bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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

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

Modulation 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

Various 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

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

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

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.
Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials
Authors: Qin Yidi , Kernan Kate F. , Fan Zhenjiang , Park Hyun-Jung , Kim Soyeon , Canna Scott W. , Kellum John A. , Berg Robert A. , Wessel David , Pollack Murray M. , Meert Kathleen , Hall Mark , Newth Christopher , Lin John C. , Doctor Allan , Shanley Tom , Cornell Tim , Harrison Rick E. , Zuppa Athena F. , Banks Russell , Reeder Ron W. , Holubkov Richard , Notterman Daniel A. , Michael Dean J. , Carcillo Joseph A.
Published: May 2022

Background

Thrombotic microangiopathy-inducedthrombocytopenia-associated multiple organ failureand hyperinflammatorymacrophage activation syndromeare important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions.

Methods

We applied consensus,k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin.

Results

Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p < 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p < 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p < 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p < 0.05). PedSep-D had the highest likelihood of developingthrombocytopenia-associated multiple organ failure(Adj OR 47.51 95% CI [18.83–136.83],p < 0.0001) andmacrophage activation syndrome(Adj OR 38.63 95% CI [13.26–137.75],p < 0.0001).

Conclusions

Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership (www.pedsepsis.pitt.edu) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.
Rehabilitation for life: the effect on physical function of rehabilitation and care in older adults after hip fracture—study protocol for a cluster-randomised stepped-wedge trial
Authors: Ipsen Jonas Ammundsen , Pedersen Lars T. , Viberg Bjarke , Nørgaard Birgitte , Suetta Charlotte , Bruun Inge H.
Published: May 2022

Background

A hip fracture is a serious event for older adults, given that approximately 50% do not regain their habitual level of physical function, and the mortality rate is high, as is the number of readmissions. The gap in healthcare delivery, as separated into two financial and self-governing sectors, might be a contributing cause of inferior rehabilitation and care for these patients. Therefore, we aim to assess the effect of continuous and progressive rehabilitation and care across sectors for older adults after hip fracture.

Methods/design

The project is designed as a stepped-wedge cluster randomised controlled trial. The study population of patients are older adults 65 years of age and above discharged after a hip fracture and healthcare professionals in primary and secondary care (municipalities and hospitals). Healthcare professionals from different sectors (hospital and municipalities) will be engaged in the empowerment-orientated praxis, through a workshop for healthcare professionals with knowledge sharing to the older adults using a digital health application (app). The rehabilitation intervention consists of 12 weeks of progressive resistance exercises initiated 1–2 days after discharge. To improve communication across sectors, a videoconference involving the patient and physiotherapists from both sectors will be conducted. On day, 3 after discharge, an outreach nurse performs a thorough assessment including measurement of vital signs. A hotline to the hospital for medical advice is a part of the intervention. The intervention is delivered as an add-on to the usual rehabilitation and care, and it involves one regional hospital and the municipalities within the catchment area of the hospital. The primary outcome is a Timed Up and Go Test 8 weeks post-surgery.

Discussion

Using a stepped-wedge design, the intervention will be assessed as well as implemented in hospital and municipalities, hopefully for the benefit of older adults after hip fracture. Furthermore, the collaboration between the sectors is expected to improve.

Trial registration

The study is approved by the Regional Scientific Ethics Committees of Southern Denmark (S-20200070) and the Danish Data Protection Agency (20-21854). Registered 9 of June 2020 at ClinicalTrials.gov, NCT04424186.
Risk factors and surgical prognosis in patients with aortic valve involvement caused by Takayasu arteritis
Authors: Shi Xuemei , Du Juan , Li Taotao , Gao Na , Fang Wei , Chen Suwei , Qiao Zhiyu , Li Chengnan , Zhu Junming , Pan Lili
Published: May 2022

Objective

Aortic valve involvement is not uncommon in patients with Takayasu arteritis (TAK) and leading to poor prognosis. The aim of our study was to explore the risk factors of aortic valve involvement and to evaluate the prognosis in TAK patients with aortic valve involvement.

Method

In this retrospective study, 172 TAK patients were divided into groups with or without aortic valve involvement to identify the risk factors. Patients who underwent aortic valve surgical treatment were followed up to assess cumulative incidence of postoperative adverse events.

Results

A total of 92 TAK patients (53.49%) had aortic valvular lesion. The infiltration of inflammatory cells was found in surgical specimens of aortic valve. Numano type IIb, elevated high-sensitivity C-reactive protein (hs-CRP) level, and dilation of ascending aorta and aortic root were statistically associated with aortic valvular lesion in TAK patients (OR [95%CI] 6.853 [1.685–27.875], p=0.007; 4.896 [1.646–14.561], p=0.004; 4.509 [1.517–13.403], p=0.007; 9.340 [2.188–39.875], p=0.003). The 1-, 5-, and 7-year cumulative incidence of postoperative adverse events were 14.7%, 14.7%, and 31.8%, respectively. Surgical methods (p=0.024, hazard ratio (HR) 0.082) and postoperatively anti-inflammatory therapy (p=0.036, HR 0.144) were identified as potential predictors of postoperative adverse events.

Conclusions

Regularly echocardiogram screening is suggested in patients with Numano type IIb and aggressive treatment should be performed early in TAK patients. As for TAK patients with aortic valve surgery, aortic root replacement seems to be the preferred option and regular anti-inflammatory therapy may reduce the occurrence of adverse events of them.
Subclinical carotid artery atherosclerosis and cognitive function in older adults
Authors: Lin Felice , Pa Judy , Karim Roksana , Hodis Howard N. , Han S. Duke , Henderson Victor W. , St. John Jan A. , Mack Wendy J.
Published: May 2022

Background

The combined effects of increased life expectancy and the considerable number of persons reaching old age will magnify the dementia epidemic in the USA. Demonstration that subclinical atherosclerosis precedes and is associated with cognitive impairment suggests a modifiable risk factor for age-associated cognitive impairment and dementia. The purpose of this study is to determine whether subclinical atherosclerosis as measured by carotid artery intima-media thickness (CIMT) is associated with changes in cognitive function over time in older adults.

Methods

This study combined longitudinal data from three clinical trials conducted between 2000 and 2013: the B-Vitamin Atherosclerosis Intervention Trial (BVAIT), the Women’s Isoflavone Soy Health (WISH) trial, and the Early versus Late Intervention Trial with Estradiol (ELITE). Participants were recruited from the general population in the Greater Los Angeles area and were free of cardiovascular disease and diabetes; no cognitive or psychiatric exclusion criteria were specified. The same standardized protocol for ultrasound image acquisition and measurement of CIMT was used in all trials. CIMT measurements performed at baseline and 2.5 years were used in these analyses. Cognitive function was assessed at baseline and 2.5 years using a battery of 14 standardized cognitive tests. All clinical trials were conducted at the University of Southern California Atherosclerosis Research Unit, Los Angeles, and had at least 2.5 years of cognitive follow-up.

Results

A total of 308 men and 1187 women, mean age of 61 years, were included in the combined longitudinal dataset for the primary analysis. No associations were found between CIMT and cognitive function at baseline or at 2.5 years. There was a weak inverse association between CIMT measured at baseline and change in global cognition assessed over 2.5 years (β (SE) = − 0.056 (0.028) units per 0.1 mm CIMT, 95% CI − 0.110, − 0.001, p = 0.046). No associations between CIMT at baseline and changes in executive function, verbal memory, or visual memory were found.

Conclusions

In this sample of healthy older adults, our findings suggest an association between subclinical atherosclerosis and change in global cognitive function over 2.5 years. Stronger associations were observed longitudinally over 2.5 years than cross-sectionally. When analysis was stratified by age group (<65 and ≥65 years old), the inverse association remained statistically significant for participants in the older age group. Subclinical atherosclerosis of the carotid artery may be a modifiable correlate of cognitive decline in middle and older age.

Trial registration

BVAIT, NCT00114400. WISH, NCT00118846. ELITE, NCT00114517.
Autologous conditioned serum (Orthokine) injection for treatment of classical trigeminal neuralgia: results of a single-center case series
Authors: Aghamohammadi Dawood , Sharifi Shahrzad , Shakouri Seyed Kazem , Eslampour Yashar , Dolatkhah Neda
Published: May 2022

Background

Despite some advances, treatment of trigeminal neuralgia remains a significant challenge. This study determines the efficacy and safety of autologous conditioned serum (Orthokine) injection into the foramen oval to treat refractory trigeminal neuralgia.

Case presentation

This is a consecutive case series from the Pain and Palliative Care Department of Imam Reza University Hospital, Tabriz, Iran. Eleven Iranian patients, eligible according to the inclusion and exclusion criteria, aged 45.64 ± 11.58 years (Four male and seven female, all Iranian) with established classical trigeminal neuralgia were injected with Orthokine (2 mL per injection) once a week for three consecutive weeks (total of four injections). Numeric rating scale scores for facial pain intensity and also carbamazepine daily dose were confirmed at pretreatment (T0) and at week 1 (T1), week 2 (T2), week 3 (T3), week 4 (T4), and month 2 (T5) posttreatment. Pain intensity was significantly reduced in the first 3 weeks of follow-up in comparison with baseline (T0 to T3) (8.18 ± 1.99 to 2.82 ± 2.13, p < 0.001), an effect that was retained at week 4 (T4) and month 2 (T5) follow-ups (2.82 ± 2.13 to 3.36 ± 2.69, p = 0.886). Carbamazepine consumption was significantly reduced in the first 3 weeks of follow-up in comparison with baseline (T0 to T3) (636.36 ± 307.48 to 200.00 ± 296.64, p = 0.003), an effect that was retained at week 4 and month 2 follow-ups (200.00 ± 296.64 to 200.00 ± 282.84, p = 0.802). There were no serious adverse events in participants.

Conclusion

Orthokine injection led to consistent pain relief and reduced carbamazepine dosage in patients with trigeminal neuralgia, with acceptable safety.
Hypoxic mesenchymal stem cell-derived extracellular vesicles ameliorate renal fibrosis after ischemia–reperfusion injure by restoring CPT1A mediated fatty acid oxidation
Authors: Gao Zhumei , Zhang Chuyue , Peng Fei , Chen Qianqian , Zhao Yinghua , Chen Liangmei , Wang Xu , Chen Xiangmei
Published: May 2022

Background

Renal fibrosis is a common pathological process of chronic kidney diseases induced by multiple factors. Hypoxic pretreatment of mesenchymal stem cells can enhance the efficacy of secreted extracellular vesicles (MSC-EVs) on various diseases, but it is not clear whether they can better improve renal fibrosis. The latest research showed that recovery of fatty acid oxidation (FAO) can reduce renal fibrosis. In this study, we aimed to examine whether hypoxic pretreatment with MSC extracellular vesicles (Hypo-EVs) can improve FAO to restore renal fibrosis and to investigate the underlying mechanism.

Methods

Hypo-EVs were isolated from hypoxia-pretreated human placenta-derived MSC (hP-MSC), and Norm-EVs were isolated from hP-MSC cultured under normal conditions. We used ischemia–reperfusion (I/R)-induced renal fibrosis model in vivo. The mice were injected with PBS, Hypo-EVs, or Norm-EVs immediately after the surgery and day 1 postsurgery. Renal function, kidney pathology, and renal fibrosis were assessed for kidney damage evaluation. For mechanistic exploration, fatty acid oxidation (FAO), mitochondrial morphological alterations, ATP production and mitochondrial mass proteins were detected in vivo. Mitochondrial membrane potential and reactive oxygen species (ROS) production were investigated in vitro.

Results

We found that Hypo-EVs confer a superior therapeutic effect on recovery of renal structure damage, restoration of renal function and reduction in renal fibrosis. Meanwhile, Hypo-EVs enhanced mitochondrial FAO in kidney by restoring the expression of a FAO key rate-limiting enzyme carnitine palmitoyl-transferase 1A (CPT1A). Mechanistically, the improvement of mitochondrial homeostasis, characterized by repaired mitochondrial structure, restoration of mitochondrial mass and ATP production, inhibition of oxidative stress, and increased mitochondrial membrane potential, partially explains the effect of Hypo-EVs on improving mitochondrial FAO and thus attenuating I/R damage.

Conclusions

Hypo-EVs suppress the renal fibrosis by restoring CPT1A-mediated mitochondrial FAO, which effects may be achieved through regulation of mitochondrial homeostasis. Our findings provide further mechanism support for development cell-free therapy of renal fibrosis.
TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling
Authors: Liu Qiang , Lei Xiaohua , Cao Zhenyu , Zhang Ju , Yan Likun , Fu Jie , Tong Qing , Qin Wei , Shao Yaoli , Liu Chun , Liu Zhiqiang , Wang Zicheng , Chu Yuan , Xu Ge , Liu Siyuan , Wen Xueyi , Yamamoto Hirofumi , Mori Masaki , Liang Xin. M. , Xu Xundi
Published: May 2022

Background

Liver fibrosis represent a major global health care burden. Data emerging from recent advances suggest TRPM8, a member of the transient receptor potential (TRP) family of ion channels, plays an essential role in various chronic inflammatory diseases. However, its role in liver fibrosis remains unknown. Herein, we assessed the potential effect of TRPM8 in liver fibrosis.

Methods

The effect of TRPM8 was evaluated using specimens obtained from classic murine models of liver fibrosis, namely wild-type (WT) and TRPM8−/− (KO) fibrotic mice after carbon tetrachloride (CCl4) or bile duct ligation (BDL) treatment. The role of TRPM8 was systematically evaluated using specimens obtained from the aforementioned animal models after various in vivo and in vitro experiments.

Results

Clinicopathological analysis showed that TRPM8 expression was upregulated in tissue samples from cirrhosis patients and fibrotic mice. TRPM8 deficiency not only attenuated inflammation and fibrosis progression in mice but also helped to alleviate symptoms of cholangiopathies. Moreover, reduction in S100A9 and increase in HNF4α expressions were observed in liver of CCl4- and BDL- treated TRPM8−/− mice. A strong regulatory linkage between S100A9 and HNF4α was also noticed in L02 cells that underwent siRNA-mediated S100A9 knockdown and S100A9 overexpressing plasmid transfection. Lastly, the alleviative effect of a selective TRPM8 antagonist was confirmed in vivo.

Conclusions

These findings suggest TRPM8 deficiency may exert protective effects against inflammation, cholangiopathies, and fibrosis through S100A9-HNF4α signaling. M8-B might be a promising therapeutic candidate for liver fibrosis.

Graphical Abstract
LRP4 is required for the olfactory association task in the piriform cortex
Authors: Yan Min , Xiong Mingtao , Wu Yongqiang , Lin Dong , Chen Peng , Chen Jiang , Liu Ziyang , Zhang Hang , Ren Dongyan , Fei Erkang , Lai Xinsheng , Zou Suqi , Wang Shunqi
Published: May 2022

Background

Low-density lipoprotein receptor-related protein 4 (LRP4) plays a critical role in the central nervous system (CNS), including hippocampal synaptic plasticity, maintenance of excitatory synaptic transmission, fear regulation, as well as long-term potentiation (LTP).

Results

In this study, we found that Lrp4 was highly expressed in layer II of the piriform cortex. Both body weight and brain weight decreased in Lrp4ECD/ECD mice without TMD (Transmembrane domain) and ICD (intracellular domain) of LRP4. However, in the piriform cortical neurons of Lrp4ECD/ECD mice, the spine density increased, and the frequency of both mEPSC (miniature excitatory postsynaptic current) and sEPSC (spontaneous excitatory postsynaptic current) was enhanced. Intriguingly, finding food in the buried food-seeking test was prolonged in both Lrp4ECD/ECD mice and Lrp4 cKO (conditional knockout of Lrp4 in the piriform cortex) mice.

Conclusions

This study indicated that the full length of LRP4 in the piriform cortex was necessary for maintaining synaptic plasticity and the integrity of olfactory function.
Power minimization for GSIC-based uplink cell-free massive MIMO-NOMA systems
Authors: Cui Tao , Liu Chengcheng , Du Peng , Song Rongfang
Published: May 2022

Non-orthogonal multiple access (NOMA) and multiple-input multiple-output (MIMO) are considered promising techniques to satisfy the demands for high spectrum efficiency and massive connectivity in future wireless communication. In this paper, a novel framework to realize transmission in cell-free massive MIMO-NOMA system with deep integration between MIMO and NOMA is proposed. A new method is developed to divide users into different groups according to their equivalent path loss, and then “group-level successive interference cancellation” (GSIC) is used to cancel the inter-group interference when demodulating the users. Based on the new framework, a rigorous closed-form expression of the achievable sum rate in uplink cell-free massive MIMO-NOMA system is derived. In addition, a parallel iterative method is used to obtain the best power control scheme. Simulations show that the proposed scheme can effectively reduce the total power consumption and outperforms the orthogonal multiple access (OMA) transmission and traditional SIC-NOMA schemes based on user clustering.
Point prevalence study of antibiotic appropriateness and possibility of early discharge from hospital among patients treated with antibiotics in a Swiss University Hospital
Authors: Moulin Estelle , Boillat-Blanco Noémie , Zanetti Giorgio , Plüss-Suard Catherine , de Vallière Serge , Senn Laurence
Published: May 2022

Background

The growing threat of multidrug resistant organisms have led to increasingly promote prudent and rational use of antimicrobials as well as early hospital discharge plan. Antibiotic stewardship programs (ASP) have been developed as multifaceted approaches to improve use of current antibiotics and are now widely applied through different strategies. Proactive interventions are still limited in Switzerland and data on antimicrobial appropriateness and early discharge strategies are lacking. We aimed to describe the opportunities of antibiotics prescriptions optimization at Lausanne University Hospital, Switzerland and evaluate the suitability for early discharge among patients receiving antibiotics. The need for outpatient medical structures was also assessed.

Methods

We conducted a point prevalence survey of antibiotic prescriptions in adult medical and surgical units with exclusion of intermediate and intensive care units. All hospitalized patients receiving a systemic antibiotic on the day of evaluation were included. An infectious diseases specialist evaluated antimicrobial appropriateness and assessed suitability for discharge according to medical and nursing observations. The need of flexible additional outpatient facility for a close medical follow-up was evaluated concomitantly.

Results

A total of 564 patients’ files were reviewed. 182 (32%) patients received one or more systemic antibiotic: 62 (34%) as a prophylaxis and 120 (66%) as a treatment with or without concomitant prophylaxis. 37/62 (60%) patients receiving prophylaxis had no indication to continue the antibacterial. Regarding the patients treated with antibiotics, 69/120 (58%) presented at least one opportunity for treatment optimization, mainly interruption of treatment. A previous ID consultation was recorded for 55/120 (46%) patients, of whom 21 (38%) could have benefited from antimicrobial therapy optimization on the day of the point assessment. 9.2% patients were eligible for discharge of whom 64% could leave the hospital with a close outpatient follow-up for infectious issues.

Conclusions

This point prevalence study offers precious indicators for tailoring future antibiotic stewardship interventions that can be combined with early discharge. Any centre considering implementing ASP should conduct this type of analysis with a pragmatic approach to gain insight into local practices and needed resources.
Age-related changes in the activation timing of postural muscles to the prime mover muscle for bilateral arm flexion during standing
Authors: Kiyota Takeo , Fujiwara Katsuo
Published: May 2022

Background

We aimed to obtain the standard values of age-related changes in the activation timing of postural muscles to the prime mover muscle (anterior deltoid [AD]) for bilateral arm flexion during standing.

Methods

The study participants were 276 children (aged 3–14 years) and 32 adults (aged 20–26 years). In response to a visual stimulus, participants raised both arms from a fully extended position as quickly as possible, stopped their arms voluntarily at a horizontal level at the shoulder, and maintained that position for 2 s. Ten test trials were performed. By using surface electromyography, the duration from the burst onset of the postural muscles to that of AD was measured as the starting time of the postural muscles (rectus abdominis [RA], erector spinae [ES], rectus femoris [RF], biceps femoris [BF], tibialis anterior [TA], gastrocnemius medialis [GcM], and soleus [SOL]). The starting time was presented as a negative value when the burst onset of the postural muscles preceded that of AD, which was defined as the preceding activation. A positive value for the starting time was defined as delayed activation.

Results

In adults, the burst onsets of ES and BF significantly preceded that of AD. In ES, the starting time preceded the onset of AD in those aged ≥ 5–6 years; no difference with adults was found at age 13–14 years. On the other hand, in BF, significant delayed activation was found at ages 3–4 to 11–12 years. While the starting time decreased with age, no significant preceding activation similar to adults was found, even at age 13–14 years. In TA, no significant difference with the onset of AD was found at age 3–6 years, and significant delayed activation was found at age ≥ 7–8 years. Significant delayed activation in GcM, SOL, RA, and RF was observed in all age groups, and no age-related changes were observed in children.

Conclusion

These findings could provide standard values from childhood to adolescence for age-related changes in anticipatory postural muscle activity during voluntary movement while standing and contribute to applications in the fields of sports and rehabilitation.
Feasibility study on calculating the Q value of shallow media by using a dense seismic array and a large-volume airgun source
Authors: Du Shen , Yu YanXiang , Xiao Liang
Published: May 2022

The feasibility of using a dense seismic array with an airgun source to study the quality factors of shallow media is verified. Data were obtained from 37 stations in the dense seismic array located in Binchuan, Yunnan Province, China, and the amplitude–distance attenuation method and the coda normalization method were applied to calculate the S-wave quality factors in the area. The amplitude–distance attenuation method yielded $${Q}_{s}^{-1}$$

Q

s

-
1

=0.0260 $$\pm$$
±
0.0103, and the frequency-dependent $${Q}_{s}^{-1}$$

Q

s

-
1

calculated by the coda normalization method can be expressed by the power law $${Q}_{s}^{-1}(f)\cong 0.0554{f}^{-0.5643}$$

Q

s

-
1

(
f
)

≅
0.0554

f

-
0.5643

. The consistency between the results of these two methods shows that a dense seismic array with an airgun source can be used to study the attenuation characteristics of shallow media. The amplitudes at some points deviate substantially from the fitted curve and thus have a certain influence on the fitting results; hence, we must select high-precision data for the calculation. Given the topography, we speculate that the anomalous stations located on the edge of the Binchuan Basin and in the western hilly area are due to the edge effect of the basin and the weak attenuation of the hilly area and that the anomalous station located in the northern Binchuan depocenter is attributable to local site factors. Compared with the $${Q}_{s}^{-1}$$

Q

s

-
1

estimated by previous studies, the $${Q}_{s}^{-1}$$

Q

s

-
1

in the Binchuan area is found to lie between those of the hard soil and sedimentary rock and is similar to the $${Q}_{s}^{-1}$$

Q

s

-
1

in the North China Basin, corresponding to the shallow velocity structure in this area.

Graphical Abstract