bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inadequate reporting quality of registered genome editing trials: an observational study
Authors: Jurić Diana , Zlatin Michael , Marušić Ana 
Published: May 2022

Abstract
Background
To assess registration completeness and safety data of trials on human genome editing (HGE) reported in primary registries and published in journals, as HGE has safety and ethical problems, including the risk of undesirable and unpredictable outcomes. Registration transparency has not been evaluated for clinical trials using these novel and revolutionary techniques in human participants.

Methods
Observational study of trials involving engineered site-specific nucleases and long-term follow-up observations, identified from the WHO ICTRP HGE Registry in November 2020 and two comprehensive reviews published in the same year. Registration and adverse events (AEs) information were collected from public registries and matching publications. Published data were extracted in May 2021.

Results
Among 81 eligible trials, most were recruiting (51.9%) phase 1 trials (45.7%). Five trials were withdrawn. Most trials investigated CAR T cells therapies (45.7%) and used CRISPR/Cas9 (35.8%) ex vivo (88.9%). Among 12 trials with protocols both registered and published, eligibility criteria, sample size, and secondary outcome measures were consistently reported for less than a half. Three trials posted results in ClinicalTrials.gov, and one reported serious AEs.

Conclusions
Incomplete registration and published data give emphasis to the need to increase the transparency of HGE trials. Further improvements in registration requirements, including phase 1 trials, and a more controlled publication procedure, are needed to augment the implementation of this promising technology.
A tutorial on the case time series design for small-area analysis
Authors: Gasparrini Antonio 
Published: May 2022

Abstract
Background
The increased availability of data on health outcomes and risk factors collected at fine geographical resolution is one of the main reasons for the rising popularity of epidemiological analyses conducted at small-area level. However, this rich data setting poses important methodological issues related to modelling complexities and computational demands, as well as the linkage and harmonisation of data collected at different geographical levels.

Methods
This tutorial illustrated the extension of the case time series design, originally proposed for individual-level analyses on short-term associations with time-varying exposures, for applications using data aggregated over small geographical areas. The case time series design embeds the longitudinal structure of time series data within the self-matched framework of case-only methods, offering a flexible and highly adaptable analytical tool. The methodology is well suited for modelling complex temporal relationships, and it provides an efficient computational scheme for large datasets including longitudinal measurements collected at a fine geographical level.

Results
The application of the case time series for small-area analyses is demonstrated using a real-data case study to assess the mortality risks associated with high temperature in the summers of 2006 and 2013 in London, UK. The example makes use of information on individual deaths, temperature, and socio-economic characteristics collected at different geographical levels. The tutorial describes the various steps of the analysis, namely the definition of the case time series structure and the linkage of the data, as well as the estimation of the risk associations and the assessment of vulnerability differences. R code and data are made available to fully reproduce the results and the graphical descriptions.

Conclusions
The extension of the case time series for small-area analysis offers a valuable analytical tool that combines modelling flexibility and computational efficiency. The increasing availability of data collected at fine geographical scales provides opportunities for its application to address a wide range of epidemiological questions.
Evaluation of elevated liver values in primary care - a series of studies on the status quo of care in Germany with special reference to alcoholic liver disease
Authors: Wangler Julian , Jansky Michael 
Published: May 2022

Abstract
Background
In primary care, elevated liver values often appear as incidental findings. As well considering the presenting symptoms, key factors in effective diagnosis are which liver values to include as indicators and when to refer patients for further diagnostics. It is also important that there is coordinated collaboration between GPs and specialists. There has hitherto been a lack of reliable findings on the status quo regarding the evaluation of (abnormally) elevated liver values in primary care.

Methods
Between 2017 and 2021, four written explorative surveys of GPs and gastroenterological specialists were conducted in various German states, aimed at taking stock of the current status of GP-based diagnostics of (abnormally) elevated liver values. In addition, interviews were conducted with 14 GPs and gastroenterological specialists. This review article discusses the overall findings of the series of studies in a condensed manner at a higher level. The article aims to derive starting points for optimising the diagnosis of liver cirrhosis in primary care.

Results
There are various challenges and problems associated with the evaluation of elevated liver values. For example, GPs draw on very different laboratory parameters, which are combined in different clusters. When elevated liver values are found, a majority of GPs prefer a controlled wait-and-see period, but often make use of direct referrals to specialists due to diagnostic uncertainties. GPs report interface problems with gastroenterological specialists, which are associated, among other things, with the preliminary evaluation that has been made and the timing of referral. Both GPs and specialists consider the introduction of an evidence-based diagnostic algorithm to be an important starting point for improving early detection and better coordination between healthcare levels.

Conclusions
Efforts should be made to contribute to greater professionalisation and standardisation of primary care diagnostics and to better structure the interaction with gastroenterological specialists. These include a wider range of training formats, the development of a validated diagnostic pathway and the mandating of a liver function test as part of the check-up. The development of a GP-based guideline for managing elevated liver values also seems advisable.
Two-megahertz impedance index prediction equation for appendicular lean mass in Korean older people
Authors: Kim Hyeoijin , Song Keon-Hyoung , Ambegaonkar Jatin P. , Chung Sochung , Jeon Kwonchan , Jiang Fang Lin , Eom Jin Jong , Kim Chul-Hyun 
Published: May 2022

Abstract
Background
Whole-body bioelectrical impedance analysis (BIA) has been accepted as an indirect method to estimate appendicular lean mass (ALM) comparable to dual-energy X-ray absorptiometry (DXA). However, single or limited frequencies currently used for these estimates may over or under-estimate ALM. Accordingly, there is a need to measure the impedance parameter with appendicular lean-specific across multiple frequencies to more accurately estimate ALM. We aimed to validate muscle-specific frequency BIA equation for ALM using multifrequency BIA (MF-BIA) with DXA as the reference.

Methods
195 community-dwelling Korean older people (94 men and 101 women) aged 70 ~ 92y participated in this study. ALM was measured by DXA and bioimpedance measures at frequencies of 5 kHz ~ 3 MHz were assessed for independent predictive variables. Regression analyses were used to find limb-specific frequencies of bioimpedance, to develop the ALM equations and to conduct the internal cross-validation. The six published equations and the final equation of MF-BIA were externally cross-validated.

Results
195 participants completed the measurements of MF-BIA and DXA. Using bivariate regression analysis, the 2 MHz impedance index explained R2 = 91.5% of variability (P < 0.001) in ALM and predictive accuracy of standard error of estimate (SEE) was 1.0822 kg ALM (P < 0.001). Multiple stepwise regression analysis obtained in the development group had an adjusted R2 of 9.28% (P < 0.001) and a SEE of 0.97 kg ALM. The cross-validation group had no significant difference between the measured ALM and the predicted ALM (17.8 ± 3.9 kg vs. 17.7 ± 3.8 kg, P = .486) with 93.1% of R2 (P < 0.001) and 1.00 kg ALM of total error. The final regression equation was as follows: ALM = 0.247ZI@2 MHz + 1.254SEXM1F0 + 0.067Xc@5 kHz + 1.739 with 93% of R2 (P < 0.001), 0.97 kg ALM of SEE (Subjective Rating as “excellent” for men and “very good” for women). In the analysis of the diagnostic level for sarcopenia of the final regression, the overall agreement was 94.9% (k = 0.779, P < 0.001) with 71.4% of sensitivity, 98.8% of specificity, 91.3 of positive prediction value and 95.3% of negative prediction value.

Conclusion
The newly developed appendicular lean-specific high-frequency BIA prediction equation has a high predictive accuracy, sensitivity, specificity, and agreement for both individual and group measurements. Thus, the high-frequency BIA prediction equation is suitable not only for epidemiological studies, but also for the diagnosis of sarcopenia in clinical settings.
How to implement geriatric co-management in your hospital? Insights from the G-COACH feasibility study
Authors: Van Grootven Bastiaan , Jeuris Anthony , Jonckers Maren , Devriendt Els , Dierckx de Casterlé Bernadette , Dubois Christophe , Fagard Katleen , Herregods Marie-Christine , Hornikx Miek , Meuris Bart , Rex Steffen , Tournoy Jos , Milisen Koen , Flamaing Johan , Deschodt Mieke 
Published: May 2022

Abstract
Background
Geriatric co-management is advocated to manage frail patients in the hospital, but there is no guidance on how to implement such programmes in practice. This paper reports our experiences with implementing the ‘Geriatric CO-mAnagement for Cardiology patients in the Hospital’ (G-COACH) programme. We investigated if G-COACH was feasible to perform after the initial adoption, investigated how well the implementation strategy was able to achieve the implementation targets, determined how patients experienced receiving G-COACH, and determined how healthcare professionals experienced the implementation of G-COACH.

Methods
A feasibility study of the G-COACH programme was performed using a one-group experimental study design. G-COACH was previously implemented on two cardiac care units. Patients and healthcare professionals participating in the G-COACH programme were recruited for this evaluation. The feasibility of the programme was investigated by observing the reach, fidelity and dose using registrations in the electronic patient record and by interviewing patients. The success of the implementation reaching its targets was evaluated using a survey that was completed by 48 healthcare professionals. The experiences of 111 patients were recorded during structured survey interviews. The experiences of healthcare professionals with the implementation process was recorded during 6 semi-structured interviews and 4 focus groups discussions (n = 27).

Results
The programme reached 91% in a sample of 151 patients with a mean age of 84 years. There was a high fidelity for the major components of the programme: documentation of geriatric risks (98%), co-management by specialist geriatrics nurse (95%), early rehabilitation (80%), and early discharge planning (74%), except for co-management by the geriatrician (32%). Both patients and healthcare professionals rated G-COACH as acceptable (95 and 94%) and feasible (96 and 74%). The healthcare professionals experienced staffing, competing roles and tasks of the geriatrics nurse and leadership support as important determinants for implementation.

Conclusions
The implementation strategy resulted in the successful initiation of the G-COACH programme. G-COACH was perceived as acceptable and feasible. Fidelity was influenced by context factors. Further investigation of the sustainability of the programme is needed.

Trial registration
ISRCTN22096382 (21/05/2020).
Paraneoplastic cerebellar degeneration with anti-Yo antibodies and an associated submandibular gland tumor: a case report
Authors: Imai Takeshi , Shinohara Kensuke , Uchino Kenji , Okuma Hirohisa , Maki Futaba , Hiruma Kiyoshi , Ariizumi Yasushi , Yamano Yoshihisa 
Published: May 2022

Abstract
Background
As a debilitating syndrome, paraneoplastic cerebellar degeneration (PCD) remains challenging to treat. Further, anti-Yo antibody (directed against human cerebellar degeneration-related protein 2) detection in patients with PCD is associated with unsatisfactory responses to existing therapies. Here, we present the case of a 60-year-old woman who developed PCD with anti-Yo antibodies and a submandibular gland tumor.

Case presentation
A 60-year-old woman presented with a 5-day history of unsteadiness of gait and inadequate coordination of her extremities, along with truncal instability. Although walking without aid was possible, dysmetria of all four limbs, trunk, and gait ataxia was observed. While routine biochemical and hematological examinations were normal, the patient’s blood was positive for anti-Yo antibodies. When the neurological symptoms deteriorated despite administration of intravenous methylprednisolone, fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) images with contrast enhancement were performed, which showed a tumor in the left submaxillary gland. She underwent total left submandibular gland resection, including the tumor; histological and immunohistochemical results revealed a salivary duct carcinoma. She was administered intravenous methylprednisolone, followed by 10 plasma exchange sessions, intravenous immunoglobulins, and cyclophosphamide therapy. Following treatment, her symptoms were not alleviated, even after the reduction of anti-Yo titers.

Conclusions
Although tumor detection was delayed, early tumor detection, diagnosis, and PCD treatment are essential because any delay can result in the progression of the disorder and irreversible neurological damage. Therefore, we recommend that the possibility of a salivary gland tumor should be considered, and whole-body dual-modality CT, including the head and neck, and FDG-PET should be performed at the earliest for patients with well-characterized paraneoplastic antibodies when conventional imaging fails to identify a tumor.
Characteristics of disease progression and genetic correlation in ambulatory Iranian boys with Duchenne muscular dystrophy
Authors: Zamani Gholamreza , Hosseinpour Sareh , Ashrafi Mahmoud Reza , Mohammadi Mahmoud , Badv Reza Shervin , Tavasoli Ali Reza , Akbari Masood Ghahvechi , Bereshneh Ali Hosseini , Malamiri Reza Azizi , Heidari Morteza 
Published: May 2022

Abstract
Background
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in the pediatric population. The manifestations of this disease include progressive muscle weakness, gait dysfunction, and motor impairment, leading to a loss of ambulation by the age of 13 years. Molecular diagnosis is the standard diagnostic tool for DMD. This study aimed to investigate disease progression and genetic patterns in Iranian ambulant boys and to find the correlation between genotypes and motor function phenotypes.

Methods
This study was performed on 152 DMD patients. Clinical history, including the disease phenotype, steroid therapy, and the North Star Ambulatory Assessment (NSAA) score, was taken for all the patients. Molecular diagnoses were confirmed by multiplex ligation-dependent probe amplification and next-generation sequencing tests.

Results
A total of 152 Iranian DMD patients were examined in this study. The mean age at the time of disease onset was 4.04 ± 2.00 years, and the mean age at diagnosis was 5.05 ± 2.08 years. The mean age of ambulation loss was 10.9 years. Contracture was reported in 38.9% of cases. In terms of age, the mean total NSAA score showed a peak at 4 years of age, with a mean NSAA score of 24. Annual changes in the NSAA score were determined for all cases, based on the mutation type and exon site. Deletion mutation was found in 79.1% of cases, duplication in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon deletion was exon 44 (5.3%), and the most common multiexon deletions were attributed to exons 45–50 and exons 45–52 (4.6%). The results did not indicate any correlation between the mutation type and age at the time of disease onset, loss of ambulation age, and wheelchair dependence; however, a significant association was found between contracture and mutation type. The results showed a significant difference in the NSAA score between the deletion and nonsense groups at the age of 3 years (P = 0.04). No significant correlation was found between the phenotype and exon site. Overall, 91.1% of the study population had a history of corticosteroid use, and 54.1% showed compliance with rehabilitation therapy.

Conclusion
This study demonstrated the phenotypes and mutational features of Iranian DMD boys and provided information regarding the natural motor history of the disease, disease progression, diagnosis, and status of DMD management in Iran. The present findings can promote the development of clinical trials and future advanced molecular therapies in Iran.
Cerebral venous sinus thrombosis and dural arteriovenous fistula associated with protein S deficiency: a case series study
Authors: Liang Hui , Xu Congjie , Xu Jiyi 
Published: May 2022

Abstract
Objective
To describe the characteristics of patients with cerebral venous sinus thrombosis (CVST) and dural arteriovenous fistula (AVF) associated with protein S (PS) deficiency.

Methods
We conducted a search of medical records in Hainan General Hospital from January 2000 to December 2020 for coexistence of CVST and dural AVF associated with PS deficiency and searched PubMed、Embase and Chinese biomedical databases (CBM) for all literature describing CVST and dural AVF with PS. We analyzed clinical characteristics, location, sequence of CVST and dural AVF, level of PS, therapeutic methods and prognosis.

Results
We presented 1 patient in our hospital’s database combined CVST and dural AVF associated with PS, plus 5 cases reported in literature. The most common symptoms were headache, generalized seizure, disturbance of consciousness. The most frequent location of CVST was at internal cerebral vein, while transverse sinus, sigmoid sinus, parietal region in dural AVF. Two patients developed dural AVF several months or years after CVST. Clinical characteristics and level of PS were summarized.

Conclusion
These findings alert physicians to consider PS deficiency in patients who suffer from CVST, especially those combined with dural AVF.
Evolution of patterns of care for women with cervical cancer in Morocco over a decade
Authors: Benider Abdellatif , Bendahhou Karima , Sauvaget Catherine , Mrabti Hind , Selmouni Farida , Muwonge Richard , Alaoui Leila , Lucas Eric , Chami Youssef , Abousselham Loubna , Bennani Maria , Errihani Hassan , Sankaranarayanan Rengaswamy , Bekkali Rachid , Basu Partha 
Published: May 2022

Abstract
Background
We conducted a Pattern-of-care (POC) study at two premier-most public-funded oncology centers in Morocco to evaluate delays in care continuum and adherence to internationally accepted treatment guidelines of cervical cancer.

Method
Following a systematic sampling method, cervical cancer patients registered at Centre Mohammed VI (Casablanca) and Institut National d’Oncologie (Rabat) during 2 months of every year from 2008 to 2017, were included in this retrospective study. Relevant information was abstracted from the medical records.

Results
A total of 886 patients was included in the analysis; 59.5% were at stage I/II. No appreciable change in stage distribution was observed over time. Median access and treatment delays were 5.0 months and 2.3 months, respectively without any significant temporal change. Concurrent chemotherapy was administered to 57.7% of the patients receiving radiotherapy. Surgery was performed on 81.2 and 34.8% of stage I and II patients, respectively. A very high proportion (85.7%) of operated patients received post-operative radiation therapy. Median interval between surgery and initiation of radiotherapy was 3.1 months. Only 45.3% of the patients treated with external beam radiation received brachytherapy. Radiotherapy was completed within 10 weeks in 77.4% patients. An overall 5-year disease-free survival (DFS) was observed in 57.5% of the patients – ranging from 66.1% for stage I to 31.1% for stage IV. Addition of brachytherapy to radiation significantly improved survival at all stages. The study has the usual limitations of retrospective record-based studies, which is data incompleteness.

Conclusion
Delays in care continuum need to be further reduced. Increased use of chemoradiation and brachytherapy will improve survival further.
Dual targeting of FGFR3 and ERBB3 enhances the efficacy of FGFR inhibitors in FGFR3 fusion-driven bladder cancer
Authors: Weickhardt Andrew J. , Lau David K. , Hodgson-Garms Margeaux , Lavis Austen , Jenkins Laura J. , Vukelic Natalia , Ioannidis Paul , Luk Ian Y. , Mariadason John M. 
Published: May 2022

Abstract
Background
Mutations and fusions in Fibroblast Growth Factor Receptor 3 (FGFR3) occur in 10–20% of metastatic urothelial carcinomas and confer sensitivity to FGFR inhibitors. However, responses to these agents are often short-lived due to the development of acquired resistance. The objective of this study was to identify mechanisms of resistance to FGFR inhibitors in two previously uncharacterised bladder cancer cell lines harbouring FGFR3 fusions and assess rational combination therapies to enhance sensitivity to these agents.

Methods
Acquired resistance to FGFR inhibitors was generated in two FGFR3 fusion harbouring cell lines, SW780 (FGFR3-BAIAP2L1 fusion) and RT4 (FGFR3-TACC3 fusion), by long-term exposure to the FGFR inhibitor BGJ398. Changes in levels of receptor tyrosine kinases were assessed by phospho-RTK arrays and immunoblotting. Changes in cell viability and proliferation were assessed by the Cell-Titre Glo assay and by propidium iodide staining and FACS analysis.

Results
Long term treatment of FGFR3-fusion harbouring SW780 and RT4 bladder cancer cell lines with the FGFR inhibitor BGJ398 resulted in the establishment of resistant clones. These clones were cross-resistant to the clinically approved FGFR inhibitor erdafitinib and the covalently binding irreversible FGFR inhibitor TAS-120, but remained sensitive to the MEK inhibitor trametinib, indicating resistance is mediated by alternate activation of MAPK signalling. The FGFR inhibitor-resistant SW780 and RT4 lines displayed increased expression of pERBB3, and strikingly, combination treatment with an FGFR inhibitor and the ATP-competitive pan-ERBB inhibitor AZD8931 overcame this resistance. Notably, rapid induction of pERBB3 and reactivation of pERK also occurred in parental FGFR3 fusion-driven lines within 24 h of FGFR inhibitor treatment, and combination treatment with an FGFR inhibitor and AZD8931 delayed the reactivation of pERBB3 and pERK and synergistically inhibited cell proliferation.

Conclusions
We demonstrate that increased expression of pERBB3 is a key mechanism of adaptive resistance to FGFR inhibitors in FGFR3-fusion driven bladder cancers, and that this also occurs rapidly following FGFR inhibitor treatment. Our findings demonstrate that resistance can be overcome by combination treatment with a pan-ERBB inhibitor and suggest that upfront combination treatment with FGFR and pan-ERBB inhibitors warrants further investigation for FGFR3-fusion harbouring bladder cancers.