bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Mutant αB Crystallin‐Induced Protein Aggregation by a Molecular Tweezer
Authors: Xu Na , Bitan Gal , Schrader Thomas , Klärner Frank‐Gerrit , Osinska Hanna , Robbins Jeffrey 
Published: September 2017

Background

Compromised protein quality control causes the accumulation of misfolded proteins and intracellular aggregates, contributing to cardiac disease and heart failure. The development of therapeutics directed at proteotoxicity‐based pathology in heart disease is just beginning. The molecular tweezer
CLR
01 is a broad‐spectrum inhibitor of abnormal self‐assembly of amyloidogenic proteins, including amyloid β‐protein, tau, and α‐synuclein. This small molecule interferes with aggregation by binding selectively to lysine side chains, changing the charge distribution of aggregation‐prone proteins and thereby disrupting aggregate formation. However, the effects of
CLR
01 in cardiomyocytes undergoing proteotoxic stress have not been explored. Here we assess whether
CLR
01 can decrease cardiac protein aggregation catalyzed by cardiomyocyte‐specific expression of mutated αB‐crystallin (Cry

AB
R

120G
).

Methods and Results

A proteotoxic model of desmin‐related cardiomyopathy caused by cardiomyocyte‐specific expression of Cry

AB
R

120G
was used to test the efficacy of
CLR
01 therapy in the heart. Neonatal rat cardiomyocytes were infected with adenovirus expressing either wild‐type Cry
AB
or Cry

AB
R

120G
. Subsequently, the cells were treated with different doses of
CLR
01 or a closely related but inactive derivative,
CLR
03.
CLR
01 decreased aggregate accumulation and attenuated cytotoxicity caused by Cry

AB
R

120G
expression in a dose‐dependent manner, whereas
CLR
03 had no effect. Ubiquitin‐proteasome system function was analyzed using a ubiquitin‐proteasome system reporter protein consisting of a short degron,
CL
1, fused to the
COOH
‐terminus of green fluorescent protein.
CLR
01 improved proteasomal function in Cry

AB
R

120G
cardiomyocytes but did not alter autophagic flux. In vivo,
CLR
01 administration also resulted in reduced protein aggregates in Cry

AB
R

120G
transgenic mice.

Conclusions

CLR
01 can inhibit Cry

AB
R

120G
aggregate formation and decrease cytotoxicity in cardiomyocytes undergoing proteotoxic stress, presumably through clearance of the misfolded protein via increased proteasomal function.
CLR
01 or related compounds may be therapeutically useful in treating the pathogenic sequelae resulting from proteotoxic heart disease.
Exposure to Violence and Carotid Artery Intima‐Media Thickness in Mexican Women
Authors: Flores‐Torres Mario H. , Lynch Rebekka , Lopez‐Ridaura Ruy , Yunes Elsa , Monge Adriana , Ortiz‐Panozo Eduardo , Cantu‐Brito Carlos , Hauksdóttir Arna , Valdimarsdóttir Unnur , Lajous Martín 
Published: September 2017

Background
Violence against women has become a global public health threat. Data on the potential impact of exposure to violence on cardiovascular disease are scarce.

Methods and Results
We evaluated the association between exposure to violence and subclinical cardiovascular disease in 634 disease‐free women from the Mexican Teachers' Cohort who responded to violence‐related items from the Life Stressor Checklist and underwent measures of carotid artery intima‐media thickness in 2012 and 2013. We defined exposure to violence as having ever been exposed to physical and/or sexual violence. Intima‐media thickness was log‐transformed, and subclinical carotid atherosclerosis was defined as intima‐media thickness ≥0.8 mm or plaque. We used multivariable linear and logistic regression models adjusted for several potential confounders. Mean age was 48.9±4.3 years. Close to 40% of women reported past exposure to violence. The lifetime prevalence of sexual violence was 7.1%, and prevalence of physical violence was 23.5% (7.7% reported both sexual and physical violence). Relative to women with no history of violence, exposure to violence was associated with higher intima‐media thickness (adjusted mean percentage difference=2.4%; 95% confidence interval 0.5, 4.3) and subclinical atherosclerosis (adjusted odds ratio=1.60; 95% confidence interval 1.10, 2.32). The association was stronger for exposure to physical violence, especially by mugging or physical assault by a stranger (adjusted mean % difference=4.6%; 95% confidence interval 1.8, 7.5, and odds ratio of subclinical carotid atherosclerosis=2.06; 95% confidence interval 1.22, 3.49).

Conclusions
Exposure to violence, and in particular assault by a stranger, was strongly associated with subclinical cardiovascular disease in Mexican middle‐aged women.
Left Atrial Size and Long‐Term Risk of Recurrent Stroke After Acute Ischemic Stroke in Patients With Nonvalvular Atrial Fibrillation
Authors: Ogata Toshiyasu , Matsuo Ryu , Kiyuna Fumi , Hata Jun , Ago Tetsuro , Tsuboi Yoshio , Kitazono Takanari , Kamouchi Masahiro , Ibayashi Setsuro , Kusuda Kenji , Fujii Kenichiro , Nagao Tetsuhiko , Okada Yasushi , Yasaka Masahiro , Ooboshi Hiroaki , Irie Katsumi , Omae Tsuyoshi , Nakane Hiroshi , Sugimori Hiroshi , Arakawa Shuji , Fukuda Kenji , Kitayama Jiro , Fujimoto Shigeru , Arihiro Shoji , Kuroda Junya , Wakisaka Yoshinobu , Fukushima Yoshihisa , Kumai Yasuhiro , Makihara Noriko , Takada Junichi 
Published: September 2017

Background
Among patients with ischemic stroke and atrial fibrillation, which ones are at high risk of recurrent stroke is unclear. This study aimed to determine whether left atrial size was associated with long‐term risk of stroke recurrence in patients with nonvalvular atrial fibrillation.

Methods and Results

In this multicenter prospective cohort study, nonvalvular atrial fibrillation patients hospitalized for acute ischemic stroke were enrolled and followed up after discharge. Indexed‐left atrial diameter was obtained by dividing left atrial diameter by body surface area. Cause‐specific and subdistribution hazard ratios of recurrent stroke were estimated by Cox proportional hazards and Fine–Gray models, respectively. Risk prediction was evaluated by integrated discrimination improvement and net reclassification improvement. In total, 1611 patients (77.8±10.2 [mean±
SD
] years, 44.5% female) were included. During follow‐up for 2.40±1.63 (mean±
SD
) years, 251 patients had recurrent stroke and 514 patients died. An increased indexed‐left atrial diameter (per 1 cm/m
2
) was significantly associated with elevated risk of stroke recurrence (hazard ratio 1.60, 95%
CI
1.30–1.98). The association was maintained when death was regarded as the competing risk and in 1464 patients who were treated with anticoagulants (hazard ratio 1.59, 95%
CI
1.27–2.00). Risk prediction for recurrent stroke was significantly improved by adding indexed‐left atrial diameter to the baseline model composed of the factors in the
CHADS
2
score or those in the
CHA
2
DS
2
‐
VAS
c score.

Conclusion
These findings suggest that left atrial enlargement is associated with an increased risk of recurrent stroke in nonvalvular atrial fibrillation patients with ischemic stroke.
Impact of Spontaneous Extracranial Bleeding Events on Health State Utility in Patients with Atrial Fibrillation: Results from the ENGAGE AF‐TIMI 48 Trial
Authors: Wang Kaijun , Li Haiyan , Kwong Winghan J. , Antman Elliott M. , Ruff Christian T. , Giugliano Robert P. , Cohen David J. , Magnuson Elizabeth A. ,   the ENGAGE AF‐TIMI 48 Trial Investigators
Published: September 2017

Background
The impact of different types of extracranial bleeding events on health‐related quality of life and health‐state utility among patients with atrial fibrillation is not well understood.

Methods and Results

The
ENGAGE AF
‐
TIMI
48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) Trial compared edoxaban with warfarin with respect to the prevention of stroke or systemic embolism in atrial fibrillation. Data from the EuroQol‐5D (
EQ
‐5D‐3L) questionnaire, prospectively collected at 3‐month intervals for up to 48 months, were used to estimate the impact of different categories of bleeding events on health‐state utility over 12 months following the event. Longitudinal mixed‐effect models revealed that major gastrointestinal bleeds and major nongastrointestinal bleeds were associated with significant immediate decreases in utility scores (−0.029 [−0.044 to −0.014;
P
<0.001] and −0.029 [−0.046 to −0.012;
P
=0.001], respectively). These effects decreased in magnitude over time, and were no longer significant for major nongastrointestinal bleeds at 9 months, but remained borderline significant for major gastrointestinal bleeds at 12 months. Clinically relevant nonmajor and minor bleeds were associated with smaller but measurable immediate impacts on utility (−0.010 [−0.016 to −0.005] and −0.016 [−0.024 to −0.008];
P
<0.001 for both), which remained relatively constant and statistically significant over the 12 months following the bleeding event.

Conclusions
All categories of bleeding events were associated with negative impacts on health‐state utility in patients with atrial fibrillation. Major bleeds were associated with relatively large immediate decreases in utility scores that gradually diminished over 12 months; clinically relevant nonmajor and minor bleeds were associated with smaller immediate decreases in utility that persisted over 12 months.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov/
. Unique identifier: NCT00781391.
Ultraviolet B Exposure Inhibits Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Mice by Expanding CD4
+
Foxp3
+
Regulatory T Cells
Authors: Hayashi Tomohiro , Sasaki Naoto , Yamashita Tomoya , Mizoguchi Taiji , Emoto Takuo , Amin Hilman Zulkifli , Yodoi Keiko , Matsumoto Takuya , Kasahara Kazuyuki , Yoshida Naofumi , Tabata Tokiko , Kitano Naoki , Fukunaga Atsushi , Nishigori Chikako , Rikitake Yoshiyuki , Hirata Ken‐ichi 
Published: September 2017

Background

Pathogenic immune responses are known to play an important role in abdominal aortic aneurysm (
AAA
) development. Ultraviolet B (
UVB
) irradiation has been demonstrated to have therapeutic potential not only for cutaneous diseases but also for systemic inflammatory diseases in mice by suppressing immunoinflammatory responses. We investigated the effect of
UVB
irradiation on experimental
AAA
.

Methods and Results

We used an angiotensin
II
–induced
AAA
model in apolipoprotein E–deficient mice fed a high‐cholesterol diet. Mice aged 10 weeks were irradiated with 5 kJ/m
2
UVB
once weekly for 6 weeks (
UVB
‐irradiated, n=38; nonirradiated, n=42) and were euthanized for evaluation of
AAA
formation at 16 weeks. Overall, 93% of angiotensin
II
–infused mice developed
AAA
, with 60% mortality possibly because of aneurysm rupture.
UVB
irradiation significantly decreased the incidence (66%) and mortality (29%) of
AAA
(
P
=0.004 and
P
=0.006, respectively).
UVB
‐irradiated mice had significantly smaller diameter
AAA
(
P
=0.008) and fewer inflammatory cells in the aortic aneurysm tissue than nonirradiated mice, along with systemic expansion of
CD
4
+
Foxp3
+
regulatory T cells and decreased effector
CD
4
+
CD
44
high
CD
62L
low
T cells in para‐aortic lymph nodes. Genetic depletion of regulatory T cells abrogated these beneficial effects of
UVB
treatment, demonstrating a critical role of regulatory T cells.

Conclusions

Our data suggest that
UVB
‐dependent expansion of regulatory T cells has beneficial effects on experimental
AAA
and may provide a novel strategy for the treatment of
AAA
.
Climate- and Environment-Induced Intervillage Migration in Southwestern Burkina Faso, West Africa
Authors: Sanfo Safiétou , Fonta William M. , Diasso Ulrich J. , Nikiéma Michel P. , Lamers John P. A. , Tondoh Jerôme E. 
Published: September 2017

AbstractThis study investigated key environmental factors causing intervillage migration by farmers. Therefore, it used household data from surveys, semistructured interviews, life histories, and focus group discussions in southwestern Burkina Faso, West Africa. The results showed that 1) when referring to the experienced historical weather and climate, farmers were aware of the effects of ongoing climate and environmental change; 2) soil degradation, land tenure insecurity, and lack of rainfall were major drivers of environment-induced migration; and 3) soil fertility, productivity, rainfall, and humidity, as well as land tenure security, were major pull factors. Farmers indirectly identified population pressure as a major driver of intervillage migration since it contributes to land degradation and land tenure insecurity. It is argued that migration implicitly adds to the natural climate and environmental stresses. When aiming to elaborate suitable land-use planning, the findings call for additional research that is needed to understand better the complex interrelationships between environmental drivers and permanent, environment-driven intervillage migration.
Mental health risks and stressors faced by urban refugees: Perceived impacts of war and community adversities among Somali refugees in Nairobi
Authors: Im Hyojin , Ferguson Aidan B , Warsame Abdilkadir H , Isse Maimuna M 
Published: September 2017

Background: There is a gap in understanding of refugee mental health risks unique to urban areas of low-income countries. Material: A qualitative rapid appraisal using focus group interviews with community stakeholders explored main stressors pervasive by Somali refugees in Nairobi, Kenya. Discussion: This study identified the intersection of war trauma and daily stressors that affect both functional and structural challenges and risk of mental health issues among Somali urban refugees. Conclusion: Findings underscore the importance of understanding mental health in the broader context of community adversities, suggesting development of contextually informed interventions responsive to complex needs of urban refugees.
The Component Timed-Up-and-Go test: the utility and psychometric properties of using a mobile application to determine prosthetic mobility in people with lower limb amputations
Authors: Clemens Sheila M , Gailey Robert S , Bennett Christopher L , Pasquina Paul F , Kirk-Sanchez Neva J , Gaunaurd Ignacio A 
Published: September 2017

Objective: Using a custom mobile application to evaluate the reliability and validity of the Component Timed-Up-and-Go test to assess prosthetic mobility in people with lower limb amputation. Design: Cross-sectional design. Setting: National conference for people with limb loss. Subjects: A total of 118 people with non-vascular cause of lower limb amputation participated. Subjects had a mean age of 48 (±13.7) years and were an average of 10 years post amputation. Of them, 54% ( n = 64) of subjects were male. Intervention: None. Main measure: The Component Timed-Up-and-Go was administered using a mobile iPad application, generating a total time to complete the test and five component times capturing each subtask (sit to stand transitions, linear gait, turning) of the standard timed-up-and-go test. The outcome underwent test–retest reliability using intraclass correlation coefficients (ICCs) and convergent validity analyses through correlation with self-report measures of balance and mobility. Results: The Component Timed-Up-and-Go exhibited excellent test–retest reliability with ICCs ranging from .98 to .86 for total and component times. Evidence of discriminative validity resulted from significant differences in mean total times between people with transtibial (10.1 (SD: ±2.3)) and transfemoral (12.76 (SD: ±5.1) amputation, as well as significant differences in all five component times ( P < .05). Convergent validity of the Component Timed-Up-and-Go was demonstrated through moderate correlations with the PLUS-M ( rs = −.56). Conclusion: The Component Timed-Up-and-Go is a reliable and valid clinical tool for detailed assessment of prosthetic mobility in people with non-vascular lower limb amputation. The iPad application provided a means to easily record data, contributing to clinical utility.
The Therapeutic Effect of Intra-articular Normal Saline Injections for Knee Osteoarthritis: A Meta-analysis of Evidence Level 1 Studies
Authors: Saltzman Bryan M. , Leroux Timothy , Meyer Maximilian A. , Basques Bryce A. , Chahal Jaskarndip , Bach Bernard R. , Yanke Adam B. , Cole Brian J. 
Published: September 2017

Background: Intra-articular normal saline (IA-NS) injections have been utilized as a placebo in a number of randomized controlled trials pertaining to the management of knee osteoarthritis (OA); however, it is believed that these “placebo” injections may have a therapeutic effect that has not been quantified in the literature. Purpose: To (1) quantify the effect of IA-NS injections on patient-reported outcomes (PROs) and (2) compare postinjection PROs to established minimal clinically important difference (MCID) criteria to demonstrate a potential therapeutic effect. Study Design: Meta-analysis. Methods: A review was conducted to identify all randomized, placebo-controlled trials on injection therapy for knee OA between 2006 and 2016. Patient demographics and PROs before the injection and at 3 and 6 months after the injection were collected for patients in the IA-NS injection group in each study. A random-effects model was used to compare preinjection scores and scores at each postinjection time point in a pairwise fashion. Results: In total, there were 14 placebo cohorts in 13 studies that were analyzed after meeting inclusion criteria for this meta-analysis. This included 1076 patients (Kellgren-Lawrence grade 1-4), with a weighted mean age of 62.53 years and mean body mass index of 28.67 kg/m2. There was only sufficient information to perform analyses of visual analog scale (VAS) pain and Western Ontario and McMaster Universities Arthritis Index (WOMAC) total scores. At 3 months after the IA-NS placebo injection, there was a significant improvement in VAS pain scores (mean difference [MD], 12.10 [95% CI, 3.27 to 20.93]; P = .007), whereas improvement in the WOMAC total scores approached but did not reach statistical significance (MD, 19.75 [95% CI, –0.50 to 40.09]; P = .06). At 6 months, both VAS pain scores (MD, 16.62 [95% CI, 12.13-21.10]; P < .00001) and WOMAC total scores (MD, 11.34 [95% CI, 7.03-15.65]; P < .00001) were significantly improved in comparison to preinjection values. Furthermore, improvements in both the VAS pain and WOMAC total scores at 6 months were clinically significant (MCID, 1.37 and 9, respectively). Conclusion: The administration of an IA-NS placebo injection yields a statistically and clinically meaningful improvement in PROs up to 6 months after the injection in patients with knee OA. This observation supports the notion that the so-called placebo effect for IA-NS injections achieves a clinically meaningful response in patients with OA when provided during comparison studies to an active treatment group (ie, hyaluronic acid).
Quality Improvement Initiative to Reduce Pediatric Intensive Care Unit Noise Pollution With the Use of a Pediatric Delirium Bundle
Authors: Kawai Yu , Weatherhead Jeffrey R. , Traube Chani , Owens Tonie A. , Shaw Brenda E. , Fraser Erin J. , Scott Annette M. , Wojczynski Melody R. , Slaman Kristen L. , Cassidy Patty M. , Baker Laura A. , Shellhaas Renee A. , Dahmer Mary K. , Shever Leah L. , Malas Nasuh M. , Niedner Matthew F. 
Published: September 2017

Objectives: Noise pollution in pediatric intensive care units (PICU) contributes to poor sleep and may increase risk of developing delirium. The Environmental Protection Agency (EPA) recommends <45 decibels (dB) in hospital environments. The objectives are to assess the degree of PICU noise pollution, to develop a delirium bundle targeted at reducing noise, and to assess the effect of the bundle on nocturnal noise pollution. Methods: This is a QI initiative at an academic PICU. Thirty-five sound sensors were installed in patient bed spaces, hallways, and common areas. The pediatric delirium bundle was implemented in 8 pilot patients (40 patient ICU days) while 108 non-pilot patients received usual care over a 28-day period. Results: A total of 20,609 hourly dB readings were collected. Hourly minimum, average, and maximum dB of all occupied bed spaces demonstrated medians [interquartile range] of 48.0 [39.0-53.0], 52.8 [48.1-56.2] and 67.0 [63.5-70.5] dB, respectively. Bed spaces were louder during the day (10AM to 4PM) than at night (11PM to 5AM) (53.5 [49.0-56.8] vs. 51.3 [46.0-55.3] dB, P < 0.01). Pilot patient rooms were significantly quieter than non-pilot patient rooms at night (n=210, 45.3 [39.7-55.9]) vs. n=1841, 51.2 [46.9-54.8] dB, P < 0.01). The pilot rooms compliant with the bundle had the lowest hourly nighttime average dB (44.1 [38.5-55.5]). Conclusions: Substantial noise pollution exists in our PICU, and utilizing the pediatric delirium bundle led to a significant noise reduction that can be perceived as half the loudness with hourly nighttime average dB meeting the EPA standards when compliant with the bundle.
Steady-state pharmacokinetics of hydroxychloroquine in patients with cutaneous lupus erythematosus
Authors: Al-Rawi H , Meggitt S J , Williams F M , Wahie S 
Published: September 2017

Background Hydroxychloroquine (HCQ), a 4-aminoquinolone antimalarial, is regarded as the oral therapy of choice for cutaneous and systemic lupus erythematosus (SLE). It is also licensed for rheumatoid arthritis (RA). Studies of HCQ-treated patients with SLE or RA have demonstrated a positive correlation between whole-blood HCQ levels and clinical response. Such studies have involved measuring whole-blood concentrations at any given time point after HCQ ingestion assuming that steady-state concentrations would undergo limited fluctuation over a daily interval because HCQ has a long half-life. This approach might not sufficiently take into account the potential intra-patient variation in HCQ blood levels that can occur over a 24-hour period. Such variation, if significant, could affect the credibility of any concentration-response relationship provided from these previous studies. Objectives The objectives of this report are to: (a) investigate the intra-patient variation in HCQ whole-blood levels and (b) suggest an optimum time for sampling patients for future studies. Methods Six patients were recruited with cutaneous lupus erythematosus who had each been on HCQ 200 mg twice daily for at least six months, so that they were at steady-state. Each patient was fasted overnight and had standardized meals and dosing schedule. Whole blood was sampled at seven time points over 24 hours. Whole-blood HCQ levels were measured with high-performance liquid chromatography using gradient elution, fluorimetric detection and chloroquine as an internal standard. The assay had a mean inter- and intra-day coefficient of variation of 10% and 5% respectively and a limit of detection of 5ng/ml. Results HCQ levels appeared to follow a biphasic pattern over the sampling period. Maximum levels were noted a median of four hours (range 2–6) after ingestion. Median intra-patient variation between trough and peak levels, ‘Cmax’ ((peak – trough)/trough × 100%), was 27% (range 8–150%). Conclusions This study demonstrated that whole-blood HCQ levels vary 27% (median, range 8–150%) within an individual over a 12-hour period. Drug levels might differ between individuals because of multiple factors, including variable adherence to medication. Measuring HCQ levels for assessment of drug adherence could be valuable in the ‘real-world’ clinical setting. This could be assessed by taking a blood sample at any time following HCQ ingestion. If patients were found to have very low or undetectable levels of HCQ, non-adherence to HCQ should be suspected.