetes observational studies: a meta-epidemiological study
Authors: Rodríguez-Gutiérrez René , Salcido-Montenegro Alejandro , González-González José Gerardo , McCoy Rozalina G
Published: April 2021

Introduction

Observational studies constitute an important evidence base for hypoglycemia in diabetes management. This requires consistent and reliable ascertainment and reporting methodology, particularly in studies of type 2 diabetes where hypoglycemia risk is heterogeneous. Therefore, we aimed to examine the definitions of hypoglycemia used by observational studies of patients with type 2 diabetes.

Research design and methods

We conducted a meta-epidemiological review of observational studies reporting on hypoglycemia or evaluating glucose-lowering medications in adults with type 2 diabetes. MEDLINE and Google Scholar were searched from January 1970 to May 2018. The definitions of non-severe, severe and nocturnal hypoglycemia were examined.

Results

We reviewed 243 studies: 47.7% reported on non-severe hypoglycemia, 77.8% on severe hypoglycemia and 16.9% on nocturnal hypoglycemia; 5.8% did not specify. Among 116 studies reporting non-severe hypoglycemia, 18.1% provided no definition, 23.3% used glucose values, 38.8% relied on patient-reported symptoms, 17.2% accepted either glucose values or patient-reported symptoms and 2.6% relied on International Classification of Disease (ICD) codes. Among 189 studies reporting severe hypoglycemia, 11.1% provided no definition, 53.4% required symptoms needing assistance, 3.7% relied on glucose values, 14.8% relied on ICD codes, 2.6% relied on ICD codes or glucose values and 15.9% required both symptoms needing assistance and glucose values. Overall, 38.2% of non-severe and 67.7% of severe hypoglycemia definitions were consistent with the International Hypoglycemia Study Group.

Conclusions

The marked heterogeneity in how hypoglycemia is defined in observational studies may contribute to the inadequate understanding and correction of hypoglycemia risk factors among patients with type 2 diabetes.
Metabolites in the association between early-life famine exposure and type 2 diabetes in adulthood over a 5-year follow-up period
Authors: Wang Yuying , Xia Fangzhen , Wan Heng , Chen Chi , Chen Yi , Zhang Wen , Wang Ningjian , Lu Yingli
Published: April 2021

Introduction

Exposure to malnutrition in early life has been found to significantly elevate type 2 diabetes risk in adulthood. However, the changes in metabolites resulting from malnutrition in early life have not been studied. The aim of this study was to identify metabolites with levels associated with type 2 diabetes resulting from exposure to China’s Great Famine (1959–1962).

Research design and methods

Participants were from SPECT-China 2014 and SPECT-China2 2019, two cross-sectional studies performed at the same site. In total, 2171 subjects participated in SPECT-China and SPECT-China2 simultaneously. The sample size of fetal-exposed (1959–1962) versus non-exposed (1963–1974) individuals was 82 vs 79 in 2014 and 97 vs 94 in 2019. Metabolomic profiling was performed between famine-exposed and non-exposed groups.

Results

Among the different famine exposure groups, the fetal-exposed group (1959–1962) had the greatest incidence rate (12.5%), with an OR of 2.11 (95% CI 1.01 to 4.44), compared with the non-exposed group (1963–1974). Moreover, compared with those in the non-exposed group (1963–1974), four metabolites (indole-3-carbinol (I3C), phosphatidylcholine (PC) (22:6(4Z,7Z,10Z,13Z,16Z,19Z)/16:1(9Z)), pyrimidine, and PC(16:1(9Z)/22:5(4Z,7Z,10Z,13Z,16Z))) showed significantly lower relative intensities in the famine and diabetes groups both in 2014 and 2019. Pyrimidine significantly mediated the association of famine exposure with diabetes, and I3C marginally mediated this association.

Conclusions

Famine exposure in the fetal period could increase type 2 diabetes risk in adults, even those in their 60s. I3C and pyrimidine are potential mediators of the effects of famine exposure on diabetes development.
Remote care for mental health: qualitative study with service users, carers and staff during the COVID-19 pandemic
Authors: Liberati Elisa , Richards Natalie , Parker Jennie , Willars Janet , Scott David , Boydell Nicola , Pinfold Vanessa , Martin Graham , Dixon-Woods Mary , Jones Peter
Published: April 2021

Objectives

To explore the experiences of service users, carers and staff seeking or providing secondary mental health services during the COVID-19 pandemic.

Design

Qualitative interview study, codesigned with mental health service users and carers.

Methods

We conducted semistructured, telephone or online interviews with a purposively constructed sample; a lived experience researcher conducted and analysed interviews with service users. Analysis was based on the constant comparison method.

Setting

National Health Service (NHS) secondary mental health services in England between June and August 2020.

Participants

Of 65 participants, 20 had either accessed or needed to access English secondary mental healthcare during the pandemic; 10 were carers of people with mental health difficulties; 35 were members of staff working in NHS secondary mental health services during the pandemic.

Results

Experiences of remote care were mixed. Some service users valued the convenience of remote methods in the context of maintaining contact with familiar clinicians. Most participants commented that a lack of non-verbal cues and the loss of a therapeutic ‘safe space’ challenged therapeutic relationship building, assessments and identification of deteriorating mental well-being. Some carers felt excluded from remote meetings and concerned that assessments were incomplete without their input. Like service users, remote methods posed challenges for clinicians who reported uncertainty about technical options and a lack of training. All groups expressed concern about intersectionality exacerbating inequalities and the exclusion of some service user groups if alternatives to remote care are lost.

Conclusions

Though remote mental healthcare is likely to become increasingly widespread in secondary mental health services, our findings highlight the continued importance of a tailored, personal approach to decision making in this area. Further research should focus on which types of consultations best suit face-to-face interaction, and for whom and why, and which can be provided remotely and by which medium.
Impact and feasibility of a tailor-made patient communication quality improvement programme for hospital-based physiotherapists: a mixed-methods study
Authors: Steenbruggen Rudi A , van Heusden-Scholtalbers Linda AG , Hoogeboom Thomas J , Maas Marjo , Brand Paul , Wees Philip van der
Published: April 2021

Background

In tailoring a quality improvement programme for hospital-based physiotherapy, the original use of video recordings was replaced by using the tracer methodology.

Objective

To examine the impact of a tailor-made quality improvement programme addressing patient communication on the professional development of hospital-based physiotherapists, and to evaluate barriers and facilitators as determinants of feasibility of the programme.

Methods

A mixed-methods study was conducted. Participants were clustered in groups per hospital and linked with an equally sized group in a nearby hospital. Within the groups, fixed couples carried out a 2-hour tracer by directly observing each other’s daily work routine. This procedure was repeated 6 months later. Data from feedback forms were analysed quantitatively, and a thematic analysis of transcripts from group interviews was conducted.

Results

Fifty hospital-based physiotherapists from 16 hospitals participated. They rated the impact of the programme on professional development, on a scale from 1 (much improvement needed) to 5 (no improvement needed), as 3.99 (SD 0.64) after the first tracer and 4.32 (SD 0.63) 6 months later; a mean improvement of 0.33 (95% CI 0.16 to 0.50). Participants scored, on a scale ranging from 1 to 5 on barriers and facilitators (feasibility), a mean of 3.45 (SD 0.95) on determinants of innovation, 3.47 (SD 0.86) on probability to use and 2.63 (SD 1.07) on the user feedback list. All participants emphasised the added value of the tracer methodology and mentioned effects on self-reflection and awareness most.

Conclusions

The tailor-made quality improvement programme, based on principles of the tracer methodology, was associated with a significant impact on professional development. Barriers and facilitators as determinants of feasibility of the programme showed the programme being feasible.
The Supportive Care sCore (SCC): trigger alert validation study in solid tumours
Authors: Chastenet Mathilde , Laurain Pierre-Antoine , Salleron Julia , Beuzeboc Philippe , Scotté Florian
Published: April 2021

Objectives

Patients’ needs are still underestimated during the course of cancer. The development of a simple and accessible screening tool to screen supportive care needs is an innovative approach to improve the cancer care pathway. The Supportive Care sCore (SCC) is a new tool developed to trigger alerts on the main supportive care needs, such as social, nutritional, physical, pain or psychological disorders. We aimed to develop and validate the SCC tool in identifying supportive care needs.

Methods

The SCC, the Edmonton Symptom Assessment System (ESAS) and the EuroQol-5 Dimension (EQ-5D) questionnaire (for quality of life) were distributed to patients with cancer over a week in an ambulatory hospital of an oncology department. Acceptability was measured by assessing the fill rate. Validity of alerts generated by the SCC was assessed by their consistency with the ESAS and EQ-5D scores.

Results

One hundred patients were included, with an average age of 67.2 years. Acceptability was good with a fill rate of over 90%. For a priori-defined risk groups by SCC with alert or not, the ESAS symptom score and quality of life differed significantly (p<0.05) between groups. We observed higher ESAS symptom scores in the alert group (nutritional alert-appetite: 4 (SD 2.4) vs 0 (SD 2.6), p<0.001; physical alert-fatigue: 4 (SD 1.7) vs 2 (SD 2.2), p<0.001; psychological alert-depressed: 3.5 (SD 2.7) vs 0 (SD 1.5), p<0.001). Quality of life was poorer in each domain of the EQ-5D in the alert group.

Conclusions

Our study demonstrates the construct validity of SCC, which holds promise in identifying supportive care needs.
Healthcare system impacts of the 2017 Manchester Arena bombing: evidence from a national trauma registry patient case series and hospital performance data
Authors: Dark Paul , Smith Martin , Ziman Harry , Carley Simon , Lecky Fiona
Published: April 2021

Introduction

In response to detonation of an improvised explosive device at the Manchester Arena on 22 May 2017, we aimed to use detailed information about injured patients flowing through hospital healthcare to objectively evaluate the preplanned responses of a regional trauma care system and to show how routinely collected hospital performance data can be used to assess impact on regional healthcare.

Methods

Data about injury severity, management and outcome for patients presenting to hospitals were collated using England’s major trauma registry for 30 days following hospital attendance. System-wide data about hospital performance were collated by National Health Service England’s North West Utilisation Management Unit and presented as Shewhart charts from 15 April 2017 to 25 June 2017.

Results

Detailed information was obtained on 153 patients (109 adults and 44 children) who attended hospital emergency departments after the incident. Within 6 hours, a network of 11 regional trauma care hospitals received a total of 138 patients (90%). For the whole patient cohort, median Injury Severity Score (ISS) was 1 (IQR 1–10) and median New ISS (NISS) was 2 (IQR 1–14). For the 75 patients (49%) attending a major trauma centre, median ISS was 7.5 (IQR 1–14) and NISS was 10 (IQR 3–22). Limb and torso body regions predominated when injuries were classified as major life threatening (Abbreviated Injury Scale>3). Ninety-three patients (61%) required hospital admission following emergency department management, with 21 (14%) requiring emergency damage control surgery and 24 (16%) requiring critical care. Three fatalities occurred during early resuscitative treatment and 150 (98%) survived to day 30. The increased system-wide hospital admissions and care activity was linked to increases in regional hospital care capacity through cancellations of elective surgery and increased community care. Consequently, there were sustained system-wide hospital service improvements over the following weeks.

Conclusions

The systematic collation of injured patient and healthcare system data has provided an objective evaluation of a regional major incident plan and provided insight into healthcare system resilience. Hospital patient care data indicated that a prerehearsed patient dispersal plan at incident scene was implemented effectively.
Non-invasive assessment of fluid responsiveness to guide fluid therapy in patients with sepsis in the emergency department: a prospective cohort study
Authors: Koopmans Nienke K , Stolmeijer Renate , Sijtsma Ben C , van Beest Paul A , Boerma Christiaan E , Veeger Nic J , ter Avest Ewoud
Published: April 2021

Background

Little is known about optimal fluid therapy for patients with sepsis without shock who present to the ED. In this study, we aimed to quantify the effect of a fluid challenge on non-invasively measured Cardiac Index (CI) in patients presenting with sepsis without shock.

Methods

In a prospective cohort study, CI, stroke volume (SV) and systemic vascular resistance (SVR) were measured non-invasively in 30 patients presenting with sepsis without shock to the ED of a large teaching hospital in the Netherlands between May 2018 and March 2019 using the ClearSight system. After baseline measurements were performed, a passive leg raise (PLR) was done to simulate a fluid bolus. Measurements were then repeated 30, 60, 90 and 120 s after PLR. Finally, a standardised 500 mL NaCl 0.9% intravenous bolus was administered after which final measurements were done. Fluid responsiveness was defined as >15% increase in CI after a standardised fluid challenge.

Measurements and main results

Seven out of 30 (23%) patients demonstrated a >15% increase in CI after PLR and after a 500 mL fluid bolus. Fluid responders had a higher estimated glomerular filtration rate (eGFR) (64 (44–78) vs 37 (23–47), p=0.009) but otherwise similar patient and treatment characteristics as non-responders. Baseline measurements of cardiac output (CO), CI, SV and SVR were unrelated to PLR fluid responsiveness. The change in CI after PLR was strongly positive correlated to the change in CI after a 500 mL NaCl 0.9% fluid bolus (r=0.88, p<0.001).

Conclusion

The results of the present study demonstrate that in patients with sepsis in the absence of shock, three out of four patients do not demonstrate a clinically relevant increase in CI after a standardised fluid challenge. Non-invasive CO monitoring in combination with a PLR test has the potential to identify patients who might benefit from fluid resuscitation and may contribute to a better tailored treatment of these patients.
Targeting resistance to radiation-immunotherapy in cold HNSCCs by modulating the Treg-dendritic cell axis
Authors: Knitz Michael W , Bickett Thomas E , Darragh Laurel B , Oweida Ayman J , Bhatia Shilpa , Van Court Benjamin , Bhuvane Shiv , Piper Miles , Gadwa Jacob , Mueller Adam C , Nguyen Diemmy , Nangia Varuna , Osborne Douglas G , Bai Xiyuan , Ferrara Sarah E , Boss Mary-Keara , Goodspeed Andrew , Burchill Matthew A , Tamburini Beth A Jirón , Chan Edward D , Pickering Curtis R , Clambey Eric T , Karam Sana D
Published: April 2021

Background

Numerous trials combining radiation therapy (RT) and immunotherapy in head and neck squamous cell carcinoma (HNSCC) are failing. Using preclinical immune cold models of HNSCC resistant to RT-immune checkpoint inhibitors, we investigate therapeutic approaches of overcoming such resistance by examining the differential microenvironmental response to RT.

Methods

We subjected two HPV-negative orthotopic mouse models of HNSCC to combination RT, regulatory T cells (Treg) depletion, and/or CD137 agonism. Tumor growth was measured and intratumorous and lymph node immune populations were compared among treatment groups. Human gene sets, genetically engineered mouse modelsDEREGandBATF3–/–, flow and time-of-flight cytometry, RNA-Seq, Treg adoptive transfer studies, and in vitro experiments were used to further evaluate the role of dendritic cells (DCs) and Tregs in these treatments.

Results

In MOC2 orthotopic tumors, we find no therapeutic benefit to targeting classically defined immunosuppressive myeloids, which increase with RT. In these radioresistant tumors, supplementing combination RT and Treg depletion with anti-CD137 agonism stimulates CD103+DC activation in tumor-draining lymph nodes as characterized by increases in CD80+and CCR7+DCs, resulting in a CD8 T cell-dependent response. Simultaneously, Tregs are reprogrammed to an effector phenotype demonstrated by increases in interferonγ+, tumor necrosis factorα+, PI3K+, pAKT+and Eomes+populations as well as decreases in CTLA4+and NRP-1+populations. Tumor eradication is observed when RT is increased to an 8 Gy x 5 hypofractionated regimen and combined with anti-CD25+ anti-CD137 treatment. In a human gene set from oral squamous cell carcinoma tumors, high Treg number is associated with earlier recurrence.

Conclusions

Regulating Treg functionality and DC activation status within the lymph node is critical for generating a T cell effector response in these highly radioresistant tumors. These findings underscore the plasticity of Tregs and represent a new therapeutic opportunity for reprogramming the tumor microenvironment in HNSCCs resistant to conventional radioimmunotherapy approaches.
Amino acids and RagD potentiate mTORC1 activation in CD8+ T cells to confer antitumor immunity
Authors: Zhang Yiwen , Hu Hongrong , Liu Weiwei , Yan Shu-Mei , Li Yuzhuang , Tan Likai , Chen Yingshi , Liu Jun , Peng Zhilin , Yuan Yaochang , Huang Wenjing , Yu Fei , He Xin , Li Bo , Zhang Hui
Published: April 2021

Background

In the tumor microenvironment, tumor cells are able to suppress antitumor immunity by competing for essential nutrients, including amino acids. However, whether amino acid depletion modulates the activity of CD8+ tumor-infiltrating lymphocytes (TILs) is unclear.

Method

In this study, we evaluated the roles of amino acids and the Rag complex in regulating mammalian target of rapamycin complex 1 (mTORC1) signaling in CD8+ TILs.

Results

We discovered that the Rag complex, particularly RagD, was crucial for CD8+ T-cell antitumor immunity. RagD expression was positively correlated with the antitumor response of CD8+ TILs in both murine syngeneic tumor xenografts and clinical human colon cancer samples. On RagD deficiency, CD8+ T cells were rendered more dysfunctional, as demonstrated by attenuation of mTORC1 signaling and reductions in proliferation and cytokine secretion. Amino acids maintained RagD-mediated mTORC1 translocation to the lysosome, thereby achieving maximal mTORC1 activity in CD8+ T cells. Moreover, the limited T-cell access to leucine (LEU), overshadowed by tumor cell amino acid consumption, led to impaired RagD-dependent mTORC1 activity. Finally, combined with antiprogrammed cell death protein 1 antibody, LEU supplementation improved T-cell immunity in MC38 tumor-bearing mice in vivo.

Conclusion

Our results revealed that robust signaling of amino acids by RagD and downstream mTORC1 signaling were crucial for T-cell receptor-initiated antitumor immunity. The characterization the role of RagD and LEU in nutrient mTORC1 signaling in TILs might suggest potential therapeutic strategies based on the manipulation of RagD and its upstream pathway.
Does postoperative cognitive decline after coronary bypass affect quality of life?
Authors: Blokzijl Fredrike , Keus Frederik , Houterman Saskia , Dieperink Willem , van der Horst Iwan C C , Reneman Michiel F , Absalom Anthony R , Mariani Massimo A
Published: April 2021

Objective

This study aimed to explore the influence of coronary artery bypass grafting (CABG) on both postoperative cognitive dysfunction and quality of life (QoL) and the association between the two patient-related outcomes.

Methods

In a prospective, observational cohort study, patients with elective, isolated CABG were included. Cognitive function was assessed using the Cogstate computerised cognitive test battery preoperatively, 3 days and 6 months after surgery. QoL was measured preoperatively and at 6 months using the RAND-36 questionnaire including the Physical Component Score (PCS) and the Mental Component Score (MCS). Regression analysis, with adjustment for confounders, was used to evaluate the association between postoperative cognitive dysfunction and QoL.

Results

A total of 142 patients were included in the study. Evidence of persistent cognitive dysfunction was observed in 33% of patients after 6 months. At 6 months, the PCS had improved in 59% and decreased in 21% of patients, and the MCS increased in 49% and decreased in 29%. Postoperative cognitive changes were not associated with QoL scores.

Conclusions

Postoperative cognitive dysfunction and decreased QoL are common 6 months after surgery, although cognitive function and QoL were found to have improved in many patients at 6 months of follow-up. Impaired cognitive function is not associated with impaired QoL at 6 months.

Trial registration number

NCT03774342.
Risk of drug-induced interstitial lung disease in hospitalised patients: a nested case–control study
Authors: Jo Taisuke , Michihata Nobuaki , Yamana Hayato , Morita Kojiro , Ishimaru Miho , Yamauchi Yasuhiro , Hasegawa Wakae , Urushiyama Hirokazu , Uda Kazuaki , Matsui Hiroki , Fushimi Kiyohide , Yasunaga Hideo , Nagase Takahide
Published: April 2021

Introduction

Information on drug-induced interstitial lung disease (DILD) is limited due to its low incidence. This study investigated the frequencies of drug categories with potential risk in patients developing DILD during hospitalisation and analysed the risk of developing DILD associated with each of these drugs.

Methods

Using a Japanese national inpatient database, we identified patients without interstitial pneumonia on admission who developed DILD and required corticosteroid therapy during hospitalisation from July 2010 to March 2016. We conducted a nested case–control study; four controls from the entire non-DILD patient cohort were matched to each DILD case on age, sex, main diagnosis, admission year and hospital. We defined 42 classified categories of drugs with 216 generic names as drugs with potential risk of DILD, and we identified the use of these drugs during hospitalisation for each patient. We analysed the association between each drug category and DILD development using conditional logistic regression analyses.

Results

We retrospectively identified 2342 patients who developed DILD. After one-to-four case–control matching, 1541 case patients were matched with 5677 control patients. Six drug categories were significantly associated with the increased occurrence of DILD. These included epidermal growth factor receptor inhibitors (OR: 16.84, 95% CI 9.32 to 30.41) and class III antiarrhythmic drugs (OR: 7.01, 95% CI 3.86 to 12.73). Statins were associated with reduced risk of DILD (OR: 0.68, 95% CI 0.50 to 0.92).

Conclusions

We demonstrated significant associations between various drug categories and DILD. Our findings provide useful information on drug categories with potential risk to help physicians prevent and treat DILD.
Distance Vertex Identification in Graphs
Authors: Chartrand Gary , Kono Yuya , Zhang Ping
Published: April 2021

A red-white coloring of a nontrivial connected graph [Formula: see text] is an assignment of red and white colors to the vertices of [Formula: see text] where at least one vertex is colored red. Associated with each vertex [Formula: see text] of [Formula: see text] is a [Formula: see text]-vector, called the code of [Formula: see text], where [Formula: see text] is the diameter of [Formula: see text] and the [Formula: see text]th coordinate of the code is the number of red vertices at distance [Formula: see text] from [Formula: see text]. A red-white coloring of [Formula: see text] for which distinct vertices have distinct codes is called an identification coloring or ID-coloring of [Formula: see text]. A graph [Formula: see text] possessing an ID-coloring is an ID-graph. The problem of determining those graphs that are ID-graphs is investigated. The minimum number of red vertices among all ID-colorings of an ID-graph [Formula: see text] is the identification number or ID-number of [Formula: see text] and is denoted by ID([Formula: see text]). It is shown that (1) a nontrivial connected graph [Formula: see text] has ID-number 1 if and only if [Formula: see text] is a path, (2) the path of order 3 is the only connected graph of diameter 2 that is an ID-graph, and (3) every positive integer [Formula: see text] different from 2 can be realized as the ID-number of some connected graph. The identification spectrum of an ID-graph [Formula: see text] is the set of all positive integers [Formula: see text] such that [Formula: see text] has an ID-coloring with exactly [Formula: see text] red vertices. Identification spectra are determined for paths and cycles.
Structural properties of multiple zeta values
Authors: Wakhare Tanay , Vignat Christophe
Published: April 2021

We study some classical identities for multiple zeta values and show that they still hold for zeta functions built from an arbitrary sequence of nonzero complex numbers. We introduce the complementary zeta function of a system, which naturally occurs when lifting identities for multiple zeta values to identities for quasisymmetric functions.
Where Responsible AI meets Reality
Authors: Rakova Bogdana , Yang Jingying , Cramer Henriette , Chowdhury Rumman
Published: April 2021

Large and ever-evolving technology companies continue to invest more time and resources to incorporate responsible Artificial Intelligence (AI) into production-ready systems to increase algorithmic accountability. This paper examines and seeks to offer a framework for analyzing how organizational culture and structure impact the effectiveness of responsible AI initiatives in practice. We present the results of semi-structured qualitative interviews with practitioners working in industry, investigating common challenges, ethical tensions, and effective enablers for responsible AI initiatives. Focusing on major companies developing or utilizing AI, we have mapped what organizational structures currently support or hinder responsible AI initiatives, what aspirational future processes and structures would best enable effective initiatives, and what key elements comprise the transition from current work practices to the aspirational future.
Lessons Learned from Designing an AI-Enabled Diagnosis Tool for Pathologists
Authors: Gu Hongyan , Huang Jingbin , Hung Lauren , Chen Xiang 'Anthony'
Published: April 2021

Despite the promises of data-driven artificial intelligence (AI), little is known about how we can bridge the gulf between traditional physician-driven diagnosis and a plausible future of medicine automated by AI. Specifically, how can we involve AI usefully in physicians' diagnosis workflow given that most AI is still nascent and error-prone (\eg in digital pathology)? To explore this question, we first propose a series of collaborative techniques to engage human pathologists with AI given AI's capabilities and limitations, based on which we prototype Impetus --- a tool where an AI takes various degrees of initiatives to provide various forms of assistance to a pathologist in detecting tumors from histological slides. We summarize observations and lessons learned from a study with eight pathologists and discuss recommendations for future work on human-centered medical AI systems.
YouTube Recommendations and Effects on Sharing Across Online Social Platforms
Authors: Buntain Cody , Bonneau Richard , Nagler Jonathan , Tucker Joshua A.
Published: April 2021

In January 2019, YouTube announced its platform would exclude potentially harmful content from video recommendations while allowing such videos to remain on the platform. While this action is intended to reduce YouTube's role in propagating such content, continued availability of these videos via hyperlinks in other online spaces leaves an open question of whether such actions actually impact sharing of these videos in the broader information space. This question is particularly important as other online platforms deploy similar suppressive actions that stop short of deletion despite limited understanding of such actions' impacts. To assess this impact, we apply interrupted time series models to measure whether sharing of potentially harmful YouTube videos in Twitter and Reddit changed significantly in the eight months around YouTube's announcement. We evaluate video sharing across three curated sets of anti-social content: a set of conspiracy videos that have been shown to experience reduced recommendations in YouTube, a larger set of videos posted by conspiracy-oriented channels, and a set of videos posted by alternative influence network (AIN) channels. As a control, we also evaluate these effects on a dataset of videos from mainstream news channels. Results show conspiracy-labeled and AIN videos that have evidence of YouTube's de-recommendation do experience a significant decreasing trend in sharing on both Twitter and Reddit. At the same time, however, videos from conspiracy-oriented channels actually experience a significant increase in sharing on Reddit following YouTube's intervention, suggesting these actions may have unintended consequences in pushing less overtly harmful conspiratorial content. Mainstream news sharing likewise sees increases in trend on both platforms, suggesting YouTube's suppression of particular content types has a targeted effect. In summary, while this work finds evidence that reducing exposure to anti-social videos within YouTube potentially reduces sharing on other platforms, increases in the level of conspiracy-channel sharing raise concerns about how producers -- and consumers -- of harmful content are responding to YouTube's changes. Transparency from YouTube and other platforms implementing similar strategies is needed to evaluate these effects further.
Using the Lenses of Emotion and Support to Understand Unemployment Discourse on Reddit
Authors: Garg Radhika , Kapadia Yash , Sengupta Subhasree
Published: April 2021

Unemployed individuals experience emotional upheaval and financial constraints, and they struggle to share their challenges and obtain support from their family members and social circles. While prior work has shown that social media platforms enable their users to safely share their turmoil, hardships, and emotional upheavals and seek support, little is known about how the unemployed use such platforms. Based on a mixed-methods analysis of data retrieved from unemployment communities on Reddit, our study reveals that redditors in these communities engage in exchanges that range from queries seeking information about job searching to discussions about sensitive topics such as the health and social implications of unemployment. Also, while redditors use mostly negative emotional tonality in their texts when initiating a new post, the comments in response provide considerable social support in the form of esteem, emotional, informational, network, and instrumental support. Based on these findings, we share the theoretical implications of our work and offer design
The Unique Challenges for Creative Small Businesses Seeking Feedback on Social Media
Authors: Kotturi Yasmine , Blaising Allie , Fox Sarah E. , Kulkarni Chinmay
Published: April 2021

Social media can be an effective source of feedback on open-ended work, such as product design. Unlike large businesses with entire teams dedicated to "social," little is understood about how small business owners-constrained both in personnel and resources-leverage the benefits of direct, informal communication channels afforded by social media. Drawing on a series of design workshops and interviews with 26 small business owners at a local feminist makerspace, we report on the unique challenges small business owners experience when seeking feedback on open-ended work via social media. We found participants carefully balanced large-scale access to diverse audiences with attempts to receive reliable feedback, and they often targeted audiences narrowly to reinstate control and build trust. In addition, the small business owners in our workshop idealized building authentic relationships with their social audiences to create collectively. To do so successfully, participants detailed the extensive behind-the-scenes work required of them such as navigating blurred personal and business identities and the self-regulation necessary to continuously stay engaged and not internalize discouraging feedback.
Modular Politics
Authors: Schneider Nathan , De Filippi Primavera , Frey Seth , Tan Joshua Z. , Zhang Amy X.
Published: April 2021

Governance in online communities is an increasingly high-stakes challenge, and yet many basic features of offline governance legacies-juries, political parties, term limits, and formal debates, to name a few-are not in the feature-sets of the software most community platforms use. Drawing on the paradigm of Institutional Analysis and Development, this paper proposes a strategy for addressing this lapse by specifying basic features of a generalizable paradigm for online governance called Modular Politics. Whereas classical governance typologies tend to present a choice among wholesale ideologies, such as democracy or oligarchy, Modular Politics would enable platform operators and their users to build bottom-up governance processes from computational components that are modular and composable, highly versatile in their expressiveness, portable from one context to another, and interoperable across platforms. This kind of approach could implement pre-digital governance systems as well as accelerate innovation in uniquely digital techniques. As diverse communities share and connect their components and data, governance could occur through a ubiquitous network layer. To that end, this paper proposes the development of an open standard for networked governance.
AI-Mediated Communication
Authors: Mieczkowski Hannah , Hancock Jeffrey T. , Naaman Mor , Jung Malte , Hohenstein Jess
Published: April 2021

AI-Mediated Communication (AI-MC) is interpersonal communication that involves an artificially intelligent system that can modify, augment, or even generate content to achieve communicative and relational goals. AI-MC is increasingly involved in human communication and has the potential to impact core aspects of human communication, such as language production, interpersonal perception and task performance. Through a between-subjects experimental design we examine how these processes are influenced when integrating AI-generated language in the form of suggested text responses (Google's smart replies) into a text-based referential communication task. Our study replicates and extends the impacts of a positivity bias in AI-generated language and introduces the adjacency pair framework into the study of AI-MC. We also find preliminary yet mixed evidence to suggest that AI-generated language has the potential to undermine some dimensions of interpersonal perception, such as social attraction. This study contributes important concepts for future work in AI-MC and offers findings with implications for the design of AI systems in human-to-human communication.