bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality improvement initiative to improve the duration of Kangaroo Mother Care in tertiary care neonatal unit of South India
Authors: Jegannathan Sathya , Natarajan Muthukumaran , Solaiappan Manikumar , Shanmugam Ramya , Tilwani Sandeep Ajit
Published: May 2022

Background

India has the highest number of preterm births and maximum number of deaths due to prematurity. Chengalpattu Government Medical College had 11 593 deliveries annually in 2020, of which 2252 of neonates were low birth weight. 2016 Cochrane review concluded that Kangaroo Mother Care (KMC) reduces the morbidity and mortality in low birthweight infants. The average duration of KMC in our unit was around 4.6 hours/baby/day.

Objective

To improve the duration of KMC in stable low birthweight babies from short duration to continuous duration (>12 hours) over 8 weeks.

Methods

The implementation phase was conducted during January 2021 and February 2021. All babies with birth weight <2 kg and who were haemodynamically stable were enrolled. QI (Qualitympovement) team included staff nurses, nursing in charge, resident doctors and consultants. Potential barriers were listed using fishbone analysis. Various possible interventions were identified and a priority matrix was formed to decide the sequence of introduction of changes. The following measures were subsequently tested by multiple PDSA (Plan Do Study Act) cycles: ensuring the availability of KMC charts, combining KMC chart with individualised weight chart, documentation of KMC duration in case sheets, increasing number of KMC chairs, opening of mother–neonatal ICU (M-NICU), KMC slings for mothers, education videos in local language and rewards for mothers.

Outcome indicator

Duration of KMC, recorded by bedside nurses on daily basis.

Results

A total of 86 newborns were enrolled. At the end of 8 weeks, average duration of KMC increased to 16.6 hours/baby/day. The intervention which was most useful in increasing KMC duration was opening of M-NICU. We were able to sustain the improvement at the end of 6 months.

Conclusion

Sequential measures taken as a part of QI initiative, helped to increase the average duration of KMC from 4.6 hours/day to 16.6 hours/day, without much additional resources.
Reducing hyperglycaemia post-kidney and liver transplant: a quality improvement initiative
Authors: Clemens Kristin K , Brahmania Mayur , Weernink Corrine , Lofty Khaled , Rjoob Hani , Berberich Amanda , Gob Alan
Published: May 2022

Background

In-hospital glycaemic management can reduce post-transplant morbidity, but is not always part of transplant care.

Objective

We aimed to reduce the mean number of postoperative days in hyperglycaemia (≥2 blood glucose >12 mmol/L in 24 hours) in kidney and liver transplant recipients by 30%. We also aimed to reduce the mean number of days between transplant admission to endocrine consult by 2.0 days.

Design, setting, participants

We conducted a quality improvement project in liver and kidney transplant recipients admitted to an academic transplant unit in Canada between 1 March 2019 and 1 May 2021.

Intervention

We developed a bedside algorithm to monitor post-transplant capillary blood glucose; the algorithm also included thresholds for nursing-initiated inpatient endocrinology consultation.

Main outcome and measures

We examined outcome (postoperative days in hyperglycaemia, days to inpatient endocrine consultation), process (nursing documentation of postoperative blood sugars) and balancing measures (nursing workload, postoperative days in hypoglycaemia) following implementation of our algorithm. We used Plan-Do-See-Act cycles to study three iterations of our algorithm, and used box plots to present outcomes before and after algorithm implementation.

Results

In the pre-intervention period, 21 transplant recipients spent a mean of 4.1 (SD 2.4) postoperative days in hyperglycaemia before endocrine consultation. The mean number of days between hospital admission to endocrine consult was 10.7 (SD 13.0) days.

In the post-intervention period, we observed a 62% reduction in postoperative days in hyperglycaemia. The mean number of days between admission and endocrine consult was reduced by 6.3 days (59% reduction).

Conclusions

Implementation of a simple, bedside algorithm for postoperative glucose monitoring and detection of hyperglycaemia in transplant patients, reduced the mean number of postoperative days in hyperglycaemia and time to inpatient endocrine consultation. Our algorithm continues to be used in our academic transplant unit.
Diagnosis and management of asthma in children
Authors: Martin Joanne , Townshend Jennifer , Brodlie Malcolm
Published: May 2022

Asthma is the the most common chronic respiratory condition of childhood worldwide, with around 14% of children and young people affected. Despite the high prevalence, paediatric asthma outcomes are inadequate, and there are several avoidable deaths each year. Characteristic asthma features include wheeze, shortness of breath and cough, which are typically triggered by a number of possible stimuli. There are several diagnostic challenges, and as a result, both overdiagnosis and underdiagnosis of paediatric asthma remain problematic.

Effective asthma management involves a holistic approach addressing both pharmacological and non-pharmacological management, as well as education and self-management aspects. Working in partnership with children and families is key in promoting good outcomes. Education on how to take treatment effectively, trigger avoidance, modifiable risk factors and actions to take during acute attacks via personalised asthma action plans is essential.

This review aimed to provide an overview of good clinical practice in the diagnosis and management of paediatric asthma. We discuss the current diagnostic challenges and predictors of life-threatening attacks. Additionally, we outline the similarities and differences in global paediatric asthma guidelines and highlight potential future developments in care. It is hoped that this review will be useful for healthcare providers working in a range of child health settings.
Mortality before and after reconfiguration of the Danish hospital-based emergency healthcare system: a nationwide interrupted time series analysis
Authors: Flojstrup Marianne , Bogh Søren Bie Bie , Bech Mickael , Henriksen Daniel Pilsgaard , Johnsen Søren Paaske , Brabrand Mikkel
Published: May 2022

Objectives

The study aimed to investigate how the ‘natural experiment’ of reconfiguring the emergency healthcare system in Denmark affected in-hospital and 30-day mortality on a national level. The reconfiguration included the centralisation of hospitals and the establishment of emergency departments with specialists present around the clock.

Design

Hospital-based cohort study.

Setting

All public hospitals in Denmark.

Participants

Patients with an unplanned contact from 1 January 2007 until 31 December 2016.

Interventions

Stepped-wedge reconfiguration of the Danish emergency healthcare system.

Main outcome measures

We determined the adjusted ORs for in-hospital mortality and HRs for 30-day mortality using logistic and Cox regression analysis adjusted for sex, age, Charlson Comorbidity Index, income, education, mandatory referral and the changes in the out of hours system in the Capital Region. The main outcomes were stratified by the time of arrival. We performed subgroup analyses on selected diagnoses: myocardial infarction, stroke, pneumonia, aortic aneurysm, bowel perforation, hip fracture and major trauma.

Results

We included 11 367 655 unplanned hospital contacts. The adjusted OR for overall in-hospital mortality after reconfiguration of the emergency healthcare system was 0.998 (95% CI 0.968 to 1.010; p=0.285), and the adjusted OR for 30-day mortality was 1.004 (95% CI 1.000 to 1.008; p=0.045)). Subgroup analyses showed some possible benefits of the reconfiguration such as a reduction in-hospital and 30-day mortality for myocardial infarction, stroke, aortic aneurysm and major trauma.

Conclusions

The Danish emergency care reconfiguration programme was not associated with an improvement in overall in-hospital mortality trends and was associated with a slight slowing of prior improvements in 30-day mortality trends.
Frailty assessment for COVID-19 follow-up: a prospective cohort study
Authors: Müller Ilena , Mancinetti Marco , Renner Anja , Bridevaux Pierre-Olivier , Brutsche Martin H , Clarenbach Christian , Garzoni Christian , Lenoir Alexandra , Naccini Bruno , Ott Sebastian , Piquilloud Lise , Prella Maura , Que Yok-Ai , Soccal Paola Marina , von Garnier Christophe , Geiser Thomas K , Funke-Chambour Manuela , Guler Sabina
Published: May 2022

Background

The Clinical Frailty Scale (CFS) is increasingly used for clinical decision making in acute care but little is known about frailty after COVID-19.

Objectives

To investigate frailty and the CFS for post-COVID-19 follow-up.

Methods

This prospective multicentre cohort study included COVID-19 survivors aged ≥50 years presenting for a follow-up visit ≥3 months after the acute illness. Nine centres retrospectively collected pre-COVID-19 CFS and prospectively CFS at follow-up. Three centres completed the Frailty Index (FI), the short physical performance battery (SPPB), 30 s sit-to-stand test and handgrip strength measurements. Mixed effect logistic regression models accounting for repeated measurements and potential confounders were used to investigate factors associated with post-COVID-19 CFS. Criterion and construct validity were determined by correlating the CFS to other concurrently assessed frailty measurements and measures of respiratory impairment, respectively.

Results

Of the 288 participants 65% were men, mean (SD) age was 65.1 (9) years. Median (IQR) CFS at follow-up was 3 (2–3), 21% were vulnerable or frail (CFS ≥4). The CFS was responsive to change, correlated with the FI (r=0.69, p<0.001), the SPPB score (r=−0.48, p<0.001) (criterion validity) and with the St George’s Respiratory Questionnaire score (r=0.59, p<0.001), forced vital capacity %-predicted (r=−0.25, p<0.001), 6 min walk distance (r=−0.39, p<0.001) and modified Medical Research Council (mMRC) (r=0.59, p<0.001). Dyspnoea was significantly associated with a higher odds for vulnerability/frailty (per one mMRC adjusted OR 2.01 (95% CI 1.13 to 3.58), p=0.02).

Conclusions

The CFS significantly increases with COVID-19, and dyspnoea is an important risk factor for post-COVID-19 frailty and should be addressed thoroughly.
Dyspnoea at the end of life: instrument development and validation-the CONFORTO Strategy
Authors: Teixeira Isadora Crosara Alves , Carvas Ana Maria Porto , Silva Ricardo Borges da , Borges Eliza , Corrêa-Faria Patrícia , Rabahi Marcelo Fouad
Published: May 2022

Objective

To describe the construction and validation of the algorithm forCriteria for inclusion;Objective of dyspnoea;Notification of patient/family/health professionals;Facial air flow;Oxygen;Relaxion and breathing;Treating causes of dyspnoea andOpioid (CONFORTO), an instrument to guide health professionals in managing dyspnoea in patients with an advance stage of the disease at the end-of-life.

Methods

The study was carried out in three stages: (1) literature review and construction of CONFORTO; (2) semantic validation; (3) application of the CONFORTO Strategy to health professionals as a test (before video lessons) and post-test (20 days after watching video lessons) methodology. The scores obtained in the pretest and post-test were compared using the Wilcoxon test.

Results

Seventy-four professionals from different internal medicine and intensive care units participated in the study. The CONFORTO Strategy involved eight acronym-forming items:Criteria for inclusion;Objective of dyspnoea;Notification of patient/family/health professionals;Facial air flow;Oxygen;Relaxion and breathing;Treating causes of dyspnoea andOpioid. The post-test indicated a significant increase in the score for the following items: facial air flow (p=0.016); oxygen (p=0.002); relaxation and breathing (p=0.002) and treating the causes of dyspnoea (p=0.011). The increase in score occurred after the training sessions with video lessons.

Conclusion

The CONFORTO Strategy proved valid and reliable for managing dyspnoea in patients with an advanced stage of the disease at the end-of-life. Because the instrument is easy-to-use, it can be used by the entire health team at any assistance-providing location, and can, thus, contribute to improving dyspnoea management for these patients.
UK Palliative trainees Research Collaborative (UK-PRC): the first 5 years – 0–100 study sites
Authors: Wakefield Donna , Etkind Simon Noah , Bemand-Qureshi Lucy , Sutherland Anna , Koffman Jonathan , Dewhurst Felicity , Noble Simon , Chamberlain Charlotte
Published: May 2022

Objectives

Palliative care research suffers from underfunding and a workforce spread across multiple settings leading to a lack of large-scale studies. To facilitate multisite research and audit we set up the UK Palliative trainees Research Collaborative (UKPRC), the first national trainee-led audit and research collaborative in palliative care. Here, we critically review the progress and potential of the UKPRC since its inception in 2016, identifying key challenges and facilitators. Members of the UKPRC steering committee collaborated to write this reflection, reviewing existing evidence regarding trainee-led research collaboratives.

Findings

The UKPRC has representation from 16/19 UK training regions. Projects are run by a core team; local collaborators collect data at each site. The collaborative is supported by academic leads and newly qualified consultants to develop a culture of continuous improvement in practice. We have conducted four national projects to date, including an audit covering 119 sites. Facilitators for our work include a focus on inclusivity and national representation; support from recently qualified consultants to ensure continuity; and taking a pragmatic approach, focusing initially on straightforward projects to build momentum. Challenges include the step from national audit to multisite, patient-facing research and maintaining continuity in a membership with high turnover.

Conclusions

There is potential to change practice through large scale data collection via the trainee-led collaborative model. Collaboration is especially important in a small specialty with limited resources. The UKPRC has demonstrated ‘proof of concept’ and has the potential to support and sustain a culture where research can flourish within palliative care.
Advance care planning imperative: High-quality patient-centred goals of care
Authors: Case Amy Allen , Epstein Andrew S , Gustin Jillian L.
Published: May 2022

Advance care planning (ACP) discussions aim to ensure goal-concordant care for patients with serious illness, throughout treatment and especially at the end of life. But recent literature has forced the field of palliative care to wrestle with the definition and impact of ACP. Are ACP discussions worthwhile? Is there a difference between ACP discussions early in a patient’s illness versus discussions occurring later when a concrete medical care decision must be made? Here, we identify elements needed to answer these questions and describe how a multisite initiative will elucidate the value of discussing and documenting what matters most to patients.
745 Thunderclap headache syndrome presenting to the emergency department: an international multicentre observational cohort study
Authors: Roberts Tom , Horner Daniel , Chu Kevin , Than Martin , Kelly Anne-Maree , Investigators HEADStudy
Published: May 2022

Background

Acute headache is a common reason for presentation to emergency departments. Some have significant structural pathology requiring further intervention. Emergency clinicians often rely on presenting headache features (such as thunderclap onset) to guide the need for neuroimaging and further investigation. It is unclear whether these features discriminate accurately or how the investigations of patients presenting with thunderclap headache differs internationally.

Objectives

To determine the proportion of patients presenting with thunderclap onset of headache from a general headache cohort and compare demographics, investigation strategy and final diagnosis, across an international sample of patients.

Methods

An international, multicentre, observational prospective cohort study. This planned sub-study focussed on patients presenting with thunderclap onset headache, with characteristics compared to the general headache cohort. The prospective observational design was chosen to capture real-world data on current international practice.

Results

The study recruited 4536 patients across 67 hospitals and 10 countries during 2019. Of this, 644 patients presented with thunderclap headache onset (14.2%). Median age was 44. The majority of patients self-referred to hospital. CT brain imaging was performed in 62.7% cases and lumbar puncture in 10.6%, with wide international variation. New Zealand reported the highest rate of neuroimaging, 78.4% of patients presenting with thunderclap headache, compared to 25.0% in Romania. All cases of subarachnoid haemorrhage (SAH) were diagnosed on CT imaging results.

When compared with the parent cohort of all headache patients presenting to the ED, those with thunderclap headache had a significantly higher rate of serious cranial pathology (13.7% vs 8.5%, p<0.001) and final diagnosis of SAH (3.6% vs 0.8% p<0.001).

Conclusions

Thunderclap headache presenting to the ED appears to correlate with a higher risk for serious intracranial pathology and/or SAH. Investigation strategies varied within this international cohort. Neuroimaging rates did not align with international guidelines, suggesting potential for further work on standardisation.
Greener gastroenterology and hepatology: the British Society of Gastroenterology Strategy for Climate Change and Sustainability
Authors: Veitch Andrew M
Published: May 2022

There is a global climate emergency, and also a global health concern related to climate change. The British Society of Gastroenterology (BSG) acknowledges these issues, and supports the concerns of its members to address them. Climate change has adverse effects on gastroenterological and liver disease, and on healthcare systems. The healthcare industry, itself, is also a major contributor to greenhouse gases. BSG has developed a strategy on Climate Change and Sustainability, which encompasses all of the activities of the society, and its members: personal, professional, organisational, political, international and research.
Faecal occult blood loss accurately predicts future detection of colorectal cancer. A prognostic model
Authors: Meester Reinier G S , van de Schootbrugge-Vandermeer Hilliene J , Breekveldt Emilie C H , de Jonge Lucie , Toes-Zoutendijk Esther , Kooyker Arthur , Nieboer Daan , Ramakers Christian R , Spaander Manon C W , van Vuuren Anneke J , Kuipers Ernst J , van Kemenade Folkert J , Nagtegaal Iris D , Dekker Evelien , van Leerdam Monique E , Lansdorp-Vogelaar Iris
Published: May 2022

Objectives

To examine the prognostic potential of repeated faecal haemoglobin (F-Hb) concentration measurements in faecal immunochemical test (FIT)-based screening for colorectal cancer (CRC).

Design

Prognostic model.

Setting

Dutch biennial FIT-based screening programme during 2014–2018.

Participants

265 881 participants completing three rounds of FIT, with negative test results (F-Hb <47 µg Hb/g faeces) in rounds 1 and 2.

Interventions

Colonoscopy follow-up in participants with a positive FIT (F-Hb ≥47 µg Hb/g faeces).

Main outcomes

We evaluated prognostic models for detecting advanced neoplasia (AN) and CRC in round 3, with as predictors, participant age, sex, F-Hb in rounds 1 and 2, and categories/combinations/non-linear transformations of F-Hb. Primary evaluation criteria included: risk prediction accuracy (calibration), discrimination of participants with versus without AN or CRC (optimism-adjusted C-statistics, range 0.5–1.0), the degree of risk stratification and C-statistics in external validation.

Results

Among study participants, 8806 (3.3%) had a positive FIT result, 3254 (1.2%) had AN detected and 557 (0.2%) had cancer. F-Hb concentrations in rounds 1 and 2 were the strongest outcome predictors, with adjusted ORs of up to 9.4 (95% CI 7.5 to 11.7) for the highest F-Hb category. Risk predictions matched the observed risk for most participants (calibration intercept −0.008 to −0.099; slope 0.982–0.998), and discriminated participants with versus without AN or CRC with C-statistics of 0.78 (95% CI 0.77 to 0.79) and 0.73 (95% CI 0.71 to 0.75), respectively. The predicted risk ranged from 0.4% to 36.7% for AN and from 0.0% to 5.5% for CRC across participants. In external validation, the model retained similar discrimination accuracy for AN (C-statistic 0.77, 95% CI 0.66 to 0.87) and CRC (C-statistic 0.78, 95% CI 0.66 to 0.91).

Conclusion

Participants at lower versus higher risk of future AN or CRC can be accurately identified based on their age, sex and particularly, prior F-Hb concentrations. Risk stratification should be considered based on this information.
PTEN as a target in melanoma
Authors: Ince Furkan Akif , Shariev Artur , Dixon Katie
Published: May 2022

PTEN is a well-known tumour suppressor protein that is frequently found to be mutated, inactivated or deleted in a wide range of different cancers. Its tumour suppressive properties result predominantly from its inhibitory effects on the PI3K-AKT signalling pathway. In melanoma, numerous different PTEN mutations have been identified in both melanoma cell lines and melanoma tissue. A number of different molecules can act on PTEN to either promote its suppression of melanoma, while other molecules may antagonise PTEN to inhibit its mechanism of action against melanoma. This review will discuss how the interactions of PTEN with other molecules may have a positive or negative impact on melanoma pathogenesis, giving rise to the potential for PTEN-targeted therapies against melanoma.
Lights on HBME-1: the elusive biomarker in thyroid cancer pathology
Authors: Cazzaniga Giorgio , Seminati Davide , Smith Andrew , Piga Isabella , Capitoli Giulia , Garancini Mattia , L'Imperio Vincenzo , Fusco Nicola , Pagni Fabio
Published: May 2022

Among the different ancillary immunohistochemical tools that pathologists may employ in thyroid nodules, the so-called Hector Battifora’s ‘MEsothelioma’ 1 (HBME-1) staining is one of the most fascinating, since its real identity is currently unknown. In the present review, the different clinical applications of HBME-1 are analysed, with main emphasis on its role in thyroid pathology with overview on less impactful fields, such as haematopathology or mesothelial lesions. Different acceptable or good diagnostic performances were recorded for HBME-1 in thyroid pathology, being used in routine practice as one of the best tools to screen thyroid malignancy both in terms of sensitivity and specificity. From a speculative point of view, after many attempts to hunt the cryptic target antigen of this antibody, its identity still remains elusive. In this setting, the application of high-throughput technologies (mainly in situ proteomics) may be the exact route to improve the knowledge about the pathophysiology of HBME-1 and to finally unveil its true identity.
Development of a LAG-3 immunohistochemistry assay for melanoma
Authors: Johnson Lori , McCune Bryan , Locke Darren , Hedvat Cyrus , Wojcik John B , Schroyer Caitlin , Yan Jim , Johnson Krystal , Sanders-Cliette Angela , Samala Sujana , Dillon Lloye M , Anderson Steven , Shuster Jeffrey
Published: May 2022

Aims

A robust immunohistochemistry (IHC) assay was developed to detect lymphocyte-activation gene 3 (LAG-3) expression by immune cells (ICs) in tumour tissues. LAG-3 is an immuno-oncology target with demonstrable clinical benefit, and there is a need for a standardised, well-characterised assay to measure its expression. This study aims to describe LAG-3 scoring criteria and present the specificity, sensitivity, analytical precision and reproducibility of this assay.

Methods

The specificity of the assay was investigated by antigen competition and withLAG3knockout cell lines. A melanin pigment removal procedure was implemented to prevent melanin interference in IHC interpretation. Formalin-fixed paraffin-embedded (FFPE) human melanoma samples with a range of LAG-3 expression levels were used to assess the sensitivity and analytical precision of the assay with a ≥1% cut-off to determine LAG-3 positivity. Interobserver and intraobserver reproducibility were evaluated with 60 samples in intralaboratory studies and 70 samples in interlaboratory studies.

Results

The LAG-3 IHC method demonstrated performance suitable for analysis of LAG-3 IC expression in clinical melanoma samples. The pretreatment step effectively removed melanin pigment that could interfere with interpretation. LAG-3 antigen competition and analysis ofLAG3knockout cell lines indicated that the 17B4 antibody clone binds specifically to LAG-3. The intrarun repeatability, interday, interinstrument, interoperator and inter-reagent lot reproducibility demonstrated a high scoring concordance (>95%). The interobserver and intraobserver reproducibility and overall interlaboratory and intralaboratory reproducibility also showed high scoring concordance (>90%).

Conclusions

We have demonstrated that the assay reliably assesses LAG-3 expression in FFPE human melanoma samples by IHC.
Evaluation of Glycemic Control in Critically ill Patients with Bacteremia: A Retrospective, Single-Center Cohort Study
Authors: Chou Alaina , Carloni Rachael , Xue Wei , Seeram Vandana , Ferreira Jason A
Published: May 2022

Dysglycemia is a common complication in hospitalized patients and has been suggested to play a significant role in the pathology and virulence of patients with bacteremia. The literature evaluating this relationship in critically ill patients, however, is limited. This retrospective, single-center cohort study aimed to investigate the relationship of glycemic control with 28-day intensive care unit (ICU)-free days in critically ill patients with bacteremia. Glycemic control was evaluated and determined based on time in targeted blood glucose range (TIR) of 70–140 mg/dL. Using a threshold of 80%, patients were then categorized into 2 groups: TIR-lo (<80%) and TIR-hi (≥80%). Unadjusted data identified a significant difference in ICU-free days (TIR-lo 21.29 days vs TIR-hi 24.08 days, p=0.007). However, due to an excess of zero ICU-free days, a zero-inflated Poisson model was used for analysis and demonstrated that patients in the TIR-lo group were 2.57 times more likely to have zero ICU-free days (p=0.033), which was attributed to mortality. Of the survivors, no difference was seen with TIR status and the number of ICU-free days (p=0.780). These findings demonstrate that glycemic control may increase the likelihood of being liberated from the ICU within a 28-day period, which the authors attributed to increased survival. However, of the patients who left the ICU, glycemic control was not associated with a significant difference in the number of ICU-free days.
Burden of arrhythmias and predictors of mortality among multiple myeloma patients with arrhythmias
Authors: Balogun Omotola , Jackson Inimfon , Oyenuga Mosunmoluwa , Oyenuga Abayomi , Etuk Aniekeme , Jackson Nsikak
Published: May 2022

Arrhythmias are a major cardiac complication reported among patients with multiple myeloma (MM), but these have not been further characterized in this population. We explored the prevalence of arrhythmias and examined the predictors of mortality among patients with MM with arrhythmias. The National Inpatient Sample data collected between 2016 and 2018 were used to conduct retrospective analyses. Multivariable logistic regression analyses were done to examine the predictors of mortality among patients with MM with arrhythmias. 16.9% of patients with MM reported a diagnosis of any arrhythmias and 70.7% of these were atrial fibrillation. Patients aged 70 years and above had 21% lower odds (adjusted OR (AOR): 0.79; 95% CI: 0.68 to 0.92) of inpatient mortality relative to younger patients. Those in the non-Hispanic black, Hispanic, and non-Hispanic other category were 1.38 (95% CI: 1.16 to 1.64), 1.53 (95% CI: 1.19 to 1.97), and 1.69 (95% CI: 1.29 to 2.21) times more likely to die during hospitalization compared with their counterparts who were non-Hispanic whites. Relative to patients with MM who were on Medicare, those on private (AOR: 1.28; 95% CI: 1.06 to 1.54) and other insurance types (AOR: 1.78; 95% CI: 1.23 to 2.58) had higher odds of mortality. Other predictors of inpatient mortality were elective admission (AOR: 0.67; 95% CI: 0.52 to 0.85) and Charlson comorbidity indices between 5–7 (AOR: 1.23; 95% CI: 1.07 to 1.41) and ≥8 (AOR: 1.45; 95% CI: 1.21 to 1.73) compared with comorbidity indices between 0 and 4. Our study adds to the body of knowledge on the need for proper diagnosis and management of cardiac arrhythmias in patients with MM. Research is needed to further assess the time of arrhythmia diagnosis and its impact on health outcomes among patients with MM.
Soluble HLA peptidome of pleural effusions is a valuable source for tumor antigens
Authors: Khazan-Kost Sofia , Cafri Gal , Melamed Kadosh Dganit , Mooshayef Navit , Chatterji Sumit , Dominissini Dan , Manor Sigal , Zisser Bracha , Broday Limor , Talalai Efrosiniia , Shemer Anat , Zadok Oranit , Ofek Efrat , Onn Amir , Admon Arie , Peled Michael
Published: May 2022

Background

Soluble human leucocyte antigen (sHLA) molecules, released into the plasma, carry their original peptide cargo and provide insight into the protein synthesis and degradation schemes of their source cells and tissues. Other body fluids, such as pleural effusions, may also contain sHLA-peptide complexes, and can potentially serve as a source of tumor antigens since these fluids are drained from the tumor microenvironment. We explored this possibility by developing a methodology for purifying and analyzing large pleural effusion sHLA class I peptidomes of patients with malignancies or benign diseases.

Methods

Cleared pleural fluids, cell pellets present in the pleural effusions, and the primary tumor cells cultured from cancer patients’ effusions, were used for immunoaffinity purification of the HLA molecules. The recovered HLA peptides were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and the resulting LC-MS/MS data were analyzed with the MaxQuant software tool. Selected tumor antigen peptides were tested for their immunogenicity potential with donor peripheral blood mononuclear cells (PBMCs) in an in vitro assay.

Results

Mass spectrometry analysis of the pleural effusions revealed 39,669 peptides attributable to 11,305 source proteins. The majority of peptides identified from the pleural effusions were defined as HLA ligands that fit the patients’ HLA consensus sequence motifs. The membranal and soluble HLA peptidomes of each individual patient correlated to each other. Additionally, soluble HLA peptidomes from the same patient, obtained at different visits to the clinic, were highly similar. Compared with benign effusions, the soluble HLA peptidomes of malignant pleural effusions were larger and included HLA peptides derived from known tumor-associated antigens, including cancer/testis antigens, lung-related proteins, and vascular endothelial growth factor pathway proteins. Selected tumor-associated antigens that were identified by the immunopeptidomics were able to successfully prime CD8+ T cells.

Conclusions

Pleural effusions contain sHLA-peptide complexes, and the pleural effusion HLA peptidome of patients with malignant tumors can serve as a rich source of biomarkers for tumor diagnosis and potential candidates for personalized immunotherapy.
Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation
Authors: Zhu Lin , Kuang Xinwei , Zhang Guanxiong , Liang Long , Liu Dandan , Hu Bin , Xie Zuozhong , Li Hui , Liu Hong , Ye Mao , Chen Xiang , Liu Jing
Published: May 2022

Background

Immune checkpoint inhibitors (ICIs) have been increasingly used in patients with various cancers and have shown efficient therapeutic outcomes. However, fewer than 40% of cases across multiple cancer types show a response to ICIs. Therefore, developing more efficient combinational approaches with ICIs and revealing the underlying mechanisms are important goals for achieving rapid clinical transformation and application.

Methods

The effects on antitumor immunity activity of albendazole (ABZ) and the synergistic effects of ABZ with CD73 blockade were investigated in the melanoma B16F10 and the Lewis lung cancer tumor-bearing immune-competent mice models. The mechanism of ABZ reducing PD-L1 protein level through suppressing UBQLN4 was identified and validated through immunoprecipitation-mass spectrometry and molecular methods. Bioinformatics and anti-PD-1 therapy melanoma patients samples analysis were used to assess the level of UBQLN4/PD-L1 in the therapeutic efficacy of anti-PD-1 therapy.

Results

ABZ induces CD8+T cell activity and subsequent immunotherapy response associated with suppression of PD-L1 protein level. Mechanistically, we revealed that ABZ promotes ubiquitin-mediated degradation of PD-L1 via suppressing UBQLN4, which was bound to PD-L1 and stabilized PD-L1 protein. Preclinically, genetic deletion or target inhibition of CD73 showed synergistic effects with ABZ treatment in the immune-competent mice models. Significantly, UBQLN4 and PD-L1 levels were higher in the tumor region of responders versus non-responders and correlated with better progression-free survival and overall survival in anti-PD-1 therapy melanoma patients.

Conclusions

Our findings revealed a previously unappreciated role of ABZ in antitumor immunity by inducing ubiquitin-mediated PD-L1 protein degradation, identified predictors for assessing the therapeutic efficacy of anti-PD-1 therapy, and provided novel therapeutic possibility by combination treatment of ABZ and CD73 blockade in cancers.
Salt-inducible kinase 3 protects tumor cells from cytotoxic T-cell attack by promoting TNF-induced NF-κB activation
Authors: Sorrentino Antonio , Menevse Ayse Nur , Michels Tillmann , Volpin Valentina , Durst Franziska Christine , Sax Julian , Xydia Maria , Hussein Abir , Stamova Slava , Spoerl Steffen , Heuschneider Nicole , Muehlbauer Jasmin , Jeltsch Katharina Marlene , Rathinasamy Anchana , Werner-Klein Melanie , Breinig Marco , Mikietyn Damian , Kohler Christian , Poschke Isabel , Purr Sabrina , Reidell Olivia , Martins Freire Catarina , Offringa Rienk , Gebhard Claudia , Spang Rainer , Rehli Michael , Boutros Michael , Schmidl Christian , Khandelwal Nisit , Beckhove Philipp
Published: May 2022

Background

Cancer immunotherapeutic strategies showed unprecedented results in the clinic. However, many patients do not respond to immuno-oncological treatments due to the occurrence of a plethora of immunological obstacles, including tumor intrinsic mechanisms of resistance to cytotoxic T-cell (TC) attack. Thus, a deeper understanding of these mechanisms is needed to develop successful immunotherapies.

Methods

To identify novel genes that protect tumor cells from effective TC-mediated cytotoxicity, we performed a genetic screening in pancreatic cancer cells challenged with tumor-infiltrating lymphocytes and antigen-specific TCs.

Results

The screening revealed 108 potential genes that protected tumor cells from TC attack. Among them, salt-inducible kinase 3 (SIK3) was one of the strongest hits identified in the screening. Both genetic and pharmacological inhibitions of SIK3 in tumor cells dramatically increased TC-mediated cytotoxicity in several in vitro coculture models, using different sources of tumor and TCs. Consistently, adoptive TC transfer of TILs led to tumor growth inhibition of SIK3-depleted cancer cells in vivo. Mechanistic analysis revealed that SIK3 rendered tumor cells susceptible to tumor necrosis factor (TNF) secreted by tumor-activated TCs. SIK3 promoted nuclear factor kappa B (NF-κB)nuclear translocation and inhibited caspase-8 and caspase-9 after TNF stimulation. Chromatin accessibility and transcriptome analyses showed that SIK3 knockdown profoundly impaired the expression of prosurvival genes under the TNF–NF-κBaxis. TNF stimulation led to SIK3-dependent phosphorylation of the NF-κB upstream regulators inhibitory-κB kinase and NF-kappa-B inhibitor alpha on the one side, and to inhibition of histone deacetylase 4 on the other side, thus sustaining NF-κB activation and nuclear stabilization. A SIK3-dependent gene signature of TNF-mediated NF-κB activation was found in a majority of pancreatic cancers where it correlated with increased cytotoxic TC activity and poor prognosis.

Conclusion

Our data reveal an abundant molecular mechanism that protects tumor cells from cytotoxic TC attack and demonstrate that pharmacological inhibition of this pathway is feasible.
Immune cell infiltration pattern in non-small cell lung cancer PDX models is a model immanent feature and correlates with a distinct molecular and phenotypic make-up
Authors: Oswald Eva , Bug Daniel , Grote Anne , Lashuk Kanstantsin , Bouteldja Nassim , Lenhard Dorothee , Löhr Anne , Behnke Anke , Knauff Volker , Edinger Anna , Klingner Kerstin , Gaedicke Simone , Niedermann Gabriele , Merhof Dorit , Feuerhake Friedrich , Schueler Julia
Published: May 2022

Background

The field of cancer immunology is rapidly moving towards innovative therapeutic strategies, resulting in the need for robust and predictive preclinical platforms reflecting the immunological response to cancer. Well characterized preclinical models are essential for the development of predictive biomarkers in the oncology as well as the immune-oncology space. In the current study, gold standard preclinical models are being refined and combined with novel image analysis tools to meet those requirements.

Methods

A panel of 14 non-small cell lung cancer patient-derived xenograft models (NSCLC PDX) was propagated in humanized NOD/Shi-scid/IL-2Rnull mice. The models were comprehensively characterized for relevant phenotypic and molecular features, including flow cytometry, immunohistochemistry, histology, whole exome sequencing and cytokine secretion.

Results

Models reflecting hot (>5% tumor-infiltrating lymphocytes/TILs) as opposed to cold tumors (<5% TILs) significantly differed regarding their cytokine profiles, molecular genetic aberrations, stroma content, and programmed cell death ligand-1 status. Treatment experiments including anti cytotoxic T-lymphocyte-associated protein 4, anti-programmed cell death 1 or the combination thereof across all 14 models in the single mouse trial format showed distinctive tumor growth response and spatial immune cell patterns as monitored by computerized analysis of digitized whole-slide images. Image analysis provided for the first time qualitative evaluation of the extent to which PDX models retain the histological features from their original human donors.

Conclusions

Deep phenotyping of PDX models in a humanized setting by combinations of computational pathology, immunohistochemistry, flow cytometry and proteomics enables the exhaustive analysis of innovative preclinical models and paves the way towards the development of translational biomarkers for immuno-oncology drugs.
Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation
Authors: Holland Elizabeth M , Molina John C , Dede Kniya , Moyer Daniel , Zhou Ting , Yuan Constance M , Wang Hao-Wei , Stetler-Stevenson Maryalice , Mackall Crystal , Fry Terry J , Panch Sandhya , Highfill Steven , Stroncek David , Little Lauren , Lee Daniel W , Shalabi Haneen , Yates Bonnie , Shah Nirali
Published: May 2022

Chimeric antigen receptor T-cells (CART) are active in relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), but relapse remains a substantial challenge. Reinfusion with the same CART product (CART2) in patients with suboptimal response or antigen positive relapse following first infusion (CART1) represents a potential treatment strategy, though early experiences suggest limited efficacy of CART2 with CD19 targeting. We report on our experience with CART2 across a host of novel CAR T-cell trials. This was a retrospective review of children and young adults with B-ALL who received reinfusion with an anti-CD19, anti-CD22, or anti-CD19/22 CART construct on one of 3 CAR T-cells trials at the National Cancer Institute (NCT01593696,NCT02315612, NCT0344839) between July 2012 and January 2021. All patients received lymphodepletion (LD) pre-CART (standard LD: 75 mg/m2fludarabine, 900 mg/m2cyclophosphamide; or intensified LD: 120 mg/m2fludarabine, 1200 mg/m2cyclophosphamide). Primary objectives were to describe response to and toxicity of CART2. Indication for CART2, impact of LD intensity, and CAR T-cell expansion and leukemia antigen expression between CART infusions was additionally evaluated. Eighteen patients proceeded to CART2 due to persistent (n=7) or relapsed antigen positive disease (n=11) following CART1. Seven of 18 (38.9%) demonstrated objective response (responders) to CART2: 5 achieved a minimal residual disease (MRD) negative CR, 1 had persistent MRD level disease, and 1 showed a partial remission, the latter with eradication of antigen positive disease and emergence of antigen negative B-ALL. Responders included four patients who had not achieved a CR with CART1. Limited cytokine release syndrome was seen following CART2. Peripheral blood CART1 expansion was higher than CART2 expansion (p=0.03). Emergence of antigen negative/dim B-ALL in 6 (33.3%) patients following CART2 contributed to lack of CR. Five of seven (71.4%) responders received intensified LD pre-CART2, which corresponded with higher CART2 expansion than in those receiving standard LD (p=0.029). Diminished CAR T-cell expansion and antigen downregulation/loss impeded robust responses to CART2. A subset of patients, however, may derive benefit from CART2 despite suboptimal response to CART1. Intensified LD may be one strategy to augment CART2 responses, though further study of factors associated with CART2 response, including serial monitoring of antigen expression, is warranted.
Tissue-resident memory T cells from a metastatic vaginal melanoma patient are tumor-responsive T cells and increase after anti-PD-1 treatment
Authors: Pizzolla Angela , Keam Simon Paul , Vergara Ismael A , Caramia Franco , Thio Niko , Wang Minyu , Kocovski Nikolce , Tantalo Daniela , Jabbari Jafar , Au-Yeung George , Sandhu Shahneen , Gyorki David E , Weppler Alison , Perdicchio Maurizio , McArthur Grant A , Papenfuss Anthony T , Neeson Paul Joseph
Published: May 2022

Background

Vaginal melanoma (VM) is a rare cancer and has a poor response to immune checkpoint blockade (ICB). CD8+Tissue Resident Memory (TRM) T cells proliferate in response to ICB and correlate with longer survival in metastatic cutaneous melanoma. However, their capacity to respond to VM and their neoantigens is not known.

Methods

Using longitudinal samples, we explored the evolution of VM mutations by whole-exome sequencing and RNAseq, we also defined the immune context using multiplex immunohistochemistry and nanostring pan cancer immune profile. Then using fresh single cell suspensions of the metastatic samples, we explored VM T cells via mass cytometry and single cell RNAseq and T cell receptor sequencing (TCRseq). Finally, we investigated TRM, pre-TRM and exhausted T cell function against melanoma neo-antigens and melanoma differentiation antigens in vitro.

Results

Primary VM was non-inflamed and devoid of CD8+TRM cells. In contrast, both metastases showed proliferating CD8+TRM were clustered at the tumor margin, with increased numbers in the second ICB-refractory metastasis. The first metastasis showed dense infiltration of CD8+T cells, the second showed immune exclusion with loss of melanoma cell Major histocompatibility complex (MHC)-I expression associated with downregulation of antigen presentation pathway gene expression. CD8+TRM from both metastases responded to autologous melanoma cells more robustly than all other CD8+T cell subsets. In addition, CD8+TRM shared TCR clones across metastases, suggesting a response to common antigens, which was supported by recognition of the same neoantigen by expanded tumor infiltrating lymphocytes.

Conclusions

In this study, we identified TRM clusters in VM metastases from a patient, but not primary disease. We showed TRM location at the tumor margin, and their superior functional response to autologous tumor cells, predicted neoantigens and melanoma differentiation antigens. These CD8+TRM exhibited the highest tumor-responsive potential and shared their TCR with tumor-infiltrating effector memory T cells. This suggests VM metastases from this patient retain strong antitumor T cell functional responses; however, this response is suppressed in vivo. The loss of VG MHC-I expression is a common immune escape mechanism which was not addressed by anti-PD-1 monotherapy; rather an additional targeted approach to upregulate MHC-I expression is required.
Can brain signals and anatomy refine contact choice for deep brain stimulation in Parkinson’s disease?
Authors: Xu San San , Lee Wee-Lih , Perera Thushara , Sinclair Nicholas C , Bulluss Kristian J , McDermott Hugh J , Thevathasan Wesley
Published: May 2022

Introduction

Selecting the ideal contact to apply subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease is time-consuming and reliant on clinical expertise. The aim of this cohort study was to assess whether neuronal signals (beta oscillations and evoked resonant neural activity (ERNA)), and the anatomical location of electrodes, can predict the contacts selected by long-term, expert-clinician programming of STN-DBS.

Methods

We evaluated 92 hemispheres of 47 patients with Parkinson’s disease receiving chronic monopolar and bipolar STN-DBS. At each contact, beta oscillations and ERNA were recorded intraoperatively, and anatomical locations were assessed. How these factors, alone and in combination, predicted the contacts clinically selected for chronic deep brain stimulation at 6 months postoperatively was evaluated using a simple-ranking method and machine learning algorithms.

Results

The probability that each factor individually predicted the clinician-chosen contact was as follows: ERNA 80%, anatomy 67%, beta oscillations 50%. ERNA performed significantly better than anatomy and beta oscillations. Combining neuronal signal and anatomical data did not improve predictive performance.

Conclusion

This work supports the development of probability-based algorithms using neuronal signals and anatomical data to assist programming of deep brain stimulation.