bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypic characterization of X-linked hypophosphatemia in pediatric Spanish population
Authors: Rodríguez-Rubio Enrique , Gil-Peña Helena , Chocron Sara , Madariaga Leire , de la Cerda-Ojeda Francisco , Fernández-Fernández Marta , de Lucas-Collantes Carmen , Gil Marta , Luis-Yanes María Isabel , Vergara Inés , González-Rodríguez Juan David , Ferrando Susana , Antón-Gamero Montserrat , Carrasco Hidalgo-Barquero Marta , Fernández-Escribano Angustias , Fernández-Maseda Mº Ángeles , Espinosa Laura , Oliet Aniana , Vicente Antonio , Ariceta Gema , Santos Fernando ,   RenalTubeGroup
Published: February 2021

Abstract
Background
X-linked hypophosphatemia (XLH) is a hereditary rare disease caused by loss-of-function mutations in PHEX gene leading tohypophosphatemia and high renal loss of phosphate. Rickets and growth retardation are the major manifestations of XLH in children, but there is a broad phenotypic variability. Few publications have reported large series of patients. Current data on the clinical spectrum of the disease, the correlation with the underlying gene mutations, and the long-term outcome of patients on conventional treatment are needed, particularly because of the recent availability of new specific medications to treat XLH.

Results
The RenalTube database was used to retrospectively analyze 48 Spanish patients (15 men) from 39 different families, ranging from 3 months to 8 years and 2 months of age at the time of diagnosis (median age of 2.0 years), and with XLH confirmed by genetic analysis. Bone deformities, radiological signs of active rickets and growth retardation were the most common findings at diagnosis. Mean (± SEM) height was − 1.89 ± 0.19 SDS and 55% (22/40) of patients had height SDS below—2. All cases had hypophosphatemia, serum phosphate being − 2.81 ± 0.11 SDS. Clinical manifestations and severity of the disease were similar in both genders. No genotype—phenotype correlation was found. Conventional treatment did not attenuate growth retardation after a median follow up of 7.42 years (IQR = 11.26; n = 26 patients) and failed to normalize serum concentrations of phosphate. Eleven patients had mild hyperparathyroidism and 8 patients nephrocalcinosis.

Conclusions
This study shows that growth retardation and rickets were the most prevalent clinical manifestations at diagnosis in a large series of Spanish pediatric patients with XLH confirmed by mutations in the PHEX gene. Traditional treatment with phosphate and vitamin D supplements did not improve height or corrected hypophosphatemia and was associated with a risk of hyperparathyroidism and nephrocalcinosis. The severity of the disease was similar in males and females.
Impact of single and combined rare diseases on adult inpatient outcomes: a retrospective, cross-sectional study of a large inpatient population
Authors: Blazsik Reka Maria , Beeler Patrick Emanuel , Tarcak Karol , Cheetham Marcus , von Wyl Viktor , Dressel Holger 
Published: February 2021

Abstract
Background
Little is known about the impact of rare diseases on inpatient outcomes.

Objective
To compare outcomes of inpatients with 0, 1, or > 1 rare disease. A catalogue of 628 ICD-10 coded rare diseases was applied to count rare diseases.

Design
Retrospective, cross-sectional study.

Subjects
165,908 inpatients, Swiss teaching hospital.

Main measures
Primary outcome: in-hospital mortality. Secondary outcomes: length of stay (LOS), intensive care unit (ICU) admissions, ICU LOS, and 30-day readmissions. Associations with single and combined rare diseases were analyzed by multivariable regression.

Key results
Patients with 1 rare disease were at increased risk of in-hospital death (odds ratio [OR]: 1.80; 95% confidence interval [CI]: 1.67, 1.95), combinations of rare diseases showed stronger associations (OR 2.78; 95% CI 2.39, 3.23). Females with 1 rare disease had an OR of 1.69 (95% CI 1.50, 1.91) for in-hospital death, an OR of 2.99 (95% CI 2.36, 3.79) if they had a combination of rare diseases. Males had an OR of 1.85 (95% CI 1.68, 2.04) and 2.61 (95% CI 2.15, 3.16), respectively. Rare diseases were associated with longer LOS (for 1 and > 1 rare diseases: increase by 28 and 49%), ICU admissions (for 1 and > 1: OR 1.64 [95% CI 1.57, 1.71] and 2.23 [95% CI 2.01, 2.48]), longer ICU LOS (for 1 and > 1 rare diseases: increase by 14 and 40%), and 30-day readmissions (for 1 and > 1: OR 1.57 [95% CI 1.47, 1.68] and 1.64 [95% CI 1.37, 1.96]).

Conclusions
Rare diseases are independently associated with worse inpatient outcomes. This might be the first study suggesting even stronger associations of combined rare diseases with in-hospital deaths, increased LOS, ICU admissions, increased ICU LOS, and 30-day readmissions.
Changes in PCSK 9 and apolipoprotein B100 in Niemann–Pick disease after enzyme replacement therapy with olipudase alfa
Authors: Garside Bethanie , Ho Jan Hoong , Kwok See , Liu Yifen , Dhage Shaishav , Donn Rachelle , Iqbal Zohaib , Jones Simon A. , Soran Handrean 
Published: February 2021

Abstract
Background
Enzyme replacement therapy (ERT) with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is being developed to treat patients with ASM deficiency (ASMD), commonly known as Niemann–Pick disease (NPD) types A or B. This study assessed the effect of ERT on lipid parameters and inflammatory markers.

Methods
Serum and plasma samples from five adults with NPD type B (NPD-B) who received olipudase alfa ERT for 26 weeks were analysed. We also collected fasting blood samples from fifteen age- and sex-matched participants as reference and comparison group. We measured fasting lipid profile, apolipoproteins B48 and B100 (apoB48 and apoB100), apolipoprotein A1 (apoA1), proprotein convertase subtilisin/klexin type 9 (PCSK9) mass, oxidised low-density lipoprotein (oxLDL), small dense low-density lipoprotein cholesterol (sdLDL-C) and tumour necrosis factor α (TNF-α).

Results
Patients with NPD-B, compared with age and sex matched reference group, had higher triglycerides, PCSK9, apoB48, oxLDL and TNF-α and lower high density lipoprotein cholesterol (HDL-C) and apoA1. Treatment with ERT was associated with improved lipid parameters including total cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C), sdLDL-C, oxLDL and apoB100. Though there was an increase in apoA1, HDL-C was slightly reduced. TNF-α showed a reduction. ApoB100 decreased in parallel with a decrease in total serum PCSK9 mass after ERT.

Conclusion
This study demonstrated that patients with NPD-B had a proatherogenic lipid profile and higher circulating TNF-α compared to reference group. There was an improvement in dyslipidaemia after olipudase alfa. It was possible that reductions in LDL-C and apoB100 were driven by reductions in TNF-α and PCSK9 following ERT.
A deleterious mutation in the ALMS1 gene in a naturally occurring model of hypertrophic cardiomyopathy in the Sphynx cat
Authors: Meurs Kathryn M. , Williams Brian G. , DeProspero Dylan , Friedenberg Steven G. , Malarkey David E. , Ezzell J. Ashley , Keene Bruce W. , Adin Darcy B. , DeFrancesco Teresa C. , Tou Sandra 
Published: February 2021

Abstract
Background
Familial hypertrophic cardiomyopathy is a common inherited cardiovascular disorder in people. Many causal mutations have been identified, but about 40% of cases do not have a known causative mutation. Mutations in the ALMS1 gene are associated with the development of Alstrom syndrome, a multisystem familial disease that can include cardiomyopathy (dilated, restrictive). Hypertrophic cardiomyopathy has not been described. The ALMS1 gene is a large gene that encodes for a ubiquitously expressed protein. The function of the protein is not well understood although it is believed to be associated with energy metabolism and homeostasis, cell differentiation and cell cycle control. The ALMS1 protein has also been shown to be involved in the regulation of cell cycle proliferation in perinatal cardiomyocytes. Although cardiomyocyte cell division and replication in mammals generally declines soon after birth, inhibition of ALMS1 expression in mice lead to increased cardiomyocyte proliferation, and deficiency of Alstrom protein has been suggested to impair post-natal cardiomyocyte cell cycle arrest. Here we describe the association of familial hypertrophic cardiomyopathy in Sphynx cats with a novel ALMS1 mutation.

Results
A G/C variant was identified in exon 12 (human exon 13) of the ALMS1 gene in affected cats and was positively associated with the presence of hypertrophic cardiomyopathy in the feline population (p < 0.0001). The variant was predicted to change a highly conserved nonpolar Glycine to a positively charged Arginine. This was predicted to be a deleterious change by three in silico programs. Protein prediction programs indicated that the variant changed the protein structure in this region from a coil to a helix. Light microscopy findings included myofiber disarray with interstitial fibrosis with significantly more nuclear proliferative activity in the affected cats than controls (p < 0.0001).

Conclusion
This study demonstrates a novel form of cardiomyopathy associated with ALMS1 in the cat. Familial hypertrophic cardiomyopathy is a disease of genetic heterogeneity; many of the known causative genes encoding for sarcomeric proteins. Our findings suggest that variants in genes involved with cardiac development and cell regulation, like the ALMS1 gene, may deserve further consideration for association with familial hypertrophic cardiomyopathy.
Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome
Authors: Forde Karina , Resta Nicoletta , Ranieri Carlotta , Rea David , Kubassova Olga , Hinton Mark , Andrews Katrina A. , Semple Robert , Irvine Alan D. , Dvorakova Veronika 
Published: February 2021

Abstract
Background
PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods.

Results
Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22–28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported.

Conclusion
We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).
Lessons from a theory of change-driven evaluation of a global mental health funding portfolio
Authors: Esponda G. Miguel , Ryan G. K. , Estrin G. Lockwood , Usmani S. , Lee L. , Murphy J. , Qureshi O. , Endale T. , Regan M. , Eaton J. , De Silva M. 
Published: February 2021

Abstract
Background
Given the underinvestment in global mental health to-date, it is important to consider how best to maximize the impact of existing investments. Theory of Change (ToC) is increasingly attracting the interest of funders seeking to evaluate their own impact. This is one of four papers investigating Grand Challenges Canada’s (GCC’s) first global mental health research funding portfolio (2012–2016) using a ToC-driven approach.

Methods
A portfolio-level ToC map was developed through a collaborative process involving GCC grantees and other key stakeholders. Proposed ToC indicators were harmonised with GCC’s pre-existing Results-based Management and Accountability Framework to produce a “Core Metrics Framework” of 23 indicators linked to 17 outcomes of the ToC map. For each indicator relevant to their project, the grantee was asked to set a target prior to the start of implementation, then report results at six-month intervals. We used the latest available dataset from all 56 projects in GCC’s global mental health funding portfolio to produce a descriptive analysis of projects’ characteristics and outcomes related to delivery.

Results
12,999 people were trained to provide services, the majority of whom were lay or other non-specialist health workers. Most projects exceeded their training targets for capacity-building, except for those training lay health workers. Of the 321,933 people screened by GCC-funded projects, 162,915 received treatment. Most projects focused on more than one disorder and exceeded all their targets for screening, diagnosis and treatment. Fewer people than intended were screened for common mental disorders and epilepsy (60% and 54%, respectively), but many more were diagnosed and treated than originally proposed (148% and 174%, respectively). In contrast, the three projects that focused on perinatal depression exceeded screening and diagnosis targets, but only treated 43% of their intended target.

Conclusions
Under- or over-achievement of targets may reflect operational challenges such as high staff turnover, or challenges in setting appropriate targets, for example due to insufficient epidemiological evidence. Differences in delivery outcomes when disaggregated by disorder suggest that these challenges are not universal. We caution implementers, funders and evaluators from taking a one-size-fits all approach and make several recommendations for how to facilitate more in-depth, multi-method evaluation of impact using portfolio-level ToC.
The mental health impact of COVID-19 outbreak: a Nationwide Survey in Iran
Authors: Shahriarirad Reza , Erfani Amirhossein , Ranjbar Keivan , Bazrafshan Amir , Mirahmadizadeh Alireza 
Published: February 2021

Abstract
Background
Disease outbreak not only carries the risk of death to the public due to the infection, but it also can lead to unbearable psychological impact on the mental health of the individuals. This study aims to explore and evaluate the burden of psychological problems on the Iranian general population during the outbreak of COVID-19.

Method
A cross-sectional web-based survey was conducted among the general population of Iran age 15 and above. Demographic variables, depression, and anxiety symptoms were evaluated using the Patient Health Questionnaire-9 and General Anxiety Disorder-7 questionnaires.

Results
Among the 8591 participants, the mean age was 34.37 (± 11.25) years and 66.4% were female while 33.6% were male. Based on our results, 1295 (15.1%) and 1733 (20.1%) of the general population had clinically significant depressive and anxiety symptoms, respectively. Based on the demographic variables, female gender was associated with a higher risk for developing depression and anxiety symptoms, whereas getting information about the disease from medical journals and articles, being older, and being married were considered as associated protective factors. In terms of depression, being a healthcare worker was an associated risk factor. On the other hand, for anxiety, having higher education was a protective factor while a higher number of individuals in a household was considered as a risk factor.

Conclusions
This study identified a major mental health problem in the Iranian population during the time of the COVID-19 outbreak. Therefore, establishing a targeted mental health support program during the time of public emergencies, such as the disease outbreak, is advised.
COVID-19 vaccines for patients with cancer: benefits likely outweigh risks
Authors: Hwang Joyce K. , Zhang Tian , Wang Andrew Z. , Li Zihai 
Published: February 2021

AbstractLess than a year since the start of the COVID-19 pandemic, ten vaccines against SARS-CoV-2 have been approved for at least limited use, with over sixty others in clinical trials. This swift achievement has generated excitement and arrives at a time of great need, as the number of COVID-19 cases worldwide continues to rapidly increase. Two vaccines are currently approved for full use, both built on mRNA and lipid nanotechnology platforms, a success story of mRNA technology 20 years in the making. For patients with cancer, questions arise around the safety and efficacy of these vaccines in the setting of immune alterations engendered by their malignancy and/or therapies. We summarize the current data on leading COVID-19 vaccine candidates and vaccination of patients undergoing immunomodulatory cancer treatments. Most current cancer therapeutics should not prevent the generation of protective immunity. We call for more research in this area and recommend that the majority of patients with cancer receive COVID vaccinations when possible.
Watchful waiting as a strategy to reduce low-value spinal imaging: study protocol for a randomized trial
Authors: Fenton Joshua J. , Jerant Anthony , Franks Peter , Gosdin Melissa , Fridman Ilona , Cipri Camille , Weinberg Gary , Hudnut Andrew , Tancredi Daniel J. 
Published: February 2021

Abstract
Background
Patients with acute low back pain frequently request diagnostic imaging, and clinicians feel pressure to acquiesce to such requests to sustain patient trust and satisfaction. Spinal imaging in patients with acute low back pain poses risks from diagnostic evaluation of false-positive findings, patient labeling and anxiety, and unnecessary treatment (including spinal surgery). Watchful waiting advice has been an effective strategy to reduce some low-value treatments, and some evidence suggests a watchful waiting approach would be acceptable to many patients requesting diagnostic tests.

Methods
We will use key informant interviews of clinicians and focus groups with primary care patients to refine a theory-informed standardized patient-based intervention designed to teach clinicians how to advise watchful waiting when patients request low-value spinal imaging for low back pain. We will test the effectiveness of the intervention in a randomized clinical trial. We will recruit 8–10 primary care and urgent care clinics (~ 55 clinicians) in Sacramento, CA; clinicians will be randomized 1:1 to intervention and control groups. Over a 3- to 6-month period, clinicians in the intervention group will receive 3 visits with standardized patient instructors (SPIs) portraying patients with acute back pain; SPIs will instruct clinicians in a three-step model emphasizing establishing trust, empathic communication, and negotiation of a watchful waiting approach. Control physicians will receive no intervention. The primary outcome is the post-intervention rate of spinal imaging among actual patients with acute back pain seen by the clinicians adjusted for rate of imaging during a baseline period. Secondary outcomes are use of targeted communication techniques during a follow-up visit with an SP, clinician self-reported use of watchful waiting with actual low back pain patients, post-intervention rates of diagnostic imaging for other musculoskeletal pain syndromes (to test for generalization of intervention effects beyond back pain), and patient trust and satisfaction with physicians.

Discussion
This trial will determine whether standardized patient instructors can help clinicians develop skill in negotiating a watchful waiting approach with patients with acute low back pain, thereby reducing rates of low-value spinal imaging. The trial will also examine the possibility that intervention effects generalize to other diagnostic tests.

Trial registration
ClinicalTrials.govNCT 04255199. Registered on January 20, 2020
Increased expression of fatty acid and ABC transporters enhances seed oil production in camelina
Authors: Cai Guangqin , Wang Geliang , Kim Sang-Chul , Li Jianwu , Zhou Yongming , Wang Xuemin 
Published: February 2021

AbstractBackgroundLipid transporters play an essential role in lipid delivery and distribution, but their influence on seed oil production in oilseed crops is not well studied.ResultsHere, we examined the effect of two lipid transporters,FAX1(fatty acid export1) andABCA9(ATP-binding cassette transporter subfamily A9) on oil production and lipid metabolism in the oilseed plantCamelina sativa. Overexpression (OE) ofFAX1andABCA9increased seed weight and size, withFAX1-OEs andABCA9-OEs increasing seed length and width, respectively, whereasFAX1/ABCA9-OEs increasing both.FAX1-OE andABCA9-OE displayed additive effects on seed oil content and seed yield. Also, OE ofFAX1andABCA9affected membrane lipid composition in developing pods, especially on phosphatidylcholine, phosphatidylethanolamine, and phosphatidylglycerol. The expression of some genes involved in seed oil synthesis, such asDGAT2,PDAT1, andLEC1, was increased in developing seeds ofFAX1- and/orABCA9-OEs.ConclusionThese results indicate that increased expression ofFAX1andABCA9can potentially be applied to improving camelina oil production.