bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceived Barriers and Motivators for Physical Activity in Women With Perinatal Depression
Authors: Badon Sylvia E. , Iturralde Esti , Nkemere Linda , Nance Nerissa , Avalos Lyndsay A.
Published: May 2021

Background: Physical activity (PA) can help reduce depression symptom severity in women with perinatal depression. However, PA is low, and barriers and motivators for PA among women with perinatal depression are not well understood.Methods: An ethnically diverse sample of women with perinatal depression was identified using a universal perinatal depression screening program. The authors conducted 8 focus groups (4 in pregnant women [n = 15] and 4 in postpartum women [n = 20]). Depression symptoms were measured using the Patient Health Questionnaire-8 at recruitment. Focus groups were analyzed using an inductive approach.Results: Pregnant participants were 27 weeks gestation, and postpartum participants were 11.5 months postpartum, on average. Depression symptoms were moderately severe (mean Patient Health Questionnaire-8 score: 16). Women identified practical barriers and motivators for PA common to perinatal women (physical health, parental responsibilities, PA tracking tools, and environmental factors) and described emotional and social factors influencing PA. Motivators included using PA to improve mood, relieve stress, boost self-image, and spend time with others. Bad mood, fear of social judgment, and feeling discouraged made it difficult to be active.Conclusion: PA interventions in women with perinatal depression should include components addressing emotional and social barriers to PA in addition to addressing additional common practical barriers to PA.
60Fe and244Pu deposited on Earth constrain the r-process yields of recent nearby supernovae
Authors: Wallner A. , Froehlich M. B. , Hotchkis M. A. C. , Kinoshita N. , Paul M. , Martschini M. , Pavetich S. , Tims S. G. , Kivel N. , Schumann D. , Honda M. , Matsuzaki H. , Yamagata T.
Published: May 2021

Natural plutonium from supernovae

The rapid neutron capture process (r-process) produces many of the heavy chemical elements, but the astrophysical settings where it occurs remain unclear. Leading candidates are neutron star mergers and some types of supernovae. Wallneret al.analyzed the plutonium content of a deep-sea crust sample, identifying a few dozen atoms of the r-process isotope plutonium- 244 that were delivered to Earth within the past few million years. There was a simultaneous signal of iron-60, which is known to be produced in supernovae. Comparing the ratios of these isotopes constrains the relative contributions of supernovae and neutron star mergers to r-process nucleosynthesis.

Science, this issue p.742
Preventing respiratory syncytial virus (RSV) disease in children
Authors: Karron Ruth A.
Published: May 2021

After many decades, promising strategies for RSV immunization are on the horizon
Mycoplasma pneumoniae P1 Genotype Indicates Severity of Lower Respiratory Tract Infections in Children
Authors: Rodman Berlot Jasna , Krivec Uroš , Mrvič Tatjana , Kogoj Rok , Keše Darja
Published: May 2021

Mycoplasma pneumoniae
strains can be classified into two major genetic groups, P1 type 1 (P1-1) and P1 type 2 (P1-2). It remains unknown if clinical manifestations of lower respiratory tract infections (LRTI) in children differ between the two genotypes.
Genesis of the mafic granophyre of the Vredefort impact structure (South Africa): Implications of new geochemical and Se and Re-Os isotope data
Authors: Reimold* Wolf Uwe , Schulz Toni , König Stephan , Koeberl Christian , Hauser Natalia , Wannek Dschamilja , Schmitt Ralf-Thomas
Published: May 2021

This contribution is concerned with the debated origin of the impact melt rock in the central uplift of the world’s largest confirmed impact structure—Vredefort (South Africa). New major- and trace-element abundances, including those of selected highly siderophile elements (HSEs), Re-Os isotope data, as well as the first Se isotope and Se-Te elemental systematics are presented for the felsic and mafic varieties of Vredefort impact melt rock known as “Vredefort Granophyre.” In addition to the long-recognized “normal” (i.e., felsic, >66 wt% SiO2) granophyre variety, a more mafic (<66 wt% SiO2) impact melt variety from Vredefort has been discussed for several years. The hypothesis that the mafic granophyre was formed from felsic granophyre through admixture (assimilation) of a mafic country rock component that then was melted and assimilated into the superheated impact melt has been pursued here by analysis of the two granophyre varieties, of the Dominion Group lava (actually meta-lava), and of epidiorite mafic country rock types. Chemical compositions, including high-precision isotope dilution–derived concentrations of selected highly siderophile elements (Re, Os, Ir, Pt, Se, Te), and Re-Os and Se isotope data support this hypothesis. A first-order estimate, based on these data, suggests that some mafic granophyre may have resulted from a significant admixture (assimilation) of epidiorite to felsic granophyre. This is in accordance with the findings of an earlier investigation using conventional isotope (Sr-Nd-Pb) data. Moreover, these outcomes are in contrast to a two-stage emplacement model for Vredefort Granophyre, whereby a mafic phase of impact melt, derived by differentiation of a crater-filling impact melt sheet, would have been emplaced into earlier-deposited felsic granophyre. Instead, all chemical and isotopic evidence so far favors formation of mafic granophyre by local assimilation of mafic country rock—most likely epidiorite—by a single intrusive impact melt phase, which is represented by the regionally homogeneous felsic granophyre.
D-lactic acidosis presenting as metabolic encephalopathy in a patient with short bowel syndrome
Authors: McHale Ciarán , Keating Eoin , O'Donovan Helen , Slattery Eoin
Published: May 2021

We present a case of D-lactic acidosis presenting as a metabolic encephalopathy secondary to small intestinal bacterial overgrowth. This patient had a known history of short bowel syndrome. Of note, this case required the alteration of treatment to promote a sustained clinical and biochemical improvement. We discuss the pathophysiological mechanisms thought to be involved. We also review the current therapies as well as potential future strategies. This case highlights the importance of the prompt clinical recognition of signs and symptoms as well as the rapid initiation of management strategies to ameliorate this condition.
Scoping review of research on self-managed medication abortion in low-income and middle-income countries
Authors: Sorhaindo Annik , Sedgh Gilda
Published: May 2021

Background

We undertook a scoping review of recent studies on self-managed medical abortion (MA) or abortion where some or all of the process is led independently by the person having the abortion, in low-income and middle-income countries (LMICs) to uncover evidence gaps and help stakeholders leverage existing evidence.

Methods

We searched five bibliographic databases for all articles published on MA between 2007 and July 2020 in LMICs. The search yielded 1294 articles. We identified 107 articles in which one or more of the three WHO-defined subtasks for MA was self-led outside of a clinic setting, and use of drugs that are part of safe, evidence-based regimens was related to the study exposure or outcome. We classified these studies by subject area, study design, country, legal context, gestational age and other categories.

Results

The 107 studies covered research in 44 countries, of which 18 have liberal abortion laws. Seventy- four articles reported on quantitative research methods, of which 14 were randomised controlled trials. Fifty-two studies focused on MA in the first trimester. Sixty-two focused on WHO subtask two (drug administration) and 32 focused on subtask three (assessing and managing abortion completion). We found little research on self-management of the entire MA process, innovative approaches to supporting self-managed MA or the needs of underserved populations.

Conclusion

We recommend syntheses of evidence on safety and efficacy of self-managed MA and preferences of people undergoing self-managed MA. We also encourage new research on topics including self-management of the entire process, the needs and experiences of underserved populations and innovative approaches to supporting people undertaking self-managed MA. The time is opportune for amplifying and expanding evidence to inform programmes and policies on self-care.
Who are dying and why? A case series study of maternal deaths in Nepal
Authors: Karkee Rajendra , Tumbahangphe Kirti Man , Maharjan Nashna , Budhathoki Bharat , Manandhar Dharma
Published: May 2021

Objectives

To identify delays and associated factors for maternal deaths in Nepal.

Design

A cross-sectional case series study of maternal deaths. An integrated verbal and social autopsy tool was used to collect quantitative and qualitative information regarding three delays. We recorded death accounts and conducted social autopsy by means of community Focus Group Discussions for each maternal death; and analysed data by framework analysis.

Setting

Sixty-two maternal deaths in six districts in three provinces of Nepal.

Results

Nearly half of the deceased women (45.2%) were primiparous and one-third had no formal education. About 40% were from Terai/Madhesi and 30.6% from lower caste. The most common place of death was private hospitals (41.9%), followed by public hospitals (29.1%). Nearly three-fourth cases were referred to higher health facilities and median time (IQR) of stay at the lower health facility was 120 (60–180) hours. Nearly half of deaths (43.5%) were attributable to more than one delay while first and third delay each contributed equally (25.8%). Lack of perceived need; perceived cost and low status; traditional beliefs and practices; physically inaccessible facilities and lack of service readiness and quality care were important factors in maternal deaths.

Conclusions

The first and third delays were the equal contributors of maternal deaths. Interventions related to birth preparedness, economic support and family planning need to be focused on poor and marginalised communities. Community management of quick transportation, early diagnosis of pregnancy risks, accommodation facilities near the referral hospitals and dedicated skilled manpower with adequate medicines, equipment and blood supplies in referral hospitals are needed for further reduction of maternal deaths in Nepal.
Barriers and facilitators to reporting deaths following Ebola surveillance in Sierra Leone: implications for sustainable mortality surveillance based on an exploratory qualitative assessment
Authors: Jalloh Mohamed F , Kinsman John , Conteh James , Kaiser Reinhard , Jambai Amara , Ekström Anna Mia , Bunnell Rebecca E , Nordenstedt Helena
Published: May 2021

Objectives

To understand the barriers contributing to the more than threefold decline in the number of deaths (of all causes) reported to a national toll free telephone line (1-1-7) after the 2014–2016 Ebola outbreak ended in Sierra Leone and explore opportunities for improving routine death reporting as part of a nationwide mortality surveillance system.

Design

An exploratory qualitative assessment comprising 32 in-depth interviews (16 in Kenema district and 16 in Western Area). All interviews were audio-recorded, transcribed and analysed using qualitative content analysis to identify themes.

Setting

Participants were selected from urban and rural communities in two districts that experienced varying levels of Ebola cases during the outbreak. All interviews were conducted in August 2017 in the post-Ebola-outbreak context in Sierra Leone when the Sierra Leone Ministry of Health and Sanitation was continuing to mandate reporting of all deaths.

Participants

Family members of deceased persons whose deaths were not reported to the 1-1-7 system.

Results

Death reporting barriers were driven by the lack of awareness to report all deaths, lack of services linked to reporting, negative experiences from the Ebola outbreak including prohibition of traditional burial rituals, perception that inevitable deaths do not need to be reported and situations where prompt burials may be needed. Facilitators of future willingness to report deaths were largely influenced by the perceived communicability and severity of the disease, unexplained circumstances of the death that need investigation and the potential to leverage existing death notification practices through local leaders.

Conclusions

Social mobilisation and risk communication efforts are needed to help the public understand the importance and benefits of sustained and ongoing death reporting after an Ebola outbreak. Localised practices for informal death notification through community leaders could be integrated into the formal reporting system to capture community-based deaths that may otherwise be missed.
Representation of racial and ethnic minority groups in cohort studies evaluating risk factors for dementia: protocol for a scoping review
Authors: Krishnan Arjun , Waite Louise M , Stanaway Fiona F
Published: May 2021

Introduction

Available evidence suggests that some racial/ethnic minority populations may be disproportionately burdened by dementia. Cohort studies are an important tool for defining and understanding the causes behind these racial and ethnic inequalities. However, ethnic minority populations may be more likely to be excluded from such research. Therefore, the aim of this study is to systematically investigate and quantify racial and ethnic minority representation in dementia risk factor research.

Methods and analysis

The elements of this protocol have been designed in accordance with the relevant sections of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols which are specifically applicable to scoping review protocols. We will include population-based cohort studies looking at risk factors for dementia incidence in our review and assess the representation of racial and ethnic minority populations in these studies. We will use multiple strategies to identify relevant studies, including a systematic search of the following electronic databases: MEDLINE (Ovid SP), Embase (Ovid SP) and Scopus. Two review authors will independently perform title and abstract screening, full-text screening and data extraction. Included cohort studies will be evaluated using a comprehensive framework to assess racial/ethnic minority representation. Logistic regression will also be performed to describe associations between cohort study characteristics and outcomes related to racial and ethnic minority representation.

Ethics and dissemination

Formal ethical approval is not required to conduct this review as no primary data are to be collected. The final results of this scoping review will be disseminated through publication in peer-reviewed journals and conference presentations.
Risk factors for severity of COVID-19: a rapid review to inform vaccine prioritisation in Canada
Authors: Wingert Aireen , Pillay Jennifer , Gates Michelle , Guitard Samantha , Rahman Sholeh , Beck Andrew , Vandermeer Ben , Hartling Lisa
Published: May 2021

Objectives

Rapid review to determine the magnitude of association between potential risk factors and severity of COVID-19, to inform vaccine prioritisation in Canada.

Setting

Ovid MEDLINE(R) ALL, Epistemonikos COVID-19 in L·OVE Platform, McMaster COVID-19 Evidence Alerts and websites were searched to 15 June 2020. Eligible studies were conducted in high-income countries and used multivariate analyses.

Participants

After piloting, screening, data extraction and quality appraisal were performed by a single experienced reviewer. Of 3740 unique records identified, 34 were included that reported on median 596 (range 44–418 794) participants, aged 42–84 years. 19/34 (56%) were good quality.

Outcomes

Hospitalisation, intensive care unit admission, length of stay in hospital or intensive care unit, mechanical ventilation, severe disease, mortality.

Results

Authors synthesised findings narratively and appraised the certainty of the evidence for each risk factor–outcome association. There was low or moderate certainty evidence for a large (≥2-fold) magnitude of association between hospitalisation in people with COVID-19, and: obesity class III, heart failure, diabetes, chronic kidney disease, dementia, age >45 years, male gender, black race/ethnicity (vs non-Hispanic white), homelessness and low income. Age >60 and >70 years may be associated with large increases in mechanical ventilation and severe disease, respectively. For mortality, a large magnitude of association may exist with liver disease, Bangladeshi ethnicity (vs British white), age >45 years, age >80 years (vs 65–69 years) and male gender among 20–64 years (but not older). Associations with hospitalisation and mortality may be very large (≥5-fold) for those aged ≥60 years.

Conclusions

Increasing age (especially >60 years) may be the most important risk factor for severe outcomes. High-quality primary research accounting for multiple confounders is needed to better understand the magnitude of associations for severity of COVID-19 with several other factors.

PROSPERO registration number

CRD42020198001.
Clinical practice guidelines and principles of care for people with dementia: a protocol for undertaking a Delphi technique to identify the recommendations relevant to primary care nurses in the delivery of person-centred dementia care
Authors: Gibson Caroline , Goeman Dianne , Yates Mark William , Pond Dimity
Published: May 2021

Introduction

Nationally and internationally it is well recognised that dementia is poorly recognised and suboptimally managed in the primary care setting. There are multiple and complex reasons for this gap in care, including a lack of knowledge, high care demands and inadequate time for the general practitioner alone to manage dementia with its multiple physical, psychological and social dimensions. The primary care nurse potentially has a role in assisting the general practitioner in the provision of evidence-based dementia care. Although dementia-care guidelines for general practitioners exist, evidence on resources to support the primary care nurse in dementia care provision is scarce. The ‘Australian Clinical Practice Guidelines and Principles of Care for People with Dementia’ provides 109 recommendations for the diagnosis and management of dementia. This protocol describes a Delphi study to identify which of the 109 recommendations contained in these multidisciplinary guidelines are relevant to the primary care nurse in the delivery of person-centred dementia care in the general practice setting.

Methods and analysis

Using a Delphi consensus online survey, an expert panel will grade each of the recommendations written in the ‘Clinical Practice Guidelines and Principles of Care for People with Dementia’ as high-to-low relevance with respect to the role of the primary care nurse in general practice. To optimise reliability of results, quality indicators will be used in the data collection and reporting of the study. Invited panel members will include Australian primary care nurses working in general practice, primary care nursing researchers and representatives of the Australian Primary Health Care Nurses Association, the peak professional body for nurses working in primary healthcare.

Ethics and dissemination

This study has been approved by The University of Newcastle Human Research Ethics Committee (HREC) (H-2019-0029).

Findings will be published in a peer-reviewed journal and presented at scientific conferences.
Economic evaluation of different routes of surgery for the management of endometrial cancer: a retrospective cohort study
Authors: Moss Esther L , Morgan George , Martin Antony , Sarhanis Panos , Ind Thomas
Published: May 2021

Objectives

The benefits of minimally invasive surgery (MIS) for endometrial carcinoma (EC) are well established although the financial impact of robotic-assisted hysterectomy (RH) compared with laparoscopic hysterectomy (LH) is disputed.

Design

Retrospective cohort study.

Setting

English National Health Service hospitals 2011–2017/2018.

Participants

35 304 women having a hysterectomy for EC identified from Hospital Episode Statistics.

Primary and secondary outcome measures

The primary outcome was the association between route of surgery on cost at intervention, 30, 90 and 365 days for women undergoing an open hysterectomy (OH) or MIS (LH/RH) for EC in England. The average marginal effect was calculated to compare RH versus OH and RH versus LH which adjusted for any differences in the characteristics of the surgical approaches. Secondary outcomes were to analyse costing data for each surgical approach by age, Charlson Comorbidity Index (CCI) and hospital MIS rate classification.

Results

A total of 35 304 procedures were performed, 20 405 (57.8%) were MIS (LH: 18 604 and RH: 1801), 14 291 (40.5%) OH. Mean cost for LH was significantly less than RH, whereas RH was significantly less than OH at intervention, 30, 90 and 365 days (p<0.001). Over time, patients who underwent RH had increasing CCI scores and by the 2015/2016 year had a higher average CCI than LH. Comparing the cost of LH and RH against CCI score identified that the costs closely reflected the patients’ CCI. Increasing disparity was also seen between the MIS and OH costs with rising age. When exploring the association between provider volume, MIS rate and surgical costs, there was an association with the higher the MIS rate the lower the average cost.

Conclusions

Further research is needed to investigate costs in matched patient cohorts to determine the optimum surgical modality in different populations.
Stigma, displacement stressors and psychiatric morbidity among displaced Syrian men who have sex with men (MSM) and transgender women: a cross-sectional study in Lebanon
Authors: Clark Kirsty , Pachankis John , Khoshnood Kaveh , Bränström Richard , Seal David , Khoury Danielle , Fouad Fouad M , Barbour Russell , Heimer Robert
Published: May 2021

Background

Displaced Syrians face psychiatric morbidity often resulting from displacement-related stressors (eg, resource scarcity). Both men who have sex with men (MSM) and transgender women among the displaced Syrians are particularly vulnerable to mental health challenges given that they also often face stigma-related stressors (eg, discrimination).

Methods

Between January and December 2019 in greater Beirut, 258 Lebanese-born MSM and transgender women and 230 displaced Syrian MSM and transgender women were recruited via respondent-driven sampling to complete an in-person survey assessing displacement-related stressors, stigma-related stressors, depression, anxiety and post-traumatic stress disorder. In the total sample, we first documented the prevalence of psychiatric morbidity among the displaced Syrians; we then assessed associations among displacement-related and stigma-related stressors and each psychiatric outcome.

Results

Sixty-three per cent of Syrian participants met criteria for depression compared with 43.8% of Lebanese participants (p<0.001); 21.3% of Syrians met criteria for severe anxiety compared with 13.1% of Lebanese participants (p<0.05) and 33.0% of Syrians met criteria for post-traumatic stress disorder compared with 18.4% of Lebanese participants (p<0.001). Among Syrian MSM and transgender women, sociodemographic characteristics, displacement-related stressors and stigma-related stressors were uniquely associated with psychiatric morbidity.

Conclusion

Displaced Syrian MSM and transgender women experience higher levels of psychiatric comorbidities than Lebanese MSM and transgender women in part due to compounding exposure to displacement-related stressors and stigma-related stressors. Informed by tenets of minority stress theory and intersectionality theory, we discuss mental health intervention implications and future directions.
Developing a theory-informed complex intervention to improve nurse–patient therapeutic engagement employing Experience-based Co-design and the Behaviour Change Wheel: an acute mental health ward case study
Authors: McAllister Sarah , Simpson Alan , Tsianakas Vicki , Canham Nick , De Meo Vittoria , Stone Cady , Robert Glenn
Published: May 2021

Objectives

Our objectives were threefold: (1) describe a collaborative, theoretically driven approach to co-designing complex interventions; (2) demonstrate the implementation of this approach to share learning with others; and (3) develop a toolkit to enhance therapeutic engagement on acute mental health wards.

Design and participants

We describe a theory-driven approach to co-designing an intervention by adapting and integrating Experience-based Co-design (EBCD) with the Behaviour Change Wheel (BCW). Our case study was informed by the results of a systematic integrative review and guided by this integrated approach. We undertook 80 hours of non-participant observations, and semistructured interviews with 14 service users (7 of which were filmed), 2 carers and 12 clinicians from the same acute ward. The facilitated intervention co-design process involved two feedback workshops, one joint co-design workshop and seven small co-design team meetings. Data analysis comprised the identification of touchpoints and use of the BCW and behaviour change technique taxonomy to inform intervention development.

Setting

This study was conducted over 12 months at an acute mental health organisation in England.

Results

The co-designedLet’s Talktoolkit addressed four joint service user/clinician priorities for change: (1) improve communication with withdrawn people; (2) nurses to help service users help themselves; (3) nurses to feel confident when engaging with service users; (4) improving team relations and ward culture. Intervention functions included training, education, enablement, coercion and persuasion; 14 behaviour change techniques supported these functions. We detail how we implemented our integrated co-design-behaviour change approach with service users, carers and clinicians to develop a toolkit to improve nurse–patient therapeutic engagement.

Conclusions

Our theory-driven approach enhanced both EBCD and the BCW. It introduces a robust theoretical approach to guide intervention development within the co-design process and sets out how to meaningfully involve service users and other stakeholders when designing and implementing complex interventions.
Assessing the correlation between swept-source optical coherence tomography lens density pattern analysis and best-corrected visual acuity in patients with cataracts
Authors: Bourdon Hugo , Trinh Liem , Robin Mathieu , Baudouin Christophe
Published: May 2021

Objective

To assess linear correlation between swept-source optical coherence tomography (SS-OCT) lens density variation and patients’ best-corrected visual acuity (BCVA).

Methods and analysis

Linear densitometry was performed on horizontal lens images from 518 eyes, obtained using SS-OCT. All densities from the anterior to the posterior side of the cataract were exported for detailed analysis. The algorithm used a classical random forest regression machine learning approach with fourfold cross-validation, meaning four batches of data from 75% of the eyes with known preoperative best-corrected visual acuity (poBCVA) were used for training a model to predict the data from the remaining 25% of the eyes. The main judgement criterion was the ability of the algorithm to identify linear correlation between measured and predicted BCVA.

Results

A significant linear correlation between poBCVA and the algorithm’s prediction was found, with Pearson correlation coefficient (R)=0.558 (95% CI: 0.496 to 0.615, p<0.001). Mean BCVA prediction error was 0.0965±0.059 logarithm of the minimal angle of resolution (logMAR), with 312 eyes (58%) having a BCVA prediction correct to ±0.1 logMAR. The best algorithm performances were achieved for 0.20 logMAR, with 79%±0.1 logMAR correct prediction. Mean, anterior cortex, nucleus and posterior cortex pixel density were all not correlated with patient BCVA.

Conclusion

Pixel density variations based on axial lens images provided by SS-OCT biometer provide reasonably accurate information for machine learning analysis to estimate patient BCVA in all types of cataracts. This study demonstrates significant linear correlation between patients’ poBCVA and the algorithmic prediction, with acceptable mean prediction error.
Influence of a 100-mile ultramarathon on heart rate and heart rate variability
Authors: Paech Christian , Schrieber Simone , Daehnert Ingo , Schmidt-Hellinger Paul Jürgen , Wolfarth Bernd , Wuestenfeld Jan , Thouet Thomas
Published: May 2021

Aims

This study aimed to investigate the impact of an ultramarathon (UM) with a distance of 100 miles on heart rate (HR) and heart rate variability (HRV).

Methods

28 runners (25 men and 3 women) underwent 24-hour Holter ECG monitoring 1 week before the UM, immediately after the UM and after a week of recovery. The influence of age, body mass index (BMI), HR and HRV on the run time and recovery was investigated.

Results

A rise in the baseline HR (18.98%) immediately after the run accompanied by a significant drop in the SD of all normal RR intervals (7.12%) 1 week after. Except for the runners’ age, BMI, HR and HRV showed no influence on the competition time. Full return of HRV to the athletes’ baseline did not occur within 1 week. There were no significant differences between finishers and non-finishers in the analysed parameters.

Conclusion

The present results show that a 100-mile run leads to an increase in sympathetic activity and thus to an increase in HR and a decrease in HRV. Also, HRV might be a suitable parameter to evaluate the state of recovery after a 100-mile run but does not help to quantify the status of recovery, as the damage to the tendomuscular system primarily characterises this after completing a UM.
Tumor hypoxia is associated with resistance to PD-1 blockade in squamous cell carcinoma of the head and neck
Authors: Zandberg Dan P , Menk Ashley V , Velez Maria , Normolle Daniel , DePeaux Kristin , Liu Angen , Ferris Robert L , Delgoffe Greg M
Published: May 2021

The majority of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (HNSCC) (R/M) do not benefit from anti-PD-1 therapy. Hypoxia induced immunosuppression may be a barrier to immunotherapy. Therefore, we examined the metabolic effect of anti-PD-1 therapy in a murine MEER HNSCC model as well as intratumoral hypoxia in R/M patients. In order to characterize the tumor microenvironment in PD-1 resistance, a MEER cell line was created from the parental line that are completely resistant to anti-PD-1. These cell lines were then metabolically profiled using seahorse technology and injected into C57/BL6 mice. After tumor growth, mice were pulsed with pimonidazole and immunofluorescent imaging was performed to analyze hypoxia and T cell infiltration. To validate the preclinical results, we analyzed tissues from R/M patients (n=36) treated with anti-PD-1 mAb, via immunofluorescent imaging for number of CD8+ T cells (CD8), Tregs and the percent area (CAIX) and mean intensity (I) of carbonic anhydrase IX in tumor. We analyzed disease control rate (DCR), progression free survival (PFS), and overall survival (OS) using proportional odds and proportional hazards (Cox) regression. We found that anti-PD-1 resistant MEER has significantly higher oxidative metabolism, while there was no difference in glycolytic metabolism. Intratumoral hypoxia was significantly increased and CD8+ T cells decreased in anti-PD-1 resistant tumors compared with parental tumors in the same mouse. In R/M patients, lower tumor hypoxia by CAIX/I was significantly associated with DCR (p=0.007), PFS, and OS, and independently associated with response (p=0.028) and PFS (p=0.04) in a multivariate model including other significant immune factors. During PD-1 resistance, tumor cells developed increased oxidative metabolism leading to increased intratumoral hypoxia and a decrease in CD8+ T cells. Lower tumor hypoxia was independently associated with increased efficacy of anti-PD-1 therapy in patients with R/M HNSCC. To our knowledge this is the first analysis of the effect of hypoxia in this patient population and highlights its importance not only as a predictive biomarker but also as a potential target for therapeutic intervention.
Potent ex vivo armed T cells using recombinant bispecific antibodies for adoptive immunotherapy with reduced cytokine release
Authors: Park Jeong A , Santich Brian H , Xu Hong , Lum Lawrence G , Cheung Nai-Kong V
Published: May 2021

Background

T cell-based immunotherapies using chimeric antigen receptors (CAR) or bispecific antibodies (BsAb) have produced impressive responses in hematological malignancies. However, major hurdles remained, including cytokine release syndrome, neurotoxicity, on-target off-tumor effects, reliance on autologous T cells, and failure in most solid tumors. BsAb armed T cells offer a safe alternative.

Methods

We generated ex vivo armed T cells (EATs) using IgG-[L]-scFv-platformed BsAb, where the anti-CD3 (huOKT3) scFv was attached to the light chain of a tumor-binding IgG. BsAb density on EAT, in vitro cytotoxicity, cytokine release, in vivo trafficking into tumors, and their antitumor activities were evaluated in multiple cancer cell lines and patient-derived xenograft mouse models. The efficacy of EATs after cryopreservation was studied, and gamma delta (γδ) T cells were investigated as unrelated alternative effector T cells.

Results

The antitumor potency of BsAb armed T cells was substantially improved using the IgG-[L]-scFv BsAb platform. When compared with separate BsAb and T cell injection, EATs released less TNF-α, and infiltrated tumors faster, while achieving robust antitumor responses. The in vivo potency of EAT therapy depended on BsAb dose for arming, EAT cell number per injection, total number of EAT doses, and treatment schedule intensity. The antitumor efficacy of EATs was preserved following cryopreservation, and EATs using γδ T cells were safe and as effective as αβ T cell-EATs.

Conclusions

EATs exerted potent antitumor activities against a broad spectrum of human cancer targets with remarkable safety. The antitumor potency of EATs depended on BsAb dose, cell number and total dose, and schedule. EATs were equally effective after cryopreservation, and the feasibility of third-party γδ-EATs offered an alternative for autologous T cell sources.
Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer
Authors: Sinha Meenal , Zhang Li , Subudhi Sumit , Chen Brandon , Marquez Jaqueline , Liu Eric V , Allaire Kate , Cheung Alexander , Ng Sharon , Nguyen Christopher , Friedlander Terence W , Aggarwal Rahul , Spitzer Matthew , Allison James P , Small Eric J , Sharma Padmanee , Fong Lawrence
Published: May 2021

Background

Sipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment.

Methods

A total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis.

Results

We found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival.

Conclusion

Combining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4.
Pretreatment metastatic growth rate determines clinical outcome of advanced melanoma patients treated with anti-PD-1 antibodies: a multicenter cohort study
Authors: Wagner Nikolaus B , Lenders Max M , Kühl Kathrin , Reinhardt Lydia , André Fiona , Dudda Milena , Ring Natalie , Ebel Chiara , Stäger Ramon , Zellweger Caroline , Lang Roland , Paar Michael , Gussek Philipp , Richtig Georg , Stürmer Suzan H , Kimeswenger Susanne , Oellinger Angela , Forschner Andrea , Leiter Ulrike , Weide Benjamin , Gassenmaier Maximilian , Schraag Amadeus , Klumpp Bernhard , Hoetzenecker Wolfram , Berking Carola , Richtig Erika , Ziemer Mirjana , Mangana Johanna , Terheyden Patrick , Loquai Carmen , Nguyen Van Anh , Gebhardt Christoffer , Meier Friedegund , Diem Stefan , Cozzio Antonio , Flatz Lukas , Röcken Martin , Garbe Claus , Eigentler Thomas K
Published: May 2021

Background

Checkpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies.

Methods

MGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB–IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR.

Results

Pretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p<0.0001), in the confirmation cohort (HR 3.62, 95% CI 2.19 to 5.98, p<0.0001) and in the independent validation cohort (HR 2.57, 95% CI 1.56 to 4.25, p=0.00023). Prior lines of systemic treatment did not influence the significance of MGR. Importantly, the prognostic impact of MGR was independent of total tumor burden, diameter of the largest metastasis, number of prior lines of systemic treatment, LDH, as well as liver and brain metastasis (discovery and confirmation cohorts: both p<0.0001). Superiority of MGR compared with these variables was confirmed in the independent multicenter validation cohort (HR 2.92, 95% CI 1.62 to 5.26, p=0.00036).

Conclusions

High pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens.
Shared inflammatory pathways and therapeutic strategies in COVID-19 and cancer immunotherapy
Authors: Iovino Lorenzo , Thur Laurel A , Gnjatic Sacha , Chapuis Aude , Milano Filippo , Hill Joshua A
Published: May 2021

COVID-19, the syndrome caused by the infection with SARS-CoV-2 coronavirus, is characterized, in its severe form, by interstitial diffuse pneumonitis and acute respiratory distress syndrome (ARDS). ARDS and systemic manifestations of COVID-19 are mainly due to an exaggerated immune response triggered by the viral infection. Cytokine release syndrome (CRS), an inflammatory syndrome characterized by elevated levels of circulating cytokines, and endothelial dysfunction are systemic manifestations of COVID-19. CRS is also an adverse event of immunotherapy (IMTX), the treatment of diseases using drugs, cells, and antibodies to stimulate or suppress the immune system. Graft-versus-host disease complications after an allogeneic stem cell transplant, toxicity after the infusion of chimeric antigen receptor-T cell therapy and monoclonal antibodies can all lead to CRS. It is hypothesized that anti-inflammatory drugs used for treatment of CRS in IMTX may be useful in reducing the mortality in COVID-19, whereas IMTX itself may help in ameliorating effects of SARS-CoV-2 infection. In this paper, we focused on the potential shared mechanisms and differences between COVID-19 and IMTX-related toxicities. We performed a systematic review of the clinical trials testing anti-inflammatory therapies and of the data published from prospective trials. Preliminary evidence suggests there might be a benefit in targeting the cytokines involved in the pathogenesis of COVID-19, especially by inhibiting the interleukin-6 pathway. Many other approaches based on novel drugs and cell therapies are currently under investigation and may lead to a reduction in hospitalization and mortality due to COVID-19.
Progression of cerebral infarction before and after thrombectomy is modified by prehospital pathways
Authors: Kollikowski Alexander M , Cattus Franziska , Haag Julia , Feick Jörn , März Alexander G , Weidner Franziska , Schuhmann Michael K , Müllges Wolfgang , Stoll Guido , Pham Mirko , Strinitz Marc
Published: May 2021

Background

Evidence of the consequences of different prehospital pathways before mechanical thrombectomy (MT) in large vessel occlusion stroke is inconclusive. The aim of this study was to investigate the infarct extent and progression before and after MT in directly admitted (mothership) versus transferred (drip and ship) patients using the Alberta Stroke Program Early CT Score (ASPECTS).

Methods

ASPECTS of 535 consecutive large vessel occlusion stroke patients eligible for MT between 2015 to 2019 were retrospectively analyzed for differences in the extent of baseline, post-referral, and post-recanalization infarction between the mothership and drip and ship pathways. Time intervals and transport distances of both pathways were analyzed. Multiple linear regression was used to examine the association between infarct progression (baseline to post-recanalization ASPECTS decline), patient characteristics, and logistic key figures.

Results

ASPECTS declined during transfer (9 (8–10) vs 7 (6-9), p<0.0001), resulting in lower ASPECTS at stroke center presentation (mothership 9 (7–10) vs drip and ship 7 (6–9), p<0.0001) and on follow-up imaging (mothership 7 (4–8) vs drip and ship 6 (3–7), p=0.001) compared with mothership patients. Infarct progression was significantly higher in transferred patients (points lost, mothership 2 (0–3) vs drip and ship 3 (2–6), p<0.0001). After multivariable adjustment, only interfacility transfer, preinterventional clinical stroke severity, the degree of angiographic recanalization, and the duration of the thrombectomy procedure remained predictors of infarct progression (R2=0.209, p<0.0001).

Conclusions

Infarct progression and postinterventional infarct extent, as assessed by ASPECTS, varied between the drip and ship and mothership pathway, leading to more pronounced infarction in transferred patients. ASPECTS may serve as a radiological measure to monitor the benefit or harm of different prehospital pathways for MT.
Evaluation of a novel flow diverter, the DiVeRt system, in an animal model
Authors: Hufnagl Clemens , Broussalis Erasmia , Cognard Christophe , Grimm Jochen , Hecker Constantin , Oellerer Andreas , Abdallah Muhammed , Griessenauer Christoph J , Killer-Oberpfalzer Monika
Published: May 2021

Background

Using a surgical aneurysm model, this study assessed the performance of a new flow diverter (FD), the DiVeRt, and evaluated the angiographic and histologic features at different periods after stent deployment.

Methods

Fifteen New Zealand White rabbits were treated 3 days prior to intervention and until euthanization with dual antiplatelets. DiVeRt was implanted in bilateral carotid aneurysms (n=30) as well as in the aorta (n=15). The rate of technical success, assessment of aneurysm occlusion (measured by the O'Kelly–Marotta grading (OKM) scale), and stent patency were examined using angiography and histologic examinations in three groups at 1, 3, and 6 months follow-up (FU). In each FU group one control animal was included and treated with the XCalibur stent (n=3).

Results

Overall, DiVeRt placement was successful and without apparent intraprocedural complications. In total, four stents in the carotid artery were occluded and in-stent stenosis was registered in two carotid (7%) and one aortic (6%) vessels. Complete or near complete aneurysm occlusion (OKM scale D1 and C3) was seen in 100% in the 1-month FU group, 70% in the 2-month FU group, and 100% in the 3-month FU group. Histology showed loose, organizing fibrous tissue matrix within the sac and adequate neck endothelialization in all vessels. All branches covered by the DiVeRt remained patent.

Conclusions

The DiVeRt system appears to be feasible and effective for the treatment of aneurysms with high rates of complete aneurysm occlusion, excellent vessel patency, and evidence of high biocompatibility. Occurrences of parent artery occlusion at follow-up did not result in clinical consequences.