bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT): protocol for a multi-centre, double-blind, placebo-controlled trial
Authors: Bhaskaran Divyalakshmi , Savage Joshua , Patel Amit , Collinson Fiona , Mant Rhys , Boele Florien , Brazil Lucy , Meade Sara , Buckle Peter , Lax Siân , Billingham Lucinda , Short Susan C. 
Published: January 2024

Abstract
Background
Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM.

Methods
ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events.

Discussion
Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development.

Trial registration
ISRCTN: 11460478. ClinicalTrials.Gov: NCT05629702.
Novel model integrating computed tomography-based image markers with genetic markers for discriminating radiation pneumonitis in patients with unresectable stage III non-small cell lung cancer receiving radiotherapy: a retrospective multi-center radiogenomics study
Authors: Li Jiaran , Li Li , Tang Shanshan , Yu Qingxi , Liu Wenju , Liu Ning , Yang Fengchang , Zhang Dexian , Yuan Shuanghu 
Published: January 2024

Abstract
Background
Chemoradiotherapy is a critical treatment for patients with locally advanced and unresectable non-small cell lung cancer (NSCLC), and it is essential to identify high-risk patients as early as possible owing to the high incidence of radiation pneumonitis (RP). Increasing attention is being paid to the effects of endogenous factors for RP. This study aimed to investigate the value of computed tomography (CT)-based radiomics combined with genomics in analyzing the risk of grade ≥ 2 RP in unresectable stage III NSCLC.

Methods
In this retrospective multi-center observational study, 100 patients with unresectable stage III NSCLC who were treated with chemoradiotherapy were analyzed. Radiomics features of the entire lung were extracted from pre-radiotherapy CT images. The least absolute shrinkage and selection operator algorithm was used for optimal feature selection to calculate the Rad-score for predicting grade ≥ 2 RP. Genomic DNA was extracted from formalin-fixed paraffin-embedded pretreatment biopsy tissues. Univariate and multivariate logistic regression analyses were performed to identify predictors of RP for model development. The area under the receiver operating characteristic curve was used to evaluate the predictive capacity of the model. Statistical comparisons of the area under the curve values between different models were performed using the DeLong test. Calibration and decision curves were used to demonstrate discriminatory and clinical benefit ratios, respectively.

Results
The Rad-score was constructed from nine radiomic features to predict grade ≥ 2 RP. Multivariate analysis demonstrated that histology, Rad-score, and XRCC1 (rs25487) allele mutation were independent high-risk factors correlated with RP. The area under the curve of the integrated model combining clinical factors, radiomics, and genomics was significantly higher than that of any single model (0.827 versus 0.594, 0.738, or 0.641). Calibration and decision curve analyses confirmed the satisfactory clinical feasibility and utility of the nomogram.

Conclusion
Histology, Rad-score, and XRCC1 (rs25487) allele mutation could predict grade ≥ 2 RP in patients with locally advanced unresectable NSCLC after chemoradiotherapy, and the integrated model combining clinical factors, radiomics, and genomics demonstrated the best predictive efficacy.
Biochemical profiles and organ dysfunction in neonates with hypoxic-ischemic encephalopathy post-hoc analysis of the THIN trial
Authors: Francke Karen Haugvik , Støen Ragnhild , Thomas Niranjan , Aker Karoline 
Published: January 2024

Abstract
Background
Therapeutic hypothermia for infants with moderate to severe hypoxic-ischemic encephalopathy is well established as standard of care in high-income countries. Trials from low- and middle-income countries have shown contradictory results, and variations in the level of intensive care provided may partly explain these differences. We wished to evaluate biochemical profiles and clinical markers of organ dysfunction in cooled and non-cooled infants with moderate/severe hypoxic-ischemic encephalopathy.

Methods
This secondary analysis of the THIN (Therapeutic Hypothermia in India) study, a single center randomized controlled trial, included 50 infants with moderate to severe hypoxic-ischemic encephalopathy randomized to therapeutic hypothermia (n = 25) or standard care with normothermia (n = 25) between September 2013 and October 2015. Data were collected prospectively and compared by randomization groups. Main outcomes were metabolic acidosis, coagulopathies, renal function, and supportive treatments during the intervention.

Results
Cooled infants had lower pH than non-cooled infants at 6–12 h (median (IQR) 7.28 (7.20–7.32) vs 7.36 (7.31–7.40), respectively, p = 0.003) and 12–24 h (median (IQR) 7.30 (7.24–7.35) vs 7.41 (7.37–7.43), respectively, p < 0.001). Thrombocytopenia (< 100 000) was, though not statistically significant, twice as common in cooled compared to non-cooled infants (4/25 (16%) and 2/25 (8%), respectively, p = 0.67).
No significant difference was found in the use of vasopressors (14/25 (56%) and 17/25 (68%), p = 0.38), intravenous bicarbonate (5/25 (20%) and 3/25 (12%), p = 0.70) or treatment with fresh frozen plasma (10/25 (40%) and 8/25 (32%), p = 0.56)) in cooled and non-cooled infants, respectively. Urine output < 1 ml/kg/h was less common in cooled infants compared to non-cooled infants at 0–24 h (7/25 (28%) vs. 16/23 (70%) respectively, p = 0.004).

Conclusions
This post hoc analysis of the THIN study support that cooling of infants with hypoxic-ischemic encephalopathy in a level III neonatal intensive care unit in India was safe. Cooled infants had slightly lower pH, but better renal function during the first day compared to non-cooled infants. More research is needed to identify the necessary level of intensive care during cooling to guide further implementation of this neuroprotective treatment in low-resource settings.

Trial registration
Data from this article was collected during the THIN-study (Therapeutic Hypothermia in India; ref. CTRI/2013/05/003693 Clinical Trials Registry – India).
The role of cadre in the community on diabetic retinopathy management and its challenges in low-middle income countries: a scoping review
Authors: Sadikin Irma Suwandi , Lestari Yeni Dwi , Victor Andi Arus 
Published: January 2024

Abstract
Introduction
Diabetes is a serious public health problem, with low- and middle-income countries (LMICs) bearing over 80% of the burden. Diabetic retinopathy (DR) is one of the most prevalent diabetic microvascular problems, and early diagnosis through eye screening programs for people with diabetes is critical to prevent vision impairment and blindness. Community-based treatments, including non-physician cadres have been recommended to enhance DR care.

Methods
The review protocol was determined and scoping review was conducted.The population, concept, and context were “cadre”, “role of cadre in the management of DR”, and LMICs”. Data were collected from databases and searches, including grey literature.

Results
Cadre can motivate people to attend a diabetic eye screening event when the rate of eye examinations is about six times higher than before the start of the intervention. Health education is a possible area for task sharing, and the cadre reported could also perform the task of vision testing. The cadre could be a good supporter and a good reminder for society. However, several challenges have been faced in this study and inadequate infrastructure is the foremost challenge found in this study. Other challenges encountered in the studies include poverty, lack of community awareness, trust issues, and low education levels contributing to poor health.

Conclusion
The current study highlighted significant gaps in the literature, which focus on the role of cadre as a community-based intervention in managing DR in LMICs. Further research is needed to develop evidence to support cost-effective screening services and cadre-related policy development in LMICs.
Gender differences in long term sickness absence
Authors: Timp Sheila , van Foreest Nicky , Roelen Corné 
Published: January 2024

Abstract
Purpose
Sickness absence is a major public health problem, given its high cost and negative impact on employee well-being. Understanding sickness absence duration and recovery rates among different groups is useful to develop effective strategies for enhancing recovery and reducing costs related to sickness absence.

Methods
Our study analyzed data from a large occupational health service, including over 5 million sick-listed employees from 2010 to 2020, out of which almost 600,000 cases were diagnosed by an occupational health physician. We classified each case according to diagnosis and gender, and performed descriptive statistical analysis for each category. In addition, we used survival analysis to determine recovery rates for each group.

Results
Mean sickness duration and recovery rate both differ significantly among groups. Mental and musculoskeletal disorders had the longest absence duration. Recovery rates differed especially during the first months of sickness absence. For men the recovery rate was nearly constant during the first 1.5 year, for women the recovery rate was relatively low in the first three months, and then stayed nearly constant for 1.5 year.

Conclusion
Across almost all diagnostic classes, it was consistently observed that women had longer average sickness absence durations than to men. Considering mental disorders and diseases of the musculoskeletal system, women had relatively lower recovery rates during the initial months compared to men. As time progressed, the recovery rates of both genders converged and became more similar.
Frequency and risk of SARS-CoV-2 reinfections in Norway: a nation-wide study, February 2020 to January 2022
Authors: Bøås Håkon , Storm Margrethe Larsdatter , Tapia German , Kristoffersen Anja Bråthen , Løvlie Astrid Louise , Størdal Ketil , Lyngstad Trude Marie , Bragstad Karoline , Hungnes Olav , Veneti Lamprini 
Published: January 2024

Abstract
Background
SARS-CoV-2 reinfection rates have been shown to vary depending on the circulating variant, vaccination status and background immunity, as well as the time interval used to identify reinfections. This study describes the frequency of SARS-CoV-2 reinfections in Norway using different time intervals and assesses potential factors that could impact the risk of reinfections during the different variant waves.

Methods
We used linked individual-level data from national registries to conduct a retrospective cohort study including all cases with a positive test for SARS-CoV-2 from February 2020 to January 2022. Time intervals of 30, 60, 90 or 180 days between positive tests were used to define potential reinfections. A multivariable Cox regression model was used to assess the risk of reinfection in terms of variants adjusting for vaccination status, demographic factors, and underlying comorbidities.

Results
The reinfection rate varied between 0.2%, 0.6% and 5.9% during the Alpha, Delta and early Omicron waves, respectively. In the multivariable model, younger age groups were associated with a higher risk of reinfection compared to older age groups, whereas vaccination was associated with protection against reinfection. Moreover, the risk of reinfection followed a pattern similar to risk of first infection. Individuals infected early in the pandemic had higher risk of reinfection than individuals infected in more recent waves.

Conclusions
Reinfections increased markedly during the Omicron wave. Younger individuals, and primary infections during earlier waves were associated with an increased reinfection risk compared to primary infections during more recent waves, whereas vaccination was a protective factor. Our results highlight the importance of age and post infection waning immunity and are relevant when evaluating vaccination polices.
Between now and later: a mixed methods study of HPV vaccination delay among Chinese caregivers in urban Chengdu, China
Authors: Yim Vivian Wan-Cheong , Wang Qianyun , Li Yifan , Qin Chuanyun , Tang Weiming , Tang Shenglan , Jit Mark , Smith Jennifer S. , Larson Heidi J. , Tucker Joseph D. , Li Jing , Lin Leesa , Wu Dan 
Published: January 2024

Abstract
Background
Adolescent girls in China have a low HPV vaccination rate. Although vaccination is recommended by the Chinese health authorities, the cost is not covered by the national immunisation programme. Vaccination delay, among other reasons such as supply shortage and poor affordability, may contribute to low uptake. This sequential mixed methods study aimed to identify potential factors of delayed HPV vaccination among Chinese adolescent girls.

Methods
Quantitative data about the attitudes and perceptions of HPV vaccination were collected from 100 caregivers of 14–18-year-old girls using an online survey in Chengdu, China. The survey data informed a subsequent qualitative study using four focus group discussions. We conducted a descriptive analysis of the survey data and a thematic analysis of the qualitative data. The findings were interpreted using a health behaviour model adapted from the Health Belief Model and the Andersen’s Behavioural Model for Health Services Use.

Results
A total of 100 caregivers – 85 were mothers and 15 were fathers – participated in the survey; 21 caregivers joined focus group discussions. When asked about their intended course of action if the 9vHPV vaccine was out-of-stock, 74% chose to delay until the 9vHPV vaccine is available while 26% would consider 2vHPV or 4vHPV vaccines or seek alternative ways to procure the vaccine. Qualitative results confirmed that caregivers preferred delaying HPV vaccination for adolescent girls. The intent to delay was influenced by systemic barriers such as supply shortage and individual-level factors such as a preference for the 9vHPV vaccine, safety concerns, inadequate health communication, and the belief that adolescents were unlikely to be sexually active.

Conclusion
In urban areas, Chinese caregivers’ intent to delay vaccination in favour of 9vHPV vaccine over receiving the more accessible options was influenced by a mix of individual and contextual factors. Focussed health communication strategies are needed to accelerate HPV vaccination among adolescents.
Understanding nursing perspective towards barriers to the optimal delivery of enteral nutrition in intensive care settings
Authors: Zaher Sara , Sumairi Futoon AL. , Ajabnoor Sarah M. 
Published: January 2024

Abstract
Background
The management process of Enteral Nutrition (EN) typically involves the interaction between a team of health care practitioners. Nurses being the closest to the patients, have crucial responsibilities and play a major role in feeding delivery along with other medical treatments. This study was conducted to investigate the perception of the nurses working in adult and paediatric intensive care Units (ICUs) regarding the EN barriers and identify the factors that influenced their perception.

Methods
The data in this cross-sectional study was collected via online survey between 15 October 2021 and January 2022. All nurses working in adult or paediatric ICUs across Saudi Arabia were eligible to participate. The tool used for the data collection was adapted from Cahill et al. (2016) and then reviewed and modified by the researchers. The survey collected information about the demographics of the nurses, and it included 24 potential EN barriers where the participants were asked to rate their importance on a scale from 1 to 5. Descriptive statistics were performed to describe the variables, univariant analysis were performed to compare the perceptions of the nurses regarding the EN barriers based on their characteristics followed by stepwise linear regression analysis.

Results
A total of 136 nurses working in adult and paediatric ICUs were included in this study. The results showed that the most important barriers as perceived by the nurses was “Frequent displacement of feeding tube, requiring reinsertion” [3.29 ± 1.28], “Delays in initiating motility agents in patients not tolerating enteral nutrition” [3.27 ± 1.24] and “Enteral formula not available on the unit”. [3.27 ± 1.24]. Our results showed that the responses of the participants statistically varied based on their work settings, gender, region, and educational level for some items in the survey (P-value ≤ 0.05). In the regression analysis, gender was the only variable statistically influenced the total Likert rating scores of the participants (r = -0.213, p-value = 0.013).

Conclusion
This study identified several barriers that exist in the nursing practice of EN in critical care settings. There are distinct differences in the perception of the nurses to these barriers based on their characteristics. Understanding such differences is important for implementing future strategies for units that needed the most help in prioritizing EN delivery.
Effects of combination therapy of antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: a systematic review and meta-analysis
Authors: Totoki Takaaki , Makino Yuto , Yamakawa Kazuma , Koami Hiroyuki , Wada Takeshi , Ito Takashi , Iba Toshiaki 
Published: January 2024

Abstract
Background
Disseminated intravascular coagulation (DIC) syndrome is a highly lethal condition characterized by the complication of multiple organ damage. Although the effects of combined antithrombin (AT) and recombinant thrombomodulin (rTM) on DIC syndrome have previously been examined, the results are inconsistent and inconclusive. Therefore, we conducted a systematic review on the combined administration of AT and rTM for the treatment of septic DIC to investigate the superiority of the combination therapy over either AT or rTM monotherapy using a random-effects analysis model.

Method
We searched electronic databases, including Medline, Cochrane Central Register of Controlled Trials, Scopus, and Igaku-Chuo Zasshi (ICHU-SHI) Japanese Central Review of Medicine Web from inception to January 2022. Studies assessing the efficacy of combined AT and rTM were included. The primary outcome was all-cause mortality, and the secondary outcome was occurrence of serious bleeding complications compared to monotherapy. We presented the pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence intervals (CI) depending on reporting results in each primary study.

Results
We analyzed seven enrolled clinical trials, all of which were observational studies. Combination therapy had a non-significant favorable association with lower 28-day mortality compared to monotherapy (HR 0.67 [0.43–1.05], OR 0.73 [0.45–1.18]). The I2 values were 60% and 72%, respectively, suggesting high heterogeneity.
As a secondary outcome, bleeding complications were similar between the two groups (pooled OR 1.11 [0.55–2.23], I2 value 55%).

Conclusions
Although the findings in this analysis could not confirm a statistically significant effect of AT and rTM combination therapy for septic DIC, it showed a promising effect in terms of improving mortality. The incidence of bleeding was low and clinically feasible. Further research is warranted to draw more conclusive results.

Trial registration
This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: 000049820).
SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells
Authors: Villacampa Alicia , Alfaro Enrique , Morales Cristina , Díaz-García Elena , López-Fernández Cristina , Bartha José Luis , López-Sánchez Francisco , Lorenzo Óscar , Moncada Salvador , Sánchez-Ferrer Carlos F. , García-Río Francisco , Cubillos-Zapata Carolina , Peiró Concepción 
Published: January 2024

Abstract
Background
Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute and post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element in human tissues reservoirs and is the main product of mRNA COVID-19 vaccines. We investigated whether the S protein alone triggers pro-inflammatory and pro-coagulant responses in primary cultures of two cell types deeply affected by SARS-CoV-2, such are monocytes and endothelial cells.

Methods
In human umbilical vein endothelial cells (HUVEC) and monocytes, the components of NF-κB and the NLRP3 inflammasome system, as well as coagulation regulators, were assessed by qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence.

Results
S protein activated NF-κB, promoted pro-inflammatory cytokines release, and triggered the priming and activation of the NLRP3 inflammasome system resulting in mature IL-1β formation in both cell types. This was paralleled by enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor, that was mediated, at least in part, by IL-1β. Additionally, S protein failed to enhance ADAMTS-13 levels to counteract the pro-coagulant activity of vWF multimers. Monocytes and HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches and gene silencing showed that TLR4 receptors mediated the effects of S protein in monocytes, but not in HUVEC.

Conclusion
S protein behaves both as a pro-inflammatory and pro-coagulant stimulus in human monocytes and endothelial cells. Interfering with the receptors or signaling pathways evoked by the S protein may help preventing immune and vascular complications driven by such an isolated viral element.