bluuebunny/crossref_metadata_2025 huggingface dataset:
Refractory post-thymectomy myasthenia gravis with onset at MGFA stage V: a case report
Authors: Zhou Rui-Qin , Li Lin-Jun , Wu Qing-Chen
Published: May 2022

Background

Post-thymectomy myasthenia gravis (PTMG) is defined as thymoma patients without signs of myasthenia gravis (MG) pre-operation, but develop MG after radical surgical resection. PTMG might be misdiagnosed not only because of its rare incidence, but also the uncertain interval between the removal of thymoma and the new onset MG. Additionally, some surgeons and anesthesiologists pay less attention to those asymptomatic thymoma patients in perioperative management, leading to the neglect of new onset PTMG, and miss the best time to treat it.

Case presentation

Majority of cases of PTMG with onset at stage I–II on the basis of Myasthenia Gravis Foundation of America (MGFA) classification have been reported, but rarely at stage V, which requiring intubation or non-invasive ventilation to avoid intubation. Herein, we presented a 70-year-old male with PTMG onset at MGFA stage V, meanwhile, he had severe pulmonary infection interfering with the diagnosis of PTMG, and eventually progressed to refractory PTMG, which requiring much more expensive treatments and longer hospital stays.

Conclusion

In the perioperative management of asymptomatic thymoma patients, careful preoperative evaluation including physical examination, electrophysiological test and acetylcholine receptor antibodies (AChR-Ab) level should be done to identify subclinical MG. Complete resection should be performed during thymectomy, if not, additional postoperative adjuvant therapy is neccessary to avoid recurrence. It’s important to identify PTMG at a early stage, especially when being interfered with by postoperative complications, such as lung infection, so that treatments could be initiated as soon as possible to avoid developing to refractory PTMG.
Rubus chingii Hu. unripe fruits extract ameliorates carbon tetrachloride-induced liver fibrosis and improves the associated gut microbiota imbalance
Authors: Wu Jianjun , Zhang Dingqi , Zhu Bo , Wang Siqi , Xu Yongbin , Zhang Congcong , Yang Hailing , Wang Shunchun , Liu Ping , Qin Luping , Liu Wei
Published: May 2022

Background

The unripe fruits of Rubus chingii Hu. (“Fu-peng-zi” in Chinese) is a well-known herbal tonic in traditional Chinese medicine (TCM) for tonifying liver and kidney. However, little is known regarding its therapeutic efficacy against liver fibrosis and the underlying mechanism.

Methods

The current research aims to explore the potential of Rubus chingii Hu. unripe fruits extract (RF) in the treatment of liver fibrosis and explore the underlying mechanism. RF was administered (450 and 900 mg·kg− 1 of body weight per day) orally to male C57BL/6 mice with CCl4-induced liver fibrosis for 3 weeks. The histopathological changes and fibrosis stage in liver tissue were assessed using hematoxylin and eosin (H&E) and Sirius red staining. The distribution of α-SMA and Col1A1 in the liver was analyzed to determine the hepatic stellate cells (HSCs) activation using immunohistochemistry and immunofluorescent analysis. Various biochemical markers in serum (ALT, AST) and liver (Hyp, IL1-β, IL6, TNF-α and MCP-1) were observed to assess the liver’s injury, fibrosis, and inflammation. In liver tissue, fibrosis-associated proteins including α-SMA, TGF-β1, Smad2/3, p-Smad2/3, and Smad4 were detected through a Western blot assay. Pyrosequencing-based analysis of bacterial 16 S ribosomal RNA from variable regions V3–V4 of fecal samples characterized the gut microbiota. Spearman’s rank correlation analysis was performed for the association between altered bacterial genera by RF and pharmacodynamics parameters.

Results

Three weeks of RF treatment can significantly lower liver inflammatory levels, pathological abnormalities, and collagen fibrous deposition in mice with CCl4-induced liver fibrosis. The expressions of α-SMA and Col1A1 were lowered by RF, while the expression levels of TGF-β/Smads signaling pathway-related proteins, including TGF-β1, p-Smad2/3, and Smad4, were dramatically decreased by RF. The RF treatment significantly increased or reduced 18 different bacterial species, restoring the CCl4-induced gut microbiota imbalance to the normal group’s levels. According to correlation analysis, the bacterial genera Bifidobacterium and Turicibacter were the most significant in restoring CCl4-induced liver fibrosis.

Conclusions

RF can reduce liver damage and delay the onset of liver fibrosis through modulating TGF-β/Smads signaling pathway. Furthermore, RF’s anti-liver fibrosis effect was related to balancing the gut microbial community, partly attained by increasing Bifidobacterium and Turicibacter in liver fibrosis.
Annual prevalence estimation of lymphatic malformation with a cutaneous component: observational study of a national representative sample of physicians
Authors: Gallagher Jack Ray , Martini J. , Carroll S. , Small A. , Teng J.
Published: May 2022

Background

Lymphatic malformations (LMs) represent a potentially life-threatening, rare disease of the lymphatic system characterized by development of abnormal vessels, outpouchings, or cysts filled with lymphatic fluid. There are three morphologic types of LMs based on the size of the individual cysts: macrocystic (typically > 2 cm), microcystic (generally < 2 cm), and mixed (includes aspects of both). Macrocystic LMs typically exist beneath the skin and often can involve vascular components and/or organs. Microcystic LMs often have a cutaneous component and clinically present with lymphorrhea, bleeding, pain, itching, malodor, and functional deficits. There are no treatments approved by the US Food and Drug Administration (FDA) for either macrocystic or microcystic lymphatic malformations. The totality of the epidemiologic literature for LM is limited to the incidence of the disease among various birth cohorts. This is the first nationally representative study to estimate the national managed prevalence for patients with microcystic LM or combined LM with a cutaneous component annually across physician specialties likely to manage this condition. We conducted a retrospective observational survey of a nationally representative sample of patient-care physicians in the United States most likely to manage lymphatic malformations with a cutaneous component (LMC). Once recruited, target physicians participated via an electronic questionnaire. We weighted study physician self-estimates of the number of LMC patients treated in the past 12 months to reflect the specialists’ corresponding proportion in the national universe. All patient information was anonymous; no personally identifiable information was collected.

Results

Of the 420 physicians who visited the study website, 316 agreed to be screened and to participate (75.2% participation rate). Our survey results indicated the estimated number of unique annually managed LMC patients by target specialists is 79,920 (CI 66,600–93,250). This number corresponds to managed prevalence of 24.1 LMC patients per 100,000 population (CI 19.6/100,000–28.4/100,000).

Conclusions

The study indicates that while rare, LMC affects a substantial number of people in the US (79,920) who are being managed by one or more specialists. By better understanding the prevalence of people living with LMC who require treatment, efforts to both increase disease awareness and to identify underserved populations in need of potential new treatments can be better focused.
Genetic determinants of syndactyly: perspectives on pathogenesis and diagnosis
Authors: Cassim Afraah , Hettiarachchi Dineshani , Dissanayake Vajira H. W.
Published: May 2022

The formation of the digits is a tightly regulated process. During embryogenesis, disturbance of genetic pathways in limb development could result in syndactyly; a common congenital malformation consisting of webbing in adjacent digits. Currently, there is a paucity of knowledge regarding the exact developmental mechanism leading to this condition. The best studied canonical interactions of Wingless‐type–Bone Morphogenic Protein–Fibroblast Growth Factor (WNT–BMP–FGF8), plays a role in the interdigital cell death (ICD) which is thought to be repressed in human syndactyly. Animal studies have displayed other pathways such as the Notch signaling, metalloprotease and non-canonical WNT-Planar cell polarity (PCP), to also contribute to failure of ICD, although less prominence has been given. The current diagnosis is based on a clinical evaluation followed by radiography when indicated, and surgical release of digits at 6 months of age is recommended. This review discusses the interactions repressing ICD in syndactyly, and characterizes genes associated with non-syndromic and selected syndromes involving syndactyly, according to the best studied canonical WNT-BMP-FGF interactions in humans. Additionally, the controversies regarding the current syndactyly classification and the effect of non-coding elements are evaluated, which to our knowledge has not been previously highlighted. The aim of the review is to better understand the developmental process leading to this condition.
Healthcare access, satisfaction, and health-related quality of life among children and adults with rare diseases
Authors: Bogart Kathleen , Hemmesch Amanda , Barnes Erica , Blissenbach Thomas , Beisang Arthur , Engel Patti ,   The Chloe Barnes Advisory Council on Rare Diseases, Tolar Jakub , Schacker Tim , Schimmenti Lisa , Brown Nicole , Morrison Kelly , Albright Tony , Klein Matt , Coleman Julia , Nelsen Karl , Blaylark Rae , LaFond Karri , Berkowitz Sheldon , Schultz Kris Ann , Hansen Kerry , Beiraghi Soraya , Joers Barbara , Tilstra David , Gaviglio Amy , Jones Lee A. , Miller Abigail , Foster Jackie
Published: May 2022

Background

Research in a variety of countries indicates that healthcare access and health-related quality of life are challenged among people with a variety of rare diseases (RDs). However, there has been little systematic research on the experiences of children and adults with RDs in the American healthcare system that identifies commonalities across RDs. This research aimed to: (1) Describe demographics, disease characteristics, diagnostic experiences, access to healthcare, knowledge about RDs, support from healthcare professionals, and patient satisfaction among people with RDs and their caregivers; (2) examine predictors of patient satisfaction among adults with RDs; (3) compare health-related quality of life and stigma to US population norms; 4) examine predictors of anxiety and depression among adults and children with RDs.

Results

This large-scale survey included (n = 1128) adults with RD or parents or caregivers of children with RDs representing 344 different RDs. About one third of participants waited four or more years for a diagnosis and misdiagnosis was common. A subset of participants reported experiencing insurance-related delays or denials for tests, treatments, specialists, or services. Approximately half of participants felt their medical and social support was sufficient, yet less than a third had sufficient dental and psychological support. Patients were generally neither satisfied or dissatisfied with their healthcare providers. Major predictors of satisfaction were lower stigma, lower anxiety, shorter diagnostic odyssey, greater physical function, and less pain interference. Adults and children with RDs had significantly poorer health-related quality of life and stigma in all domains compared to US norms. Predictors of both anxiety and depression were greater stigma/poor peer relationships, fatigue, sleep disturbance, limited ability to participate in social roles, and unstable disease course.

Conclusions

People in the U.S. with RDs have poor health-related quality of life and high stigma. These factors are related to patient satisfaction and healthcare access, including diagnostic delays and misdiagnosis. Advocacy work is needed in order to improve healthcare access and ultimately health-related quality of life for children and adults with RDs.
Understanding the role of SGLT2 inhibitors in glycogen storage disease type Ib: the experience of one UK centre
Authors: Halligan Rebecca K. , Dalton R. Neil , Turner Charles , Lewis Katherine A. , Mundy Helen R.
Published: May 2022

Background

Glycogen storage disease type Ib (GSD Ib) is a severe disorder of carbohydrate metabolism due to bi-allelic variants in SLC37A4. It is associated with neutropaenia and neutrophil dysfunction, which has recently been attributed to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5AG6P) within neutrophils. Treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors, such as empagliflozin, is a novel therapy that reduces 1,5-anhydroglucitol (1,5AG) in plasma.

Results

We report our experience in treating 8 paediatric GSD Ib patients with empagliflozin with a cumulative treatment time greater than 12 years. Treatment with a median dose of 5 mg (0.22 mg/kg height weight) of empagliflozin resulted in improvement in bowel health, growth, and laboratory parameters. Plasma 1,5AG levels reduced by a median of 78%. Baseline 1,5AG levels in our cohort were higher than in adult patients with GSD Ib. Hypoglycaemia on empagliflozin treatment occurred in 50% of our cohort.

Conclusion

We report the largest single centre cohort of GSD Ib patients treated with empagliflozin to date. Treatment with SGLT2 inhibitors is a novel and favourable treatment option for neutropaenia and neutrophil dysfunction in GSD Ib. We suggest a low starting dose of empagliflozin with careful titration due to the risk of hypoglycaemia. The interpretation of 1,5AG levels and their role in treatment monitoring is yet to be established, and requires ongoing research.
Single-cell sequencing: a promising approach for uncovering the mechanisms of tumor metastasis
Authors: Han Yingying , Wang Dan , Peng Lushan , Huang Tao , He Xiaoyun , Wang Junpu , Ou Chunlin
Published: May 2022

Single-cell sequencing (SCS) is an emerging high-throughput technology that can be used to study the genomics, transcriptomics, and epigenetics at a single cell level. SCS is widely used in the diagnosis and treatment of various diseases, including cancer. Over the years, SCS has gradually become an effective clinical tool for the exploration of tumor metastasis mechanisms and the development of treatment strategies. Currently, SCS can be used not only to analyze metastasis-related malignant biological characteristics, such as tumor heterogeneity, drug resistance, and microenvironment, but also to construct metastasis-related cell maps for predicting and monitoring the dynamics of metastasis. SCS is also used to identify therapeutic targets related to metastasis as it provides insights into the distribution of tumor cell subsets and gene expression differences between primary and metastatic tumors. Additionally, SCS techniques in combination with artificial intelligence (AI) are used in liquid biopsy to identify circulating tumor cells (CTCs), thereby providing a novel strategy for treating tumor metastasis. In this review, we summarize the potential applications of SCS in the field of tumor metastasis and discuss the prospects and limitations of SCS to provide a theoretical basis for finding therapeutic targets and mechanisms of metastasis.
Artificial intelligence in Emergency Medical Services dispatching: assessing the potential impact of an automatic speech recognition software on stroke detection taking the Capital Region of Denmark as case in point
Authors: Scholz Mirjam Lisa , Collatz-Christensen Helle , Blomberg Stig Nikolaj Fasmer , Boebel Simone , Verhoeven Jeske , Krafft Thomas
Published: May 2022

Background and purpose

Stroke recognition at the Emergency Medical Services (EMS) impacts the stroke treatment and thus the related health outcome. At the EMS Copenhagen 66.2% of strokes are detected by the Emergency Medical Dispatcher (EMD) and in Denmark approximately 50% of stroke patients arrive at the hospital within the time-to-treatment. An automatic speech recognition software (ASR) can increase the recognition of Out-of-Hospital cardiac arrest (OHCA) at the EMS by 16%. This research aims to analyse the potential impact an ASR could have on stroke recognition at the EMS Copenhagen and the related treatment.

Methods

Stroke patient data (n = 9049) from the years 2016–2018 were analysed retrospectively, regarding correlations between stroke detection at the EMS and stroke specific, as well as personal characteristics such as stroke type, sex, age, weekday, time of day, year, EMS number contacted, and treatment. The possible increase in stroke detection through an ASR and the effect on stroke treatment was calculated based on the impact of an existing ASR to detect OHCA from CORTI AI.

Results

The Chi-Square test with the respective post-hoc test identified a negative correlation between stroke detection and females, the 1813-Medical Helpline, as well as weekends, and a positive correlation between stroke detection and treatment and thrombolysis. While the association analysis showed a moderate correlation between stroke detection and treatment the correlation to the other treatment options was weak or very weak. A potential increase in stroke detection to 61.19% with an ASR and hence an increase of thrombolysis by 5% in stroke patients calling within time-to-treatment was predicted.

Conclusions

An ASR can potentially improve stroke recognition by EMDs and subsequent stroke treatment at the EMS Copenhagen. Based on the analysis results improvement of stroke recognition is particularly relevant for females, younger stroke patients, calls received through the 1813-Medical Helpline, and on weekends.

Trial registration

This study was registered at the Danish Data Protection Agency (PVH-2014-002) and the Danish Patient Safety Authority (R-21013122).
Impact of critical illness and withholding of early parenteral nutrition in the pediatric intensive care unit on long-term physical performance of children: a 4-year follow-up of the PEPaNIC randomized controlled trial
Authors: Vanhorebeek Ilse , Jacobs An , Mebis Liese , Dulfer Karolijn , Eveleens Renate , Van Cleemput Hanna , Wouters Pieter J. , Verlinden Ines , Joosten Koen , Verbruggen Sascha , Van den Berghe Greet
Published: May 2022

Background

Many critically ill children face long-term developmental impairments. The PEPaNIC trial attributed part of the problems at the level of neurocognitive and emotional/behavioral development to early use of parenteral nutrition (early-PN) in the PICU, as compared with withholding it for 1 week (late-PN). Insight in long-term daily life physical functional capacity after critical illness is limited. Also, whether timing of initiating PN affects long-term physical function of these children remained unknown.

Methods

This preplanned follow-up study of the multicenter PEPaNIC randomized controlled trial subjected 521 former critically ill children (253 early-PN, 268 late-PN) to quantitative physical function tests 4 years after PICU admission in Leuven or Rotterdam, in comparison with 346 age- and sex-matched healthy children. Tests included handgrip strength measurement, timed up-and-go test, 6-min walk test, and evaluation of everyday overall physical activity with an accelerometer. We compared these functional measures for the former critically ill and healthy children and for former critically ill children randomized to late-PN versus early-PN, with multivariable linear or logistic regression analyses adjusting for risk factors.

Results

As compared with healthy children, former critically ill children showed less handgrip strength (p < 0.0001), completed the timed up-and-go test more slowly (p < 0.0001), walked a shorter distance in 6 min (p < 0.0001) during which they experienced a larger drop in peripheral oxygen saturation (p ≤ 0.026), showed a lower energy expenditure (p ≤ 0.024), performed more light and less moderate physical activity (p ≤ 0.047), and walked fewer steps per day (p = 0.0074). Late-PN as compared with early-PN did not significantly affect these outcomes.

Conclusions

Four years after PICU admission, former critically ill children showed worse physical performance as compared with healthy children, without impact of timing of supplemental PN in the PICU. This study provides further support for de-implementing the early use of PN in the PICU.

Trial registration ClinicalTrials.gov, NCT01536275; registered on February 22, 2012.
Efficacy of contralaterally controlled functional electrical stimulation compared to cyclic neuromuscular electrical stimulation and task-oriented training for recovery of hand function after stroke: study protocol for a multi-site randomized controlled trial
Authors: Knutson Jayme S. , Friedl Amy S. , Hansen Kristine M. , Harley Mary Y. , Barrett A. M. , Raghavan Preeti , Plow Ela B. , Gunzler Douglas D. , Chae John
Published: May 2022

Background

Multi-site studies in stroke rehabilitation are important for determining whether a technology and/or treatment can be successfully administered by sites other than the originating site and with similar positive outcomes. This study is the first multi-site clinical trial of a novel intervention for post-stroke upper limb rehabilitation called contralaterally controlled functional electrical stimulation (CCFES). Previous pilot and single-site studies showed positive effects of CCFES on upper limb impairment and hand dexterity in stroke survivors. The main purpose of this study is to confirm and demonstrate the efficacy of CCFES in a larger group of most likely responders across multiple clinical sites.

Methods

Up to 129 stroke survivors with moderate to severe upper extremity hemiparesis at 4 clinical trial sites will be randomized to CCFES, cyclic neuromuscular electrical stimulation (cNMES), or task-oriented-training (TOT). Participants will receive 12 weeks of group-specific therapy. Blinded assessments of upper limb impairment and activity limitation, quality of life, and neurophysiology will be used to compare outcomes at baseline, after treatment, and up to 6 months post-treatment. The primary endpoint is change in dexterity from baseline to 6 months post-treatment.

Discussion

Loss of hand function following stroke is a major rehabilitation problem affecting millions of people per year globally. More effective rehabilitation therapies are needed to restore hand function in these individuals. This study will determine whether CCFES therapy produces greater improvements in upper extremity function than cNMES or TOT, and will begin to elucidate the different mechanisms underlying each of the three treatments. This multi-site study is a critical step in advancing a novel method of rehabilitation toward clinical translation and widespread dissemination.

Trial registration

ClinicalTrials.govNCT03574623. Registered prior to first enrollment; July 2, 2018.
How to embed qualitative research in trials: insights from the feasibility study of the SAFER trial programme
Authors: Powell Alison , Hoare Sarah , Modi Rakesh , Williams Kate , Dymond Andrew , Chapman Cheryl , Griffin Simon , Mant Jonathan , Burt Jenni
Published: May 2022

Qualitative research can enhance the design, conduct and interpretation of trials. Despite this, few trials incorporate qualitative methods, and those that do may not realise their full potential. In this commentary, we highlight how qualitative research can contribute to the design, conduct and day-to-day running of a trial, outlining the working arrangements and relationships that facilitate these contributions. In doing so, we draw on (i) existing frameworks on the role of qualitative research alongside trials and (ii) our experience of integrated qualitative research conducted as part of the feasibility study of the SAFER trial (Screening for Atrial Fibrillation with ECG to Reduce stroke), a cluster randomised controlled trial of screening people aged 70 and above for atrial fibrillation in primary care in England. The activities and presence of the qualitative team contributed to important changes in the design, conduct and day-to-day running of the SAFER feasibility study, and the subsequent main trial, informing diverse decisions concerning trial documentation, trial delivery, timing and content of measures and the information given to participating patients and practices. These included asking practices to give screening results to all participants and not just to ‘screen positive’ participants, and greater recognition of the contribution of practice reception staff to trial delivery. These changes were facilitated by a ‘one research team’ approach that underpinned all formal and informal working processes from the outset and maximised the value of both qualitative and trial coordination expertise. The challenging problems facing health services require a combination of research methods and data types. Our experience and the literature show that the benefits of embedding qualitative research in trials are more likely to be realised if attention is given to both structural factors and relationships from the outset. These include sustained and sufficient funding for qualitative research, embedding qualitative research fully within the trial programme, providing shared infrastructure and resources and committing to relationships based on mutual recognition of and respect for the value of different methods and perspectives. We outline key learning for the planning of future trials.

Trial registration: Screening for atrial fibrillation with ECG to reduce stroke ISRCTN16939438 (feasibility study); Screening for atrial fibrillation with ECG to reduce stroke – a randomised controlled trial ISRCTN72104369.
Brief Educational Video plus Telecare to Enhance Recovery for Older Emergency Department Patients with Acute Musculoskeletal Pain: an update to the study protocol for a randomized controlled trial
Authors: Hurka-Richardson Karen , Platts-Mills Timothy F. , McLean Samuel A. , Weinberger Morris , Stearns Sally C. , Bush Montika , Quackenbush Eugenia , Chari Srihari , Aylward Aileen , Kroenke Kurt , Kerns Robert D. , Weaver Mark A. , Keefe Francis J. , Berkoff David , Meyer Michelle L.
Published: May 2022

Background

This update describes changes to the Brief Educational Tool to Enhance Recovery (BETTER) trial in response to the COVID-19 pandemic.

Methods/design

The original protocol was published in Trials. Due to the COVID-19 pandemic, the BETTER trial converted to remote recruitment in April 2020. All recruitment, consent, enrollment, and randomization now occur by phone within 24 h of the acute care visit. Other changes to the original protocol include an expansion of inclusion criteria and addition of new recruitment sites. To increase recruitment numbers, eligibility criteria were expanded to include individuals with chronic pain, non-daily opioid use within 2 weeks of enrollment, presenting musculoskeletal pain (MSP) symptoms for more than 1 week, hospitalization in past 30 days, and not the first time seeking medical treatment for presenting MSP pain. In addition, recruitment sites were expanded to other emergency departments and an orthopedic urgent care clinic.

Conclusions

Recruiting from an orthopedic urgent care clinic and transitioning to remote operations not only allowed for continued participant enrollment during the pandemic but also resulted in some favorable outcomes, including operational efficiencies, increased enrollment, and broader generalizability.

Trial registration

ClinicalTrials.gov NCT04118595. Registered on October 8, 2019.
Self-guided virtual reality therapy for social anxiety disorder: a study protocol for a randomized controlled trial
Authors: Hildebrand Anne Sophie , Roesmann Kati , Planert Jari , Machulska Alla , Otto Esra , Klucken Tim
Published: May 2022

Background

Social anxiety disorder (SAD) is a highly prevalent mental disorder associated with enormous stress and suffering. Cognitive behavior therapy (CBT) is the first-line treatment for SAD, yet its accessibility is often constrained with long waiting times. Digital therapeutic applications, including psychoeducation and self-guided behavioral experiments in virtual reality (VR), could facilitate access and reduce waiting times. The study aims to investigate if ultra-short-time therapy involving self-guided digital therapeutic applications with VR components can reduce the severity of SAD.

Methods

Forty SAD patients will participate in this randomized controlled trial. Half will get access to a self-guided, digital therapeutic application with exposure-based behavioral experiments in VR, while the other half will receive a control treatment. Both treatments include four therapeutic appointments. Changes in the severity of SAD will be measured after each appointment and on a 6-week follow-up assessment and will be compared between groups, with the change in SAD measured at baseline- and post-assessment as primary outcome.

Discussion

Self-guided digital therapeutic applications including ultra-short-time therapy combined with VR could help reduce the waiting time for patients and relieve the health system. The results of this study may inform psychotherapists regarding the potential of self-guided digital therapeutic applications including exposure-based behavioral experiments in VR for SAD and will provide important insight for future research on VR therapy.

Trial registration

Current Controlled Trials ISRCTN18013983. Registered on 1 February 2022.
Elucidating treatment targets and mediators within a confirmatory efficacy trial: study protocol for a randomized controlled trial of cognitive-behavioral therapy vs. light therapy for winter depression
Authors: Rohan Kelly J. , Franzen Peter L. , Roeckelin Kathryn A. , Siegle Greg J. , Kolko David J. , Postolache Teodor T. , Vacek Pamela M.
Published: May 2022

Background

This study is a confirmatory efficacy trial of two treatments for winter seasonal affective disorder (SAD): SAD-tailored group cognitive-behavioral therapy (CBT-SAD) and light therapy (LT). In our previous efficacy trial, post-treatment outcomes for CBT-SAD and LT were very similar, but CBT-SAD was associated with fewer depression recurrences two winters later than LT (27.3% in CBT-SAD vs. 45.6% in LT). CBT-SAD engaged and altered a specific mechanism of action, seasonal beliefs, which mediated CBT-SAD’s acute antidepressant effects and CBT-SAD’s enduring benefit over LT. Seasonal beliefs are theoretically distinct from LT’s assumed target and mechanism: correction of circadian phase. This study applies the experimental therapeutics approach to determine how each treatment works when it is effective and to identify the best candidates for each. Biomarkers of LT’s target and effect include circadian phase angle difference and the post-illumination pupil response. Biomarkers of CBT-SAD’s target and effect include decreased pupillary and sustained frontal gamma-band EEG responses to seasonal words, which are hypothesized as biomarkers of seasonal beliefs, reflecting less engagement with seasonal stimuli following CBT-SAD. In addition to determining change mechanisms, this study tests the efficacy of a “switch” decision rule upon recurrence to inform clinical decision-making in practice.

Methods

Adults with SAD (target N = 160) will be randomzied to 6-weeks of CBT-SAD or LT in winter 1; followed in winter 2; and, if a depression recurrence occurs, offered cross-over into the alternate treatment (i.e., switch from LT➔CBT-SAD or CBT-SAD➔LT). All subjects will be followed in winter 3. Biomarker assessments occur at pre-, mid-, and post-treatment in winter 1, at winter 2 follow-up (and again at mid-/post-treatment for those crossed-over), and at winter 3 follow-up. Primary efficacy analyses will test superiority of CBT-SAD over LT on depression recurrence status (the primary outcome). Mediation analyses will use parallel process latent growth curve modeling.

Discussion

Consistent with the National Institute of Mental Health’s priorities for demonstrating target engagement at the level of Research Domain Criteria-relevant biomarkers, this work aims to confirm the targets and mechanisms of LT and CBT-SAD to maximize the impact of future dissemination efforts.

Trial registration

ClinicalTrials.gov identifier: NCT03691792. Registered on October 2, 2018.
Comparison of BARD®LIFESTREAM™ covered balloon-expandable stent versus GORE® VIABAHN™ covered self-expandable stent in treatment of aortoiliac obstructive disease: study protocol for a prospective randomized controlled trial (NEONATAL trial)
Authors: Qi Yuhan , Wang Jiarong , Zhao Jichun , Huang Bing , Xiong Fei , Du Xiaojiong , Chen Xiyang , Guo Qiang , Wang Tiehao , Yuan Ding
Published: May 2022

Background

Covered stent has become one of the mainstream therapies for aortoiliac obstructive disease (AIOD), with a higher patency rate than bare metal stent. Covered balloon-expandable (CBE) stent can be placed more accurately with higher a radial support force, while covered self-expanding (CSE) stent has greater elasticity and higher trackability. However, there is no level I evidence regarding the comparison safety and efficacy between the CSE stent and CBE stent in AIOD to date. Therefore, this study aims to compare the efficacy and safety of CBE stent (BARD®LIFESTREAM™) and CSE stent (GORE® VIABAHN™) in AIOD.

Methods

This trial is a prospective, single-center, parallel, noninferiority, randomized controlled trial. A total of 106 patients will be enrolled and these patients will be randomized to either the CBE stent group or the CSE stent group. The primary end point of the study is the occurrence of target lesion revascularization (TLR) at 12 months after the intervention.

Discussion

To our knowledge, the ballooN sElf cOver steNt AorToiliAc occuLusive (NEONATAL) trial is the first RCT to compare CBE and CSE stent in AIOD patients. The main aim is to compare the TLR of the target lesion between CBE stent and CSE stent at 12 months post-procedure. The results of clinical trials may contribute to establishing a strategic guideline for choosing the optimal type of covered stent in the treatment of AIOD patients.

Trial registration

Chinese Clinical Trials Registry ChiCTR2100046734. Registered on 27 May 2021
E-Consent—a guide to maintain recruitment in clinical trials during the COVID-19 pandemic
Authors: Almeida-Magana Ricardo , Maroof Hanna , Grierson Jack , Clow Rosie , Dinneen Eoin , Al-Hammouri Tarek , Muirhead Nicola , Brew-Graves Chris , Kelly John , Shaw Greg
Published: May 2022

Background

The COVID-19 pandemic has posed daunting challenges when conducting clinical research. Adopting new technologies such as remote electronic consent (e-Consent) can help overcome them. However, guidelines for e-Consent implementation in ongoing clinical trials are currently lacking. The NeuroSAFE PROOF trial is a randomized clinical trial evaluating the role of frozen section analysis during RARP for prostate cancer. In response to the COVID-19 crisis, recruitment was halted, and a remote e-Consent solution was designed. The aim of this paper is to describe the process of implementation, impact on recruitment rate, and patients’ experience using e-Consent.

Methods

A substantial amendment of the protocol granted the creation of a remote e-Consent framework based on the REDCap environment, following the structure and content of the already approved paper consent form. Although e-Consent obviated the need for in-person meeting, there was nonetheless counselling sessions performed interactively online. This new pathway offered continuous support to patients through remote consultations. The whole process was judged to be compliant with regulatory requirements before implementation.

Results

Before the first recruitment suspension, NeuroSAFE PROOF was recruiting an average of 9 patients per month. After e-Consent implementation, 63 new patients (4/month) have been enrolled despite a second lockdown, none of whom would have been recruited using the old methods given restrictions on face-to-face consultations. Patients have given positive feedback on the use of the platform. Limited troubleshooting has been required after implementation.

Conclusion

Remote e-Consent-based recruitment was critical for the continuation of the NeuroSAFE PROOF trial during the COVID-19 pandemic. The described pathway complies with ethical and regulatory guidelines for informed consent, while minimizing face-to-face interactions that increase the risk of COVID-19 transmission. This guide will help researchers integrate e-Consent to ongoing or planned clinical trials while uncertainty about the course of the pandemic continues.

Trial registration

NeuroSAFE PROOF trial NCT03317990. Registered on 23 October 2017. Regional Ethics Committee reference 17/LO/1978.
Behavioural optimisation to address trial conduct challenges: case study in the UK-REBOA trial
Authors: Lawrie Louisa , Duncan Eilidh M. , Jansen Jan O. , Campbell Marion K. , Brunsdon Dan , Skea Zoë , Coffey Taylor , Cochran Claire , Gillies Katie
Published: May 2022

Background

Clinical trials comprise multiple processes at various stages of the trial lifecycle. These processes often involve complex behaviours such as recruiting vulnerable patient populations and clinicians having to deliver complex trial interventions successfully. Few studies have utilised a behavioural framework to assess challenges and develop strategies for effective trial recruitment and delivery of trial interventions. This study reports the application of an innovative methodological approach to understand core trial processes, namely recruitment and intervention delivery, using a behavioural science approach to develop strategies designed to mitigate trial process problems.

Methods

The UK-REBOA trial aims to evaluate the clinical and cost-effectiveness of resuscitative endovascular balloon occlusion of the aorta (a novel intervention) in injured patients with exsanguinating haemorrhage. A behavioural investigation (‘diagnosis’) was conducted using theory-informed (Theoretical Domains Framework, TDF) semi-structured interviews with site staff from the UK-REBOA trial to examine trial processes which could be improved in relation to trial recruitment and delivery of the intervention. Interviews were analysed using the TDF to identify influences on behaviour, which were then mapped to techniques for behaviour change and developed into potential solutions.

Results

The behavioural diagnosis of the challenges experienced during trial processes highlighted factors relevant to a range of TDF domains: Skills, Environmental context and resources, Beliefs about capabilities, Beliefs about consequences, Social influences, and Memory, attention, and decision-making processes. Within the solution development phase, we identified 24 suitable behaviour change techniques that were developed into proposed solutions to target reported process problems with the aim of changing behaviour to improve recruitment and/or intervention delivery. Proposed solutions included targeted changes to trial training content, suggestions to restructure the environment (e.g. reinforced the purpose of the trial with information about the social and environmental consequences) and other strategies to reduce barriers to recruitment and intervention delivery.

Conclusions

This study demonstrates the feasibility of applying a behavioural approach to investigate (‘diagnose’) behavioural trial process problems and subsequently develop and implement targeted solutions (‘treatment’) in an active trauma trial. Understanding the factors that affected behaviour, attitudes and beliefs in this trauma trial allowed us to implement theoretically informed, evidence-based solutions designed to enhance trial practices.

Trial registration

ISRCTN 16,184,981
The effect of delivery ball and warm shower on the childbirth experience of nulliparous women: a randomized controlled clinical trial
Authors: Sharifipour Parvaneh , Kheirkhah Masoomeh , Rajati Mojgan , Haghani Hamid
Published: May 2022

Introduction

Childbirth is a unique experience that affects women’s life. Midwives can play an effective role in creating positive birth experiences for women using non-pharmacological and supportive methods. Accordingly, this study aims to determine the effect of delivery balls and warm showers on childbirth experiences of primiparous women.

Methods

This clinical trial was conducted on primiparous pregnant women who referred to the Motazedi Hospital in Kermanshah, Iran. Sampling was done from eligible individuals by a continuous method, and pregnant women were assigned to the three groups of delivery balls plus warm showers or A (n = 35), delivery balls or B (n = 35), and control or C (n = 35). The use of the ball at the dilation of 4 cm was similar in the two groups of A and B, but the first group used a warm shower at the dilatation of 7 cm as well. The control group also received routine delivery care. Besides, demographic information forms consisting of the pregnancy history and some information about the mother and her infant were completed. Additionally, childbirth experience questionnaires (CEQ) were completed by the women two hours after childbirth. The analysis of intervention effects was performed as per-protocol analysis.

Results

There was a statistically significant difference in the mean score of the childbirth experience between the two groups of A and C (p = 0.001) after the intervention as well as between the groups of B and C (p = 0.001).

Conclusion

The use of delivery balls and warm showers was effective in creating a positive childbirth experience. To create a positive childbirth experience in mothers, the use of both interventions (delivery balls and warm showers) is recommended.

Trial registration

TCTR20200408002. Prospectively registered on March 21, 2020.
Recent large-scale philophthalmosis outbreak in Portugal: inefficacy of common antihelminthic agents
Authors: Heneberg Petr , Casero María
Published: May 2022

Background

Parasitic conjunctivitis caused byPhilophthalmusspp. is a common ophthalmic disease in birds, with localized outbreaks occurring worldwide. There is no consensus on treating this disease; mechanical removal is considered a standard recommendation, but is associated with disease relapses within days or weeks.

Methods

From 2015 to 2020, we examined 4295Larus michahellisandLarus fuscusgulls in southern Portugal for the presence ofPhilophthalmusspp. Due to the need to treat dozens of infected gulls in the rescue station, we tested three treatment regimens aimed at targetingPhilophthalmus lucipetusin the infected gulls: (I) the ophthalmic application of levamisole; (II) the oral application of milbemycin in combination with praziquantel; and (III) the subcutaneous application of ivermectin.

Results

The outbreak of philophthalmosis in gulls in southern Portugal has been ongoing since the first cases were reported in 2015–2016. The prevalence of philophthalmosis has fluctuated annually, peaking a maximum of 10.3% inL. fuscusin 2017 and at 2.1% inL. michahellisin 2016. The infection intensity peaked at a median of 11.5 eye-flukes per host bird inL. fuscusin 2016 and a median of six eye-flukes per host bird inL. michahellisin 2017. Nine gulls were infected with >50 eye-flukes. None of the treatment options were effective at treatingP. lucipetusinfections: the numbers of eye-flukes in the infected birds did not decrease, and the clinical signs of the disease did not change.

Conclusions

An outbreak of philophthalmosis in southern Portugal has massively affected two species of gulls in the region. Two previously suggested philophthalmosis treatments (ocular levamisole and praziquantel given orally), as well as a third mode of treatment with a previously failed compound (ivermectin administered subcutaneously) were used. However, the treatments did not affect the numbers ofP. lucipetusin the eyes of the treated gulls. Further research should address ophthalmic gel formulations or sub-conjunctival delivery mode for antihelminthic drugs that are effective againstPhilophthalmusspp. in vitro.

Graphical abstract
Assessing the diagnostic value of a potential screening tool for detecting early interstitial lung disease at the onset of inflammatory rheumatic diseases
Authors: Hoffmann Tobias , Oelzner Peter , Franz Marcus , Teichgräber Ulf , Renz Diane , Förster Martin , Böttcher Joachim , Kroegel Claus , Schulze P. Christian , Wolf Gunter , Pfeil Alexander
Published: May 2022

Background

Interstitial lung disease (ILD) is a severe pulmonary complication in inflammatory rheumatic diseases (IRD) and associated with significantly increased morbidity and mortality. That is why ILD screening at a very early stage, at the onset of IRD, is essential. The objective of the present study was to evaluate the diagnostic value and utility of a stepwise approach as a potential ILD screening tool in patients with newly diagnosed IRD.

Methods

Consecutively, 167 IRD patients were enrolled. To homogenize the study cohort, an age and gender matching was performed. The case-control study included 126 patients with new onset of IRD (mainly connective tissue diseases [CTD], small vessel vasculitis, and myositis). We applied a stepwise screening algorithm in which all patients underwent pulmonary function testing (PFT) and/or additional chest radiography. If there was at least one abnormal finding, pulmonary high-resolution computed tomography (HRCT) was subsequently performed.

Results

With our stepwise diagnostic approach, we identified 63 IRD patients with ILD (ILD group) and 63 IRD patients without ILD (non-ILD group). A reduced diffusing capacity for carbon monoxide (DLCO) < 80% showed a sensitivity of 83.6% and a specificity of 45.8% compared to chest X-ray with 64.2% and 73.6%, respectively, in detecting ILD. The combination of reduced DLCO and chest X-ray revealed a sensitivity of 95.2% and a specificity of 38.7%. The highest sensitivity (95.2%) and specificity (77.4%) were observed for the combination of reduced DLCO, chest X-ray, and pulmonary HRCT. The most common pulmonary abnormalities on HRCT were ground-glass opacities (GGO; 36.5%), followed by non-specific interstitial pneumonia (NSIP; 31.8%) and usual interstitial pneumonia (UIP; 9.5%).

Conclusions

The combination of reduced DLCO (< 80%), chest X-ray, and pulmonary HRCT yielded the highest sensitivity and specificity in detecting ILD at the onset of IRD. Therefore, this stepwise approach could be a new screening algorithm to identify IRD patients with pulmonary involvement already at the time of the initial IRD diagnosis.
Advances in the study of OSA and diabetic foot
Authors: Lin Jiayu , Song Hailing , Liang Meihong , Cai Zeqiang , Chen Tan , Lin Zhenyu , Zhang Jinying
Published: May 2022

Diabetic foot is one of the most serious and painful chronic complications of diabetic patients, especially elderly diabetic patients. It has a high rate of death, disability and amputation. Obstructive sleep apnea (OSA) is a treatable chronic sleep disorder. Existing evidence suggests that OSA may promote the development and delay the healing of diabetic foot, and continuous positive airway pressure therapy may promote the healing of ulcers. Therefore, in the multidisciplinary diagnosis and treatment of diabetes, cooperation with sleep medicine should be strengthened, and the basic and clinical research on diabetic foot combined with OSA should be strengthened, so as to reduce the amputation rate, improve the cure rate and reduce the incidence of cardiovascular events.