bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beyond the clinical context: the process of losing oneself living with Huntington’s disease
Authors: Varela Luz-Estella , Arias María-Mercedes , Martorell-Poveda María-Antonia , Giraldo Clara V. , Estrada-Acuña Rosa A. 
Published: May 2022

Abstract
Background
People with Huntington's disease (HD) have increased functional and cognitive dependence. While numerous clinical, genetic, and therapeutic management studies have been carried out, few studies have investigated the disease from the personal experience and the context of people living with HD. To better serve these patients, our purpose is to understand, from the perspective of the patient and their families, how people with HD cope with their daily lives outside the clinical setting.

Methods
Thirty-three affected or at-risk people participated in this study. Participants were interviewed at their homes on distinct occasions during a family visit. We analyzed the data using Grounded Theory, which allowed us to understand how people live with the disease on their own terms.

Results
Living with HD is a process that begins with acceptance or denial that one is at risk for the disease or, growing awareness of the condition due to motor, behavioral, and cognitive changes, and, finally, loss of autonomy with physical dependence on another person, and loss of sense of self and family.

Conclusion
While the daily life of patients before disease onset was characterized by physical and mental/cognitive independence, with HD they become increasingly trapped in their bodies, and their complications are due to the lack of effective curable therapy.
Key measurement concepts and appropriate clinical outcome assessments in pediatric achondroplasia clinical trials
Authors: Aldhouse Natalie V. J. , Kitchen Helen , Johnson Chloe , Marshall Chris , Pegram Hannah , Pease Sheryl , Collins Sam , Baker Christine L. , Beaverson Katherine , Crews Chandler , Massey Jill , Wyrwich Kathleen W. 
Published: May 2022

Abstract
Background
This study aimed to identify fit-for-purpose clinical outcome assessments (COAs) to evaluate physical function, as well as social and emotional well-being in clinical trials enrolling a pediatric population with achondroplasia. Qualitative interviews lasting up to 90 min were conducted in the US with children/adolescents with achondroplasia and/or their caregivers. Interviews utilized concept elicitation methodology to explore experiences and priorities for treatment outcomes. Cognitive debriefing methodology explored relevance and understanding of selected COAs.

Results
Interviews (N = 36) were conducted with caregivers of children age 0–2 years (n = 8) and 3–7 years (n = 7) and child/caregiver dyads with children age 8–11 years (n = 15) and 12–17 years (n = 6). Children/caregivers identified pain, short stature, impacts on physical functioning, and impacts on well-being (e.g. negative attention/comments) as key bothersome aspects of achondroplasia. Caregivers considered an increase in height (n = 9/14, 64%) and an improvement in limb proportion (n = 11/14, 71%) as successful treatment outcomes. The Childhood Health Assessment Questionnaire (CHAQ) and Quality of Life in Short Stature Youth (QoLISSY-Brief) were cognitively debriefed. CHAQ items evaluating activities, reaching, and hygiene were most relevant. QoLISSY-Brief items evaluating reaching, height bother, being treated differently, and height preventing doing things others could were most relevant. The CHAQ and QoLISSY-Brief instructions, item wording, response scales/options and recall period were well understood by caregivers and adolescents age 12–17. Some children aged 8–11 had difficulty reading, understanding, or required caregiver input. Feedback informed minor amendments to the CHAQ and the addition of a 7-day recall period to the QoLISSY-Brief. These amendments were subsequently reviewed and confirmed in N = 12 interviews with caregivers of children age 0–11 (n = 9) and adolescents age 12–17 (n = 3).

Conclusions
Achondroplasia impacts physical functioning and emotional/social well-being. An increase in height and improvement in limb proportion are considered to be important treatment outcomes, but children/adolescents and their caregivers expect that a successful treatment should also improve important functional outcomes such as reach. The CHAQ (adapted for achondroplasia) and QoLISSY-Brief are relevant and appropriate measures of physical function and emotional/social well-being for pediatric achondroplasia trials; patient-report is recommended for age 12–17 years and caregiver-report is recommended for age 0–11 years.
Mapping the PIK3CA-related overgrowth spectrum (PROS) patient and caregiver journey using a patient-centered approach
Authors: Rodríguez-Laguna Lara , Davis Kristen , Finger Mellenee , Aubel Dawn , Vlamis Robin , Johnson Craig 
Published: May 2022

Abstract
Background
PROS disorders are driven by somatic, gain-of-function mutations in PIK3CA that result in hyperactivation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway. PROS encompasses a broad spectrum of overlapping phenotypes (including overgrowth and vascular malformations) that vary significantly in their severity; every case is unique, leading to different, complex experiences. Here, we aim to describe the PROS experience from the patients’ and caregivers’ points of view, from onset to diagnosis to treatment and support.

Results
The PROS patient journey was developed using a literature review, an ethnography study, health care professional (HCP) research, and social listening. It was then validated with patients, caregivers, and patient advocates. Physician research included 94 PROS centers and other vascular anomaly centers throughout the United States and Europe. Ethnographic research included 24 patients, caregivers, and/or advocates; selected data from 223 patients were reviewed. Key priority areas of need were identified, along with barriers to and potential enablers of quality care. Visual mapping of the PROS patient and family journey was developed to identify key personal health and system issues, and opportunities for improvements throughout patients’ lifespans. Maps were also developed for 3 specific conditions: Klippel–Trénaunay syndrome (K–T); congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal anomalies (CLOVES) syndrome; and megalencephaly-capillary malformation syndrome (M-CM). Overall, most patients with PROS conditions and their families struggle with a long path to diagnosis, access to genetic testing, and finding qualified specialists. Following diagnosis, patients and families are frequently challenged with major medical events, comorbidities, unpredictability, frequent hospitalization, impact on school and work, the need for multidisciplinary care, unwanted attention, adverse impact on mental and emotional health, and financial pressures. Lack of effective pain management emerged as a substantial issue. Challenges and barriers to quality care shift throughout patients’ lifespans; transition from pediatric to adult care can be especially difficult.

Conclusions
This patient journey in PROS was created in collaboration with patients, caregivers, and advocates as key partners. This novel methodology, which could be applied elsewhere, can more accurately identify areas of unmet need, barriers to care, education topics, and assist HCPs to understand the patient and family perspective.
Various vascular malformations are prevalent in Finnish pseudoxanthoma elasticum (PXE) patients: a national registry study
Authors: Pelttari Saku , Väärämäki Suvi , Vanakker Olivier , Verschuere Shana , Uusitalo Hannu , Huhtala Heini , Hinkka Tero , Pörsti Ilkka , Nevalainen Pasi I. 
Published: May 2022

Abstract
Background
Pseudoxanthoma elasticum (PXE, OMIM# 264800) is an inborn error of metabolism causing ectopic soft tissue calcification due to low plasma pyrophosphate concentration. We aimed to assess the prevalence of PXE in Finland and to characterize the Finnish PXE population. A nationwide registry search was performed to identify patients with ICD-10 code Q82.84. Information was gathered from available medical records which were requisitioned from hospitals and health centers. Misdiagnosed patients and patients with insufficient records were excluded.

Results
The prevalence of PXE in Finland was 1:260,000 with equal sex distribution. Patients with high conventional cardiovascular risk had more visual and vascular complications than patients with low risk. Four patients (19%) had at least one vascular malformation. A high proportion (33%) of ABCC6 genotypes were of the common homozygous c.3421C > T, p.Arg1141Ter variant. Nine other homozygous or compound heterozygous allelic variants were found.

Conclusions
The prevalence of diagnosed PXE appears to be lower in Finland than in estimates from other countries. Decreased visual acuity is the most prevalent complication. We suggest that various vascular malformations may be an unrecognized feature of PXE.
The impact of FDA and EMA regulatory decision-making process on the access to CFTR modulators for the treatment of cystic fibrosis
Authors: Costa Enrico , Girotti Silvia , Pauro Francesca , Leufkens Hubert G. M. , Cipolli Marco 
Published: May 2022

Abstract
Background
Over the past decade, a new class of drugs called CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown to be able to improve clinical outcomes in patient with Cystic Fibrosis. In this analysis, we have extensively reviewed the regulatory pathways and decisions adopted by FDA and EMA to speed up the development, the review and the approval of these drugs, with the aim of identifying possible clinical and public health implications associated with differences.

Results
CFTR modulators have been developed towards addressing three main genetic domains: (1) F508del homozygous (F508del/F508del), (2) F508del heterozygous, and (3) genotypes not carrying F508del mutation; and expanded from adult to paediatric population. Programs to expedite the reviewing and licensing of CFTR modulators were extensively adopted by FDA and EMA. All CFTR modulators have been licensed in the US as orphan drugs, but in the EU the orphan status for LUM/IVA was not confirmed at the time of marketing authorization as results from the pivotal trial were not considered clinically significant. While FDA and EMA approved CFTR modulators on the basis of results from phase III double-blind RCTs, main differences were found on the extension of indications: FDA accepted non-clinical evidence considering a recovery of the CFTR function ≥ 10% based on chloride transport, a reliable indicator to correlate with improvement in clinical outcomes. By contrast, EMA did not deem preclinical data sufficient to expand the label of CFTR modulators without confirmatory clinical data.

Conclusions
Regulators played an important role in fostering the development and approval of CFTR modulators. However, differences were found between FDA and EMA in the way of reviewing and licensing CFTR modulators, which extended beyond semantics affecting patients’ eligibility and access: FDA’s approach was more mechanistic/biology-driven while the EMA’s one was more oriented by clinical evidence. This might refer to the connection between the EMA and the Member States, which tends to base decisions on pricing and reimbursement on clinical data rather than pre-clinical ones. Here we have proposed a two-step personalized-based model to merge the ethical commitment of ensuring larger access to all potential eligible patients (including those harboring very rare mutations) with the one of ensuring access to clinically assessed and effective medicines through Real World Data.
Circadian clocks, cognition, and Alzheimer’s disease: synaptic mechanisms, signaling effectors, and chronotherapeutics
Authors: Hoyt Kari R. , Obrietan Karl 
Published: May 2022

AbstractModulation of basic biochemical and physiological processes by the circadian timing system is now recognized as a fundamental feature of all mammalian organ systems. Within the central nervous system, these clock-modulating effects are reflected in some of the most complex behavioral states including learning, memory, and mood. How the clock shapes these behavioral processes is only now beginning to be realized. In this review we describe recent findings regarding the complex set of cellular signaling events, including kinase pathways, gene networks, and synaptic circuits that are under the influence of the clock timing system and how this, in turn, shapes cognitive capacity over the circadian cycle. Further, we discuss the functional roles of the master circadian clock located in the suprachiasmatic nucleus, and peripheral oscillator populations within cortical and limbic circuits, in the gating of synaptic plasticity and memory over the circadian cycle. These findings are then used as the basis to discuss the connection between clock dysregulation and cognitive impairments resulting from Alzheimer’s disease (AD). In addition, we discuss the conceptually novel idea that in AD, there is a selective disruption of circadian timing within cortical and limbic circuits, and that it is the disruption/desynchronization of these regions from the phase-entraining effects of the SCN that underlies aspects of the early- and mid-stage cognitive deficits in AD. Further, we discuss the prospect that the disruption of circadian timing in AD could produce a self-reinforcing feedback loop, where disruption of timing accelerates AD pathogenesis (e.g., amyloid deposition, oxidative stress and cell death) that in turn leads to a further disruption of the circadian timing system. Lastly, we address potential therapeutic approaches that could be used to strengthen cellular timing networks and, in turn, how these approaches could be used to improve cognitive capacity in Alzheimer’s patients.
The relationship between previous pulmonary tuberculosis and risk of lung cancer in the future
Authors: Qin Yongwei , Chen Yujie , Chen Jinliang , Xu Kuang , Xu Feifan , Shi Jiahai 
Published: May 2022

AbstractVarious investigations have expanded the views that tuberculosis is an important risk factor for lung cancer occurrence. Lung cancer originates from chronic inflammation and infection. It is becoming clearer that Mycobacterium tuberculosis (M.tb) in tuberculosis patients meticulously schemes multiple mechanisms to induce tumor formation and is indispensable to participate in the occurrence of lung cancer. In addition, some additional factors such as age, sex and smoking, accelerate the development of lung cancer after Mycobacterium tuberculosis infection. The clarification of these insights is fostering new diagnoses and therapeutic approaches to prevention of the patients developing from tuberculosis into lung cancer.
Consistency of reports of violence from northern Rakhine state in August 2017
Authors: Trager Sarah , Leigh Jennifer , Woods Andrea , Parmar Parveen , Petty Agnes , Haar Rohini , Beyrer Chris 
Published: May 2022

Abstract
Background
In August 2017, Myanmar’s Armed Forces, the Tatmadaw, launched an orchestrated attack on hundreds of Rohingya-majority villages in northern Rakhine state. This study seeks to validate the consistency of previous reports of violence against the Rohingya people in the region carried out by the Tatmadaw, Border Guard Police, and Rakhine villagers in the late summer and early fall of 2017.

Methods
Internal validation data is from a three-armed study. Data analyzed in the external triangulation was sourced through a literature review of known, publicly available surveys and interviews. Both sets of data documented instances of violence against the Rohingya people in northern Rakhine state during the late summer and early fall of 2017. Consistency was evaluated across five indicators of violence: arson, presence of mass graves, reports of sexual violence and human injuries, as well as human fatalities, across 611 locales in northern Rakhine state. Further analysis was conducted to measure consistency of reports by locale and across locales by indicator.

Results
Overall, an internal validation of 94 hamlets found that 98% of these locales were consistent across at least four of the five indicators (80% + consistency). Arson and reports of human injuries were the most consistent indicators across locales (100% and 99% consistency, respectively) and sexual violence was the least consistent indicator, with 84% of participating locales exhibiting consistent reports of sexual violence between the qualitative and quantitative data. Similarly, an external validation of 57 locations found that 50 of the 57 locations (88%) were consistent across indicators. Arson was the most consistent across sources (96%), whereas source agreement across locations was the least consistent for reports of sexual violence (58%).

Conclusion
The government of Myanmar has denied involvement in the 2017 attacks on Rohingya communities in northern Rakhine state and purports that reports of the violence and destruction are overstated. However, consistent reporting from multiple sources on the same locales clearly underscores the veracity of the evidence documented, both by investigative groups and as recounted by Rohingya survivors of violence. It is our hope that this cataloging and comparison of available data, along with this study’s assessment of its consistency, will aid ongoing accountability efforts.
Mental health stigma at primary health care centres in Lebanon: qualitative study
Authors: Abi Hana Racha , Arnous Maguy , Heim Eva , Aeschlimann Anaïs , Koschorke Mirja , Hamadeh Randa S. , Thornicroft Graham , Kohrt Brandon A. , Sijbrandij Marit , Cuijpers Pim , El-Chammay Rabih 
Published: May 2022

Abstract
Background
Mental health-related stigma is a global public health concern and a major barrier to seeking care. In this study, we explored the role of stigma as a barrier to scaling up mental health services in primary health care (PHC) centres in Lebanon. We focused on the experiences of Healthcare Providers (HCPs) providing services to patients with mental health conditions (MHCs), the views of policy makers, and the perceptions of stigma or discrimination among individuals with MHCs. This study was conducted as part of INDIGO-PRIMARY, a larger multinational stigma reduction programme.

Methods
Semi-structured qualitative interviews (n = 45) were carried out with policy makers (n = 3), PHC management (n = 4), PHC staff (n = 24), and service users (SUs) (n = 14) between August 2018 and September 2019. These interviews explored mental health knowledge, attitudes and behaviour of staff, challenges of providing treatment, and patient outcomes. All interviews were coded using NVivo and a thematic coding framework.

Results
The results of this study are presented under three themes: (1) stigma at PHC level, (2) stigma outside PHC centres, and (3) structural stigma. SUs did not testify to discrimination from HCPs but did describe stigmatising behaviour from their families. Interestingly, at the PHC level, stigma reporting differed among staff according to a power gradient. Nurses and social workers did not explicitly report incidents of stigma but described patients with MHCs as uncooperative, underscoring their internalized negative views on mental health. General practitioners and directors were more outspoken than nurses regarding the challenges faced with mental health patients. Mental health professionals revealed that HCPs still hold implicitly negative views towards patients with MHCs however their attitude has improved recently. Our analysis highlights five layers of stigma affecting SUs.

Conclusion
This qualitative study reveals that stigma was still a key concern that affects patients with MHC. SUs reported experiencing overt stigmatising behaviour in the community but less explicit discrimination in a PHC setting. Our findings emphasise the importance of (1) combatting structural stigma through legal reform, (2) addressing interpersonal stigma, (3) committing PHC management to deliver high quality mental health integrated services, and (4) reducing intrapersonal stigma by building public empathy.
Elevated transcription and glycosylation of B3GNT5 promotes breast cancer aggressiveness
Authors: Miao Zhaorui , Cao Qianhua , Liao Ruocen , Chen Xingyu , Li Xiaoli , Bai Longchang , Ma Chenglong , Deng Xinyue , Dai Zhijun , Li Jun , Dong Chenfang 
Published: May 2022

Abstract
Background
Basal-like breast cancer (BLBC) is the most aggressive subtype of breast cancer because of its aggressive biological characteristics and no effective targeted agents. However, the mechanism underlying its aggressive behavior remain poorly understood. β1,3-N-acetylglucosaminyltransferase V (B3GNT5) overexpression occurs specifically in BLBC. Here, we studied the possible molecular mechanisms of B3GBT5 promoting the aggressiveness of BLBC.

Methods
The potential effects of B3GNT5 on breast cancer cells were tested by colony formation, mammosphere formation, cell proliferation assay, flow cytometry and Western blotting. The glycosylation patterns of B3GNT5 and associated functions were determined by Western blotting, quantitative real-time PCR and flow cytometry. The effect of B3GNT5 expression on BLBC was assessed by in vitro and in vivo tumorigenesis model.

Results
In this study, we showed that B3GNT5 copy number amplification and hypomethylation of B3GNT5 promoter contributed to the overexpression of B3GNT5 in BLBC. Knockout of B3GNT5 strongly reduced surface expression of SSEA-1 and impeded cancer stem cell (CSC)-like properties of BLBC cells. Our results also showed that B3GNT5 protein was heavily N-glycosylated, which is critical for its protein stabilization. Clinically, elevated expression of B3GNT5 was correlated with high grade, large tumor size and poor survival, indicating poor prognosis of breast cancer patients.

Conclusions
Our work uncovers the critical association of B3GNT5 overexpression and glycosylation with enhanced CSCs properties in BLBC. These findings suggest that B3GNT5 has the potential to become a prognostic marker and therapeutic target for BLBC.