bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuro-ophthalmologic outcomes of standard versus hypo-fractionated stereotactic radiotherapy of AVPM
Authors: Zach Leor , Agami Amir , Furman Orit , Attia Moshe , Cohen Zvi , Mizrachi Iris Ben-Bassat , Tam Guy , Zibly Zion , Nissim Ouzi , Spiegelmann Roberto , Huna-Baron Ruth
Published: August 2021

Background

Most anterior visual pathway meningiomas (AVPM) are benign and slow-growing, but these tumors may affect visual functions, including visual acuity (VA) and visual field (VF). Due to location, most are treated non-surgically by fractionated stereotactic radiotherapy (FSRT), aiming to prevent tumor progression and visual functions deterioration. Unfortunately, FSRT in itself may affect visual functions. The current preferred treatment regimen (in terms of safety and effectiveness) is undetermined. While most cases are treated with conventional fractionation (cFSRT)—50.4–54 Gy in 28–30 fractions of 1.8–2 Gy, advances in technology have allowed shortening of total treatment length to hypofractionation (hSRT)—25-27 Gy in 3–5 fractions of 5–9 Gy. Our aim was to evaluate the association of radiotherapy regimen for treating AVPM (cFSRT vs. hSRT) with visual function outcomes (VA, VF) at the last neuro-ophthalmologic evaluation.

Methods

We conducted a retrospective cohort study of AVPM cases treated at Sheba Medical Center during 2004–2015. We compared cFSRT and hSRT regimens regarding visual function (VA, VF) outcomes at the last neuro-ophthalmologic evaluation. VA was determined by the logarithm of the minimum angle of resolution (LogMAR). VF was determined by the mean deviation (MD). A clinically relevant change in VA was defined as 0.2 LogMAR.

Results

48 patients (13 receiving hSRT, 35 receiving cFSRT) were included, with a median follow-up of 55 months. No significant difference was evident regarding LogMAR or MD of involved eyes at the last evaluation. Six (17%) patients in the cFSRT group experienced clinically relevant VA deterioration in the involved eye, compared with six (46%) in hSRT (p = 0.06).

Conclusion

Our findings, using comprehensive and meticulous investigation of visual outcomes, suggest that hSRT may be associated with higher risk for VA and VF deterioration in AVPM especially in ONSM. We recommend the use of cFSRT for ONSM.
A novel classification for medial malleolar fracture based on the 3-D reconstruction CT
Authors: Hu Fangke , Bu Guoyun , Liang Jun , Huang Haijing , He Jinquan
Published: August 2021

Background

Fracture of the medial malleolus is one of the most frequent injuries treated surgically; however, the classification of the fracture has not attracted much attention and a good classification system is still lacking.

Methods

Consecutive cases of medial malleolus fractures were prospectively enrolled. Based on the 3-D reconstruction CT morphology and centered on the posterior colliculus of the medial malleolus, we classified the fractures into 4 types: type 1 with no involvement of the posterior colliculus, type 2 with partial involvement of posterior colliculus, type 3 with the entire involvement of posterior colliculus, and type 4 with the fracture line 4 vertically extended from the intercollicular groove to the comminuted fracture of the posterior malleolus. Statistical analyses were performed to evaluate the clinical significance of the classification.

Results

There were 273 cases prospectively enrolled. The distribution of the cases was type 1 of 12.1%, type 2 of 41.0%, type 3 of 30.0%, and type 4 of 16.8%. Statistics showed that the new classification had significant associations but did not totally depend on the classical ankle fracture classifications. Results showed that the new classification had implications in the severity of ankle fractures. From type 1 to type 4, the ankle joint was more and more unstable. Furthermore, comminuted medial malleolar fractures could be subdivided, and the new classification could provide useful information for surgical decision-making.

Conclusions

The novel classification was a useful system to describe the 3-D geometry of the fractured medial malleolus.
The D-dimer level predicts the prognosis in patients with lung cancer: a systematic review and meta-analysis
Authors: Ma Mingsheng , Cao Run , Wang Wei , Wang Biying , Yang Yichen , Huang Yunchao , Zhao Guangqiang , Ye Lianhua
Published: August 2021

Objective

Although the significance of increased plasma D-dimer levels in activating coagulation and fibrinolysis has been reported, it is still controversial whether it can be used to predict the prognosis of lung cancer patients. This meta-analysis was performed to explore the beneficial role of plasma D-dimer as a prognostic factor in lung cancer patients according to a larger sample capacity.

Materials and methods

MEDLINE, EMBASE, and Cochrane Central databases were searched from inception to January 2021. The data are mainly hazard ratio(HR) with 95% confidence interval (CI) and Kaplan–Meier survival curves. The publication bias was examined by Egger’s test.

Results

Finally, a total of 28 studies, enrolling 8452 patients were included in the current meta-analysis. Our results showed that the OS (HR = 1.742, 95%CI:1.542–1.969, P < 0.001) and PFS (HR = 1.385, 95%CI:1.169–1.641, P = 0.003) in the high D-dimer group were significantly lower than those in the low D-dimer group. Subgroup analysis suggested that localization, detection methods and disease stage had an important effect on the prognosis.

Conclusion

This meta-analysis revealed that the high plasma D-dimer level leads to lower survival than in the low D-dimer level, which might provide an important clue for high plasma D-dimer level as an independent factor of poor prognosis in patients with lung cancer.
A retrospective study on the impact of bar flipping on the recurrence of pectus excavatum after the Nuss procedure
Authors: Fan Yu-Jiun , Lo Po-Cheng , Hsu Yuan-Yu , Tzeng I-Shiang , Wei Bo-Chun , Cheng Yeung-Leung
Published: August 2021

Background

The Nuss procedure is widely used to correct pectus excavatum. Bar displacement is a common complication associated with this procedure. How the flipping of the bar affects pectus excavatum recurrence has not been reported. In our study, we discuss this and also offer an easier method to determine bar flipping.

Methods

This retrospective study analyzed pectus excavatum patients who underwent primary Nuss repair from August 2014 to December 2018. The preoperative and postoperative Haller indices were measured on chest radiographs (cxrHI). The slope angle of bar flipping (α) was measured on lateral chest radiographs. The improvement index after surgical repair was calculated by: ([preoperative cxrHI-postoperative cxrHI]/preoperative cxrHI × 100). The impact of α on the improvement index was analyzed using one-way analysis of variance and receiver operating characteristic tests.

Results

In this study, 359 adult and adolescent patients with an average age of 23.9 ± 7.7 years were included. We formed four subgroups based on the α value: α ≤ 10° (n = 131), α = 11–20° (n = 154), α = 21–30° (n = 51), and α > 30° (n = 23). The mean improvement indices in these groups were 27%, 28%, 26%, and 13%, respectively. Patients with α > 30° were associated with a significantly poorer improvement index than those from the other subgroups (p < 0.001).

Conclusions

The α value is an alternative measurement method for presenting the radiological outcomes after the Nuss procedure. An α > 30° indicates a possible recurrence of pectus excavatum after the Nuss repair. Surgical revision may be considered in patients with an α > 30°, while monitoring should be considered in the other patient groups.
The emerging possibility of the use of geniposide in the treatment of cerebral diseases: a review
Authors: Zhang Wenwen , Zhang Fangling , Hu Qichao , Xiao Xiaolin , Ou Linbo , Chen Yuan , Luo Shiqing , Cheng Yonghong , Jiang Yinxiao , Ma Xiao , Zhao Yanling
Published: August 2021

With the advanced discoveries in the field of pathogenesis, a series of cerebral diseases, such as cerebral ischaemia, Alzheimer's disease, and depression, have been found to have multiple signalling targets in the microenvironment. Only a few existing agents have been shown to have curative effects due to this specific circumstance. In recent decades, active ingredients isolated from natural plants have been shown to be crucial for original drug development. Geniposide, mainly extracted fromGardenia jasminoidesEllis, is representative of these natural products. Geniposide demonstrates various biological activities in the treatment of cerebral, cardiovascular, hepatic, tumorous, and other diseases. The multiple protective effects of geniposide on the brain have especially drawn increasing attention. Thus, this article specifically reviews the characteristics of current models of cerebral ischaemia and illustrates the possible effects of geniposide and its pathogenetic mechanisms on these models. Geniposide has been shown to significantly reduce the area of cerebral infarction and alleviate neuronal damage and necrosis mainly by inhibiting inflammatory signals, including NLRP3, TNF-α, IL-6, and IL-1β. Neuronal protection was also involved in activating the PI3K/Akt and Wnt/catenin pathways. Geniposide was able to increase autophagy and inhibit apoptosis by regulating the function of mTOR in treating Alzheimer's disease. Geniposide has also been shown to act as a glucagon-like peptide-1 receptor (GLP-1R) agonist to reduce amyloid plaques and inhibit oxidative stress to alleviate memory impairment as well as synaptic loss. Moreover, geniposide has been shown to exert antidepressant effects primarily by regulating the hypothalamic–pituitary–adrenal (HPA) axis. Detailed explorations have shown that the biological activities of inhibiting inflammatory cytokine secretion, alleviating oxidative stress, and suppressing mitochondrial damage are also involved in the mechanism of action of geniposide. Therefore, geniposide is a promising agent awaiting further exploration for the treatment of cerebral diseases via various phenotypes or signalling pathways.
Quality of mental health services and rights of people receiving treatment in inpatient services in Finland: a cross-sectional observational survey with the WHO QualityRights Tool Kit
Authors: Lantta Tella , Anttila Minna , Välimäki Maritta
Published: August 2021

Background

This article aims to review the quality of mental health services and the rights of the people receiving treatment in inpatient hospital care in Finland using the World Health Organization’s QualityRights Tool Kit as a part of a randomized controlled trial VIOLIN. So far, reports on the QualityRights Tool Kit have mainly been from low- and middle-income countries or countries lacking resources for health services. Reports from countries with well-resourced health care systems, such as the Nordic countries, are still quite few.

Methods

A cross-sectional observational survey was conducted on 13 closed inpatient psychiatric wards (acute, rehabilitation, forensic psychiatric) at eight hospitals in Finland. The data for the survey were gathered through a document review, observations, and group interviews among staff members, service users and family members. The STROBE checklist for cross-sectional studies was followed in the reporting.

Results

Finnish mental health services are partially or fully achieving the standards set by the WHO QualityRights Tool Kit (final scores: 2.5–2.9 out of 3). The highest final score out of the five themes (2.9/3) was achieved under Freedom from torture or cruel, inhuman or degrading treatment or punishment and from exploitation, violence and abuse. The lowest final score out of the five themes (2.5/3) was achieved under the right to exercise legal capacity and the right to personal liberty and the security of person.

Conclusions

According to the findings, Finnish mental health services appear to be of high quality. However, we have identified some gaps in quality, which we have addressed in a national randomized controlled trial VIOLIN. Improvements can be realized through shared decision making and relaying information to service users.
LncRNA-MSC-AS1 inhibits the ovarian cancer progression by targeting miR-425-5p
Authors: Zhao Yinling , Yuan Donglan , Zhu Dandan , Xu Tianhui , Huang Aihua , Jiang Li , Liu Chiwen , Qian Hua , Bu Xinhua
Published: August 2021

Background

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) were reported to be aberrantly expressed and related to the pathogenesis of ovarian cancer. However, the role and regulatory mechanism of MSC-AS1 in ovarian cancer has yet to be fully elucidated.

Methods

Expression of lncRNA MSC-AS1 (MSC-AS1) and microRNA-425-5p (miR-425-5p) in the ovarian cancer tissue samples and cell lines was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The functions of MSC-AS1 on ovarian cancer cell proliferation, cell cycle and apoptosis were determined using MTT, colony formation and flow cytometry analyses. The protein expression levels were evaluated using western blot assay. The targeting relationship MSC-AS1 and miR-425-5p was verified via dual-luciferase reporter assay.

Results

MSC-AS1 expression level was lowly expressed, while miR-425-5p level was highly in ovarian cancer tissues and cells. Elevation of MSC-AS1 has the ability to significantly inhibit cell proliferation and facilitate cell apoptosis in SKOV3 and A2780 cells. Moreover, MSC-AS1 targeted and negatively modulated miR-425-5p. MiR-425-5p up-regulation has been proved to partially reverse the tumor suppressive function of MSC-AS1 overexpression

Conclusion

MSC-AS1 sponged miR-425-5p to inhibit the ovarian cancer progression. These findings may provide a promising therapeutic target for the treatment of ovarian cancer.
Efficacy of PD-1/PD-L1 inhibitors in ovarian cancer: a single-arm meta-analysis
Authors: Zhu Jue , Yan Lifeng , Wang Qiming
Published: August 2021

Several studies have evaluated the efficacy of PD-1/PD-L1 inhibitors in ovarian cancer; however, the response rate varies. This study aims to explore the efficacy of anti-PD-1/PD-L1 therapy in ovarian cancer. A quantitative meta-analysis was performed through a systematic search in PubMed, Web of Science, and the Cochrane Library. The pooled ORR was calculated and compared. Fifteen trials were included in this meta-analysis. Our analyses showed that the pooled ORR of all included studies was 19% (95% CI: 13%, 27%). Single PD-1/PD-L1 inhibitors had the lowest ORR of 9% (95% CI: 7%, 12%), while the combination of PD-1/PD-L1 inhibitors and chemotherapy had the highest ORR of 36% (95% CI: 24%, 51%). This study showed that PD-1/PD-L1 inhibitors alone have limited efficacy for ovarian cancer. The combination of PD-1/PD-L1 inhibitors and chemotherapy could be chosen as the recommended modality for further study.
Pre-injury dispensing of psychoactive prescription drugs in a ten years trauma population: a retrospective registry analysis
Authors: Torp Henrik Andreas , Skurtveit Svetlana , Skaga Nils Oddvar , Gustavsen Ingebjørg , Gran Jon Michael , Rosseland Leiv Arne
Published: August 2021

Background

The use of psychoactive prescription drugs is associated with increased risk of traumatic injury, and has negative impact on clinical outcome in trauma patients. Previous studies have focused on specific drugs or subgroups of patients. Our aim was to examine the extent of psychoactive drug dispensing prior to injury in a comprehensive population of trauma patients.

Methods

The Oslo University Hospital Trauma Registry provided data on all trauma patients admitted to the trauma centre between 2005 and 2014. We linked the data to Norwegian Prescription Database data from 2004. Opioids, benzodiazepines, z-hypnotics, gabapentinoids, and centrally acting sympathomimetics dispensed during the year before trauma of each patient were identified. We determined the pre-trauma annual prevalence of dispensing and mean annual cumulative defined daily doses (DDD) for each drug class, and compared results with corresponding figures in the general population, using standardised ratios. For each drug class, dispensing 14 days preceding trauma was analysed in patients sustaining severe injury and compared with patients sustaining non-severe injury.

Results

12,713 patients (71% male) were included. Median age was 36 years. 4891 patients (38%) presented with severe injury (Injury Severity Score > 15). The ratio between annual prevalence of dispensed prescriptions for trauma patients and the general population, adjusted for age and sex, was 1.5 (95% confidence interval 1.4–1.6) for opioids, 2.1 (2.0–2.2) for benzodiazepines, 1.7 (1.6–1.8) for z-hypnotics, 1.9 (1.6–2.2) for gabapentinoids, and 1.9 (1.6–2.2) for centrally acting sympathomimetics. Compared with the general population, mean annual cumulative DDD of opioids and benzodiazepines dispensed to trauma patients were more than two and three times as high, respectively, in several age groups below 70 years. The prevalence of dispensing 14 days pre-trauma was higher in severely injured patients for opioids, benzodiazepines, and z-hypnotics compared with patients without severe injury.

Conclusions

Our results support previous findings that the prevalence of psychoactive drug use is high among trauma patients. In terms of both frequency and amounts, the pre-injury dispensing of psychoactive drugs to trauma patients supersedes that of the general population, especially in younger patients.
Idle peripheral intravenous cannulation: an observational cohort study of pre-hospital and emergency department practices
Authors: Evison Hugo , Sweeny Amy , Ranse Jamie , Carrington Mercedes , Marsh Nicole , Byrnes Joshua , Rickard Claire M. , Carr Peter J. , Keijzers Gerben
Published: August 2021

Background

Unused('idle')peripheral intravenous catheters (PIVC) are those not used within 24 hours of insertion. There is little data on cannulation practices and idle PIVC rates in emergency settings, especially the pre-hospital environment.

Methods

This was an observational cohort study set in south-east Queensland, Australia using data from a large tertiary level emergency department (ED) and the local statutory ambulance service. Demographic, clinical and PIVC data were collected over two periods; 9 February–18 March 2017 and 5 January–4 February 2018. Adult patients were included if they were allocated an Australasian triage scale (ATS) category between 2 and 5, and had a PIVC inserted in the pre-hospital setting or ED. PIVC use was defined as idle if no fluids, medications or contrast were administered intravenously within 24 hours of insertion. Comparisons between pre-hospital and ED practice and idle PIVC status were undertaken using descriptive statistics and logistic regression.

Results

A total of 1249 patients with a PIVC (372 pre-hospital; 877 ED) were included. Overall, 366 PIVCs (29.3%; 95% CI 26.9%–31.9%) remained idle at 24 hours. In the pre-hospital group, 147 (39.5%) PIVCs inserted were not used pre-hospital, and 74 (19.9%) remained idle. In comparison, 292 (33.3%) PIVCs placed in the ED remained idle. ED staff more frequently inserted PIVCs in the antecubital fossa than paramedics (65.5% vs. 49.7%), where forearm PIVC insertion was more common pre-hospital than in ED (13.7% vs. 7.4%). Nursing staff inserted idle PIVCs at a rate of (35.1%) compared to doctors (29.6%) and paramedics (19.9%). Having a PIVC inserted in the ED was the only factor significantly (p ≤ .001) predicting an idle outcome (Odds Ratio: 2.4; 95% CI 1.7–3.3).

Conclusion

One-third of PIVCs inserted within the emergency setting remained idle, suggesting unnecessary risk and costs. Pre-hospital and ED PIVC insertion practices differed, with idle PIVCs 2.4 times more prevalent if inserted in the ED than pre-hospital and with greater use of antecubital insertion. Reasons for these differences are not well understood and requires more targeted research.
Italian consensus on the therapeutic management of uncomplicated acute hematogenous osteomyelitis in children
Authors: Krzysztofiak Andrzej , Chiappini Elena , Venturini Elisabetta , Gargiullo Livia , Roversi Marco , Montagnani Carlotta , Bozzola Elena , Chiurchiu Sara , Vecchio Davide , Castagnola Elio , Tomà Paolo , Rossolini Gian Maria , Toniolo Renato Maria , Esposito Susanna , Cirillo Marco , Cardinale Fabio , Novelli Andrea , Beltrami Giovanni , Tagliabue Claudia , Boero Silvio , Deriu Daniele , Bianchini Sonia , Grandin Annalisa , Bosis Samantha , Ciarcià Martina , Ciofi Daniele , Tersigni Chiara , Bortone Barbara , Trippella Giulia , Nicolini Giangiacomo , Lo Vecchio Andrea , Giannattasio Antonietta , Musso Paola , Serrano Elena , Marchisio Paola , Donà Daniele , Garazzino Silvia , Pierantoni Luca , Mazzone Teresa , Bernaschi Paola , Ferrari Alessandra , Gattinara Guido Castelli , Galli Luisa , Villani Alberto
Published: August 2021

Background

Acute hematogenous osteomyelitis (AHOM) is an insidious infection of the bone that more frequently affects young males. The etiology, mainly bacterial, is often related to the patient’s age, but it is frequently missed, owing to the low sensitivity of microbiological cultures. Thus, the evaluation of inflammatory biomarkers and imaging usually guide the diagnosis and follow-up of the infection. The antibiotic treatment of uncomplicated AHOM, on the other hand, heavily relies upon the clinician experience, given the current lack of national guidelines for the management of this infection.

Methods

A systematic review of the studies on the empirical treatment of uncomplicated AHOM in children published in English or Italian between January 1, 2009, and March 31, 2020, indexed on Pubmed or Embase search engines, was carried out. All guidelines and studies reporting on non-bacterial or complicated or post-traumatic osteomyelitis affecting newborns or children older than 18 years or with comorbidities were excluded from the review. All other works were included in this study.

Results

Out of 4576 articles, 53 were included in the study. Data on different topics was gathered and outlined: bone penetration of antibiotics; choice of intravenous antibiotic therapy according to the isolated or suspected pathogen; choice of oral antibiotic therapy; length of treatment and switch to oral therapy; surgical treatment.

Conclusions

The therapeutic management of osteomyelitis is still object of controversy. This study reports the first Italian consensus on the management of uncomplicated AHOM in children of pediatric osteomyelitis, based on expert opinions and a vast literature review.
Population or family history based BRCA gene tests of breast cancer? A systematic review of economic evaluations
Authors: Meshkani Zahra , Aboutorabi Ali , Moradi Najmeh , Langarizadeh Mostafa , Motlagh Ali Ghanbari
Published: August 2021

Background

Nearly 56% of at-risk carriers are not identified and missed as a result of the current family-history (FH) screening for genetic testing. The present study aims to review the economic evaluation studies on BRCA genetic testing strategies for screening and early detection of breast cancer.

Methods

This systematic literature review is conducted within the Cochrane Library, PubMed, Scopus, Web of Science, ProQuest, and EMBASE databases. In this paper, the relevant published economic evaluation studies are identified by following the standard Cochrane Collaboration methods and adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement reporting some recommendations for articles up to March 2020. Thereafter, the inclusion and exclusion criteria are applied to screen the articles. Disagreements are resolved through a consensus meeting. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist is used in the evaluation of quality. Finally, a narrative synthesis is performed. To compare the different levels of incremental cost-effectiveness ratio (ICER), the net present value is calculated based on a discount rate of 3% in 2019.

Results

Among 788 initially retrieved citations, 12 studies were included. More than 60% of the studies were originated from high-income countries and were published after 2016. It is noteworthy that most of the studies evaluated the payer perspective. Moreover, the robustness of the results were analyzed through one-way and probabilistic sensitivity analyses in nearly 66% of these studies. Nearly, 25% of the studies are focused and defined population-based and family history BRCA tests as comparators; afterwards, the cost-effectiveness of the former was confirmed. The highest and lowest absolute values for the ICERs were $65,661 and $9 per quality adjusted life years, respectively. All studies met over 70% of the CHEERs criteria checklist, which was considered as 93% of high quality on average as well.

Conclusions

The genetic BRCA tests for the general population as well as unselected breast cancer patients were cost-effective in high and upper-middle income countries and those with prevalence of gene mutation while population-based genetic tests for low-middle income countries are depended on the price of the tests.
Cytotoxic and targeted therapy for BRCA1/2-driven cancers
Authors: Imyanitov Evgeny N.
Published: August 2021

Tumors arising in BRCA1/2 germline mutation carriers usually demonstrate somatic loss of the remaining BRCA1/2 allele and increased sensitivity to platinum compounds, anthracyclines, mitomycin C and poly (ADP-ribose) polymerase inhibitors (PARPi). Exposure to conventional platinum-based therapy or PARPi results in the restoration of BRCA1/2 function and development of resistance to systemic therapy, therefore, there is a need for other treatment options. Some studies suggested that the use of specific drug combinations or administration of high-dose chemotherapy may result in pronounced tumor responses. BRCA1/2-driven tumors are characterized by increased immunogenicity; promising efficacy of immune therapy has been demonstrated in a number of preclinical and clinical investigations. There are outstanding issues, which require further consideration. Platinum compounds and PARPi have very similar mode of antitumor action and are likely to render cross-resistance to each other, so their optimal position in cancer treatment schemes may be a subject of additional studies. Sporadic tumors with somatically acquired inactivation of BRCA1/2 or related genes resemble hereditary neoplasms with regard to the spectrum of drug sensitivity; the development of user-friendly BRCAness tests presents a challenge. Many therapeutic decisions are now based on the BRCA1/2 status, so the significant reduction of the turn-around time for predictive laboratory assays is of particular importance.
Protecting clinical trials in cystic fibrosis during the SARS-CoV-2 pandemic: risks and mitigation measures
Authors: van Koningsbruggen-Rietschel Silke , Dunlevy Fiona , Bulteel Veerle , Hayes Kate , Verbrugge Anne , Janssens Hettie M. , Dufeu Nadine , Simmonds Nicholas J. , Dupont Lieven J. , Downey Damian G.
Published: August 2021

The SARS-CoV-2 pandemic has disrupted clinical trials worldwide. The European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) has tracked clinical trial disruption by surveying its 58 trial sites across 17 European countries and collated information on measures to mitigate the impact of the pandemic and ensure trial continuity. Here, we present recommendations on how to reduce the risk of SARS-CoV-2 exposure to patients and trial staff by implementing remote trial visits where possible, using home assessments, video and phone calls, electronic consent, and home delivery of study drugs. We discuss the practicalities of remote source data verification, protocol amendments, changing trial site location, and staff absences and home working. We outline recommendations on how to protect trial outcomes, including home assessments, safety reporting, protocol deviations, and recruitment challenges. Finally, we discuss the importance of continued access to study drugs via extension trials for some patients. This guidance was co-created from the shared knowledge and experience of sites in our network and was re-distributed directly to all ECFS-CTN sites to help mitigate the impact of further waves of the SARS-CoV-2 pandemic. We will also use this guidance to assist companies, academia, and consortia with future protocol design and risk mitigation plans. This guidance can be applied to clinical trials in other diseases and could help sites that are not supported by clinical trial networks.
Protocol for the Controlled evaLuation of Angiotensin Receptor blockers for COVID-19 respIraTorY disease (CLARITY): a randomised controlled trial
Authors: Hockham Carinna , Kotwal Sradha , Wilcox Arlen , Bassi Abhinav , McGree James , Pollock Carol , Burrell Louise M. , Bathla Nikita , Kunigari Mallikarjuna , Rathore Vinay , John Michael , Lin Enmoore , Jenkins Christine , Ritchie Angus , McLachlan Andrew , Snelling Thomas , Jones Mark , Jha Vivekanand , Jardine Meg ,   on behalf of the CLARITY Investigators
Published: August 2021

Background

SARS-CoV-2 binds to membrane-bound angiotensin-converting enzyme 2 (ACE2) which may result in downregulation of membrane-bound ACE2. ACE2 is a key regulator of the renin-angiotensin system (RAS) and is responsible for degrading angiotensin II and thereby counteracting its pro-inflammatory, pro-fibrotic effects mediated through the angiotensin II type 1 receptor (AT1R). As AT1R is directly blocked by angiotensin receptor blockers (ARBs), these agents may offer a safe, low-cost solution for reducing COVID-19 respiratory outcomes.

Methods and discussion

CLARITY is a pragmatic, adaptive, two-arm, multi-centre, comparative effectiveness phase III randomised controlled trial that examines whether ARBs reduce COVID-19 severity among high-risk patients. Recruiting in India and Australia, the trial will compare treatment with a maximum tolerated daily dose of an ARB to standard of care. Treatment allocation is blinded in India but open-label in Australia due to interruptions to placebo supply in the latter. The primary endpoint is a 7-point ordinal scale of clinical states, ranging from no limitation of activities (category 1) to death (category 7), assessed on day 14. Secondary outcomes include the 7-point scale assessed at day 28 and 28- and 90-day mortality. The design adapts the sample size based on accumulating data via frequent interim analyses and the use of predictive probability to determine whether the current sample size is sufficient or continuing accrual would be futile. The trial commenced recruitment on 18 August 2020.

Trial registration

ClinicalTrials.gov, NCT04394117. Registered on 19 May 2020. Clinical Trial Registry of India: CTRI/2020/07/026831)
2-Hydroxybenzylamine (2-HOBA) to prevent early recurrence of atrial fibrillation after catheter ablation: protocol for a randomized controlled trial including detection of AF using a wearable device
Authors: O’Neill Matthew J. , Yoneda Zachary T. , Crawford Diane M. , Ye Fei , Ao Mingfang , Pitchford Lisa M. , Rathmacher John A. , Murray Katherine T. , Akers Wendell S. , Roden Dan M. , Michaud Gregory F. , Shoemaker M. Benjamin
Published: August 2021

Background

Although catheter ablation is an effective therapy for atrial fibrillation (AF), the most common cardiac arrhythmia encountered in clinical practice, AF ablation generates inflammation and oxidative stress in the early postoperative period predisposing to recurrence of AF. Isolevuglandins (IsoLGs) are reactive lipid mediators of oxidative stress injury that rapidly react with endogenous biomolecules to compromise their function. 2-Hydroxybenzylamine (2-HOBA), a potent small molecule scavenger of IsoLGs, sequesters the reactive species as inert adducts. This mechanism, coupled with reported safety in humans, supports the investigation of 2-HOBA as a novel therapeutic to reduce AF caused by oxidative stress, such as that which occurs after catheter ablation. Accordingly, we seek to test the hypothesis that treatment with 2-HOBA will decrease early recurrence of AF and other atrial arrhythmias following AF ablation by decreasing IsoLG adducts with native biomolecules.

Methods

The proposed trial will randomly assign 162 participants undergoing cryo- or radiofrequency catheter ablation for AF to 2-HOBA (N = 81) or placebo (N = 81). Individuals will begin the study drug 3 days prior to ablation and continue for 28 days. Participants will be given a wearable smartwatch capable of detecting and recording atrial arrhythmias. They will be instructed to record ECGs daily with additional ECGs if they experience symptoms of AF or when alerted by the smartwatch AF detection alarm. The primary clinical endpoint will be an episode of AF, atrial tachycardia, or atrial flutter lasting 30 s or more within 28 days post-AF ablation. Secondary measures will be the change in IsoLG adduct levels from blood samples collected immediately pre-ablation and post-ablation and reduction in AF burden as calculated from the smartwatch.

Discussion

The proposed trial will test the hypothesis that 2-HOBA reduces post-ablation atrial arrhythmias through sequestration of reactive IsoLG species. The results of this study may improve the understanding of the role of IsoLGs and oxidative stress in AF pathogenesis and provide evidence to advance 2-HOBA and related compounds as a new therapeutic strategy to treat AF.

Trial registration

ClinicalTrials.gov NCT04433091. Registered on June 3, 2020.
Rational engineering of Saccharomyces cerevisiae towards improved tolerance to multiple inhibitors in lignocellulose fermentations
Authors: Brandt Bianca A. , García-Aparicio Maria D. P. , Görgens Johann F. , van Zyl Willem H.
Published: August 2021

Background

The fermentation of lignocellulose hydrolysates to ethanol requires robust xylose-capable Saccharomycescerevisiae strains able to operate in the presence of microbial inhibitory stresses. This study aimed at developing industrial S.cerevisiae strains with enhanced tolerance towards pretreatment-derived microbial inhibitors, by identifying novel gene combinations that confer resistance to multiple inhibitors (thus cumulative inhibitor resistance phenotype) with minimum impact on the xylose fermentation ability. The strategy consisted of multiple sequential delta-integrations of double-gene cassettes containing one gene conferring broad inhibitor tolerance (ARI1, PAD1 or TAL1) coupled with an inhibitor-specific gene (ADH6, FDH1 or ICT1). The performances of the transformants were compared with the parental strain in terms of biomass growth, ethanol yields and productivity, as well as detoxification capacities in a synthetic inhibitor cocktail, sugarcane bagasse hydrolysate as well as hardwood spent sulphite liquor.

Results

The first and second round of delta-integrated transformants exhibited a trade-off between biomass and ethanol yield. Transformants showed increased inhibitor resistance phenotypes relative to parental controls specifically in fermentations with concentrated spent sulphite liquors at 40% and 80% v/v concentrations in 2% SC media. Unexpectedly, the xylose fermentation capacity of the transformants was reduced compared to the parental control, but certain combinations of genes had a minor impact (e.g. TAL1 + FDH1). The TAL1 + ICT1 combination negatively impacted on both biomass growth and ethanol yield, which could be linked to the ICT1 protein increasing transformant susceptibility to weak acids and temperature due to cell membrane changes.

Conclusions

The integration of the selected genes was proven to increase tolerance to pretreatment inhibitors in synthetic or industrial hydrolysates, but they were limited to the fermentation of glucose. However, some gene combination sequences had a reduced impact on xylose conversion.
Risk of dementia in patients with toxoplasmosis: a nationwide, population-based cohort study in Taiwan
Authors: Yang Hung-Yi , Chien Wu-Chien , Chung Chi-Hsiang , Su Ruei-Yu , Lai Chung-Yu , Yang Chuan-Chi , Tzeng Nian-Sheng
Published: August 2021

Background

Approximately 25–30% of individuals worldwide are infected with Toxoplasma gondii (T. gondii), which is difficult to detect in its latent state. We aimed to evaluate the association between toxoplasmosis, the risk of dementia, and the effects of antibiotics in Taiwan.

Methods

This nationwide, population-based, retrospective cohort study was conducted using the Longitudinal Health Insurance Database containing the records of 2 million individuals retrieved from Taiwan’s National Health Insurance Research Database. Fine–Gray competing risk analysis was used to determine the risk for the development of dementia in the toxoplasmosis cohort relative to the non-toxoplasmosis cohort. A sensitivity analysis was also conducted. The effects of antibiotics (sulfadiazine or clindamycin) on the risk of dementia were also analyzed.

Results

We enrolled a total of 800 subjects, and identified 200 patients with toxoplasmosis and 600 sex- and age-matched controls without toxoplasmosis infection in a ratio of 1:3, selected between 2000 and 2015. The crude hazard ratio (HR) of the risk of developing dementia was 2.570 [95% confidence interval (CI) = 1.511–4.347, P < 0.001]. After adjusting for sex, age, monthly insurance premiums, urbanization level, geographical region, and comorbidities, the adjusted HR was 2.878 (95% CI = 1.709–4.968, P < 0.001). Sensitivity analysis revealed that toxoplasmosis was associated with the risk of dementia even after excluding diagnosis in the first year and the first 5 years. The usage of sulfadiazine or clindamycin in the treatment of toxoplasmosis was associated with a decreased risk of dementia.

Conclusions

This finding supports the evidence that toxoplasmosis is associated with dementia and that antibiotic treatment against toxoplasmosis is associated with a reduced risk of dementia. Further studies are necessary to explore the underlying mechanisms of these associations.

Graphical Abstract
The parasite Schistocephalus solidus secretes proteins with putative host manipulation functions
Authors: Berger Chloé Suzanne , Laroche Jérôme , Maaroufi Halim , Martin Hélène , Moon Kyung-Mee , Landry Christian R. , Foster Leonard J. , Aubin-Horth Nadia
Published: August 2021

Background

Manipulative parasites are thought to liberate molecules in their external environment, acting as manipulation factors with biological functions implicated in their host’s physiological and behavioural alterations. These manipulation factors are part of a complex mixture called the secretome. While the secretomes of various parasites have been described, there is very little data for a putative manipulative parasite. It is necessary to study the molecular interaction between a manipulative parasite and its host to better understand how such alterations evolve.

Methods

Here, we used proteomics to characterize the secretome of a model cestode with a complex life cycle based on trophic transmission. We studied Schistocephalus solidus during the life stage in which behavioural changes take place in its obligatory intermediate fish host, the threespine stickleback (Gasterosteus aculeatus). We produced a novel genome sequence and assembly of S. solidus to improve protein coding gene prediction and annotation for this parasite. We then described the whole worm’s proteome and its secretome during fish host infection using LC–MS/MS.

Results

A total of 2290 proteins were detected in the proteome of S. solidus, and 30 additional proteins were detected specifically in the secretome. We found that the secretome contains proteases, proteins with neural and immune functions, as well as proteins involved in cell communication. We detected receptor-type tyrosine-protein phosphatases, which were reported in other parasitic systems to be manipulation factors. We also detected 12 S. solidus-specific proteins in the secretome that may play important roles in host–parasite interactions.

Conclusions

Our results suggest that S. solidus liberates molecules with putative host manipulation functions in the host and that many of them are species-specific.

Graphical abstract
Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan
Authors: Rosa-Teijeiro Chloé , Wagner Victoria , Corbeil Audrey , d’Annessa Ilda , Leprohon Philippe , do Monte-Neto Rubens L. , Fernandez-Prada Christopher
Published: August 2021

Background

The evolution of drug resistance is one of the biggest challenges in leishmaniasis and has prompted the need for new antileishmanial drugs. Repurposing of approved drugs is a faster and very attractive strategy that is gaining supporters worldwide. Different anticancer topoisomerase 1B (TOP1B) inhibitors have shown strong antileishmanial activity and promising selective indices, supporting the potential repurposing of these drugs. However, cancer cells and Leishmania share the ability to become rapidly resistant. The aim of this study was to complete a whole-genome exploration of the effects caused by exposure to topotecan in order to highlight the potential mechanisms deployed by Leishmania to favor its survival in the presence of a TOP1B inhibitor.

Methods

We used a combination of stepwise drug resistance selection, whole-genome sequencing, functional validation, and theoretical approaches to explore the propensity of and potential mechanisms deployed by three independent clones of L. infantum to resist the action of TOP1B inhibitor topotecan.

Results

We demonstrated that L. infantum is capable of becoming resistant to high concentrations of topotecan without impaired growth ability. No gene deletions or amplifications were identified from the next-generation sequencing data in any of the three resistant lines, ruling out the overexpression of efflux pumps as the preferred mechanism of topotecan resistance. We identified three different mutations in the large subunit of the leishmanial TOP1B (Top1BF187Y, Top1BG191A, and Top1BW232R). Overexpression of these mutated alleles in the wild-type background led to high levels of resistance to topotecan. Computational molecular dynamics simulations, in both covalent and non-covalent complexes, showed that these mutations have an effect on the arrangement of the catalytic pentad and on the interaction of these residues with surrounding amino acids and DNA. This altered architecture of the binding pocket results in decreased persistence of topotecan in the ternary complex.

Conclusions

This work helps elucidate the previously unclear potential mechanisms of topotecan resistance in Leishmania by mutations in the large subunit of TOP1B and provides a valuable clue for the design of improved inhibitors to combat resistance in both leishmaniasis and cancer. Our data highlights the importance of including drug resistance evaluation in drug discovery cascades.

Graphical abstract
Functional significance of gain-of-function H19 lncRNA in skeletal muscle differentiation and anti-obesity effects
Authors: Li Yajuan , Zhang Yaohua , Hu Qingsong , Egranov Sergey D. , Xing Zhen , Zhang Zhao , Liang Ke , Ye Youqiong , Pan Yinghong , Chatterjee Sujash S. , Mistretta Brandon , Nguyen Tina K. , Hawke David H. , Gunaratne Preethi H. , Hung Mien-Chie , Han Leng , Yang Liuqing , Lin Chunru
Published: August 2021

Background

Exercise training is well established as the most effective way to enhance muscle performance and muscle building. The composition of skeletal muscle fiber type affects systemic energy expenditures, and perturbations in metabolic homeostasis contribute to the onset of obesity and other metabolic dysfunctions. Long noncoding RNAs (lncRNAs) have been demonstrated to play critical roles in diverse cellular processes and diseases, including human cancers; however, the functional importance of lncRNAs in muscle performance, energy balance, and obesity remains elusive. We previously reported that the lncRNA H19 regulates the poly-ubiquitination and protein stability of dystrophin (DMD) in muscular dystrophy.

Methods

Here, we identified mouse/human H19-interacting proteins using mouse/human skeletal muscle tissues and liquid chromatography–mass spectrometry (LC-MS). Human induced pluripotent stem-derived skeletal muscle cells (iPSC-SkMC) from a healthy donor and Becker Muscular Dystrophy (BMD) patients were utilized to study DMD post-translational modifications and associated proteins. We identified a gain-of-function (GOF) mutant of H19 and characterized the effects on myoblast differentiation and fusion to myotubes using iPSCs. We then conjugated H19 RNA gain-of-function oligonucleotides (Rgof) with the skeletal muscle enrichment peptide agrin (referred to as AGR-H19-Rgof) and evaluated AGR-H19-Rgof’s effects on skeletal muscle performance using wild-type (WT) C57BL/6 J mice and its anti-obesity effects using high-fat diet (HFD)- and leptin deficiency-induced obese mouse models.

Results

We demonstrated that both human and mouse H19 associated with DMD and that the H19 GOF exhibited enhanced interaction with DMD compared to WT H19. DMD was found to associate with serine/threonine-protein kinase MRCK alpha (MRCKα) and α-synuclein (SNCA) in iPSC-SkMC derived from BMD patients. Inhibition of MRCKα and SNCA-mediated phosphorylation of DMD antagonized the interaction between H19 and DMD. These signaling events led to improved skeletal muscle cell differentiation and myotube fusion. The administration of AGR-H19-Rgof improved the muscle mass, muscle performance, and base metabolic rate of WT mice. Furthermore, mice treated with AGR-H19-Rgof exhibited resistance to HFD- or leptin deficiency-induced obesity.

Conclusions

Our study suggested the functional importance of the H19 GOF mutant in enhancing muscle performance and anti-obesity effects.
Physical and psychological health outcomes of a sitting light volleyball intervention program on adults with physical disabilities: a non-randomized controlled pre-post study
Authors: Leung Ka-Man , Chung Pak-Kwong , Chu William , Ng Kwok
Published: August 2021

Background

People with physical disabilities (PWPD) have limited opportunities to participate in sport activities. Sitting light volleyball (SLVB) is an adapted sport that combines light volleyball and paralympic sitting volleyball. This study examined the effectiveness of an SLVB intervention program to improve the physical and psychological health outcomes of PWPD in Hong Kong, China.

Methods

Thirty-two PWPD [13 women; SLVB group, n = 18; control group (CG), n = 14] with an average age of 48.89 years (SD = 14.42 years) participated in a 16-week intervention consisting of basic SLVB skills, and they also received instructions on the required posture, team tactics, and SLVB rules. Physical (i.e., muscular strength, muscular endurance, body composition, flexibility, and aerobic endurance) and psychological (i.e., physical activity enjoyment and quality of life) health outcomes were measured before and after the intervention.

Results

Individuals in the SLVB group exhibited statistically significant improvements in cardiovascular endurance [F(1,29) = 4.23, p = .049], body composition [F(1,23) = 6.67, p = .017], and physical activity enjoyment [F(1,29) = 16.94, p = .001] compared with adults in the CG.

Conclusions

Participating in SLVB has physical and psychological benefits for adults with physical disabilities in this study.

Registration number of trial registry: The trial is registered at chictr.org.cn, number ChiCTR2000032971 on 17/05/2020.