bluuebunny/crossref_metadata_2025 huggingface dataset:
Subcutaneous drainage of refractory lower limb oedema at the end of life
Authors: Hooper Dawn Marie , Roach Peter Edward
Published: December 2024

Severe, refractory lower limb oedema can be a significant burden for patients with advanced metastatic malignancy. Despite this challenge, management strategies are often limited to analgesia, as well as pressure care and nursing care with positioning and dressings. The evidence for subcutaneous drainage in this setting largely consists of case reports, and it is infrequently practised in palliative care units (PCUs). In this case report, a patient with advanced metastatic ovarian cancer in her final weeks of life is discussed. Her severe lower limb oedema resulted in frequent pain and severe limitations on her mobility. The symptoms resulted in a multidisciplinary approach from the palliative care team, part of which included the use of subcutaneous drainage. The process of initiating this procedure in the PCU, details of the procedure and the benefit from it are described.
A cycle of invisibilisation: a qualitative study of Brazilian health system factors shaping access to long COVID care
Authors: Aveling Emma-Louise , Caldas Bárbara , Sabaine Brenda , Portela Margareth Crisóstomo , Soares Letícia , Cornish Flora
Published: December 2024

Introduction

Long COVID (LC), an often-debilitating infection-associated chronic condition (IACC), affects millions of people globally. Globally, LC patients struggle to access timely, appropriate care, often experiencing disbelief, misunderstandings or being diverted from healthcare. Few studies have examined health system factors influencing LC healthcare access, especially in the Global South. Drawing on the concept of candidacy, we examine health system factors influencing access to LC care in Brazil’s public healthcare system (Sistema Único de Saúde, SUS) and theorise implications for equitable access to public healthcare for IACCs globally.

Methods

We conducted a patient-engaged, qualitative study in the city of Rio de Janeiro. 29 individual semi-structured interviews were conducted with SUS professionals from administrative leaders to multidisciplinary primary and specialist care staff (November 2022 to July 2023). Verbatim transcripts were analysed using a pragmatic thematic analysis.

Results

LC patients’ candidacy for care is invisibilised within SUS through multiple, interacting processes. Interplay of an over-burdened health system, prioritisation of resources in response to (flawed) evidence of demand, misalignment of LC patient capacities and demands of navigating fragmented services, complex referral processes, professionals’ lack of LC knowledge and disregard of the severity and morbidity of a chronic condition amid acute demands, led to the under-recognition of LC by healthcare professionals. Professionals’ under-recognition perpetuates administrators’ de-prioritisiation of resources, policies and training necessary to ensure access to appropriate care, creating a cycle of invisibilisation.

Conclusion

Urgent action to disrupt a cycle of invisibilisation is essential to mitigate patients’ suffering and intensification of inequalities. Disrupting this pernicious cycle requires more than narrow clinical education efforts. Improved surveillance, education, patient involvement, attention to moral injury and building on existing multidisciplinary strengths may enhance access to LC care. Doing so offers wider benefits beyond patients with LC. We call for a paradigm shift in clinical approaches to IACCs.
Factors influencing adherence to home based pulmonary rehabilitation programme by high risk patients awaiting lung surgery: mixed methods study
Authors: Yang Xiaoyi , Tang Wenfeng , Xu Lian , Chen Ailian , Zeng Fanshu
Published: December 2024

Objective

Preoperative home based pulmonary rehabilitation (HPR) can reduce postoperative complications in lung surgery patients. This study aimed to investigate the level of adherence to a preoperative HPR programme in high risk patients awaiting lung surgery, and factors influencing adherence.

Design

A mixed methods explanatory sequential design consisting of a quantitative questionnaire survey and a qualitative interview study.

Setting

The study was conducted at a tertiary hospital in Chongqing, China.

Participants

186 high risk patients awaiting lung surgery were enrolled in the preoperative HPR programme. All 186 patients participated in the quantitative questionnaire survey. 13 of the 186 patients were selected to participate in the qualitative interview study.

Results

Quantitative questionnaire results revealed an adherence rate of 52.3%. Marital status, residence location, exercise habit, smoking index and pulmonary function were identified as independent influencers of adherence (p<0.05). Qualitative interviews identified poor health, lack of family and social support, adverse weather condition, arduous preoperative examination and unfit exercise intensity as barriers to adherence, and perceived health benefits, family support, and flexibility and convenience in exercise time and space as factors encouraging adherence.

Conclusions

High risk patients awaiting lung surgery adhered to preoperative HPR at a moderate level. A tiered approach can be used to develop personalised HPR protocols based on patients’ individual needs and situations to improve adherence and maximise the benefits of HPR.
Influences on safety of intrapartum electronic fetal heart rate monitoring practices: a scoping review
Authors: Kelly Sarah , Lamé Guillaume , Dixon-Woods Mary , Liberati Elisa , Kyriacou Harry , Dunn Harry , Egerton Alice , Kok Zi Qi , Jones Kathryn , Zheng Xueying Nancy , Kuhn Isla , Draycott Tim J , Winter Cathy , Burt Jenni
Published: December 2024

Objectives

Suboptimal intrapartum electronic fetal heart rate monitoring using cardiotocography has remained a persistent problem (EFM-CTG). We aimed to identify the range of influences on the safety of using EFM-CTG in practice.

Design

Scoping review to identify influences related to the practice of intrapartum EFM.

Data sources

MEDLINE, Embase, CINAHL, Web of Science, Scopus, British Nursing Index, Cochrane Library, from 1 January 2001 to 25 August 2024, and grey literature.

Eligibility criteria

Articles that reported potential influences on the clinical practice of intrapartum EFM-CTG in hospital-based intrapartum maternity care settings, including primary studies, secondary analyses, reviews, reports, conference abstracts and investigations relevant to maternity and obstetrics, in English. Evaluations of technological modifications to traditional EFM-CTG monitoring and analysis were excluded.

Data extraction and synthesis

We extracted influences on EFM-CTG from the included studies. Findings were synthesised using a best-fit framework approach, structured using an existing 19-domain framework of contributory factors for patient safety incidents in hospitals.

Results

142 articles and 14 reports were included. Our synthesis identified influences on EFM practice across all 19 domains of the contributory factors framework, including those relating to cognitive, social and organisational factors and interactions between professional work and tools used for fetal monitoring.

Conclusion

Reducing avoidable harm associated with electronic fetal monitoring requires a systems approach based on a sound understanding of the full range of influences on practice.
Which clinical trial designs and statistical approaches have been used in assessments of orphan maintenance by the European Medicines Agency between 2012 and 2022? A cross-sectional study.
Authors: Windfuhr Fabian , Larsson Kristina , Framke Theodor , Lasch Florian
Published: December 2024

Objectives

In the European Union, a new orphan medicinal product must demonstrate ‘significant benefit’ over approved medicinal products targeting the same indication. To demonstrate a significant benefit, comparisons between the new product and the already approved medicinal products—either directly by a head-to-head comparison within a clinical trial or indirectly as a cross-trial comparison—are necessary. In this study, we investigate the types of trial designs and statistical approaches used for demonstrating a significant benefit of a new orphan medicinal product against approved comparators used between 2012 and 2022.

Design

This is a cross-sectional study based on the European Medicines Agency's ‘orphan maintenance’ assessment documents between 2012 and 2022. All documents were manually reviewed to extract structured data on the following outcome measures:

For every comparison between a new orphan medicinal product and a comparator used for demonstrating a significant benefit as part of an orphan maintenance procedure, we recorded the type and design of the data source and the type of statistical methodology used for the comparison.

Results

We identified 151 EMA orphan maintenance procedures with a positive decision that required the demonstration of a significant benefit. Within these 151 procedures, 418 comparisons between medicinal products were identified. Indirect comparisons are the most common approach for comparing the new orphan medicinal product to a relevant comparator (44%, 182/418), followed by qualitative comparisons (39%, 162/418) and direct comparisons (18%, 74/418). Among the indirect comparisons, naive side-by-side comparisons are most often used (71%, 129/182), whereas inferential approaches that adjust for population differences and quantify the uncertainty of the comparison are used less often (29%, 53/182). Although there is no clear time trend in the prevalence of any specific comparison type, we find that inferential indirect comparison methods approximately doubled between the first and second half of the reviewed time frame.

Conclusions

Indirect comparisons play an important role in demonstrating a significant benefit in the assessment of orphan products. Further work is needed to evaluate the appropriateness of different methodologies.
Epidemiology, management and patient needs in myasthenia gravis: an Italian multistakeholder consensus based on Delphi methodology
Authors: Habetswallner Francesco , Iorio Raffaele , Annicchiarico Giuseppina , Limongelli Giuseppe , Uccheddu Maria Bonaria , Galeone Carlotta , Mariani Paolo , Mantegazza Renato
Published: December 2024

Objectives

To provide comprehensive information on the burden of myasthenia gravis (MG) in Italy, including the unmet needs of patients and several other aspects related to the disease, based on skilled viewpoints of MG experts.

Design

Iterative analysis conducted in accordance with the best practices of the Delphi method, including anonymity, controlled feedback, and statistical stability of consensus.

Setting and participants

24 clinicians, 18 public health experts and 4 patient associations experts completed all the Delphi iterations between 18 April and 3 July 2023, for a total of 46 participants from several Italian Regions.

Outcome measures

Five areas of investigation related to MG were examined: epidemiology in Italy and characteristics of disease; diagnostic issues and Italian patient journey; unmet needs during the acute and chronic phases of MG; quality of life; public health management of MG. Consensus in the Delphi iterations was defined by both the percentage level of agreement between panellists or the median value of the responses.

Results

We reported a high level of agreement (ie, >66.7% of panellists) on the prevalence and incidence of disease in Italy and on several management issues. A strong impact of MG on the quality of life of patients also emerged. Cross-agreement was achieved among different subgroups of panellists (ie, clinicians, public health experts and patient associations representatives) for most items proposed.

Conclusions

This study provided guidance for educational and practical aspects of MG in Italy, highlighted disease severity and its role on patients’ quality of life. A few gaps related to the handling of MG in Italy also emerged.
Protocol to assess bottlenecks inhibiting the scaling up of evidence-based family planning practices in low-income and middle-income countries using mixed methods
Authors: Kabra Rita , Church Kathryn , Allagh Komal Preet , Saad Abdulmumin , Ali Moazzam , Steyn Petrus , Kiarie James
Published: December 2024

Introduction

Scaling up evidence-based practices (EBPs) in family planning (FP), as recommended by the WHO, has increasingly been accepted by global health actors as core to their mission, goals and activities. National policies, strategies, guidance, training materials, political commitment and donor support exist in many countries to adopt and scale up a range of EBPs, including postpregnancy FP, task sharing for FP and the promotion of social and behaviour change (SBC) for FP. While there has been some success in implementing these practices, coverage remains inadequate in many countries. To gain a better understanding of the factors that may be hindering the sustained scale-up of these interventions, WHO has developed an assessment protocol to systematically identify the health systems’ ‘bottlenecks’ to implementation and to then identify solutions and develop strategies to address them.

Methods and analysis

A mixed method approach that includes document review, secondary data analysis (from surveys, service delivery data and case studies) and key informant interviews with policymakers, programme managers, health providers and community groups will be used to identify bottlenecks. This will be followed by a workshop to prioritise bottlenecks and characterise their root causes. Finally, solutions for the root causes of prioritised bottlenecks will be proposed. The protocol is structured in a modular format, with separate modules on postpregnancy FP, task sharing and SBC. Assessment themes and questions are informed by a wide body of literature on the three programmatic components, as well as studies on health policy implementation and scale-up.

Ethics and dissemination

The protocol was exempt from ethical review by the WHO ethics committee. The findings of the bottleneck analysis will be presented at local, national and international conferences and disseminated through peer-reviewed publications and webinars.
Is it feasible to treat polycystic ovarian syndrome with or without insulin resistance using glucokinase activators as novel hypoglycaemic medications? A protocol for a systematic review and meta-analysis
Authors: Zeng Genping , Lu Xijing , Li Peiyin , Zeng Tan , Lin Zitong , Miao Yuxi , Yuan Shuo , Liu Xiaojing , Zeng Lei
Published: December 2024

Introduction

A variety of hypoglycaemic drugs are used to treat polycystic ovarian syndrome (PCOS), but their efficacy remains insufficient. Glucokinase activators (GKAs) are a unique class of hypoglycaemic medications with emerging potential, notably in significantly reducing insulin resistance (IR). Nevertheless, the efficacy of GKAs in treating PCOS, particularly in the absence or presence of IR, remains uncertain. The meta-analysis protocol aims to address this knowledge gap, furnish evidence-based data to support potential revisions in PCOS treatment guidelines and promote the utilisation of GKAs in clinical settings.

Methods and analysis

A comprehensive search will be conducted across the Cochrane Central Register of Controlled Trials, PubMed, Web of Science, Embase, Medline, Scopus, CNKI, Wanfang and VIP databases to identify randomised controlled trials investigating the use of GKAs in the treatment of PCOS, irrespective of the presence of IR. The search will encompass all available studies without language restrictions and cover the period from the inception of each database to 10 April 2024. Disputes will be resolved by talking with a third expert following the screening of articles and data extraction by two reviewers. The primary outcomes of interest encompass changes in anthropometric parameters, menstrual frequency, sex hormone levels, and glucose metabolism, while secondary objectives include lipid metabolism and adverse events. The methodological quality of each study will be assessed using Version 2 of the Cochrane Collaboration tool for assessing Risk of Bias (RoB 2.0), and the Grade of Recommendations, Assessment, Development and Evaluation (GRADE) technique will be used to assess the quality of evidence and degree of recommendation. The study duration of this study will be from 5 April 2024 to 10 April 2025.

Ethics and dissemination

Since this study just analyses data that are readily available to the public and does not directly involve patient participation, ethical approval is not necessary. The findings will be made public by being published in a medical journal that is subject to peer review.

PROSPERO registration number

CRD42024535633.
Exploring aspects of mentoring for black and minoritised healthcare professionals in the UK: a nominal group technique study
Authors: Sriram Vimal , Atwal Anita , McKay Elizabeth A
Published: December 2024

Objective

Mentoring plays a crucial role in career development, particularly for black and minoritised ethnic (BME) professionals. However, existing literature lacks clarity on the impact of mentoring and how best to deliver for career success. This study aimed to ascertain perceptions and build consensus on what is important in mentoring for BME healthcare professionals.

Design

Nominal group technique: The participants in the group followed a structured stepwise process of introduction, silent idea generation, each participant presenting ideas in turn, open discussion and priority voting based on common themes generated during the discussion. This was followed by the creation of a model covering the important aspects of mentoring for BME healthcare professionals.

Setting

UK.

Participants

A nominal group technique workshop with 12 participants briefed on this technique.

Results

There was strong agreement about the most highly rated attributes. Participants emphasised the significance of psychosocial mentoring, highlighting trust, intimacy and clear communication of expectations between mentor and mentee. Discussions on race and racism in mentoring were considered essential. Mentoring circles were proposed as complementary to one-to-one mentoring, offering peer support. Participants stressed the importance of allies in the mentoring process, highlighting the need for authenticity, humility and courage in challenging established norms.

Conclusion

This study helped create a mentoring model tailored to the needs of BME health and care professionals. This model highlights the importance of sponsorship, allyship, surface characteristics and peer support in fostering career progression for BME mentees. Key elements include mentor honesty, humility and awareness of bias and race issues, alongside skills for effective mentoring relationships. This model provides a mechanism for supporting and mentoring BME workers in healthcare for career advancement.
What are the general public’s expectations about the likely duration of common acute infections? A cross-sectional survey of Australian residents
Authors: Boaitey Kwame Peprah , Bakhit Mina , Jones Mark , Hoffmann Tammy
Published: December 2024

Objectives

To explore the general public’s expectations about the likely duration of acute infections that are commonly managed in primary care and if care is sought for these infections, reasons for doing so.

Design

A cross-sectional online survey.

Participants

A nationwide sample of 589 Australian residents, ≥18 years old with representative quotas for age and gender, recruited via an online panel provider.

Outcome measures

For eight acute infections, participants’ estimated duration of each, time until they would seek care, and reasons for seeking care.

Results

For four infections, participants’ mean estimates of duration were within an evidence-based range—common cold (7.2 days), sore throat (5.2 days), acute otitis media (6.2 days) and impetigo (8.3 days); and >70% of the participants estimated a duration within the range. However, participants’ estimated mean duration was shorter than evidence-based estimates for acute cough (7.6 days), sinusitis (5.6 days), conjunctivitis (5.7 days) and uncomplicated urinary tract infections (UTIs; 5.4 days); and >60% of the participants underestimated the duration. Of the 589 participants, 365 (62%) indicated they were unlikely to routinely seek care for self-limiting infections. Most common reasons for care-seeking were severe or worsening symptoms, a desire for quick recovery and fear of progression to complications. After being shown typical durations, the proportion of participants who reported having no concerns waiting for spontaneous resolution while managing symptoms with over-the-counter medications ranged across the infections and was highest for common cold (68%) and lowest for UTI (31%).

Conclusion

Participants underestimated the duration of some infections compared with evidence-based estimates and were accurate in their estimates for other infections. Many stated that they would not be concerned about waiting for illnesses to self-resolve after learning the typical duration. Communicating the expected duration of common acute infections during routine consultations can help manage patients’ expectations of recovery and need to seek care.
Evaluating the CURB-65 score for in-hospital mortality prediction in COVID-19 patients: insights into dysglycaemia
Authors: Mohamed Farzahna , Prim Brent A , Zamparini Jarrod , Millen Aletta , Raal Frederick , Kalla Ismail Sikander
Published: December 2024

Introduction

While the CURB-65 score predicts mortality in community-acquired pneumonia (CAP), its performance in COVID-19 CAP is suboptimal. Hyperglycaemia correlates with an increased mortality in COVID-19. This analysis aims to enhance predictive accuracy for in-hospital mortality among COVID-19 patients by augmenting the CURB-65 score with objective variables, including markers of dysglycaemia.

Design

A single-centre retrospective observational analysis assessed the effectiveness of the CURB-65 score in predicting in-hospital mortality among adult patients with moderate to severe COVID-19 from March to September 2020. Using a binary logistic regression model, two extended CURB-65 scores which include markers of dysglycemia are proposed to enhance the predictive capability of the CURB-65 score for in-hospital mortality.

Results

Among 517 patients admitted, 117 (22.6%) died. Using the CURB-65 score, 393 patients (76%) were classified as low risk, 91 (17.6%) as medium risk and 33 (6.4%) as high risk. 37 patients were diagnosed with new-onset dysglycaemia, of which 22 (59.5%) died (p<0.001). Of those with dysglycaemia who died, 41% and 23% were classified as low risk and high risk using the CURB-65 score. The CURB-65 score demonstrated a modest area under the receiver operator characteristic curve (AUC) of 0.75 (95% CI 0.70 to 0.81) for in-hospital mortality in COVID-19 CAP. An Extended CURB-65 Score 1, incorporating an admission of fasting plasma glucose (FPG) and neutrophil to lymphocyte ratio, showed improved prognostic performance with an AUC of 0.80 (95% CI 0.76 to 0.85). When lactate and lactate dehydrogenase were added to these parameters (Extended CURB-65 Score 2), the AUC was 0.82 (95% CI 0.78 to 0.86). The integrated discrimination index showed an 11% and 24% higher discrimination slope when using the Extended CURB-65 Scores 1 and 2, respectively.

Conclusions

The addition of common biochemical parameters including an admission FPG enhances the prognostic performance of CURB-65 for in-hospital mortality among patients with COVID-19.
How are motivational interviewing techniques associated with US healthcare employees’ mental health help-seeking behaviours when using the interactive screening programme
Authors: Frey Jodi Jacobson , Deng Yali , Osteen Philip J , Imboden Rachel , Mosby Amanda , Ware Orrin , Bazell Alicia , Phillips Danielle
Published: December 2024

Introduction

Suicide rates for healthcare workers, coupled with mental health challenges, continue to increase in the USA. This study aimed to assess how the Interactive Screening Programme (ISP) is being used by US healthcare employees and how ISP counsellors’ use of motivational interviewing (MI) techniques was associated with employee help-seeking outcomes.

Methods

We used a retrospective one-group study to analyse secondary deidentified ISP interactive counselling dialogue (written communications between the ISP counsellor and ISP user) (time frame 2009–2019) from 5922 healthcare employees at 15 US workplaces. Help-seeking outcomes included referral requests, commitment to mental health services and improved willingness to seek mental health services. Key exposures included counsellors’ use of MI techniques.

Results

45% of ISP users scored in high distress on their ISP screening. Among ISP users in high distress, over 25% engaged in ISP dialogue and 63% of those who engaged in dialogue requested a referral. Bivariate analysis showed ISP users more likely to request referrals included women, younger employees, those with higher distress levels and those not currently receiving mental health services. Counsellors’ use of the MI technique, asking questions, was associated with approximately three times the odds of requesting referral (OR=3.12, p<0.001), higher odds of service commitment (OR=2.18, p<0.001) and improved willingness towards services (OR=2.21, p<0.001), compared with no questions asked during ISP dialogue. Asking questions also demonstrated a large effect size for all three dependent variables.

Conclusion

Results support the use of the MI techniques, especially asking questions, with ISP dialogue to encourage healthcare employees’ mental health help-seeking.
GrB-Fc-KS49, an anti-EMP2 granzyme B fusion protein therapeutic alters immune cell infiltration and suppresses breast cancer growth
Authors: Mohamedali Khalid A , Aguirre Brian , Lu Cheng-Hsiang , Chandla Anubhav , Kejriwal Nidhi , Liu Lucia , Chan Ann M , Cheung Lawrence H , Kok SuYin , Duarte Sergio , Alvarez de Cienfuegos Ana , Casero David , Rosenblum Michael G , Wadehra Madhuri
Published: December 2024

Background

Granzyme B (GrB) is a key effector molecule, delivered by cytotoxic T lymphocytes and natural killer cells during immune surveillance to induce cell death. Fusion proteins and immunoconjugates represent an innovative therapeutic approach to specifically deliver a deadly payload to target cells. Epithelial membrane protein-2 (EMP2) is highly expressed in invasive breast cancer (BC), including triple-negative BC (TNBC), and represents an attractive therapeutic target.

Methods

We designed a novel fusion protein (GrB-Fc-KS49) composed of an active GrB fused to an anti-EMP2 single-chain antibody tethered through the immunoglobulin G heavy chain (Fc) domain. We assessed the construct’s GrB enzymatic activity, anti-EMP2 binding affinity, and cytotoxicity against a panel of BC cells. The construct’s pharmacokinetics (PK), toxicity profile, and in vivo efficacy were also evaluated.

Results

GrB-Fc-KS49 exhibited comparable GrB enzymatic activity to commercial GrB, as well as high affinity to an EMP2 peptide, with the dissociation constant in the picomolar range. The fusion protein rapidly internalized into EMP2+cancer cells and showed in vitro cytotoxicity to cell lines expressing surface EMP2, with half-maximal cytotoxicity (IC50) values below 100 nM for most positive lines. Ex vivo stability at 37°C indicated a half-life exceeding 96 hours while in vivo PK indicated a biexponential plasma clearance, with a moderate initial clearance (t1/2α=18.4 hours) and a much slower terminal clearance rate (t1/2β=73.1 hours). No toxicity was measured in a Chem16 panel between the control and the GrB-Fc-KS49. In vivo, the GrB-Fc-KS49 showed efficacy against a TNBC syngeneic (4T1/FLuc) mouse model, reducing tumor volume and cell proliferation and increasing cell death compared with controls. Treatment using an EMT6 mouse model confirmed these results. In addition to a significant impact on cell proliferation, GrB-Fc-KS49 treatment also resulted in a dramatic increase of tumor-infiltrating CD45+ cells and redistribution of tumor-associated macrophages. Transcriptomic analysis of tumors post-treatment confirmed the remodeling of the immune tumor microenvironment by the GrB-Fc-KS49 immunotoxin.

Conclusions

GrB-Fc-KS49 showed high specificity and cytotoxicity towards EMP2-positive cells. In vivo, it reduced tumor burden and increased the recruitment of immune cells into the tumor, suggesting that GrB-Fc-KS49 is a promising therapeutic candidate against BC.
Neuropsychiatric manifestations following chimeric antigen receptor T cell therapy for cancer: a systematic review of clinical outcomes and management strategies
Authors: Fleischer Anna , Kurth Sophia , Duell Johannes , Topp Max , Strunz Patrick-Pascal , Mersi Julia , Rasche Leo , Sanges Carmen , Hudecek Michael , Einsele Hermann , Maatouk Imad
Published: December 2024

Background

Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative modality in the treatment of patients with cancer. However, it is increasingly evident that this therapeutic approach is not without its challenges. The unique nature of CAR-T cells as living drugs introduces a distinct set of side effects. As the application of CAR-T cell therapy expands to treat a broader range of diseases, it becomes increasingly important to devise effective strategies for handling the associated toxicities. Challenges in treating patients with CAR-T cells include addressing complications such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and cytopenias. This comprehensive review seeks to systematically identify, categorize and elucidate all previously described neurological and psychological side effects associated with CAR-T cell therapy, shedding light on the pertinent laboratory findings that underscore these phenomena.

Methods

PubMed, Springer Link, and ScienceDirect were systematically searched for empirical studies on adult patients with cancer receiving CAR-T cell therapy for hemato-oncological malignancies. Quality assessment was conducted using Version 2 of the Cochrane risk-of-bias tool (RoB 2) for randomized trials and adherence to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist for observational studies. The synthesis of findings was conducted via a narrative approach, consolidating the diverse array of data into a coherent framework.

Results

From an initial pool of 2,276 citations, 546 studies met the inclusion criteria, exhibiting a rich tapestry of heterogeneity in terms of study characteristics and patient samples. The incidence of neuropsychological symptoms varied notably across different CAR-T cell products and hematological malignancies. Among the most frequently reported neuropsychological symptoms were aphasia, attention deficits, impaired consciousness, and disorientation, alongside a constellation of other symptoms including confusion, cognitive impairment, memory loss, writing difficulties, fatigue, headache, agitation, tremor, seizures, and psychomotor retardation. Early intervention strategies, including corticosteroids and tocilizumab, have shown the potential to reduce the intensity of neuropsychological symptoms and prevent their progression to critical complications.

Conclusion

These insights underscore the imperative of extending neuropsychological assessments beyond the conventional Immune Effector Cell-Associated Encephalopathy score framework.
Oncolytic vaccinia virus armed with anti-CD47 nanobody elicit potent antitumor effects on multiple tumor models via enhancing innate and adoptive immunity
Authors: Li Zengpeng , Li Mengyuan , Yang Liu , Chen Jie , Ye Qian , Qian Wenbin , Wang Shibing
Published: December 2024

Objective

Targeting CD47 for cancer immunotherapy has been studied in many clinical trials for the treatment of patients with advanced tumors. However, this therapeutic approach is often hampered by on-target side effects, physical barriers, and immunosuppressive tumor microenvironment (TME).

Methods

To improve therapeutic efficacy while minimizing toxicities, we engineered an oncolytic vaccinia virus (OVV) encoding an anti-CD47 nanobody (OVV-αCD47nb). We demonstrated the specific binding activity of αCD47nb secreted from the virus-infected cells to CD47 and that both secreted αCD47nb and OVV-αCD47nb blocked the “don’t eat me” signal of macrophages.

Results

Intratumorally injected OVV-αCD47nb continuously releases the αCD47nb in tumor tissues, thereby conferring superior systemic activity against breast and colon tumor cells and prolonging survival compared with OVV control. Furthermore, treatment with OVV-αCD47nb also remodeled the TME, as shown by increased T cell infiltration, CD8+T cell activation and tumor-associated macrophages polarization, significantly enhancing innate and adoptive immunity. Additionally, the inclusion of programmed cell death protein-1 inhibiting boosted the anticancer efficacy of OVV-αCD47nb and raised the full response rate in tumor-bearing animals.

Conclusion

Overall, our findings highlight the therapeutic potential of OVV-αCD47nb for breast and colon cancer, and demonstrate its ability to modulate the immune cell profiles within tumors. This has established a rationale for further exploring OVV-αCD47nb as a potential therapy in the clinic.
CAR-T cell therapy in developing countries: how long should we wait?
Authors: Gautam Sanjivan , Gautam Balram , Shilpakar Ramila , K C Sudhamshu , Kurmi Om P
Published: December 2024

Low- and middle-income countries (LMICs) face a significant burden of cancer prevalence and incidence. However, the survival rates for patients with cancer in these regions are notably lower than those in high-income countries, primarily due to late diagnosis and limited access to advanced treatments. Chimeric antigen receptor (CAR) T-cell therapy has demonstrated promising outcomes in certain terminally ill patients with cancer, yet access to this treatment remains limited in LMICs, including Nepal.

The Center for Regenerative Medicine in Nepal has initiated efforts to make CAR-T cell therapy accessible to patients with cancer at a substantially reduced cost. This initiative includes successful research to test the feasibility of local laboratory capabilities using reagents sourced locally or from developed countries. Additionally, a Good Manufacturing Practicies (GMP) grade CAR-T cell manufacturing facility is being established to commence clinical manufacturing. This endeavor has encountered several challenges, including technical difficulties, regulatory barriers, and resource limitations, which could provide valuable insights for other developing countries. This experience from Nepal highlights the importance of interdisciplinary collaboration, shared knowledge, funding, and innovative solutions from the global scientific community to achieve equitable access to advanced medical treatments.
Krebs von den Lungen-6 surveillance in immune checkpoint inhibitor-induced pneumonitis
Authors: Matsukane Ryosuke , Nakamura Shoji , Minami Haruna , Tsubouchi Kazuya , Yoneshima Yasuto , Hata Kojiro , Yasukochi Sai , Suetsugu Kimitaka , Okamoto Isamu , Hirota Takeshi
Published: December 2024

Background

The immune-related adverse event (irAE), pneumonitis, is a potentially fatal complication of immune checkpoint inhibitors (ICIs). Preventing its progression is crucial, emphasizing the need for effective screening tests. We evaluated the feasibility of using Krebs von den Lungen-6 (KL-6), a marker for interstitial pneumonitis, as a screening tool for pneumonitis.

Methods

We examined 500 patients with cancer divided into two groups: those with cancer other than non-small cell lung cancer (NSCLC) (Group 1, n=382) and those with NSCLC (Group 2, n=118). KL-6 levels were monitored before and during ICI treatment and analyzed for their correlation with pneumonitis.

Results

In Group 1, 37 patients (9.7%) developed pneumonitis. KL-6 levels were significantly elevated at irAE onset (pre: 222.0 U/mL, post: 743.0 U/mL, p<0.0001). Receiver operating characteristic curve analysis showed an area under the curve (AUC) of 0.903 (sensitivity 81.1%, specificity 91.6%) with a cut-off value 1.52 times pre-KL-6 levels, indicating that KL-6 is a reliable biomarker for pneumonitis. In these patients, the KL-6 level increased regardless of pneumonitis severity and was significantly elevated in patients with both symptomatic (pre: 205.0 U/mL, post: 674.5 U/mL, p<0.0001) and asymptomatic pneumonitis (pre: 314.0 U/mL, post: 743.0 U/mL, p<0.0001) at irAE onset. After irAE treatment, KL-6 levels in steroid-responsive patients remained unchanged; however, steroid-unresponsive patients had a significant increase in KL-6 levels at 1 month (1078 U/mL, p=0.031) compared with at irAE onset (678.0 U/mL). In Group 2, 24 patients (20.3%) developed irAE pneumonitis, with KL-6 levels elevated (pre: 360.5 U/mL, post: 506.5 U/mL, p=0.029) and an AUC of 0.683, indicating that KL-6 was less reliable in patients with NSCLC.

Conclusions

KL-6 is a viable screening biomarker in ICI-induced pneumonitis, particularly in patients without NSCLC. In patients with NSCLC, the significance of KL-6 monitoring is limited as it is not effective for detecting ICI-induced pneumonitis; their treatment is typically managed by pulmonary specialists. Early detection through KL-6 monitoring facilitates timely intervention for ICI-induced pneumonitis, potentially preventing treatment interruptions and reducing the need for immunosuppressants.
Heavy-quark dominance and fine structure of excited heavy baryons $$\Sigma _{Q}$$, $$\Xi '_{Q}$$ and $$\Omega _{Q}$$
Authors: Li Zhen-Yu , Yu Guo-Liang , Wang Zhi-Gang , Gu Jian-Zhong
Published: December 2024

In the framework of the relativized quark model, the calculation of spin-orbit interactions is improved by considering the contribution from the light-quark cluster in a singly heavy baryon. It modifies the energy level splitting of the orbital excitation significantly and causes the emergence of fine structures for

$$\Sigma _{Q}$$

Σ
Q

,

$$\Xi '_{Q}$$

Ξ
Q
′

and

$$\Omega _{Q}$$

Ω
Q

baryons. Based on this improvement, we systematically analyze the fine structures and retest the heavy quark dominance mechanism. This mechanism is found to be violated in the 1P-wave states of the

$$\Sigma _{c}$$

Σ
c

,

$$\Xi '_{c}$$

Ξ
c
′

and

$$\Omega _{c}$$

Ω
c

baryons although it remains effective overall, which may help to understand the nature of the heavy quarks and strong interactions. With the predicted fine structures, we make the precise assignments of those observed heavy baryons which once could not be accurately explained due to their close mass values. The method used in this work is instructive and applicable for the study of more complex exotic hadrons, such as the heavy tetraquarks and pentaquarks.
Numerical Simulation Analysis of a Crude Oil Droplet’s Motion Through a Stagnant Aqueous Phase
Authors: Al-Shimmery Abouther , Al-Azzawi Ali , Hussein Mudhaffar Yacoub , Alshara Ahmed , Mohammed Mohammed Razzaq
Published: December 2024

In this study, computational fluid dynamics (CFDs) simulation analysis was used to predict the dynamic of crude oil droplets in an American Petroleum Institute (API) oil–water separator unit. To mimic the whole separation process (i.e., the oil droplets rising movement) in the API oil–water separator unit, a single oil droplet rising in a stagnant water column has been used. Three main factors were investigated, namely, crude oil specifications (in terms of specific gravity [S.G.] and viscosity), radius of the oil droplet and the position of the oil droplet. The rising velocity of the droplet of the crude oil was characterized in terms of terminal velocity and the centre of the gravity. Generally, the CFD (COMSOL Multiphysics software) analysis succeeded to visualize the hypothetical bath of the crude oil droplet. The results illustrated that the rising velocity increased with decreasing the S.G. and inversely decreased with increasing the viscosity of the crude oil. In addition, the increase in the crude oil droplet diameter had a direct effect on the increasing of the rising velocity. Moreover, it was found that the terminal velocity increased with decreasing the water column over the oil droplet.
Effects of Transcutaneous Electrical Acupoint Stimulation on the Incidence of Hypoxia in Elderly Patients Undergoing Painless Gastrointestinal Endoscopy: A Randomized Controlled Trial
Authors: Zhou Wenyu , Wang Yu , Ye Pengcheng , Hu Song , Li Siyu , Wang Mingxia , Sheng Duanyang , Chen Yuanli , Shen Wang , Zhang Yi , Liu Feng , Zhang Wei , Lv Xin , Wang Xiangrui , Yang Hao
Published: December 2024

Background: Hypoxia is not uncommon in elderly patients during painless gastrointestinal endoscopy. This study aimed to determine the effectiveness of transcutaneous electrical acupoint stimulation (TEAS) in reducing the occurrence of hypoxia symptoms in elderly patients.

Methods: Patients were randomly and equally grouped into sham control (n = 109) or TEAS group (n = 109) by using the random number table method. Patients in the TEAS group received electrical stimulation at the bilateral ST36 points 30 min before the examination until the end of the painless gastrointestinal endoscopy. Patients in the control group only had electrodes attached to bilateral nonacupoints in a similar pattern as the TEAS group without electrical stimulation. The primary endpoints measured were the incidence of hypoxia and severe hypoxia. The secondary endpoints included propofol dosage, sedation‐related adverse events, hemodynamic parameters, surgical duration, patient recovery time, pain score, patient satisfaction, anesthesiologist satisfaction, and endoscopist satisfaction.

Results: Of the 251 patients who participated in this study, 218 patients ended up completing the final study. The primary outcome was that, compared with group control, the incidence of hypoxia in group TEAS was reduced by 11% (19.3% vs. 8.3%, p = 0.018) and the incidence of severe hypoxia did not show a significant change (7.3% vs. 2.8%, p = 0.122). And there was a significant decrease in the occurrence of patients requiring emergency airway assistance (increased oxygen flow: 16.5% vs. 6.4%, p = 0.019, jaw thrust: 11.0% vs. 3.7%, p = 0.038, mask‐assisted ventilation: 5.5% vs. 1.8%, p = 0.015).

Conclusion: TEAS can reduce the incidence of hypoxia in elderly patients undergoing painless gastrointestinal endoscopy.

Trial Registration: ClinicalTrials.gov identifier: ChiCTR2200059465.
Finite state machine for retro arcade fighting game development
Authors: Firdaus Muhammad Bambang , Waksito Alan Zulfikar , Tejawati Andi , Taruk Medi , Anam M. Khairul , Irsyad Akhmad
Published: December 2024

Traditional fighting games are a competitive genre where players engage in one-on-one combat, aiming to reduce their opponent's health points to zero. These games often utilize two-dimensional (2D) graphics, enabling players to execute various character movements such as punching, jumping, and crouching. This research investigates the effectiveness of the finite state machine (FSM) method in developing a combo system for a retro fighting game, focusing on its implementation within the Godot Engine. The FSM method, which structures game behavior through states, events, and actions, is central to the game's control system. By employing the game development life cycle (GDLC) methodology, this study ensures a systematic and structured approach to game design. Special attention is given to the regulation of the combo hit system for the game's protagonist in Brawl Tale. The research culminates in the successful development of the retro fighting game Brawl Tale, demonstrating that the FSM method significantly enhances the fluidity and responsiveness of character movements. The findings suggest that the FSM method is an effective tool for simplifying and improving gameplay mechanics in retro-style fighting games.
Managing cyber resilience literacy for consumers
Authors: Antipova Tatiana , Riurean Simona
Published: December 2024

It seems inevitable that digitalization will have a profound and irreversible impact on our lives, and it seems reasonable to suppose that our world will never be the same again. Objectives of this study is to gain insight into consumers’ understanding of cyber security threats and their willingness to enhance their cyber resilience. To achieve this, a survey was conducted using AI tools such as Open ChatGPT, Copilot and PI. The survey was distributed selectively among consumers via Google Form. The results of the survey conducted during the study indicated that the majority of respondents (72%) expressed interest in attending online interactive seminars to gain more knowledge about managing cybersecurity threats. However, respondents with the lowest cyber resilience knowledge did not express the same level of interest. With technology becoming an increasingly important aspect in our everyday lives, it is becoming ever clearer that cybersecurity posture relies on the behavior consumers and organizations. Based on the rule that ‘never trust, always verify’ we designed ‘cybersecurity zero-trust framework model’ for consumers that allows them to protect themselves against cybersecurity threats. In an ever-shifting landscape of cybersecurity, it is important to recognize the value of continuous education as a necessity, not just an option.
Memory management of firewall filtering rules using modified tree rule approach
Authors: Hakani Dhwani , Mann Palvinder Singh
Published: December 2024

Firewalls are essential for safety and are used for protecting a great deal of private networks. A firewall’s goal is to examine every incoming and outgoing data before granting access. A notable kind of conventional firewall is the rule-based firewall. However, when it comes to job performance, traditional listed-rule firewalls are limited, and they become useless when utilized with some networks that have extremely big firewall rule sets. This study proposes a model firewall architecture called “TreeRule Firewall,” which has benefits and functions effectively in large-scale networks like “cloud.” In order to improve cloud network security, this study suggests a modified tree rule firewall (MTRF cloud) that eliminates rule discrepancies. For the matching firewall policy, this work creates a tree rule firewall. There are no duplicate rules created by the proposed improved tree rule firewall. Also, memory utilization of different size rules is compared.
The integration of discrete contourlet transform in OFDM framework for future wireless communication
Authors: Mohamed Nerma Mohamed Hussien , Ahmed Abdo Adam Mohamed
Published: December 2024

In the upcoming era, the forthcoming sixth-generation (6G) wireless communication network will demand highly efficient technology to support extensive capacity, ultra-high speeds, low latency, scalability, and adaptability. While the current fifth-generation (5G) wireless communication system relies on OFDM technology, the evolution towards a beyond 5G wireless communication system necessitates a new OFDM framework. This study introduces a novel OFDM system that integrates the discrete Contourlet transform. A comparative analysis has been conducted among the proposed system, conventional OFDM, and curvelet-based OFDM systems. The results indicate that the proposed system offers improvements in bit error rate (BER), reduced computational complexity, decreased peak-to-average power ratio (PAPR), and enhanced power spectrum density (PSD) when contrasted with both the traditional and curvelet-based systems.