bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coding undiagnosed rare disease patients in health information systems: recommendations from the RD-CODE project
Authors: Angin Céline , Mazzucato Monica , Weber Stefanie , Kirch Kurt , Abdel Khalek Waed , Ali Houda , Maiella Sylvie , Olry Annie , Jannot Anne-Sophie , Rath Ana 
Published: January 2024

Abstract
Background
In European Union countries, any disease affecting less than 5 people in 10,000 is considered rare. As expertise is scarce and rare diseases (RD) are complex, RD patients can remain undiagnosed for many years. The period of searching for a diagnosis, called diagnostic delay, sometimes leads to a diagnostic dead end when the patient’s disease is impossible to diagnose after undergoing all available investigations. In recent years, extensive efforts have been made to support the implementation of ORPHA nomenclature in health information systems (HIS) so as to allow RD coding. Until recently, the nomenclature only encompassed codes for specific RD. Persons suffering from a suspected RD who could not be diagnosed even after full investigation, could not be coded with ORPHAcodes. The recognition of the RD status is necessary for patients, even if they do not have a precise diagnosis. It can facilitate reimbursement of care, be socially and psychologically empowering, and grant them access to scientific advances.

Results
The RD-CODE project aimed at making those patients identifiable in HIS in order to produce crucial epidemiological data. Undiagnosed patients were defined as patients for whom no clinically-known disorder could be confirmed by an expert center after all reasonable efforts to obtain a diagnosis according to the state-of-the-art and diagnostic capabilities available. Three recommendations for the coding of undiagnosed RD patients were produced by a multi-stakeholder panel of experts: 1/ Capture the diagnostic ascertainment for all rare disease cases; 2/ Use the newly created ORPHAcode (ORPHA:616874 “Rare disorder without a determined diagnosis after full investigation”), available in the Orphanet nomenclature: as the code is new, guidelines are essential to ensure its correct and homogeneous use for undiagnosed patients’ identification in Europe and beyond; 3/ Use additional descriptors in registries.

Conclusions
The recommendations can now be implemented in HIS (electronic health records and/or registries) and could be a game-changer for patients, clinicians and researchers in the field, enabling assessment of the RD population, including undiagnosed patients, adaptation of policy measures including financing for care and research programs, and to improved access of undiagnosed patients to research programs.
Review of published 467 achondroplasia patients: clinical and mutational spectrum
Authors: Zhang XinZhong , Jiang Shan , Zhang Rui , Guo Siyi , Sheng Qiqi , Wang Kaili , Shan Yuanyuan , Liao Lin , Dong Jianjun 
Published: January 2024

Abstract
Aim
Achondroplasia is the most common of the skeletal dysplasias that cause fatal and disabling growth and developmental disorders in children, and is caused by a mutation in the fibroblast growth factor receptor, type 3 gene(FGFR3). This study aims to analyse the clinical characteristics and gene mutations of ACH to accurately determine whether a patient has ACH and to raise public awareness of the disease.

Methods
The database of Pubmed, Cochrane Library, Wanfang and CNKI were searched with terms of “Achondroplasias” or “Skeleton-Skin-Brain Syndrome” or “Skeleton Skin Brain Syndrome” or “ACH” and “Receptor, Fibroblast Growth Factor, Type 3” or “FGFR3”.

Results
Finally, four hundred and sixty-seven patients with different FGFR3 mutations were enrolled. Of the 138 patients with available gender information, 55(55/138, 40%) were female and 83(83/138, 60%) were male. Among the patients with available family history, 47(47/385, 12%) had a family history and 338(338/385, 88%) patients were sporadic. The age of the patients ranged from newborn babies to 36 years old. The mean age of their fathers was 37 ± 7 years (range 31–53 years). Patients came from 12 countries and 2 continents, with the majority being Asian (383/432, 89%), followed by European (49/432, 11%). Short stature with shortened arms and legs was found in 112(112/112) patients, the abnormalities of macrocephaly in 94(94/112) patients, frontal bossing in 89(89/112) patients, genu valgum in 64(64/112) patients and trident hand were found in 51(51/112) patients. The most common mutation was p.Gly380Arg of the FGFR3 gene, which contained two different base changes, c.1138G > A and c.1138G > C. Ten rare pathogenic mutations were found, including c.831A > C, c.1031C > G, c.1043C > G, c.375G > T, c.1133A > G, c.1130T > G, c.833A > G, c.649A > T, c.1180A > T and c.970_971insTCTCCT.

Conclusion
ACH was caused by FGFR3 gene mutation, and c.1138G > A was the most common mutation type. This study demonstrates the feasibility of molecular genetic testing for the early detection of ACH in adolescents with short stature, trident hand, frontal bossing, macrocephaly and genu valgum.
Transpalpebral electrical stimulation for the treatment of retinitis pigmentosa: study protocol for a series of N-of-1 single-blind, randomized controlled trial
Authors: Zhou Wei , Huang Ziyang , Xu Kai , Li Yamin , Li Xiaoyu , Li Jiaxian , Jin Yu , Snellingen Torkel , Liang Lina 
Published: January 2024

Abstract
Background
Retinitis pigmentosa (RP) is an inherited disease characterized by a progressive loss of rod photoreceptors of the eye, leading to irreversible blindness. To date, to our knowledge, no clinical prospective studies have been undertaken that could document the effect of interventions that could reverse or reduce the progression of this disease. The application of microcurrent stimulation (ES) of the eye in the treatment of chronic eye diseases such as glaucoma and age-related macular degeneration has been used over several decades and has been reported to have beneficial effects to reduce the progression of these blinding diseases and has been supported by animal studies and smaller clinical studies, but to date, no large randomized clinical trials on the use of microcurrent therapy have been published. More recent clinical reports have also shown beneficial effects of ES on slowing the progression of RP but also lacks data from robust prospective clinical outcome studies. To our knowledge, this is the first prospective randomized study to evaluate the safety and clinical effectiveness of transpalpebral electrical stimulation (TpES) on the progression of RP.

Methods
Randomized prospective study using N-of-1 trial 3 single-blind, crossover comparisons. The intervention period of each comparison is divided into treatment period and control period which are randomized arranged. Twelve participants will be strictly recruited in N-of-1 trial by the researcher in accordance with the inclusion and exclusion criteria. The main outcome of interest examined after each cycle of the 8-week intervention period is the assessment of the visual field (VF). Other variables of interest are best corrected visual acuity (BCVA), retinal function using electroretinogram (ERG), and visual function using NEI VFQ-25 questionnaire. Objective assessments of retinal changes will be undertaken using optical coherence tomography (OCT) and fundus autofluorescence (FAF).

Discussion
The trial will evaluate the efficacy and safety of microcurrent stimulation on RP and provide high-quality evidence for clinical application through N-of-1 trial.

Trial registration
Chinese Clinical Trial Registry; ChiCTR2300067357; https://www.chictr.org.cn/showproj.html?proj=174635. Registered on 5 January 2023
Associate Principal Investigators and the HEAL-COVID trial: good for trainees, good for trials
Authors: Newman Joseph , Wild Philip ,   HEAL-COVID Collaboration, Summers Charlotte , Toshner Mark 
Published: January 2024

Abstract
Background
The NIHR’s Associate Principal Investigator (API) Scheme in the United Kingdom was expanded nationally in 2020 with the aim of training clinicians to become Principal Investigators for clinical research in the future. The HEAL-COVID adaptive platform trial is an urgent public health study registered with the API Scheme. Within eighteen months of opening, the trial had recruited almost 1200 patients with over 100 active sites. Here we describe our experiences of APIs working on the trial with two broad objectives. Firstly, we aim to explore through qualitative methods the impact that the scheme has had on the APIs’ professional development. Secondly, we aim to quantify the impact that the APIs have had on the recruitment of patients into the trial.

Methods
The professional backgrounds of the APIs are described from data from their application forms to the scheme. The HEAL-COVID API Network is described from records of the monthly meetings. The APIs’ experiences are reviewed from data from the NIHR exit surveys at 6 months and from a reflective practice exercise at the final network meeting. Data of patient recruitment to HEAL-COVID was analysed for centres with and without APIs via a multivariate analysis.

Results
Forty-two APIs were registered with the HEAL-COVID trial with a diversity of backgrounds in terms of gender, country, profession, grade and specialty. Eleven monthly network meetings took place with the dual objectives of facilitating trial activity and providing educational content. Fourteen APIs completed the NIHR survey with all reporting Good Clinical Practice completion, local promotional activity of the trial, patient recruitment and support from their respective PI. Sites with at least one API recruited over 3.5 times more patients than sites without an API (medians 4 vs 14.5, p < 0.05), independent of factors including type of hospital or number of inpatient beds.

Discussion
This study adds to the growing literature that the NIHR’s API Scheme is effective in meeting its objectives in providing research training to clinicians, thus building a workforce of future clinical researchers. Moreover, data from the HEAL-COVID trial shows that sites with an API are associated with higher recruitment. Overall, registering a trial with the API Scheme not only trains future clinical researchers, but it is also likely to increase the number of patients recruited (amongst other benefits), increasing the efficiency of trials and improving access for patients.
Development of chromatographic methods to determine multivitamins formulation depending on their solubility and polarity: comparative study using three greenness assessment tools
Authors: Galal Sara Abdel Basset , Elzanfaly Eman Saad , Hussien Emad Mohamed , Amer Enas Abdel Hakim , Zaazaa Hala Elsayed 
Published: January 2024

AbstractHigh performance liquid chromatography is one of the techniques of choice for the separation and quantitative determination of drugs in mixture form. Ipriflavone, ascorbic acid, pyridoxine, vitamin D3, and lysine are formulated together as an adjuvant combination in osteoporosis. In this work, we developed and validated two complementary high performance liquid chromatographic methods to determine the five compounds in their pharmaceutical dosage form. The first method (method A) was capable of determining ipriflavone, ascorbic acid, pyridoxine, and vitamin D3 in their bulk and combined pharmaceutical formulation. The method is based on Liquid Chromatographic separation with UV detection at 254 nm using Agilent Eclipse XDB-C18 column with a mobile phase consisting of 25 mM ammonium acetate buffer (pH 4.2): methanol in gradient mode. Due to the high polarity of lysine, it was difficult to achieve satisfactory retention on reversed phase columns. So, we separated it on a strong cation exchange column (Exsil 100 SCX) without derivatization with a mobile phase consisting of 10 mM sodium dihydrogen phosphate and 200 mM sodium chloride (pH 6) with UV detection at 210 nm (method B). Validation of the proposed methods was performed according to ICH guidelines Q2(R1). The proposed methods proved to be valid for selective analysis of the stated drugs in their bulk and combined pharmaceutical formulation. Greenness assessment of the developed methods was evaluated using three assessment tools: ESA, GAPI and the most recently developed tool AGREE, showing a satisfactory comprehensive guide of the greenness of the developed methods.
Chromatographic analysis of triple cough therapy; bromhexine, guaiafenesin and salbutamol and pharmaceutical impurity: in-silico toxicity profile of drug impurity
Authors: Sharkawi Marco M. Z. , Safwat Mark T. , Abdelaleem Eglal A. , Abdelwahab Nada S. 
Published: January 2024

AbstractBromhexine (BR), guaiafenesin (GUF) and salbutamol (SAL) are formulated as Ventocough syrup® (with and without sugar), labeled to contain propyl paraben and sodium benzoate as inactive ingredients. They are used to make coughing more productive and easier. A crucial element and a major issue in the pharmaceutical industry is the control of organic related impurities to obtain safe and effective treatment. Guaiacol (GUL) is reported to be GUF related impurity that was proved to be extremely toxic (toxic rating class 5), and its use should be banned. In this work, In-Silico study and ADMET estimation were conducted to predict GUL pharmacokinetic properties and its toxicity profile. Additionally, two chromatographic methods were conducted to analyze the studied components along with GUF impurity in the presence of the labeled dosage form excipients. The In-Silico study assured that GUL has oral rat acute toxicity and it is considered to be skin sensitizer. On the other hand, the developed TLC- densitometeric method depended on using a mobile phase mixture of hexane: methylene chloride: triethylamine (5.0:6.0:0.3, by volume) as a developing system. UV-Scanning was performed immediately at 275 nm for SAL, GUF and GUL, while scanning at 310 nm was used for scanning BR. Linearity was established in the ranges of 0.25–4.0, 0.25–4.0, 0.5–8.0 and 0.1–1.6 µg/band for BR, SAL, GUF and GUL, respectively. In the developed HPLC method, separation was performed on X-Bridge® C18 column (250 × 4.6 mm, 5 μm) using a solvent mixture of 0.05M disodium hydrogen phosphate pH 3 with aqueous phosphoric acid: methanol (containing 0.3%, v/v triethylamine) (40:60, v/v). Detection was done at 225 nm and separation was achieved within 10 min. Linearity was proved in the range of 2–50 µg/mL for the proposed drugs. Validation of the developed methods was done and all the calculated parameters were within the acceptable limits recommended by ICH guidelines. After that, methods were used to examine the potency of the selected marketed dosage forms and concentrations of all drugs were within the acceptable limits. Additionally, complete separation between the studied drugs and the additives were observed. The developed methods can be used during routine quality control analysis of the proposed drugs when the required issues concern on sensitivity, selectivity and analysis time.
Graphical Abstract
A nonhuman primate model with Alzheimer’s disease-like pathology induced by hippocampal overexpression of human tau
Authors: Jiang Zhouquan , Wang Jing , Qin Yongpeng , Liu Shanggong , Luo Bin , Bai Fan , Wei Huiyi , Zhang Shaojuan , Wei Junjie , Ding Guoyu , Ma Long , He Shu , Chen Rongjie , Sun Ying , Chen Yi , Wang Lu , Xu Hao , Wang Xiangyu , Chen Gong , Lei Wenliang 
Published: January 2024

Abstract
Background
Alzheimer’s disease (AD) is one of the most burdening diseases of the century with no disease-modifying treatment at this time. Nonhuman primates (NHPs) share genetic, anatomical, and physiological similarities with humans, making them ideal model animals for investigating the pathogenesis of AD and potential therapies. However, the use of NHPs in AD research has been hindered by the paucity of AD monkey models due to their long generation time, ethical considerations, and technical challenges in genetically modifying monkeys.

Methods
Here, we developed an AD-like NHP model by overexpressing human tau in the bilateral hippocampi of adult rhesus macaque monkeys. We evaluated the pathological features of these monkeys with immunostaining, Nissl staining, cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), positron emission tomography (PET), and behavioural tests.

Results
We demonstrated that after hippocampal overexpression of tau protein, these monkeys displayed multiple pathological features of AD, including 3-repeat (3R)/4-repeat (4R) tau accumulation, tau hyperphosphorylation, tau propagation, neuronal loss, hippocampal atrophy, neuroinflammation, Aβ clearance deficits, blood vessel damage, and cognitive decline. More interestingly, the accumulation of both 3R and 4R tau is specific to NHPs but not found in adult rodents.

Conclusions
This work establishes a tau-induced AD-like NHP model with many key pathological and behavioural features of AD. In addition, our model may potentially become one of the AD NHP models adopted by researchers worldwide since it can be generated within 2 ~ 3 months through a single injection of AAVs into the monkey brains. Hence, our model NHPs may facilitate mechanistic studies and therapeutic treatments for AD.
Treatment strategy for heart failure complicated with complete left bundle branch block and atrial tachycardia: a case report
Authors: Wang Jian , Zhang Qing-Qing , Lin Jie , Yuan Wei , Wang Li-Chun , Wu Yu-Cheng 
Published: January 2024

Abstract
Background
For patients with heart failure combined with complete left bundle branch block, cardiac resynchronization therapy is an important therapeutic method. If these patients also have atrial tachycardia, how to choose a treatment strategy deserves discussion.

Case presentation
A Chinese woman in her early 70s was admitted due to recurrent episodes of chest distress and asthma for 1 year. Physical and laboratory examinations showed filling of the jugular vein, lung rales, left enlargement of the heart boundary, edema of the lower limbs and elevation of N-terminal pro b-type natriuretic peptide. An electrocardiogram showed atrial tachycardia and a left bundle branch block. An echocardiography revealed enlargement of the left ventricle and left ventricular systolic dysfunction. After obtaining informed consent, the treatment strategy decided upon by the team was to use biventricular cardiac resynchronization therapy treatment and to not intervene for the atrial tachycardia, with left bundle branch area pacing as a backup. Due to twisted and narrow coronary vein branches, traditional biventricular pacing failed, and then, left bundle branch area pacing was attempted successfully. A follow-up echocardiography at 1 year showed improved systolic function. The outcomes for this patient are favorable, but the choice of interventional strategy is worthy of discussion in this case.

Conclusion
For patients with heart failure combined with left bundle branch block and atrial tachycardia, left bundle branch area pacing can replace traditional biventricular pacing for cardiac resynchronization therapy treatment, and the therapeutic effect is significant. However, multiple factors need to be considered when formulating strategies, including whether there is bundle branch block under sinus rhythm, the success and recurrence rate of atrial tachycardia ablation, the response of cardiac resynchronization therapy, the costs of different strategies, and instrument implantation issues.
Impact of direct ICU admission of pneumococcal meningitis in France: a retrospective analysis of a French medico-administrative (PMSI) database
Authors: Thy Michael , Dupuis Claire , Mageau Arthur , Mourvillier Bruno , Bouadma Lila , Ruckly Stéphane , Perozziello Anne , Strukov Andrey , Van-Gysel Damien , de Montmollin Etienne , Sonneville Romain , Timsit Jean-François 
Published: January 2024

Abstract
Background
Current guidelines for adult patients with pneumococcal meningitis (PM) recommend initial management in intermediate or intensive care units (ICU), but evidence to support these recommendations is limited. We aimed to describe ICU admission practices of patients with PM.

Methods
We conducted a retrospective analysis of the French medico administrative database of consecutive adult patients with PM and sepsis criteria hospitalized between 2011 and 2020. We defined two groups, “Direct ICU” corresponding to a direct ICU admission and “Delayed ICU” corresponding to a secondary ICU admission.

Results
We identified 4052 patients hospitalized for a first episode of PM, including 2006 “Direct ICU” patients (50%) and 2046 “delayed ICU” patients (50%). The patients were mainly males [n = 2260 (56%)] with median age of 61 years [IQR 50–71] and a median Charlson index of 1 [0–3]. Among them, median SAPS II on admission was 46 [33–62], 2173 (54%) had a neurological failure on admission with 2133 (53%) in coma, 654 (16%) with brainstem failure, 488 (12%) with seizures and 779 (19%) with focal signs without coma. PM was frequently associated with pneumonia [n = 1411 (35%)], and less frequently with endocarditis [n = 317 (8%)]. The median ICU length of stay and hospital length of stay were 6 days [2–14] and 21 days [13–38], respectively. In-hospital mortality was 27% (n = 1100) and 640 (16%) patients were secondarily transferred to rehabilitation care unit. Direct ICU group was significantly more severe but after adjustment for age, sex, comorbidities, organ failures on admission and admission from home, direct ICU admission was significantly associated with a lower mortality (Odds ratio 0.67 [0.56–0.80], p < 0.01). This corresponded to one death avoided for 11 PM directly admitted in ICU.

Conclusions
Among patients with PM and sepsis, direct ICU admission was associated with lower mortality rates when compared to delayed admission.
How to improve the structural stabilities of halide perovskite quantum dots: review of various strategies to enhance the structural stabilities of halide perovskite quantum dots
Authors: Kim Dokyum , Yun Taesun , An Sangmin , Lee Chang-Lyoul 
Published: January 2024

AbstractHalide perovskites have emerged as promising materials for various optoelectronic devices because of their excellent optical and electrical properties. In particular, halide perovskite quantum dots (PQDs) have garnered considerable attention as emissive materials for light-emitting diodes (LEDs) because of their higher color purities and photoluminescence quantum yields compared to conventional inorganic quantum dots (CdSe, ZnSe, ZnS, etc.). However, PQDs exhibit poor structural stabilities in response to external stimuli (moisture, heat, etc.) owing to their inherent ionic nature. This review presents recent research trends and insights into improving the structural stabilities of PQDs. In addition, the origins of the poor structural stabilities of PQDs and various methods to overcome this drawback are discussed. The structural degradation of PQDs is mainly caused by two mechanisms: (1) defect formation on the surface of the PQDs by ligand dissociation (i.e., detachment of weakly bound ligands from the surface of PQDs), and (2) vacancy formation by halide migration in the lattices of the PQDs due to the low migration energy of halide ions. The structural stabilities of PQDs can be improved through four methods: (1) ligand modification, (2) core–shell structure, (3) crosslinking, and (4) metal doping, all of which are presented in detail herein. This review provides a comprehensive understanding of the structural stabilities and opto-electrical properties of PQDs and is expected to contribute to future research on improving the device performance of perovskite quantum dot LEDs (PeLEDs).