bluuebunny/crossref_metadata_2025 huggingface dataset:
Price, income and exchange rate asymmetric elasticities of oil consumption in Greece, Ireland, Italy, Portugal and Spain
Authors: Uche Emmanuel
Published: February 2022

The dynamic relationship between oil price variations, changing income, exchange rate deviations and oil consumption has preoccupied the minds of many energy researchers albeit contradicting submissions. On this note, this study seeks to evaluate the possible asymmetric impact of the aforementioned variables on oil consumption in selected European countries, including Greece, Ireland, Italy, Portugal and Spain between 2000Q1 and 2018Q4. To that effect, after ascertaining the existence of cointegration, the study applied the nonlinear ARDL technique in evaluating the asymmetric effects of oil price, income and exchange rate on oil consumption in these countries. The cointegration tests reveals a long‐run relationship among the variables in all the countries. Also discovered is an asymmetric pass‐through from oil prices to oil consumption in Portugal, Ireland and Spain. Whereas in Ireland, Italy and Spain, an asymmetric relationship exists between oil consumption and national income, while asymmetric effects flow from the exchange rate to oil consumption in Ireland and Spain. Therefore, to ensure optimal resource allocations in these countries, the existence of asymmetric effects must not be taken for granted. Meanwhile, a one‐size‐fits‐all strategy may not yield the expected results in these countries.
Crude – energy crops nexus in light of biofuel policies: An empirical investigation from India
Authors: Shahani Rakesh , Taneja Anishka , Goel Anusha
Published: February 2022

The present study makes an attempt to empirically investigate the impact of crude prices on energy crops for India (wheat, sugarcane and soybean) during the period Jan 2016–Dec 2020 by taking daily closing spot prices of these energy crops and crude. The models applied to study the relation are autoregressive distributed lag (ARDL) (for linear) and NARDL (for non‐Linear) variables. The study results proved the existence of long‐run co‐integration for wheat (ARDL) and crude and soybean (NARDL). Further, it was also seen that crude was the only variable impacting wheat both in the short and long run. However, co‐integration for sugarcane was not proven by the study. The adjustment towards equilibrium from short‐run dis‐equilibrium was rather slow for wheat (ARDL) and crude (NARDL), both at 0.5 per cent per period while it was at 12 per cent per period for soybean. The short‐run causality tests showed causality moving from crude to wheat. The above results do give an indication that there is a long‐term co‐integration among crude and two energy crops, namely, soybean and wheat, however, these results were not proved for the main crop; sugarcane. Now since the thrust of the government lies on sugarcane to meet its biofuel targets and co‐integration is not being proved under the present study for this crop, it may be concluded that the initial impact of the National Policy on Biofuels is not clearly visible from the results of the study.
Existence and Believability
Authors: Kauss Dominik
Published: February 2022

This paper argues that true singular existentials are rationally indubitable. After the claim is clarified and motivated (Section 1), it is defended against objections inspired by Cartesian skepticism and semantic externalism (Section 2), a Fregean fine‐grained conception of propositional content (Section 3), Kripke's causal theory of reference (Section 4), a Stalnakerian coarse‐grained conception of propositional content (Section 5), as well as Evans's account of descriptive reference fixing (Section 6). The discussion is brought to a close by concluding that either true singular existentials are a priori or apriority is not necessary for rational indubitability (Section 7).
Exploring the utility of nursing student‐led health fairs: Educating the college population
Authors: Matsuda Yui , Halstead Valerie , Falcon Ashley , Valdes Beatriz , Salani Deborah A. , Reaves Régine P.
Published: February 2022

Objective

The purpose of this study is to examine public health nursing (PHN) students’ experiences delivering peer‐to‐peer health education to college students during a health fair.

Design

A qualitative, descriptive research design was used.

Sample

Senior‐level nursing students (n = 13) completing the clinical portion of a PHN course.

Measurements

A semi‐structured focus group guide consisting of 10 questions and follow‐up probes was used to elicit PHN student experiences. Focus groups were recorded, transcribed, and analyzed using a thematic analysis technique.

Results

Five main themes were identified: (1) benefits of health fairs in general, (2) benefits of nursing‐student‐led health fairs, (3) negatives of nursing‐student‐let health fairs, (4) importance of interaction, and (5) suggestions for maximizing the potential of nursing student‐led health fairs.

Conclusions

Although challenges exist, PHN students experienced several benefits from the provision of peer‐to‐peer health education. College campuses represent a unique clinical site that allows nursing students to utilize their insider status to better assess, understand, and provide tailored health education to the college community. This clinical site has shown to provide positive experiences for nursing students and is critical in developing essential nursing skills and building confidence for future clinical rotations.
Association of HLA‐DM and HLA class II genes with antibody response induced by inactivated Japanese encephalitis vaccine
Authors: He Jihong , Chen Jun , Han Xue , Gu Qin , Liang Jiangli , Sun Mingbo , Liu Shuyuan , Yao Yufeng , Shi Li
Published: February 2022

HLA class II molecules, HLA‐DR, DP and DQ, together with HLA II‐like protein DM, play a dominant role in the processing and presentation of antigens, which may influence vaccine effectiveness. We previously demonstrated that variations in the HLA‐DRB1, DPB1 and DQB1 genes may affect the neutralising antibody (NAb) response induced by the inactivated Japanese encephalitis vaccine (IJEV). In the present study, we genotyped HLA‐DPA1, DQA1, DMA and DMB genes and used previous HLA‐DRB1, DPB1 and DQB1 data to evaluate the association of these genes with IJEV‐induced NAbs, at both the seroconversion and geometric mean titres (GMTs). We confirmed the seropositive association of DQB1*02:01 and NAbs (0.156 vs. 0.075, p_adj = 0.018; OR = 2.270; 95% CI = 1.285–3.999) and seronegative association of DQB1*02:02 (0.014 vs. 0.09, p_adj = 0.0002; OR = 0.130; 95% CI = 0.047–0.400). Furthermore, the DMB*01:03–DMA*01:01–DPA1*01:03–DPB1*04:01 haplotype was associated with a negative response (0.020 vs. 0.074; p_adj = 0.03; OR = 0.250; 95% CI = 0.097–0.649), whereas DRB1*15:02–DMB*01:01–DMA*01:01 was associated with a positive response (0.034 vs. 0; p_adj = 0.044). In addition, DRB1*12:02, DRB1*13:02, DPB1*04:01, DPB1*05:01, DPB1*09:01, DQA1*06:01 and DQA1*01:02 were associated with a higher GMT of NAbs, whereas DRB1*11:01, DPB1*13:01 and DQA1*05:05 were associated with a lower GMT of NAbs. In conclusion, the present study suggests that variations in the HLA‐DM and HLA class II genes, as well as their combined allotypes, may influence the IJEV NAbs at seroconversion and GMT levels.
Integrating LGBTQ+ health into medical education
Authors: Raygani Sawye , Mangosing Daryl , Clark Kristen D. , Luong Sean , Flentje Annesa , Sarah Gabriel
Published: February 2022

Background

LGBTQ+ people experience significant barriers in accessing health care including inadequate provider knowledge and stigma in health care settings. Undergraduate medical education programs have increased efforts to integrate LGBTQ+ health topics, such as comprehensive sexual history taking and gender‐affirming practices, into their curriculums to provide clinically inclusive care for LGBTQ+ patients.

Approach

A Topic Steward was appointed to oversee the integration of LGBTQ+ health topics throughout the existing undergraduate medical curriculum. The aim was to expand the LGBTQ+ health curriculum for undergraduate medical students through teaching comprehensive sexual history taking; offering specialty‐specific LGBTQ+ health education through clerkships; describing the difference between sex assigned at birth, gender identity, and gender expression; describing the difference between sexual orientation and sexual behaviour; identifying health care disparities that LGBTQ+ people experience; and developing an inclusive approach to providing medical care for LGBTQ+ patients.

Evaluation

The program started in July 2017 with UCSFSOM students in their first, second, or third years (~150 medical students per year) participating in the integrated curriculum that included didactic lectures, small group discussions, and LGBTQ+ clerkship opportunities. The hours of LGBTQ+ health curriculum at the UCSFSOM increased from 4.5 hours to 15–20 hours in approximately 2 years under the Topic Steward approach.

Implications

The next step is to develop standardised tools for assessing LGBTQ+ health competencies for medical students. This involves integrating more questions regarding LGBTQ+ health topics in traditional exams at UCSFSOM and developing specialty‐specific assessment instruments that other medical schools could administer to test core competencies in LGBTQ+ health.
Decontextualisation for framing effect reduction
Authors: Bou Khalil Rami , Sleilaty Ghassan , Kassab Anthony , Nemr Elie
Published: February 2022

Background

The aim of this study is to demonstrate the presence of a framing effect that influences residents' decision‐making and to assess decontextualisation as an intervention strategy to reduce the influence of framing on their decision.

Methods

This is a randomised controlled trial in which researchers sent an evaluation questionnaire to all residents of … University including clinical vignettes, with questions formulated in two different ways on the same subject and a decontextualisation test involving logical reasoning problems. The researchers then sent to all participants different clinical vignettes evaluating the same dimensions as those addressed in the previous part.

Results

The response rate was 86 (28.2%), of which they included 52 (60.4%) in the analysis. The framing effect was present in 37 (71.1%) of responses and then decreased to 35 (67.3%) after the decontextualisation test, especially at the level of the type of framing involving risky decision‐making (p = 0.03).

Discussion

Decontextualisation is an effective strategy for reducing bias related to the framing effect among residents, particularly the type of framing involving risky decision‐making. In medical teaching, decontextualisation exercises may help improve critical thinking and reduce the framing effect.
Effect of Human Synovial Fluid From Osteoarthritis Patients and Healthy Individuals on Lymphatic Contractile Activity
Authors: Michalaki Eleftheria , Nepiyushchikh Zhanna , Rudd Josephine M. , Bernard Fabrice C. , Mukherjee Anish , McKinney Jay M. , Doan Thanh N. , Willett Nick J. , Dixon J. Brandon
Published: February 2022

The lymphatic system has been proposed to play a crucial role in preventing the development and progression of osteoarthritis (OA). As OA develops and progresses, inflammatory cytokines and degradation by-products of joint tissues build up in the synovial fluid (SF) providing a feedback system to exacerbate disease. The lymphatic system plays a critical role in resolving inflammation and maintaining overall joint homeostasis; however, there is some evidence that the lymphatics can become dysfunctional during OA. We hypothesized that the functional mechanics of lymphatic vessels (LVs) draining the joint could be directly compromised due to factors within SF derived from osteoarthritis patients (OASF). Here, we utilized OASF and SF derived from healthy (non-OA) individuals (healthy SF (HSF)) to investigate potential effects of SF entering the draining lymph on migration of lymphatic endothelial cells (LECs) in vitro, and lymphatic contractile activity of rat femoral LVs (RFLVs) ex vivo. Dilutions of both OASF and HSF containing serum resulted in a similar LEC migratory response to the physiologically endothelial basal medium-treated LECs (endothelial basal medium containing serum) in vitro. Ex vivo, OASF and HSF treatments were administered within the lumen of isolated LVs under controlled pressures. OASF treatment transiently enhanced the RFLVs tonic contractions while phasic contractions were significantly reduced after 1 h of treatment and complete ceased after overnight treatment. HSF treatment on the other hand displayed a gradual decrease in lymphatic contractile activity (both tonic and phasic contractions). The observed variations after SF treatments suggest that the pump function of lymphatic vessel draining the joint could be directly compromised in OA and thus might present a new therapeutic target.
Blast trauma affects production and perception of mouse ultrasonic vocalizations
Authors: Burke Kali , Ohman Kathleen A. , Manohar Senthilvelan , Dent Micheal L.
Published: February 2022

Blast trauma from explosions affects hearing and communication in a significant proportion of soldiers. Many veterans report difficulty communicating, especially in noisy and reverberant environments, which contributes to complex mental health problems including anxiety and depression. However, the relationship between communication and perceptual problems after a blast has received little scientific attention. In the current studies, the effects of blast trauma on the production and perception of ultrasonic vocalizations (USVs) by CBA/CaJ mice, a common animal model for hearing and communication disorders, was explored. Overall, mice change the total number of vocalizations, the proportion produced of each syllable category, and the peak frequency, bandwidth, and duration of their vocalizations after blast exposure. Further, the perception of USVs is affected after blast trauma, with an immediate worsening of detection for most USV categories in the first 1–5 days after blasts, which later recovers. This study is the first to examine changes in the production and perception of communication signals after blast traumas in mice and is an important step towards developing treatments for blast-induced hearing and communication disorders.
Acoustic waveguide based on cascaded Luneburg lens
Authors: Zhao Liuxian , Horiuchi Timothy , Yu Miao
Published: February 2022

This paper investigates the acoustic Luneburg Lens (ALL) as a design framework for guiding acoustic wave propagation. In this study, an acoustic waveguide is proposed based on the characteristics of both acoustic wave focusing and collimation of cascaded ALLs. The continuous variation of the refractive index of the ALL is achieved by using lattice unit cells with a graded filling ratio. A cascaded ALL waveguide device is fabricated based on the additive manufacturing technique. The experimental results obtained with this device are consistent with the numerical simulations and theoretical calculations.
Using Profanity and Negative Sentiments: An Analysis of Ultimate Fighting Championship Fighters’ Trash Talk on Fans’ Social Media Engagement and Viewership Habits
Authors: Tereso Duarte , Moro Sérgio , Ramos Pedro , Calapez Teresa , Costa Joana M. , Ratts Tyler
Published: February 2022

The rise in popularity of combat sports has afforded fighters an enhanced celebrity status, especially across online platforms that provide fans the opportunity to engage with and discuss their favorite athletes. Given this growth, fighters’ behaviors, both inside and outside of the arena, can have a strong influence on fans’ consumption and social media activity. To evaluate this relationship, this study investigated the effect of combat sports fighters’ trash talking on subsequent fans’ behaviors by collecting and analyzing 516 fighter responses during prefight press conferences and 32,360 fan tweets on Twitter during Ultimate Fighting Championship events. Results demonstrated that fights featuring polarizing and popular athletes generated the highest pay-per-view numbers, and higher levels of profanity speech during trash talking were associated with higher engagement in pay-per-view consumption and Twitter usage.
Pore structure controls stability and molecular flux in engineered protein cages
Authors: Adamson Lachlan S. R. , Tasneem Nuren , Andreas Michael P. , Close William , Jenner Eric N. , Szyszka Taylor N. , Young Reginald , Cheah Li Chen , Norman Alexander , MacDermott-Opeskin Hugo I. , O’Mara Megan L. , Sainsbury Frank , Giessen Tobias W. , Lau Yu Heng
Published: February 2022

Protein cages are a common architectural motif used by living organisms to compartmentalize and control biochemical reactions. While engineered protein cages have featured in the construction of nanoreactors and synthetic organelles, relatively little is known about the underlying molecular parameters that govern stability and flux through their pores. In this work, we systematically designed 24 variants of the
Thermotoga maritima
encapsulin cage, featuring pores of different sizes and charges. Twelve pore variants were successfully assembled and purified, including eight designs with exceptional thermal stability. While negatively charged mutations were better tolerated, we were able to form stable assemblies covering a full range of pore sizes and charges, as observed in seven new cryo-EM structures at 2.5- to 3.6-Å resolution. Molecular dynamics simulations and stopped-flow experiments revealed the importance of considering both pore size and charge, together with flexibility and rate-determining steps, when designing protein cages for controlling molecular flux.
New constraints on axion-like dark matter using a Floquet quantum detector
Authors: Bloch Itay M. , Ronen Gil , Shaham Roy , Katz Ori , Volansky Tomer , Katz Or
Published: February 2022

Dark matter is one of the greatest mysteries in physics. It interacts via gravity and composes most of our universe, but its elementary composition is unknown. We search for nongravitational interactions of axion-like dark matter with atomic spins using a precision quantum detector. The detector is composed of spin-polarized xenon gas that can coherently interact with a background dark matter field as it traverses through the galactic dark matter halo. Conducting a 5-month-long search, we report on the first results of the Noble and Alkali Spin Detectors for Ultralight Coherent darK matter (NASDUCK) collaboration. We limit ALP-neutron interactions in the mass range of 4 × 10
−15
to 4 × 10
−12
eV/
c
2
and improve upon previous terrestrial bounds by up to 1000-fold for masses above 4 × 10
−13
eV/
c
2
. We also set bounds on pseudoscalar dark matter models with quadratic coupling.
P2X4 and P2X7 are essential players in basal T cell activity and Ca
2+
signaling milliseconds after T cell activation
Authors: Brock Valerie J. , Wolf Insa M. A. , Er-Lukowiak Marco , Lory Niels , Stähler Tobias , Woelk Lena-Marie , Mittrücker Hans-Willi , Müller Christa E. , Koch-Nolte Friedrich , Rissiek Björn , Werner René , Guse Andreas H. , Diercks Björn-Philipp
Published: February 2022

Initial T cell activation is triggered by the formation of highly dynamic, spatiotemporally restricted Ca
2+
microdomains. Purinergic signaling is known to be involved in Ca
2+
influx in T cells at later stages compared to the initial microdomain formation. Using a high-resolution Ca
2+
live-cell imaging system, we show that the two purinergic cation channels P2X4 and P2X7 not only are involved in the global Ca
2+
signals but also promote initial Ca
2+
microdomains tens of milliseconds after T cell stimulation. These Ca
2+
microdomains were significantly decreased in T cells from

P2rx4
−/−

and

P2rx7
−/−

mice or by pharmacological inhibition or blocking. Furthermore, we show a pannexin-1–dependent activation of P2X4 in the absence of T cell receptor/CD3 stimulation. Subsequently, upon T cell receptor/CD3 stimulation, ATP release is increased and autocrine activation of both P2X4 and P2X7 then amplifies initial Ca
2+
microdomains already in the first second of T cell activation.
Antigen cross-presentation in young tumor-bearing hosts promotes CD8
+
T cell terminal differentiation
Authors: Moustaki Ardiana , Crawford Jeremy Chase , Alli Shanta , Fan Yiping , Boi Shannon , Zamora Anthony E. , McDonald Natalie M. N. , Wu Gang , Nakitandwe Joy , Newman Scott , Foy Scott , Silkov Antonina , Thomas Paul G. , Pappo Alberto , Dyer Michael A. , Stewart Elizabeth , Federico Sara , Youngblood Ben
Published: February 2022

The immune system undergoes a progressive functional remodeling with age. Understanding how age bias shapes antitumor immunity is essential in designing effective immunotherapies, especially for pediatric patients. Here, we explore antitumor CD8
+
T cell responses generated in young (prepubescent) and adult (presenescent) mice. Using an MHCI-deficient tumor model, we observed that tumor-reactive CD8
+
T cells expanded in young tumor-bearing (TB) mice acquired a terminally differentiated phenotype characterized by overexpression of inhibitory receptors and the transcription factor Tox1. Furthermore, tumor-infiltrating CD8
+
T cells from young tumors yielded a poor cytokine response compared with CD8
+
T cells infiltrating adult tumors. Young migratory dendritic cells (migDCs) from the draining lymph nodes (dLNs), and mononuclear phagocytic cells (MPCs) infiltrating young tumors, were more competent in capturing and cross-presenting tumor antigen, leading to enhanced priming of CD8
+
T cells in dLNs and their subsequent terminal differentiation in the tumors. Single-cell transcriptional profiling of tumor-infiltrating MPCs demonstrated that young MPCs are polarized toward an inflammatory, effector phenotype. Consistent with our observations in young versus adult TB mice, analysis of immune infiltrates from pediatric solid tumors showed a correlation between tumor-infiltrating CD8
+
T cells with an exhaustion phenotype and the frequency of PD-L1–expressing monocytes/macrophages. Collectively, these data indicate that a young tissue microenvironment contributes to the generation of an immune response skewed toward a less pliable terminal effector state, thus narrowing the window for immunotherapeutic interventions.
High-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells
Authors: Chen Jennifer S. , Chow Ryan D. , Song Eric , Mao Tianyang , Israelow Benjamin , Kamath Kathy , Bozekowski Joel , Haynes Winston A. , Filler Renata B. , Menasche Bridget L. , Wei Jin , Alfajaro Mia Madel , Song Wenzhi , Peng Lei , Carter Lauren , Weinstein Jason S. , Gowthaman Uthaman , Chen Sidi , Craft Joe , Shon John C. , Iwasaki Akiko , Wilen Craig B. , Eisenbarth Stephanie C.
Published: February 2022

T follicular helper (T
FH
) cells are the conventional drivers of protective, germinal center (GC)–based antiviral antibody responses. However, loss of T
FH
cells and GCs has been observed in patients with severe COVID-19. As T cell–B cell interactions and immunoglobulin class switching still occur in these patients, noncanonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both T
FH
-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Although T
FH
-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. We found by epitope mapping and B cell receptor sequencing that T
FH
cells focused the B cell response, and therefore, in the absence of T
FH
cells, a more diverse clonal repertoire was maintained. These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation.
A waning Saxothuringian Ocean evidenced in the Famennian tephra-bearing siliceous succession of the Bardo Unit (Central Sudetes, SW Poland)
Authors: Racki Grzegorz , Mazur Stanisław , Narkiewicz Katarzyna , Pisarzowska Agnieszka , Bardziński Waldemar , Kołtonik Katarzyna , Szymanowski Dawid , Filipiak Paweł , Kremer Barbara
Published: February 2022

A tephra-rich cherty-clayey Famennian succession within the major Brzeźnica olistostrome in the Bardo Mountains, Central Sudetes, SW Poland, preserves a record of the lost ocean later incorporated into the Variscan orogenic belt. Fluctuating but mostly oligotrophic regimes and low primary production levels were influenced by weak up-welling below the perennial oxygen minimum zone, which controlled the interplay between biosiliceous and siliciclastic deposition in the oceanic basin, with episodic oxygen deficiency. The Hangenberg Black Shale has been identified in this oceanic setting based on its characteristics described worldwide (including mercury enrichments). A tectonic uplift of the sediment source area near the Devonian-Carboniferous boundary, recorded in the distinguishing provenance signal of old continental crust, was paired with a global transgression, anoxia, and volcanic episode in an interglacial interval. Assuming paleogeographic affinity with the Bavarian facies of the Saxothuringian terrane, we interpret the allochthonous sediments as part of an accretionary prism that was gravitationally redeposited into the late orogenic basin in front of advancing Variscan nappes. The oceanic basin parental to the Bardo pelagic succession is therefore thought to represent a tract of the waning Saxothuringian Ocean in the Peri-Gondwanan paleogeographic domain that was eventually subducted beneath the Brunovistulian margin of Laurussia. The sediments of the Bardo Ocean basin also include a distal record of Famennian explosive volcanic activity that was likely related to a continental magmatic arc whose remnants are preserved as the Vrbno Group of the East Sudetes.
Supplemental Material: 3-D seismic chronostratigraphy of reefs and drifts in the Browse Basin, NW Australia
Authors: Thronberens Sebastian , al. et
Published: February 2022

Table S1: Location of all wells used for seismic calibration in this study.
What should pulmonary rehabilitation look like for people living with post-tuberculosis lung disease in the Bishkek and Chui region of the Kyrgyz Republic? A qualitative exploration
Authors: Mademilov Maamed , Mirzalieva Gulzada , Yusuf Zainab K , Orme Mark W , Bourne Claire , Akylbekov Azamat , Jones Amy V , Miah Ruhme B , Jones Rupert , Barton Andy , Malcolm Dominic , Sooronbaev Talant , Singh Sally J
Published: February 2022

Objective

After experiencing tuberculosis (TB), many people develop post-tuberculosis lung disease (PTBLD). Pulmonary rehabilitation (PR) centrally comprising of education and exercise is recommended internationally for people living with chronic respiratory diseases. However, no such service exists in Kyrgyzstan. This study investigated the opinions of healthcare professionals who would be expected to be potential future referrers to PR and adults living with PTBLD about what a PR programme could look like in Kyrgyzstan.

Design

A qualitative study using interviews and focus groups. Grounded theory and thematic analysis were used for data collection and analysis.

Participants

63 participants; 15 referrers (12 male, 3 female; 12 pulmonolgists, 3 TB specialists) and 48 adults (26 male, 22 female) living with PTBLD.

Setting

Participants were recruited from hospital settings in Bishkek and Chuy Region, Kygryzstan.

Methods

Fifteen semistructured interviews were conducted with referrers and nine focus group discussions were conducted with adults living with PTBLD.

Results

Five key themes were developed: (1) living with PTBLD; (2) attitude to PR, which emphasised the perceived importance and potential benefits of implemention; (3) barriers/facilitators to PR, which included time and cost, and the importance of appropriate communication in enabling participation; (4) interventional components of PR, which described culturally and demographically appropriate physical activities including rhythmic movements, dance and volleyball; and (5) psychosocial support, which demonstrated the importance of psychological support for patients coping with the effects of stigma.

Conclusions

Potential referrers and adults living with PTBLD expressed their support for the implementation of PR. The culture-specific and population-specific issues highlighted in this work demonstrate the need to address stigma and provide certain types of exercise training/education modules for this specific clinical population. In other respects the currently known attitudes/barriers to PR, identified in Western research, appear to apply. The principles of culturally adapting PR may be helpful for those looking to establish similar clinical services in other low-income and middle-income countries and in Central Asia in particular.

Trial registration number

ISRCTN11122503.
Study protocol: retrospectively mining multisite clinical data to presymptomatically predict seizure onset for individual patients with Sturge-Weber
Authors: Vedmurthy Pooja , Pinto Anna L R , Lin Doris D M , Comi Anne M , Ou Yangming
Published: February 2022

Introduction

Secondary analysis of hospital-hosted clinical data can save time and cost compared with prospective clinical trials for neuroimaging biomarker development. We present such a study for Sturge-Weber syndrome (SWS), a rare neurovascular disorder that affects 1 in 20 000–50 000 newborns. Children with SWS are at risk for developing neurocognitive deficit by school age. A critical period for early intervention is before 2 years of age, but early diagnostic and prognostic biomarkers are lacking. We aim to retrospectively mine clinical data for SWS at two national centres to develop presymptomatic biomarkers.

Methods and analysis

We will retrospectively collect clinical, MRI and neurocognitive outcome data for patients with SWS who underwent brain MRI before 2 years of age at two national SWS care centres. Expert review of clinical records and MRI quality control will be used to refine the cohort. The merged multisite data will be used to develop algorithms for abnormality detection, lesion-symptom mapping to identify neural substrate and machine learning to predict individual outcomes (presence or absence of seizures) by 2 years of age. Presymptomatic treatment in 0–2 years and before seizure onset may delay or prevent the onset of seizures by 2 years of age, and thereby improve neurocognitive outcomes. The proposed work, if successful, will be one of the largest and most comprehensive multisite databases for the presymptomatic phase of this rare disease.

Ethics and dissemination

This study involves human participants and was approved by Boston Children’s Hospital Institutional Review Board: IRB-P00014482 and IRB-P00025916 Johns Hopkins School of Medicine Institutional Review Board: NA_00043846. Participants gave informed consent to participate in the study before taking part. The Institutional Review Boards at Kennedy Krieger Institute and Boston Children’s Hospital approval have been obtained at each site to retrospectively study this data. Results will be disseminated by presentations, publication and sharing of algorithms generated.
Diagnostic error experiences of patients and families with limited English-language health literacy or disadvantaged socioeconomic position in a cross-sectional US population-based survey
Authors: Bell Sigall K , Dong Joe , Ngo Long , McGaffigan Patricia , Thomas Eric J , Bourgeois Fabienne
Published: February 2022

Background

Language barrier, reduced self-advocacy, lower health literacy or biased care may hinder the diagnostic process. Data on how patients/families with limited English-language health literacy (LEHL) or disadvantaged socioeconomic position (dSEP) experience diagnostic errors are sparse.

Method

We compared patient-reported diagnostic errors, contributing factors and impacts between respondents with LEHL or dSEP and their counterparts in the 2017 Institute for Healthcare Improvement US population-based survey, using contingency analysis and multivariable logistic regression models for the analyses.

Results

596 respondents reported a diagnostic error; among these, 381 reported LEHL or dSEP. After adjusting for sex, race/ethnicity and physical health, individuals with LEHL/dSEP were more likely than their counterparts to report unique contributing factors: "(No) qualified translator or healthcare provider that spoke (the patient’s) language" (OR and 95% CI 4.4 (1.3 to 14.9)); "not understanding the follow-up plan" (1.9 (1.1 to 3.1)); "too many providers… but no clear leader" (1.8 (1.2 to 2.7)); "not able to keep follow-up appointments" (1.9 (1.1 to 3.2)); "not being able to pay for necessary medical care" (2.5 (1.4 to 4.4)) and "out-of-date or incorrect medical records" (2.6 (1.4 to 4.8)). Participants with LEHL/dSEP were more likely to report long-term emotional, financial and relational impacts, compared with their counterparts. Subgroup analysis (LEHL-only and dSEP-only participants) showed similar results.

Conclusions

Individuals with LEHL or dSEP identified unique and actionable contributing factors to diagnostic errors. Interpreter access should be viewed as a diagnostic safety imperative, social determinants affecting care access/affordability should be routinely addressed as part of the diagnostic process and patients/families should be encouraged to access and update their medical records. The frequent and disproportionate long-term impacts from self-reported diagnostic error among LEHL/dSEP patients/families raises urgency for greater prevention and supportive efforts.
Immediate smoking cessation support versus usual care in smokers attending a targeted lung health check: the QuLIT trial
Authors: Buttery Sara C , Williams Parris , Mweseli Rebecca , Philip Keir Elmslie James , Sadaka Ahmed , Bartlett Emily Catharine , Devaraj Anand , Kemp Samuel V , Addis Jamie , Derbyshire Jane , Chen Michelle , Morris Katie , Laverty Anthony , Hopkinson Nicholas S
Published: February 2022

Objectives

Lung cancer screening programmes offer an opportunity to address tobacco dependence in current smokers. The effectiveness of different approaches to smoking cessation in this context has not yet been established. We investigated if immediate smoking cessation support, including pharmacotherapy, offered as part of a lung cancer screening programme, increases quit rates compared to usual care (Very Brief Advice to quit and signposting to smoking cessation services).

Materials and methods

We conducted a single-blind randomised controlled trial of current smokers aged 55–75 years attending a Targeted Lung Health Check. On randomly allocated days smokers received either (1) immediate support from a trained smoking cessation counsellor with appropriate pharmacotherapy or (2) usual care. The primary outcome was self-reported quit rate at 3 months. We performed thematic analysis of participant interview responses.

Results

Of 412 people attending between January and March 2020, 115 (27.9%) were current smokers; 46% female, mean (SD) 62.4 (5.3) years. Follow-up data were available for 84 smokers. At 3 months, quit rates in the intervention group were higher 14/48 (29.2%) vs 4/36 (11%) (χ23.98, p=0.04). Participant interviews revealed four smoking-cessation related themes: (1) stress and anxiety, (2) impact of the COVID-19 pandemic, (3) CT scans influencing desire to quit and (4) individual beliefs about stopping smoking.

Conclusion

The provision of immediate smoking cessation support is associated with a substantial increase in quit rates at 3 months. Further research is needed to investigate longer-term outcomes and to refine future service delivery.

Trial registration number

ISRCTN12455871.
Targeting KDM4C enhances CD8+ T cell mediated antitumor immunity by activating chemokine CXCL10 transcription in lung cancer
Authors: Jie Xiaohua , Chen Yunshang , Zhao Ye , Yang Xijie , Xu Yingzhuo , Wang Jian , Meng Rui , Zhang Sheng , Dong Xiaorong , Zhang Tao , Yang Kunyu , Xu Shuangbing , Wu Gang
Published: February 2022

Background

Although immune checkpoint blockade (ICB) has been proven to achieve a persistent therapeutic response in various tumor types, only 20%–40% of patients benefit from this treatment. Radiotherapy (RT) can enhance tumor immunogenicity and improve the ICB response, but the outcome achieved by combining these two modalities remains clinically unsatisfactory. We previously uncovered that lysine-specific demethylase 4C (KDM4C) is a regulator of radiosensitivity in lung cancer. However, the role of KDM4C in antitumor immunity has not yet been investigated.

Methods

Infiltrating immune cells in our mouse tumor model were screened by flow cytometry. An in vivo subcutaneous transplanted tumor model and in vitro conditioned culture model were constructed to detect the quantitative and functional changes in CD8+ T cells. RNA sequencing and chromatin immunoprecipitation-PCR assays were used to explore the downstream regulatory mechanism of KDM4C in antitumor immunity. A C57BL/6 mouse tumor model was developed to evaluate the efficacy and safety of a triple therapy (the KDM4C-specific inhibitor SD70 plus RT and an anti-PD-L1 antibody) in lung cancer in vivo.

Results

Genetical or pharmacological inhibition of KDM4C specifically increased CD8+ T cell infiltration; promoted the proliferation, migration and activation of CD8+ T cells; and alleviated CD8+ T cell exhaustion in mouse tumor tissues. Mechanistically, KDM4C inhibition increased the binding of H3K36me3 to the CXCL10 promoter region, thus inducing CXCL10 transcription and enhancing the CD8+ T cell mediated antitumor immune response. More importantly, among the tested regimens, the triple therapy achieved the best therapeutic efficacy with tolerable toxicity in lung cancer.

Conclusions

Our data reveal a crucial role for KDM4C in antitumor immunity in lung cancer and indicate that targeting KDM4C in combination with radioimmunotherapy might be a promising synergistic strategy in lung cancer.
RNA splicing analysis contributes to reclassifying variants of uncertain significance and improves the diagnosis of monogenic disorders
Authors: He Wen-Bin , Xiao Wen-Juan , Dai Cong-Ling , Wang Yu-Rong , Li Xiu-Rong , Gong Fei , Meng Lan-Lan , Tan Chen , Zeng Si-Cong , Lu Guang-Xiu , Lin Ge , Tan Yue-Qiu , Hu Hao , Du Juan
Published: February 2022

Background

Numerous variants of uncertain significance (VUSs) have been identified by whole exome sequencing in clinical practice. However, VUSs are not currently considered medically actionable.

Objective

To assess the splicing patterns of 49 VUSs in 48 families identified clinically to improve genetic counselling and family planning.

Methods

Forty-nine participants with 49 VUSs were recruited from the Reproductive and Genetic Hospital of CITIC-Xiangya. Bioinformatic analysis was performed to preliminarily predict the splicing effects of these VUSs. RT-PCR and minigene analysis were used to assess the splicing patterns of the VUSs. According to the results obtained, couples opted for different methods of reproductive interventions to conceive a child, including prenatal diagnosis and preimplantation genetic testing (PGT).

Results

Eleven variants were found to alter pre-mRNA splicing and one variant caused nonsense-mediated mRNA decay, which resulted in the reclassification of these VUSs as likely pathogenic. One couple chose to undergo in vitro fertilisation with PGT treatment; a healthy embryo was transferred and the pregnancy is ongoing. Three couples opted for natural pregnancy with prenatal diagnosis. One couple terminated the pregnancy because the fetus was affected by short-rib thoracic dysplasia and harboured the related variant. The infants of the other two couples were born and were healthy at their last recorded follow-up.

Conclusion

RNA splicing analysis is an important method to assess the impact of sequence variants on splicing in clinical practice and can contribute to the reclassification of a significant proportion of VUSs. RNA splicing analysis should be considered for genetic disease diagnostics.
Cost-effectiveness model of renal cell carcinoma (RCC) surveillance in hereditary leiomyomatosis and renal cell carcinoma (HLRCC)
Authors: Thompson Alexander J , Alwan Yousef M , Ramani Vijay A C , Evans D Gareth , Maher Eamonn R , Woodward Emma R
Published: February 2022

Purpose

To determine the cost-effectiveness of annual renal imaging surveillance (RIS) in hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is associated with a 21% risk to age 70 years of RCC. Presentations with advanced renal cell cancer (RCC) are associated with poor outcomes whereas RIS detects early-stage RCC; however, evidence for the cost-effectiveness of RIS is lacking.

Methods

We developed a decision-analytic model to compare, at different age starting points (11 years, 18 years, 40 years, 60 years), the costs and benefits of lifetime contrast-enhanced renal MRI surveillance (CERMRIS) vs no surveillance in HLRCC. Benefits were measured in life-years gained (LYG), quality-adjusted life years (QALYs) and costs in British Pounds Sterling (GBP). Net monetary benefit (NMB) was calculated using a cost-effectiveness threshold of £20 000/QALY. One-way sensitivity and probabilistic analyses were also performed.

Results

In the base-case 11-year age cohort, surveillance was cost-effective (Incremental_NMB=£3522 (95% CI −£2747 to £7652); Incremental_LYG=1.25 (95% CI 0.30 to 1.86); Incremental_QALYs=0.29 (95% CI 0.07 to 0.43)] at an additional mean discounted cost of £2185/patient (95% CI £430 to £4144). Surveillance was also cost-effective in other age cohorts and dominated a no surveillance strategy in the 40 year cohort [Incremental_NMB=£12 655 (95% CIs −£709 to £21 134); Incremental_LYG=1.52 (95% CI 0.30 to 2.26); Incremental_QALYs=0.58 (95% CI 0.12 to 0.87) with a cost saving of £965/patient (95% CI −£4202 to £2652).

Conclusion

Annual CERMRI in HLRCC is cost-effective across age groups modelled.
Neurofibromatosis type 1 families with first-degree relatives harbouring distinct NF1 pathogenic variants. Genetic counselling and familial diagnosis: what should be offered?
Authors: Garcia Belen , Catasus Nuria , Ros Andrea , Rosas Inma , Negro Alejandro , Guerrero-Murillo Mercedes , Valero Ana Maria , Duat-Rodriguez Anna , Becerra Juan Luis , Bonache Sandra , Lázaro Garcia Conxi , Comas Carmina , Bielsa Isabel , Serra Eduard , Hernández-Chico Concepción , Martin Yolanda , Castellanos Elisabeth , Blanco Ignacio
Published: February 2022

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in NF1. Recently, NF1 testing has been included as a clinical criterion for NF1 diagnosis. Additionally, preconception genetic counselling in patients with NF1 focuses on a 50% risk of transmitting the familial variant as the risk of having a sporadic NF1 is considered the same as the general population.

Methods

829 individuals, 583 NF1 sporadic cases and 246 patients with NF1 with documented family history, underwent genetic testing for NF1. Genotyping and segregation analysis of NF1 familial variants was determined by microsatellite analysis and NF1 sequencing.

Results

The mutational analysis of NF1 in 154 families with two or more affected cases studied showed the co-occurrence of two different NF1 germline pathogenic variants in four families. The estimated mutation rate in those families was 3.89×10–3, 20 times higher than the NF1 mutation rate (~2×10−4) (p=0.0008). Furthermore, the co-occurrence of two different NF1 germline pathogenic variants in these families was 1:39, 60 times the frequency of sporadic NF1 (1:2500) (p=0.003). In all cases, the de novo NF1 pathogenic variant was present in a descendant of an affected male. In two cases, variants were detected in the inherited paternal wild-type allele.

Conclusions

Our results, together with previous cases reported, suggest that the offspring of male patients with NF1 could have an increased risk of experiencing de novo NF1 pathogenic variants. This observation, if confirmed in additional cohorts, could have relevant implications for NF1 genetic counselling, family planning and NF1 genetic testing.
It’s about time: on the need of a temporal language for ecologically dimensioned medical humanities and public health scholarship
Authors: Zielke Julia
Published: February 2022

The COVID-19 pandemic has highlighted multiple system dependencies that urge us to rethink our relationship with other humans, non-humans and their various environments. Whereas a growing body of literature highlights the need for ecologically dimensioned medical humanities, focusing on where and how our healths unfold relationally through their ecologies, this paper argues that little attention has been paid to the when of health. In reply, this paper sets out to expand this understanding, first by grounding the ecological argument for medical humanities in a wider net of relational ontologies, and second by highlighting the need to think temporally, specifically multitemporally, about the relationalities of health. The paper advances the sociological concepts of ‘time’ and ‘temporalities’ to help us think about various tempi, rhythms, urgencies and legacies of how health unfolds unevenly into the future.