bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell membrane-anchored and tumor-targeted IL-12 T-cell therapy destroys cancer-associated fibroblasts and disrupts extracellular matrix in heterogenous osteosarcoma xenograft models
Authors: Hu Jiemiao , Lazar Alexander J , Ingram Davis , Wang Wei-Lien , Zhang Wendong , Jia Zhiliang , Ragoonanan Dristhi , Wang Jian , Xia Xueqing , Mahadeo Kris , Gorlick Richard , Li Shulin
Published: January 2024

Background

The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression, metastasis, and the poor response of many solid tumors to immunotherapy. CAF-targeted chimeric antigen receptor-T cell therapy cannot infiltrate ECM-rich tumors such as osteosarcoma.

Method

In this study, we used RNA sequencing to assess whether the recently invented membrane-anchored and tumor-targeted IL-12-armed (attIL12) T cells, which bind cell-surface vimentin (CSV) on tumor cells, could destroy CAFs to disrupt the ECM. We established an in vitro model of the interaction between osteosarcoma CAFs and attIL12-T cells to uncover the underlying mechanism by which attIL12-T cells penetrate stroma-enriched osteosarcoma tumors.

Results

RNA sequencing demonstrated that attIL12-T cell treatment altered ECM-related gene expression. Immunohistochemistry staining revealed disruption or elimination of high-density CAFs and ECM in osteosarcoma xenograft tumors following attIL12-T cell treatment, and CAF/ECM density was inversely correlated with T-cell infiltration. Other IL12-armed T cells, such as wild-type IL-12-targeted or tumor-targeted IL-12-T cells, did not disrupt the ECM because this effect depended on the engagement between CSV on the tumor cell and its ligand on the attIL12-T cells. Mechanistic studies found that attIL12-T cell treatment elevated IFNγ production on interacting with CSV+tumor cells, suppressing transforming growth factor beta secretion and in turn upregulating FAS-mediated CAF apoptosis. CAF destruction reshaped the tumor stroma to favor T-cell infiltration and tumor inhibition.

Conclusions

This study unveiled a novel therapy—attIL12-T cells—for targeting CAFs/ECM. These findings are highly relevant to humans because CAFs are abundant in human osteosarcoma.
Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation
Authors: Ma Chao , Chen Peng , Du Jishan , Wang Lu , Lu Ning , Sun Jiaojun , Qilong Xu , Wang Yu , Dou Liping , Liu Dai-Hong
Published: January 2024

Background

Cytomegalovirus (CMV) reactivation after unmanipulated haploidentical stem cell transplantation (SCT) frequently occurs, causing life-threatening morbidities and transplantation failure. Pre-emptive therapy upon the detection of CMV viremia using antiviral agents is currently the standard of care but it was associated with significant toxicity. The CMV antigen-specific cytotoxic T lymphocyte therapy was limited by the time-consuming manufacture process and relatively low success rate. More effective and safer approaches for the treatment of CMV reactivation after haploidentical SCT are in urgent need.

Methods

A single-arm, open-label, phase I clinical trial evaluating the safety and efficacy of CMV-targeting T cell receptor-engineered T (CMV-TCR-T) cell therapy as the first-line pre-emptive therapy for patients with CMV reactivation after haploidentical peripheral blood SCT (PBSCT) was conducted in the Chinese PLA General Hospital. Six patients with CMV reactivation after haploidentical SCT were adoptively transferred by one to three doses of SCT donors-derived CMV-TCR-T cells. This trial was a dose-escalation study with doses ranging from 1×103CMV-TCR-T cells/kg body weight per dose to 5×105CMV-TCR-T cells/kg per dose.

Results

Except for the grade 1 cytokine release syndrome observed in one patient and mild fever in two patients, no other adverse events were observed. Four patients had response within a month after CMV-TCR-T cell infusion without the administration of any antiviral agents. The other two patients who initially did not respond to CMV-TCR-T cell therapy had salvage ganciclovir and foscarnet administration and then had rapid CMV clearance. The CMV-TCR-T cells displayed overall robust expansion and persistence in the peripheral blood after infusion. The CMV-TCR-T cells were first detected in the peripheral blood of these patients 3–7 days after the first dose of CMV-TCR-T infusion, rapidly expanded and persisted for at least 1–4 months, providing long-term protection against CMV reactivation. In one patient, the CMV-TCR-T cells started to expand even when the anti-graft-versus-host disease reagents were still being used, further indicating the proliferation potential of CMV-TCR-T cells.

Conclusions

Our study first showed CMV-TCR-T cell as a highly feasible, safe and effective first-line pre-emptive treatment for CMV reactivation after haploidentical PBSCT.

Trial registration number

ClinicalTrials.gov Registry (NCT05140187).
Clearing soluble MIC reverses the impaired function of natural killer cells from patients with multiple myeloma
Authors: Kim Sojeong , Chung Haerim , Kwak Jeong-Eun , Kim Yu Ri , Park Chung Hyun , Kim Yeonhee , Cheong June-Won , Wu Jennifer , Shin Eui-Cheol , Cho Hyunsoo , Kim Jin Seok
Published: January 2024

Background

Major histocompatibility complex (MHC) class I chain-related protein (MIC) is a stress-induced ligand released from multiple myeloma (MM) cells during progression, and soluble MIC impairs natural killer group 2D (NKG2D) activating receptor-mediated recognition and function of natural killer (NK) cells. However, whether clearing soluble MIC with a monoclonal antibody (mAb) can restore NK cell activity of MM patients remains undetermined.

Methods

We analyzed The Cancer Genome Atlas (TCGA) Multiple Myeloma Research Foundation (MMRF) CoMMpass data set to examine the prognostic significance ofMICexpression in MM. We examined the level of soluble MIC in paired peripheral blood (PB) and bone marrow (BM) plasma of patients with MM at diagnosis by ELISA. We evaluated the correlation between the level of soluble MIC and immunophenotype of NK cells from MM patients by multicolor flow cytometry. We also generated MIC-overexpressing MM cell line and characterized the cytotoxic function of patient NK cells in the presence of soluble MIC, and examined the impact of clearing soluble MIC with a humanized mAb (huB10G5).

Results

We characterize the importance of MICA in MM by revealing the significantly better overall survival of patients with highMICAexpression from TCGA MMRF CoMMpass data set. The level of soluble MICA is more highly elevated in MM than in precursor stages, and the concentration of soluble MICA is higher in BM plasma than in PB. The concentration of soluble MICA in BM was correlated with myeloma burden, while it was negatively correlated with the frequency of NKG2D+NK cells in diagnostic BM aspirates of MM patients. Soluble MICA downregulated NKG2D expression and decreased cytotoxicity of MM patient NK cellsex vivo, which were reversed by a humanized soluble MIC-clearing mAb (huB10G5) with enhanced degranulation of NK cells.

Conclusions

Our findings indicate targeting soluble MIC with huB10G5 might be a viable therapeutic approach to promote NKG2D-dependent cellular immunotherapy outcome in MM.
mRNA vaccines against SARS-CoV-2 induce divergent antigen-specific T-cell responses in patients with lung cancer
Authors: Song No-Joon , Chakravarthy Karthik B , Jeon Hyeongseon , Bolyard Chelsea , Reynolds Kelsi , Weller Kevin P , Reisinger Sarah , Wang Yi , Li Anqi , Jiang Sizun , Ma Qin , Barouch Dan H , Rubinstein Mark P , Shields Peter G , Oltz Eugene M , Chung Dongjun , Li Zihai
Published: January 2024

Background

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is highly transmissible and evades pre-established immunity. Messenger RNA (mRNA) vaccination against ancestral strain spike protein can induce intact T-cell immunity against the Omicron variant, but efficacy of booster vaccination in patients with late-stage lung cancer on immune-modulating agents including anti-programmed cell death protein 1(PD-1)/programmed death-ligand 1 (PD-L1) has not yet been elucidated.

Methods

We assessed T-cell responses using a modified activation-induced marker assay, coupled with high-dimension flow cytometry analyses. Peripheral blood mononuclear cells (PBMCs) were stimulated with various viral peptides and antigen-specific T-cell responses were evaluated using flow cytometry.

Results

Booster vaccines induced CD8+T-cell response against the ancestral SARS-CoV-2 strain and Omicron variant in both non-cancer subjects and patients with lung cancer, but only a marginal induction was detected for CD4+T cells. Importantly, antigen-specific T cells from patients with lung cancer showed distinct subpopulation dynamics with varying degrees of differentiation compared with non-cancer subjects, with evidence of dysfunction. Notably, female-biased T-cell responses were observed.

Conclusion

We conclude that patients with lung cancer on immunotherapy show a substantial qualitative deviation from non-cancer subjects in their T-cell response to mRNA vaccines, highlighting the need for heightened protective measures for patients with cancer to minimize the risk of breakthrough infection with the Omicron and other future variants.
VB-111 (ofranergene obadenovec) in combination with nivolumab in patients with microsatellite stable colorectal liver metastases: a single center, single arm, phase II trial
Authors: Coffman-D'Annibale Kelley , Myojin Yuta , Monge Cecilia , Xie Changqing , Hrones Donna Mabry , Wood Bradford J , Levy Elliot B , Kleiner David , Figg William Douglas , Steinberg Seth M , Redd Bernadette , Greten Tim F
Published: January 2024

Background

Microsatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces an immune response and disrupts neovascularization. Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and antitumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response.

Methods

This was a phase II study of adult patients with histologically-confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1×1013viral particles was given intravenously 2 weeks prior to starting biweekly nivolumab 240 mg and continued every 6 weeks. The combination continued until disease progression or unacceptable toxicity. The primary objectives were overall response rate and safety/tolerability. Secondary objectives included median overall survival and progression-free survival. Correlative studies were performed on paired tumor biopsies and blood.

Results

Between August 2020 and December 2021, 14 patients were enrolled with median age 50.5 years (40–75), and 14% were women. Median follow-up was 5.5 months. Of the 10 evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, 2 patients had stable disease. Median overall survival was 5.5 months (95% CI: 2.3 to 10.8), and median progression-free survival was 1.8 months (95% CI: 1.4 to 1.9). The most common grade 3–4 treatment-related adverse events were fever/chills, influenza-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (26.0 months). Immune analysis of peripheral blood mononuclear cells showed an increase of PD-1highKi67highCD8+T cells and HLA-DRhighT cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs.

Conclusion

In patients with MSS CLM, VB-111 and nivolumab did not improve overall response rate or survival but were tolerated with minimal toxicities. While challenging to distinguish between antiviral or antitumor, correlative studies demonstrated an immune response with activation and proliferation of CD8+T cells systemically that was poorly sustained.

Trial registration number

NCT04166383.
Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy
Authors: Horvat Natalie K. , Karpovsky Isaac , Phillips Maggie , Wyatt Megan M. , Hall Margaret A. , Herting Cameron J. , Hammons Jacklyn , Mahdi Zaid , Moffitt Richard A. , Paulos Chrystal M. , Lesinski Gregory B.
Published: January 2024

Background

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease, with a survival rate of ~12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted the outcomes in patients with PDAC, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMMs) for PDAC are considered a “gold-standard” as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and the cost of colony maintenance.

Methods

Using flow cytometry and immunohistochemistry, we characterized the immunological features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC (C57BL/6) models using two mouse cell lines, KPC-Luc and MT-5, isolated from C57BL/6 KPC-GEMM (KrasLSL-G12D/+p53−/−and KrasLSL-G12D/+p53LSL-R172H/+, respectively).

Results

The MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate the KPC-Luc tumors, which have less stroma, although CD4+and CD8+T cells were similarly detected in the MT-5 tumors compared with KPC-GEMM in mice. Interestingly, we found that chimeric antigen receptor (CAR) T cells redirected to recognize mesothelin on these tumors that signal via CD3ζ and 41BB (Meso-41BBζ-CAR T cells) infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors.

Conclusions

Our data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve an indepth study of how to overcome barriers that limit antitumor activity of adoptively transferred T cells.
Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): a single-arm phase Ib clinical trial
Authors: Jiang Ning , Zhang Jingyuan , Guo Zhen , Wu Yinan , Zhao Lijun , Kong Cheng , Song Xue , Gu Lingling , Zhao Yang , Li Si , He Xia , Ren Binhui , Zhu Xiangzhi , Jiang Ming
Published: January 2024

Background

The optimal dosages, timing, and treatment sequencing for standard-of-care neoadjuvant chemoradiotherapy necessitate re-evaluation when used in conjunction with immune checkpoint inhibitors for patients with resectable, locally advanced esophageal squamous cell carcinoma (RLaESCC). The SCALE-1 phase Ib study aimed to evaluate the safety and efficacy of short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab in this patient population.

Methods

RLaESCC patients with clinical stages cT3-4aN0M0/cT1-4aN+M0 received neoadjuvant paclitaxel (135 mg/m2), carboplatin (area under the curve=5), and toripalimab (240 mg) every 3 weeks for two cycles. Short-course neoadjuvant radiotherapy (30 Gy in 12 fractions; 5 days per week) was administered between neoadjuvant immune-chemotherapy (nICT) doses. Esophagectomies were scheduled 4–6 weeks after completing neoadjuvant treatment. The primary endpoint was safety, with secondary endpoints including pathological complete response (pCR) rate, postoperative complications, progression-free survival (PFS), and overall survival (OS). Exploratory biomarker analysis used gene expression profiles via the nCounter platform.

Results

Of the 23 patients enrolled, all completed neoadjuvant radiotherapy, while 21 cases finished full nICT doses and cycles. Common grade 3/4 adverse events included neutropenia (57%), leukopenia (39%), and skin rash (30%). No grade 3 or higher esophagitis or pneumonitis occured. Twenty patients underwent surgery, and 11 achieved pCR (55%). Two patients (10%) experienced grade IIIb surgical complications. At the database lock, a 2-year PFS rate of 63.8% (95% CI 43.4% to 84.2%) and 2-year OS rate was 78% (95% CI 64.9% to 91.1%) were achieved. Tumor immune microenvironment analysis indicated that tumors with pCR exhibited significantly higher pretreatment T-cell-inflamed score and post-treatment reshaping of antitumor immunity.

Conclusions

Combining short-course neoadjuvant radiotherapy with chemotherapy and toripalimab demonstrated favorable safety and promising efficacy in RLaESCC patients.

Trial registration number

ChiCTR2100045104.
Rates of cortical thinning in Alzheimer’s disease signature regions associate with vascular burden but not with β-amyloid status in cognitively normal adults at age 70
Authors: Keuss Sarah E , Coath William , Cash David M , Barnes Josephine , Nicholas Jennifer M , Lane Christopher A , Parker Thomas D , Keshavan Ashvini , Buchanan Sarah M , Wagen Aaron Z , Storey Mathew , Harris Matthew , Lu Kirsty , James Sarah-Naomi , Street Rebecca , Malone Ian B , Sudre Carole H , Thomas David L , Dickson John C , Barkhof Frederik , Murray-Smith Heidi , Wong Andrew , Richards Marcus , Fox Nick C , Schott Jonathan M
Published: January 2024

Background

Consistent patterns of reduced cortical thickness have been identified in early Alzheimer’s disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear.

Methods

Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral β-amyloid (Aβ) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years).

Results

In a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aβ status did not. Among Aβ positive participants (n=56), there was some evidence that greater global Aβ standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08).

Conclusions

Cortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aβ-positivity, robust Aβ-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.
Long-term disability progression in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: a retrospective analysis of 101 patients
Authors: Uzawa Akiyuki , Mori Masahiro , Masuda Hiroki , Uchida Tomohiko , Muto Mayumi , Ohtani Ryohei , Aoyama Shinji , Kuwabara Satoshi
Published: January 2024

Background

Anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4Ab+NMOSD) is an inflammatory disorder of the central nervous system with relapse-dependent progression. Few studies have reported the effects of prednisolone and biologics on disability progression in AQP4Ab+NMOSD, although it is established that they prevent clinical relapses. This retrospective study investigated long-term disability progression and the effects of therapeutic interventions on disability progression in AQP4Ab+NMOSD.

Methods

This study included a total of 101 patients with AQP4Ab+NMOSD. Disease progression was investigated in the following two cohorts: (1) duration from disease onset to Expanded Disability Status Scale (EDSS) 3.0 in patients who did or did not receive oral prednisolone or biologics before reaching EDSS 3.0 and (2) duration from disease onset to EDSS 6.0 in patients who did or did not receive oral prednisolone or biologics before reaching EDSS 6.0.

Results

Approximately half of the untreated patients reached EDSS 3.0 and 6.0 at 10 and 46 months after disease onset, respectively. In addition, 88% and 71% of the untreated patients reached EDSS 3.0 and 6.0 within 10 years after disease onset, respectively. Disability progression, clinical relapses and attack severity were suppressed by prednisolone and biologics.

Conclusions

AQP4Ab+NMOSD is a severely disabling disease. Treatment interventions using prednisolone and biologics are useful in suppressing disability progression in AQP4Ab+NMOSD.
Inequitable barriers and opportunities for leadership and professional development, identified by early-career to mid-career allied health professionals
Authors: Mizzi Laura , Marshall Patrick
Published: January 2024

Introduction

Interprofessional leadership is essential to sustain the National Health Service (NHS) in pressured times, which should include the NHS’s third largest clinical workforce in England: allied health professionals (AHPs) (AHPs as defined by NHS England: Art therapists; Dramatherapists; Music therapists; Dietitians; Occupational therapists; Operating department practitioners; Orthoptists; Osteopaths; Paramedics; Physiotherapists; Podiatrists, Prosthetists and Orthotists; Radiographers; Speech and language therapists). Therefore, a feasibility study was undertaken, to explore the views of AHPs working in early to mid-career positions, regarding the barriers and opportunities they encounter, in both leadership and career development.

Methods

Twenty-seven participants, representing 8 of the 14 AHP professions across England, were interviewed across 10 focus groups.

Results

Thematic analysis (TA) generated four themes, including the barriers and opportunities for AHP leadership development and career progression. Further TA identified three overarching themes: equitable and interprofessional leadership development; an equitable and structured AHP career pathway; and having AHP leaders at a strategical and/or very senior level. These overarching themes were subsumed under the umbrella category: equity of opportunity and voice. The AHPs, who were interviewed, reported inequitable access to both career and leadership development, compared with other professions, such as nurses, doctors and pharmacists.

Discussion

Further work is needed to ensure that interprofessional representation, within senior leadership levels, includes AHPs; which the data suggests would directly benefit all AHPs’ leadership and career development. Recommendations for organisations to facilitate leadership and career development were developed from the TA and at a system-wide level. Further research would be beneficial to gather the views of the six AHP professions not interviewed in this study and from other organisations, such as independent practice. However, this feasibility study does attempt to represent the voices of AHPs, which can be lacking in both organisations and research.
Introducing a framework to support the identification and tackling of health inequalities within specialised services
Authors: McGill Shaun , Davies Nathan , Addei Dianne , Bharkhada Dhiren , Elleray Rebecca , Wilson Robert , Day Matthew
Published: January 2024

Background

The potential for addressing healthcare inequalities in prescribed specialised services has historically been overlooked. There is evidence that prescribed specialised services can exacerbate inequalities even though they are often accessed at the end of complex pathways and by relatively small numbers of people. Leadership is required to facilitate a systematic approach to identifying and addressing inequalities in this area.

Methods

A rapid literature review of articles from 2015 onwards and engagement with stakeholders was used to inform the development of a framework that both supports the identification of health inequalities within specialised services and provides recommendations for how to address them.

Results

The framework aligns with existing national approaches in England to addressing health inequalities in other healthcare settings. It is prepopulated with features of services that may create inequalities and recommended ways of addressing them and can be readily adapted to suit population specific needs.

Conclusion

The potential for addressing health inequalities should be considered at all points along a healthcare pathway. Local service leaders need to be empowered and encouraged to identify and deliver on opportunities for change to continually improve patient access, experience and outcomes.
Agricultural exposure and risk of ovarian cancer in the AGRIculture and CANcer (AGRICAN) cohort
Authors: Renier Marine , Hippert Juliette , Weiswald Louis-Bastien , Tual Séverine , Meryet-Figuiere Matthieu , Vigneron Nicolas , Marcotullio Elisabeth , Baldi Isabelle , Lebailly Pierre
Published: January 2024

Background

Ovarian cancer is rare with a poor prognosis and few established risk factors. Hormones and reproductive factors significantly impact its development, suggesting a potential link with endocrine disrupters.

Methods

In the AGRICAN cohort, 59 391 female farmers completed data on lifelong agricultural exposures and reproductive life. Cox models with attained age as timescale (HR and 95% CI) were used. The role of hormonal factors as potential confounders was considered along with specific time windows for exposure (childhood, puberty and menopause). Female farmers were the reference group (for the principal analyses).

Results

Between enrolment (2005–2007) and the end of follow-up (31 December 2017), 262 incident ovarian cancers were identified. An increased risk was observed for females involved in pigs (HR=2.12 (95% CI 1.27 to 3.52)) including during puberty (HR=1.83 (95% CI 1.13 to 2.94)), fruit-growing (HR=2.17 (95% CI 1.09 to 4.30)) and potato seed treatment (HR=2.81 (95% CI 1.29 to 6.09)). Conversely, females born on farms growing grain cereals (HR=0.64 (95% CI 0.46 to 0.90)) or pig-breeding (HR=0.78 (95% CI 0.55 to 1.12)) presented a reduced risk of ovarian cancer. Triazine herbicide exposure was not associated with ovarian cancer. The effect of agricultural exposures remained unchanged in multivariate models considering contraception, parity, puberty age, menopause age and body mass index.

Conclusion

This study is the first to assess the association between specific agricultural exposures and ovarian cancer comprehensively. Some of the positive associations observed suggest that some pesticide exposure (especially during puberty) could play a role in the development of ovarian cancer. On the other hand, agricultural exposure during early life could have a protective effect, as observed for lung cancer among farmers. Finally, we did not confirm the previous putative effect of exposure to triazine herbicides.
Occupational physical demands and menstrual cycle irregularities in flight attendants and teachers
Authors: Johnson Candice Y , Grajewski Barbara , Lawson Christina C , MacDonald Leslie A , Rocheleau Carissa M , Whelan Elizabeth A
Published: January 2024

Objectives

Flight attendants perform physically demanding work such as lifting baggage, pushing service carts and spending the workday on their feet. We examined if more frequent exposure to occupational physical demands could explain why previous studies have found that flight attendants have a higher reported prevalence of menstrual cycle irregularities than other workers.

Methods

We conducted a cross-sectional analysis of 694 flight attendants and 120 teachers aged 18–44 years from three US cities. Eligible participants were married, had not had a hysterectomy or tubal ligation, were not using hormonal contraception and were not recently pregnant. Participants reported menstrual cycle characteristics (cramps, pain, irregular cycles, flow, bleed length, cycle length) and occupational physical demands (standing, lifting, pushing/pulling, bending/twisting, overall effort). We used modified Poisson regression to examine associations between occupation (flight attendant, teacher) and menstrual irregularities; among flight attendants, we further examined associations between occupational physical demands and menstrual irregularities.

Results

All occupational physical demands were more commonly reported by flight attendants than teachers. Flight attendants reported more frequent menstrual cramps than teachers, and most occupational physical demands were associated with more frequent or painful menstrual cramps. Lifting heavy loads was also associated with irregular cycles.

Conclusions

Occupational physical demands were associated with more frequent and worse menstrual pain among flight attendants. The physical demands experienced by these workers may contribute to the high burden of menstrual irregularities reported by flight attendants compared with other occupational groups, such as teachers.
Personalised care packages for people with rheumatoid arthritis: a mixed-methods study
Authors: Dey Mrinalini , Busby Amanda , Isaacs John D , Pratt Arthur , Ndosi Mwidimi , Young Adam , Lempp Heidi , Nikiphorou Elena
Published: January 2024

Objectives

Disease management in rheumatoid arthritis (RA) requires holistic assessment. We aimed to design personalised care packages suitable for people with RA.

Methods

This study was conducted using a mixed-methods approach and exploratory sequential design. Consensus workshops were held, involving people with RA and healthcare professionals (HCPs) treating them. Subsequently, an online survey sought views on future care packages for people with RA at relevant disease progression/stages, based on (1) results from previous quantitative data analyses (eg, socioeconomic/clinical factors), and (2) themes identified during workshops.

Results

Two conceptual care pathways were identified: (1) around the time of RA diagnosis, an early opportunity to influence the disease course; (2) for individuals with established RA, emphasising the importance of ‘the right MDT member at the right time’.

Three care packages were suggested: (1) early care package (around RA diagnosis): introduction to MDT; (2) continuity of care package (established RA): primary/secondary providers; and (3) personalised holistic care package: integral to packages 1 and 2, implemented alongside allied health professionals.

The survey received 41 responses; 82.9% agreed that people with RA need a consistent ‘early care package’ at diagnosis. 85.4% approved of additional care packages tailored to individuals’ clinical, psychological and social needs when moving to different stages of their long-term disease. Fleiss’ Kappa calculations demonstrated fair level of agreement among respondents.

Conclusion

Two care pathways, with three tailored care packages, were identified, with potential to improve management of people with RA. Future research will help to determine if such care packages can impact clinical (including patient-reported) outcomes.
History of pre-eclampsia does not appear to be a risk factor for vascular phenotype in women with systemic sclerosis
Authors: De Moreuil Claire , Diot Elizabeth , Agard Christian , Belhomme Nicolas , Lescoat Alain , Queyrel Viviane , Tieulie Nathalie , Truchetet Marie-Elise , Pugnet Grégory , Berthier Sabine , Smets Perrine , Subran Benjamin , Lidove Olivier , Keraen Jeremy , Mekinian Arsène , Chatelus Emmanuel , Pasquier Elisabeth , Brenaut Emilie , Rouvière Bénedicte , Delplanque Mathieu , Lucier Sandy , Courtois-Communier Emmanuelle , Devauchelle-Pensec Valérie , Hachulla Eric
Published: January 2024

Background

Vascular phenotype is associated with a poor prognosis in systemic sclerosis (SSc). The identification of its risk factors could facilitate its early detection.

Objectives

To explore risk factors for a vascular phenotype of SSc, among them a history of pre-eclampsia.

Methods

This observational multicentre case–control study enrolled adult women fulfilling European Alliance of Associations for Rheumatology 2013 diagnosis criteria for SSc and having a pregnancy history≥6 months before SSc diagnosis in 14 French hospital-based recruiting centres from July 2020 to July 2022. Cases had specific vascular complications of SSc defined as history of digital ischaemic ulcers, pulmonary arterial hypertension, specific cardiac involvement or renal crisis. Women with SSc were included during their annual follow-up visit and filled in a self-administered questionnaire about pregnancy. A case report form was completed by their physician, reporting data on medical history, physical examination, clinical investigations and current medication. The main outcome was the presence/absence of a personal history of pre-eclampsia before SSc diagnosis, according to the validated pre-eclampsia questionnaire.

Results

378 women were included: 129 cases with a vascular phenotype and 249 matched controls. A history of pre-eclampsia was reported in 5 (3.9%) cases and 12 (4.8%) controls and was not associated with a vascular phenotype (OR=0.96, 95% CI 0.28 to 3.34, p=0.9). Besides, Rodnan skin score and disease duration≥5 years were risk factors for vascular phenotype.

Conclusions

In women with SSc and a pregnancy history≥6 months before SSc, a history of pre-eclampsia is not associated with a vascular phenotype.
Chronic abdominal aortic occlusive disease related to antiphospholipid syndrome: a rare presentation
Authors: Jiang Hui , Shi Yu , Liu Wei , Liu Bao , Chen Yue-Xin , Zhou Yangzhong , Huang Can , Wang Qian , Tian Xinping , Zhao Yan , Li Mengtao , Zeng Xiaofeng , Zhao Jiuliang
Published: January 2024

Objective

Chronic abdominal aortic occlusive disease (CAAOD) is an uncommon manifestation of antiphospholipid syndrome (APS), impacting cardiovascular health and peripheral arterial circulation. We investigated CAAOD in antiphospholipid antibodies (aPL)-positive patients, aimed to offer comprehensive clinical and radiological insights.

Methods

aPL-positive patients with arterial thrombotic events were categorised into CAAOD and non-CAAOD. Extensive data, including clinical features, radiological images and outcomes, were analysed.

Results

This case-control study involved 114 patients who experienced arterial events from 2013 to 2021, revealing 12 patients with abdominal aortic stenosis or occlusion. The CAAOD group, predominantly young (36.67±11.83) males (75.00%), exhibited significantly higher rates of critical smoking habits (66.67% vs 25.49%, p=0.006) and hyperhomocysteinaemia (66.67% vs 31.37%, p=0.026). Radiological findings showed long-segment infrarenal aorta stenosis in CAAOD, occasionally involving renal and common iliac arteries. The lesions presented varying degrees of stenosis, including smooth lumen narrow and total vascular occlusion. Treatment modalities typically involved interventions or surgery, complementing anticoagulation therapy.

Conclusion

The study shed light on the rare occurrence of CAAOD in APS, highlighting the roles of smoking and hyperhomocysteinaemia as notable risk factors. These findings emphasised the significance of early diagnosis and management of CAAOD.
Difficult-to-treat psoriatic arthritis (D2T PsA): a scoping literature review informing a GRAPPA research project
Authors: Singla Shikha , Ribeiro Andre , Torgutalp Murat , Mease Philip J , Proft Fabian
Published: January 2024

Background

Psoriatic arthritis (PsA) is a multifaceted condition with a broad spectrum of manifestations and a range of associated comorbidities. A notable segment of patients with PsA remains resistant to even advanced therapeutic interventions. This resistance stems from myriad causes, including inflammatory and non-inflammatory factors.

Objectives

To collate and critically assess the various definitions and criteria of difficult-to-treat (D2T PsA present in the literature.

Methods

Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, we conducted a scoping review in July 2023, searching PubMed, American College of Rheumatology Convergence 2022, European Alliance of Associations for Rheumatology Congress 2023, Google Scholar and cited articles. Selection was made by two independent authors using Rayyan software, and conflicts were adjudicated by a third author. Eligibility criteria for PubMed focused on all article designs that were written in English, with full-text available, from the past decade, excluding only those not defining D2T PsA or targeting other populations.

Results

From the 565 references sourced, 15 studies were analysed, revealing considerable variations in defining both ‘active disease’ and ‘resistant PsA’, which was most often termed ‘D2T’ PsA.

Conclusion

The definitions and criteria for D2T PsA and for ‘active disease’ are notably heterogeneous, with considerable variation across sources. The ongoing Group for Research and Assessment of Psoriasis and Psoriatic Arthritis initiative stands to bridge these definitional gaps and aims to provide guidance for clinicians and illuminate a path for pharmaceuticals and regulatory agencies to follow.
Severe methotrexate toxicity in elderly patients under diuretics
Authors: Kumar Cara , Kuhn Matthias , Herrmann Kristine , Leuchten Nicolai , Aringer Martin
Published: January 2024

Objectives

To explore the toxicity of low-dose methotrexate (MTX), an uncommon, but life-threatening event.

Methods

We analysed the presentation, course and risk factors of all patients admitted to the rheumatology ward with severe low-dose MTX toxicity. These patients were compared with patients without signs of relevant MTX toxicity.

Results

The 12 patients admitted for MTX toxicity included 7 patients with rheumatoid arthritis, 2 with psoriatic arthritis or psoriasis, 2 patients with giant cell arteritis and 1 with myositis. 1 patient died from infections, while 11 survived under folinic acid administration. All patients suffering from severe MTX toxicity were older than 70 years and were therefore compared with 400 patients who were also older than 70 years, but without MTX toxicity. Of these 400 control patients, the group of patients not on MTX (n=232) had more renal impairment than the group of patients on MTX (n=168). Compared with the 168 MTX-treated patients without toxicity, the 12 patients with life-threatening toxic events had a lower median estimated glomerular filtration rate (eGFR) at the routine visit preceding the acute event (64 (range 32–77) vs 69 (range 8 to >90) mL/min x 1.73, p=0.0251). A multivariate analysis found that patients with toxicity were more frequently treated with diuretics (6/12 vs 24/168), proton pump inhibitors (PPIs; 10/12 vs 70/168) and levetiracetam (2/12 vs 1/168).

Conclusions

Patients older than 70 years with lower eGFR and being on diuretics, but also on PPIs and levetiracetam, have a significantly higher risk for MTX toxicity.
Sunglasses for painful red eye
Authors: Keohane Sean , Potts James , Taubert Mark
Published: January 2024

We present the case of a 62-year-old man who developed an acutely painful red eye with severe photophobia while in an oncology ward after spinal radiotherapy. In a joint effort between palliative care, oncology and ophthalmology clinicians, he was diagnosed with herpes simplex viral keratitis. This was treated with topical and systemic antiviral medication, as well as corticosteroids. Alongside analgesics, he also benefited from a pair of sunglasses for severe, painful photophobia.
Safety and efficacy of glibenclamide on cerebral oedema following aneurysmal subarachnoid haemorrhage: a randomised, double-blind, placebo-controlled clinical trial
Authors: Feng Xuebing , Zhang Tongyu , Wang Ning , Qu Xin , Qi Meng , Zhao Hao , Zhang Hongqi , Xu Yueqiao
Published: January 2024

Background

Glibenclamide has garnered attention due to its multifaceted neuroprotective effects in cases of acute central nervous system injury. We initiated a trial to explore the effectiveness and safety of a high dose of glibenclamide in the management of cerebral oedema following aneurysmal subarachnoid haemorrhage (aSAH).

Methods

This trial constituted a single-centre, randomised clinical study. Half of the 56 patients assigned to the glibenclamide group received 15 mg of glibenclamide tablets daily for 10 days (5 mg, three times/day). The primary outcome was the proportion of patients achieving the subarachnoid haemorrhage early brain oedema score dichotomy (defined as Subarachnoid Haemorrhage Early Brain Oedema Score 0–2) at the 10-day postmedication. The secondary outcome of cerebral oedema was the concentration of sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) in the plasma and cerebrospinal fluid.

Results

We enrolled 56 patients diagnosed with aSAH, who were admitted to the neurosurgery intensive care unit between 22 August 2021 and 25 April 2023. The primary outcome revealed that the glibenclamide group exhibited a notably higher proportion of mild cerebral oedema in comparison to the placebo group (60.7% vs 42.9%, adjusted OR: 4.66, 95% CI 1.14 to 19.10, p=0.032). Furthermore, the concentration of SUR1-TRPM4 in the cerebrospinal fluid of the glibenclamide group was significantly higher than the placebo group (p=0.0002; p=0.026), while the plasma TRPM4 concentration in the glibenclamide group was significantly lower than the placebo group (p=0.001).

Conclusion

Oral administration of high-dose glibenclamide notably reduced radiological assessment of cerebral oedema after 10 days of medication. Significant alterations were also observed in the concentration of SUR1-TRPM4 in plasma and cerebrospinal fluid. However, it is worth noting that glibenclamide was associated with a higher incidence of hypoglycaemia. Larger trials are warranted to evaluate the potential benefits of glibenclamide in mitigating swelling and then improving neurological function.

Trial registration number

ChiCTR2100049908.
Perspectives on reforming the tobacco tax administration system in Bangladesh to enhance public health
Authors: Huque Rumana , Kashfi Fatema , Khalil Ibrahim , Islam Hamidul , Alam Syed Mahbubul , Ahmed Nasiruddin
Published: January 2024

Background

Taxation is the most cost-effective instrument to regulate the consumption of tobacco products. However, weak tax administration can compromise the effectiveness of taxation. This paper aimed to understand the process of the current tobacco tax administration system in Bangladesh, identify gaps and outline the policy priorities to strengthen the tobacco tax administration process in Bangladesh.

Methods

A sequential qualitative study was conducted in two linked phases: (a) document review and evidence synthesis; and (b) 20 key informant interviews and one workshop with relevant stakeholders to validate the findings generated from both phases.

Results

The complex tax system combined with weak tax administration leads to tax evasion in Bangladesh. The processes of procuring and collecting banderoles and tax stamps vary between cigarette and biri companies, and across large and small tax-paying companies. The use of banderoles at the factory level is maintained manually, and there is no system to routinely verify the authenticity of banderoles. Many unregistered small-scale tobacco manufacturing units often reuse the banderoles on new packs. Shortage of staff with inadequate training at the National Board of Revenue restricts adequate tobacco market monitoring. Electronic tax stamps and banderoles combined with a secure digital tracking and tracing system should be introduced to better monitor the supply, distribution and sale of tobacco products. Training needs to be provided to develop capacity of relevant officials.

Conclusion

The tobacco tax administration needs to be strengthened to increase the government’s tobacco tax revenue and protect public health.
Body composition and respiratory outcomes in children: a population-based prospective cohort study
Authors: Wu Tong , Santos Susana , Quezada‐Pinedo Hugo G , Vernooij Meike W. , Jaddoe Vincent W.V. , Klein Stefan , Duijts Liesbeth , Oei Edwin H.G.
Published: January 2024

Background

Body composition might influence lung function and asthma in children, but its longitudinal relations are unclear. We aimed to identify critical periods for body composition changes during childhood and adolescence in relation to respiratory outcomes in adolescents.

Methods

In a population-based prospective cohort study, we measured body mass index, fat mass index (FMI), lean mass index (LMI) and the ratio of android fat mass divided by gynoid fat mass (A/G ratio) by dual-energy X-ray absorptiometry at 6, 10 and 13 years. At 13 years, lung function was measured by spirometry, and current asthma was assessed by questionnaire.

Results

Most prominently and consistently, higher FMI and A/G ratio at age 13 years were associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and forced expiratory flow after exhaling 75% of FVC (FEF75) (range Z-score difference −0.13 (95% CI −0.16 to –0.10) to −0.08 (95% CI −0.11 to –0.05) per SD score increase), and higher LMI at all ages was associated with higher FEF75(range Z-score difference 0.05 (95% CI 0.01 to 0.08) to 0.09 (95% CI 0.06 to 0.13)). Between the ages of 6 and 13 years, normal to high FMI and A/G ratio were associated with lower FEV1/FVC and FEF75(range Z-score difference −0.20 (95% CI −0.30 to –0.10) to −0.17 (95% CI −0.28 to –0.06)) and high to high LMI with higher FEF75(range Z-score difference0.32 (95% CI 0.23 to 0.41)). Body composition changes were not associated with asthma.

Conclusion

Adolescents with higher total and abdominal fat indices may have impaired lung function, while those with a higher lean mass during childhood and adolescence may have better small airway function. Public health measures should focus on a healthy body composition in adolescents to minimise respiratory morbidity.