bluuebunny/crossref_metadata_2025 huggingface dataset:
The factors associated with the trend in incidence of Bacteraemia and associated mortality over 30 years
Authors: García-Rodríguez J. F. , Mariño-Callejo A.
Published: February 2023

Background

Studies have reported increased incidence of BSI over the past decades and indicate that it is necessary to investigate the causes. The aim of this study was to determine the factors affecting trends in the incidence of bacteraemias and associated mortality.

Methods

We conducted a retrospective cohort study assessing prospectively collected data of all clinically significant bacteraemias between 1991 and 2020 in a 450-bed hospital. We determined the evolution of bacteraemia-associated incidence, adjusted 30-day mortality and performed multivariable logistic regression to compare the evolution of variables associated with mortality between 5-year periods.

Results

6777 episodes were included, 59.7% males, age 66.5 ± 18.2, 39.4% ≥ 75 years. The incidence total increased: 43.8/100,000/year in 1991–1995 to 205 in 2016–2020; community-acquired bacteraemia (24.9 to 139) and hospital-acquired (0.36/1000 inpatients-days to 1.09). Bacteraemia with source in vascular catheter, urinary and biliary tract increased. The 30-day mortality rate of patients was 1179/6777 (17.4%) in the whole series and population-adjusted mortality incidence increased from 11.4/100,000 in 1991–1996 to 28.4 in 2016–2020 (RR 2.49, 95% CI 2.01–3.08). Mortality was higher in men (18.2% vs 16.3%) and those over 74 years (22.2% vs 14.3%). Appropriate empirical antimicrobial treatment improved (66.5% to 73.1%), 30-day mortality of patients decreased from 26.1 to 13.9%. When comparing the evolution of the factors associated with mortality between 1991 and 1996 vs 2016–2020, the frequency of some variables associated with higher mortality increased: male sex (OR 1.38, 95% CI 1.10–1,74), age (OR 1.02, 1.01–10.3), immunosuppressive treatment (OR 3.1, 2.09–4.6), polymicrobial bacteraemia (OR 1.76, 1.12–2.79), and others decreased: severe sepsis/septic shock (OR 0.70, 0.52–0.93), spontaneous bacterial peritonitis in cirrhosis (OR 0.06, 0.02–0.23), endocarditis (OR 0.54, 0.35–0.83); on the other hand, the frequency of factors associated with lower mortality increased: urinary (OR 1.67, 95% CI 1.23–2.27) and bile tract source (OR 1.59, 1.04–2.43), and adequate empirical treatment (OR 1.42, 95% CI 1.10–1.83).

Conclusions

The incidence of bacteraemia increased due to more elderly, co-morbid patients undergoing procedures and more device related bacteraemia. The percentage of mortality decreased because adequate empirical treatment improved, decreased spontaneous bacterial peritonitis in cirrhosis and endocarditis, and increased bacteraemia of urinary and biliary tract source.
Candida bloodstream infection among children hospitalised in three public-sector hospitals in the Metro West region of Cape Town, South Africa
Authors: Gebremicael Mulugeta Naizgi , Nuttall James J. C. , Tootla Hafsah D. , Khumalo Amanda , Tooke Lloyd , Salie Shamiel , Muloiwa Rudzani , Rhoda Natasha , Basera Wisdom , Eley Brian S.
Published: February 2023

Background

Candida bloodstream infection (BSI) causes appreciable mortality in neonates and children. There are few studies describing the epidemiology of Candida BSI in children living in sub-Saharan Africa.

Methods

A retrospective descriptive study was conducted at three public sector hospitals in Cape Town, South Africa. Demographic and clinical details, antifungal management and patient outcome data were obtained by medical record review. Candida species distribution and antifungal susceptibility testing results were obtained from the National Health Laboratory Service database.

Results

Of the 97 Candida BSI episodes identified during a five-year period, 48/97 (49%) were Candida albicans (C. albicans), and 49/97 (51%) were non-C. albicans species. The overall incidence risk was 0.8 Candida BSI episodes per 1000 admissions at Red Cross War Memorial Children’s Hospital. Of the 77/97 (79%) Candida BSI episodes with available clinical information, the median age (interquartile range) at the time of BSI was 7 (1–25) months, 36/77 (47%) were associated with moderate or severe underweight-for-age and vasopressor therapy was administered to 22/77 (29%) study participants. Most of the Candida BSI episodes were healthcare-associated infections, 63/77 (82%). Fluconazole resistance was documented among 17%, 0% and 0% of C. parapsilosis, C. tropicalis and C. albicans isolates, respectively. All Candida isolates tested were susceptible to amphotericin B and the echinocandins. The mortality rate within 30 days of Candida BSI diagnosis was 13/75 (17%). On multivariable analysis, factors associated with mortality within 30 days of Candida BSI diagnosis included vasopressor therapy requirement during Candida BSI, adjusted Odds ratio (aOR) 53 (95% confidence interval 2–1029); hepatic dysfunction, aOR 13 (95% CI 1–146); and concomitant bacterial BSI, aOR 10 (95% CI 2–60).

Conclusion

The study adds to the limited number of studies describing paediatric Candida BSI in sub-Saharan Africa. Non-C. Albicans BSI episodes occurred more frequently than C. albicans episodes, and vasopressor therapy requirement, hepatic dysfunction and concomitant bacterial BSI were associated with an increase in 30-day mortality.
Association between epidemiologic case definition categories and adverse clinical outcome in patients with Clostridiodes difficile infection in San Francisco County, California: a five-year retrospective cohort study
Authors: Siraw Bekure B. , Reingold Arthur L. , Meyahnwi Didien
Published: February 2023

Background

Understanding the predictors of adverse clinical outcomes following incident Clostridiodes difficile infection (CDI) can help clinicians identify which patients are at risk of complications and help prioritize the provision of their care. In this study, we assessed the associations between epidemiologic case definition categories and adverse clinical outcomes in patients with CDI in San Francisco County, California.

Methods

We conducted a retrospective cohort study using CDI surveillance data (n = 3274) from the California Emerging Infections Program for the time period 2016 to 2020. After independent associations were established, two multivariable logistic and log-binomial regression models were constructed for the final statistical analysis.

Result

The mean cumulative incidence of CDI cases was 78.8 cases per 100,000 population. The overall recurrence rate and the 30-day all-cause mortality rate were 11.1% and 4.5%, respectively. After adjusting for potential confounders, compared to the community associated CDI cases, healthcare facility onset (AOR = 3.1; 95% CI [1.3–7]) and community-onset-healthcare facility associated (AOR = 2.4; 95% CI [1.4–4.3]) CDI cases were found to have higher odds of all-cause 30-day mortality. Community onset-healthcare facility-associated CDI case definition category was found to be significantly associated with an increased risk of recurrence of CDI (ARR = 1.7; 95% CI [1.2–2.4]).

Conclusion

Although the incidence of community-associated CDI cases has been rising, the odds of all-cause 30-day mortality and the risk of recurrent CDI associated with these infections are lower than healthcare facility onset and community-onset healthcare facility-associated CDI cases.
Safety and tolerability of adjunct non-invasive vagus nerve stimulation in people with parkinson’s: a study protocol
Authors: Sigurdsson Hilmar P. , Hunter Heather , Alcock Lisa , Wilson Ross , Pienaar Ilse , Want Elizabeth , Baker Mark R. , Taylor John-Paul , Rochester Lynn , Yarnall Alison J.
Published: February 2023

Background

Parkinson’s disease (PD) is the fastest growing neurological condition worldwide. Recent theories suggest that symptoms of PD may arise due to spread of Lewy-body pathology where the process begins in the gut and propagate transynaptically via the vagus nerve to the central nervous system. In PD, gait impairments are common motor manifestations that are progressive and can appear early in the disease course. As therapies to mitigate gait impairments are limited, novel interventions targeting these and their consequences, i.e., reducing the risk of falls, are urgently needed. Non-invasive vagus nerve stimulation (nVNS) is a neuromodulation technique targeting the vagus nerve. We recently showed in a small pilot trial that a single dose of nVNS improved (decreased) discrete gait variability characteristics in those receiving active stimulation relative to those receiving sham stimulation. Further multi-dose, multi-session studies are needed to assess the safety and tolerability of the stimulation and if improvement in gait is sustained over time.

Design

This will be an investigator-initiated, single-site, proof-of-concept, double-blind sham-controlled randomised pilot trial in 40 people with PD. Participants will be randomly assigned on a 1:1 ratio to receive either active or sham transcutaneous cervical VNS. All participants will undergo comprehensive cognitive, autonomic and gait assessments during three sessions over 24 weeks, in addition to remote monitoring of ambulatory activity and falls, and exploratory analyses of cholinergic peripheral plasma markers. The primary outcome measure is the safety and tolerability of multi-dose nVNS in PD. Secondary outcomes include improvements in gait, cognition and autonomic function that will be summarised using descriptive statistics.

Discussion

This study will report on the proportion of eligible and enrolled patients, rates of eligibility and reasons for ineligibility. Adverse events will be recorded informing on the safety and device tolerability in PD. This study will additionally provide us with information for sample size calculations for future studies and evidence whether improvement in gait control is enhanced when nVNS is delivered repeatedly and sustained over time.

Trial registration

This trial is prospectively registered at www.isrctn.com/ISRCTN19394828. Registered August 23, 2021.
Correlates of repeat pregnancies among adolescent girls and young women in sub-Saharan Africa
Authors: Ahinkorah Bright Opoku , Aboagye Richard Gyan , Okyere Joshua , Seidu Abdul-Aziz , Budu Eugene , Yaya Sanni
Published: February 2023

Background

Adolescent girls and young women are vulnerable populations who are at risk of several adverse sexual and reproductive health outcomes, including unintended pregnancies, sexually transmitted infections, unsafe abortions, and death from pregnancy-related complications. In this study, we examined the correlates of repeat pregnancies among adolescent girls and young women in sub-Saharan Africa (SSA).

Methods

We extracted data from the most recent Demographic and Health Surveys (DHS) of 31 countries in SSA. Countries whose surveys were conducted from 2010 to 2020 were included in the study. A total of 108,572 adolescent girls and young women (15–24 years) were included in the study. We used a multilevel mixed-effect binary logistic regression analysis to examine the correlates of repeat pregnancies among adolescent girls and young women in SSA.

Results

We found that adolescent girls and young women aged 20–24 [aOR = 2.36; 95%CI = 2.22, 2.51], those married [aOR = 7.52; 95%CI = 6.81, 8.30], living with a partner [aOR = 7.51; 95%CI = 6.87, 8.21], and those who had sexual intercourse before age 20 [aOR = 1.41; 95%CI = 1.33, 1.51] had higher odds of experiencing repeat pregnancies compared to those aged 15–19, those never in a union, those whose first sexual intercourse occurred at age 20 and above, respectively. Respondents exposed to listening to radio [aOR = 1.12; 95%CI = 1.06, 1.18] and those who justified intimate partner violence [aOR=1.13; 95%CI = 1.07, 1.19] had higher odds of experiencing repeat pregnancies compared to those who never listened to radio and those who did not justify intimate partner violence, respectively. Young women who had attained secondary or higher educational level [aOR = 0.83; 95%CI = 0.78, 0.90], those exposed to reading newspaper or magazine [aOR = 0.90; 95%CI = 0.82, 0.98], those residing in rural areas [aOR = 0.92; 95%CI = 0.86, 0.98], and those belonging to the richer [aOR = 0.87; 95%CI = 0.80, 0.95] and richest [aOR = 0.68; 95%CI = 0.61, 0.76] wealth quintile were less likely to experience repeat pregnancies.

Conclusion

The correlates of repeat pregnancies include age, age at first sexual intercourse, marital status, exposure to media, justification of intimate partner violence, wealth index, educational attainment, and place of residence. The findings underscore the need for governments and policymakers in SSA to implement policies that target the most at-risk groups: those with no formal education, the poor, and adolescent girls. Our findings also highlight the need to strengthen advocacy against the justification of intimate partner violence and intensify girl-child education.
Obstetric and perinatal outcomes following frozen and fresh embryo transfer in patients with endometrial hyperplasia and carcinoma: a retrospective study in a high-volume reproductive center
Authors: Zong Xuan , Guo Yaxing , Li Hongzhen , Li Rong , Qiao Jie
Published: February 2023

Background

There is ongoing debate regarding which embryo transfer procedure can achieve a higher live birth rate. Research has suggested that frozen ET might be beneficial for certain populations, such as hyper-responders. This study aimed to compare outcomes of pregnancies between frozen and fresh embryo transfer cycles in patients with endometrial hyperplasia and carcinoma.

Methods

This retrospective cohort study was conducted at a high-volume reproductive center from January 2010 to January 2022. Patients who were diagnosed with endometrial hyperplasia with atypia and endometrial carcinoma were included. They all underwent in vitro fertilization after conservative treatment. The primary outcome was live birth after frozen and fresh embryo transfer cycles, and secondary outcomes included perinatal complications and other pregnancy outcomes.

Results

Overall, 259 ET cycles (130 fresh and 129 frozen) were included. The rate of live births per embryo transfer cycle of the whole cohort was 20.8% (54/259), and no significant between-group difference was found after adjusting for potential confounding factors (23.8% vs. 17.8%; adjusted OR, 0.47; 95% CI, 0.21-1.06; p=0.068). Compared to fresh embryo transfer group, the incidence of total maternal complications in the frozen embryo transfer group was significantly higher (30.4% vs. 6.5%, p=0.019). Analyzing each complication as a separate entity, patients in the frozen embryo transfer group had a higher incidence of hypertensive disorders of pregnancy (p=0.028). Multiple logistic regression analysis showed that frozen embryo transfer was related with an increased occurrence of maternal complications (OR, 6.68, 95% CI, 1.01-44.19, p=0.040).

Conclusions

Among patients with endometrial hyperplasia and carcinoma, the rate of live births was comparable between both embryo transfer procedures, while frozen embryo transfer might be associated with a higher risk of maternal complications compared to that with fresh embryo transfer.
Depletion of SOD2 enhances nasopharyngeal carcinoma cell radiosensitivity via ferroptosis induction modulated by DHODH inhibition
Authors: Amos Alvan , Jiang Ning , Zong Dan , Gu Jiajia , Zhou Jiawei , Yin Li , He Xia , Xu Yong , Wu Lirong
Published: February 2023

Background

Recurrence due to the development of radioresistance remains a major challenge in the clinical management of nasopharyngeal carcinoma. The objective of this study was to increase the sensitivity of nasopharyngeal carcinoma cells to ionizing radiation by enhancing oxidative stress and ferroptosis caused by disrupting the mitochondrial anti-oxidant enzyme system.

Methods

Oxidative stress cell model was constructed by SOD2 knockdown using shRNA. The expression and activity of DHODH was suppressed by siRNA and brequinar in SOD2 depleted cells. Protein levels were determined by western blotting and ferroptosis was assessed by C11 BODIPY and malondialdehyde assay. Cell viability was evaluated using CCK-8 assay while radiotoxicity was assessed by colony formation assay. Cellular ATP level was determined by ATP assay kits, ROS was determined by DCFD and DHE, while mitochondrial oxygen consumption was determined by seahorse assay. Data were analyzed by two-tailed independent t-test.

Results

Radiation upregulated SOD2 expression and SOD2 depletion increased cellular O2.−, malondialdehyde, and the fluorescence intensity of oxidized C11 BODIPY. It also resulted in mitochondrial damage. Its depletion decreased colony formation both under ionizing and non-ionizing radiation conditions. The ferroptosis inhibitor, deferoxamine, rescued cell viability and colony formation in SOD2 depleted cells. Cellular level of malondialdehyde, fluorescence intensity of oxidized C11 BODIPY, O2.− level, ATP, and mitochondrial oxygen consumption decreased following DHODH inhibition in SOD2 depleted cells. Cell viability and colony formation was rescued by DHODH inhibition in SOD2 depleted cells.

Conclusion

Inducing oxidative stress by SOD2 inhibition sensitized nasopharyngeal carcinoma cells to ionizing radiation via ferroptosis induction. This was found to be dependent on DHODH activity. This suggests that DHODH inhibitors should be used with caution during radiotherapy in nasopharyngeal carcinoma patients.
The effect of different combinations of physical activity and natural environment videos on children's attention levels between class breaks
Authors: Luo Xiao , Tao Meng , Lu Jiahao , Lu Li , He Xiaolong
Published: February 2023

Background

Physical activity intervention and watching natural environment videos have been proven to improve young children’s attention levels. However, evidence comparing the improvement effects of different combinations of the two activities has rarely been reported. By comparing the differences in the improvement effects of four combinations of physical activities and watching natural environment videos on young children’s attention levels, this study can enrich the evidence in this research field and also provide a reference for arranging effective intervention methods for children’s attention recovery between classes.

Method

A total of 152 children aged 4 to 6 years were recruited and randomly divided into four intervention groups: (1) physical activity intervention first and thereafter watching a natural environment video group (activity + video group), (2) watching a natural environment video first and thereafter the physical activity intervention group (video + activity group), (3) physical activity-based group, and (4) natural environment video-based group. Physical activity involved 4 min of moderate-intensity basic physical fitness combination training. The subjects wore the Pico Neo pioneer version of the VR glasses all-in-one machine to watch a natural environment video. Thereafter, population sociological variables and daily physical activity levels were investigated. Auditory and visual sustained attention tests were performed before and after intervention in each group.

Result

The auditory attention post-test scores of the four groups showed an improvement trend compared with the pretest scores. In particular, the activity + video group (F = 10.828; ɳp2 = 0.226; p = 0.002) and natural environment video-based group (F = 9.452; ɳp2 = 0.203; p = 0.004) have the best improvement effect. For visual attention, only the activity + video group showed a significant improvement trend (F = 4.287; ɳp2 = 0.104; p = 0.045), while the other three groups showed a downward trend in scores.

Conclusions

Among the different intervention combinations, the physical activity intervention first and watching natural environment videos thereafter group has the best effect on improving children’s attention during recess. Physical activity interventions at the end of recess adversely affect young children’s visual attention levels at the beginning of the class. Therefore, this study recommends that children should not engage in physical activity interventions in the second half of the class break. Lastly, the current research recommends presenting the content of physical activity interventions first and further improving their attention thereafter by watching natural environment videos.
Protocol for the Open Sky School: a two-arm clustered randomized controlled trial to test the effectiveness of a nature-based intervention on mental health of elementary school children
Authors: Loose Tianna , Côté Sylvana , Malboeuf-Hurtubise Catherine , Beaudet Jean-Philippe Ayotte , Lessard Geneviève , Chadi Nicholas , Gauvin Lise , Morin Isabelle Ouellet , Geoffroy Marie-Claude
Published: February 2023

Background

This article outlines the protocol for a trial to test the effectiveness of a nature-based intervention called Open Sky School to reduce mental health problems among elementary school children. Experimental studies show that contact with nature (e.g. walks in parks) improve mental health. A growing number of teachers have been applying outdoor education within the regular school curriculum and evidence suggests that such teaching methods could improve students’ mental health but a randomized controlled trial has never been conducted.

Methods

A two-arm clustered randomized controlled trial will be conducted in elementary schools across Québec, Canada. Following informed consent by teachers, parents and students, schools will be randomly assigned 1:1 to the intervention or the control group with a total of 2500 5-6th grade students and 100 teachers expected to participate. The intervention will take place outdoors in a green-space (2 h per week for 12 weeks) and include a toolkit of 30 activities to foster well-being (e.g. mindfulness) and academic competencies (e.g. mathematics). Questionnaires will be administered to teachers and students before, immediately after and 3 months after the intervention. The primary outcome will be reductions of mental health problems in children from pre-to-post test (Social Behavior Questionnaire: self and teacher reports). Secondary outcomes include depression, positive and negative affect, nature connectedness, and pro-environmental behaviors among children. We will explore, immediate benefits on teacher’s well-being and positive and negative affect and sustained benefits among students at 3 months follow-up. For the primary outcome, we will explore moderators including child’s sex, child’s disability status, the green-space of neighbourhoods, the school’s socio-economic position and teacher’s experience.

Discussion

In conducting the first randomized controlled trial of the Open Sky School, our results could provide empirical evidence on the effectiveness of nature-based interventions in reducing mental health problems among elementary school children.

Trial registration

This study was registered with clinicaltrials.gov: NCT05662436 on December 22, 2022.
Impact of a machine learning algorithm on time to palliative care in a primary care population: protocol for a stepped-wedge pragmatic randomized trial
Authors: Heinzen Ethan P. , Wilson Patrick M. , Storlie Curtis B. , Demuth Gabriel O. , Asai Shusaku W. , Schaeferle Gavin M. , Bartley Mairead M. , Havyer Rachel D.
Published: February 2023

Background

As primary care populations age, timely identification of palliative care need is becoming increasingly relevant. Previous studies have targeted particular patient populations with life-limiting disease, but few have focused on patients in a primary care setting. Toward this end, we propose a stepped-wedge pragmatic randomized trial whereby a machine learning algorithm identifies patients empaneled to primary care units at Mayo Clinic (Rochester, Minnesota, United States) with high likelihood of palliative care need.

Methods

42 care team units in 9 clusters were randomized to 7 wedges, each lasting 42 days. For care teams in treatment wedges, palliative care specialists review identified patients, making recommendations to primary care providers when appropriate. Care teams in control wedges receive palliative care under the standard of care.

Discussion

This pragmatic trial therefore integrates machine learning into clinical decision making, instead of simply reporting theoretical predictive performance. Such integration has the possibility to decrease time to palliative care, improving patient quality of life and symptom burden.

Trial registration

Clinicaltrials.gov NCT04604457, restrospectively registered 10/26/2020.

Protocol

v0.5, dated 9/23/2020
Association between career adaptability and turnover intention among nursing assistants: the mediating role of psychological capital
Authors: Sun Changxian , Xing Yurong , Wen Yuting , Wan Xia , Ding Yaping , Cui Yan , Xu Wenhui , Wang Xiaoxiao , Xia Hongling , Zhang Qian , Yuan Min
Published: February 2023

Background

High turnover intention of nursing assistants was detrimental to the sustainability of long-term care. Career adaptability is an important determinant in reducing turnover intention, but little research has explored the mechanism from the perspective of psychological capital. The aim of this study was to analyze the association between career adaptability and turnover intention and to examine the mediating role of psychological capital between career adaptability and turnover intention among nursing assistants in mainland China.

Methods

A cross-sectional online study was conducted among 276 nursing assistants from eight nursing homes in Nanjing, China. The participants’ career adaptability, psychological capital, and turnover intention were obtained. SPSS 26.0 and Amos 24.0 software were employed for statistical analysis.

Results

Career adaptability was positively related to psychological capital and negatively linked to turnover intention (P < 0.01). Psychological capital played a fully mediating role (β = -0.085, P < 0.05) in the relationship between career adaptability and turnover intention, and the largest indirect effect was generated through the curiosity dimension.

Conclusions

The management of long-term care facilities should focus on assessing the level of career adaptability of nursing assistants. The overall improvement of career adaptability and psychological capital is conducive in reducing turnover intention. Targeted interventions are recommended to improve career adaptability and reduce turnover intentions by increasing career curiosity. Online career adaptability programs can be developed for nursing assistant students to improve their psychological capital and facilitate career transitions.
Widespread amyloidogenicity potential of multiple myeloma patient-derived immunoglobulin light chains
Authors: Sternke-Hoffmann Rebecca , Pauly Thomas , Norrild Rasmus K. , Hansen Jan , Tucholski Florian , Høie Magnus Haraldson , Marcatili Paolo , Dupré Mathieu , Duchateau Magalie , Rey Martial , Malosse Christian , Metzger Sabine , Boquoi Amelie , Platten Florian , Egelhaaf Stefan U. , Chamot-Rooke Julia , Fenk Roland , Nagel-Steger Luitgard , Haas Rainer , Buell Alexander K.
Published: February 2023

Background

In a range of human disorders such as multiple myeloma (MM), immunoglobulin light chains (IgLCs) can be produced at very high concentrations. This can lead to pathological aggregation and deposition of IgLCs in different tissues, which in turn leads to severe and potentially fatal organ damage. However, IgLCs can also be highly soluble and non-toxic. It is generally thought that the cause for this differential solubility behaviour is solely found within the IgLC amino acid sequences, and a variety of individual sequence-related biophysical properties (e.g. thermal stability, dimerisation) have been proposed in different studies as major determinants of the aggregation in vivo. Here, we investigate biophysical properties underlying IgLC amyloidogenicity.

Results

We introduce a novel and systematic workflow, Thermodynamic and Aggregation Fingerprinting (ThAgg-Fip), for detailed biophysical characterisation, and apply it to nine different MM patient-derived IgLCs. Our set of pathogenic IgLCs spans the entire range of values in those parameters previously proposed to define in vivo amyloidogenicity; however, none actually forms amyloid in patients. Even more surprisingly, we were able to show that all our IgLCs are able to form amyloid fibrils readily in vitro under the influence of proteolytic cleavage by co-purified cathepsins.

Conclusions

We show that (I) in vivo aggregation behaviour is unlikely to be mechanistically linked to any single biophysical or biochemical parameter and (II) amyloidogenic potential is widespread in IgLC sequences and is not confined to those sequences that form amyloid fibrils in patients. Our findings suggest that protein sequence, environmental conditions and presence and action of proteases all determine the ability of light chains to form amyloid fibrils in patients.
Glucagon-like peptide-1 receptor agonists and diabetic retinopathy: nationwide cohort and Mendelian randomization studies
Authors: Zheng Deqiang , Li Ning , Hou Rui , Zhang Xiaoyu , Wu Lijuan , Sundquist Jan , Sundquist Kristina , Ji Jianguang
Published: February 2023

Background

The ability of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to decrease certain microvascular events has called for the investigation of GLP-1 RAs against diabetic retinopathy (DR), but the evidence is limited. By combining data from observational and Mendelian randomization (MR) studies, we aimed to investigate whether GLP-1 RAs decrease the risk of DR.

Methods

We combined data from several Swedish Registers and identified patients with incident type 2 diabetes being treated with GLP-1 RAs between 2006 and 2015, and matched them to diabetic patients who did not use GLP-1 RAs as the comparisons. The Cox proportional hazards models were applied to assess the risk of DR. We further performed the summary-data-based MR (SMR) analyses based on the Genotype-Tissue Expression databases and the Genome-Wide Association Study of DR from the FinnGen consortium.

Results

A total of 2390 diabetic patients were treated with GLP-1 RAs and the incidence of DR was 5.97 per 1000 person-years. Compared with diabetic patients who did not use GLP-1 RAs having an incidence of 12.85 per 1000 person-years, the adjusted hazard ratio (HR) of DR was 0.42 [95% confidence interval (CI), 0.29–0.61]. Genetically-predicted GLP1R expression (the target of GLP-1 RAs) showed an inverse association with background [odds ratio (OR)=0.83, 95% CI, 0.71–0.97] and severe nonproliferative DR (OR=0.72, 95% CI, 0.53–0.98), and a non-significant association with overall (OR=0.97, 95% CI, 0.92–1.03) and proliferative DR (OR=0.98, 95% CI, 0.91–1.05).

Conclusions

Both observational and mendelian randomization analyses showed a significantly lower risk of DR for patients treated with GLP-1 RAs, which calls for further studies to validate these findings.
Changes in biomarkers of redox status in serum and saliva of dogs with hypothyroidism
Authors: Arostegui Luis G. González , Prieto Alberto Muñoz , Marín Luis Pardo , López Gregorio García , Tvarijonaviciute Asta , Madrigal Jose Joaquín Cerón , Rubio Camila Peres
Published: February 2023

Background

Hypothyroidism is the most common endocrine disorder diagnosed in dogs, leading to deleterious effects on a dog’s life quality. This study aims to evaluate changes in the redox status in canine hypothyroidism. For this purpose, a comprehensive panel of antioxidants and oxidants biomarkers were measured in serum and saliva of 23 dogs with hypothyroidism, 21 dogs with non-thyroidal illness, and 16 healthy dogs. Among the antioxidants, cupric reducing antioxidant capacity (CUPRAC), ferric reducing ability of plasma (FRAP), Trolox equivalent antioxidant capacity (TEAC), thiol, paraoxonase type 1 (PON-1) and glutathione peroxidase (GPx) were determined in serum and CUPRAC, ferric reducing ability of saliva (FRAS) and TEAC in saliva. The oxidant biomarkers included were total oxidant status (TOS), peroxide-activity (POX-Act), reactive oxygen-derived compounds (d-ROMs), advanced oxidation protein products (AOPP), and thiobarbituric acid reactive substances (TBARS) in serum and AOPP and TBARS in saliva.

Results

Results showed a significantly higher TEAC, PON-1, GPx, TOS, POX-Act, and d-ROMs, and a significantly lower AOPP in serum of dogs with hypothyroidism. Meanwhile, significantly lower FRAS and AOPP were observed in saliva of dogs with hypothyroidism. Once salivary concentrations were corrected based on their total protein concentrations, the only analyte showing significant changes was TBARS which was significantly higher in dogs with hypothyroidism.

Conclusions

Our results show that dogs with hypothyroidism present alterations in the redox status in both serum and saliva. This study should be considered a preliminary study and further research addressing these changes should be made using larger populations.
Targeting influenza A virus by splicing inhibitor herboxidiene reveals the importance of subtype-specific signatures around splice sites
Authors: Han Yi-Ju , Lee Kuo-Ming , Wu Guan-Hong , Gong Yu-Nong , Dutta Avijit , Shih Shin-Ru
Published: February 2023

Background

The association between M segment splicing and pathogenicity remains ambiguous in human influenza A viruses. In this study, we aimed to investigate M splicing in various human influenza A viruses and characterize its physiological roles by applying the splicing inhibitor, herboxidiene.

Methods

We examined the M splicing of human H1N1 and H3N2 viruses by comparing three H1N1 and H3N2 strains, respectively, through reverse transcriptase-polymerase chain reaction (RT-PCR) analyses. We randomly selected M sequences of human H1N1, H2N2, and H3N2 viruses isolated from 1933 to 2020 and examined their phylogenetic relationships. Next, we determined the effects of single nucleotide variations on M splicing by generating mutant viruses harboring the 55C/T variant through reverse genetics. To confirm the importance of M2 splicing in the replication of H1N1 and H3N2, we treated infected cells with splicing inhibitor herboxidiene and analyzed the viral growth using plaque assay. To explore the physiological role of the various levels of M2 protein in pathogenicity, we challenged C57BL/6 mice with the H1N1 WSN wild-type strain, mutant H1N1 (55T), and chimeric viruses including H1N1 + H3wt and H1N1 + H3mut. One-tailed paired t-test was used for virus titer calculation and multiple comparisons between groups were performed using two-way analysis of variance.

Results

M sequence splice site analysis revealed an evolutionarily conserved single nucleotide variant C55T in H3N2, which impaired M2 expression and was accompanied by collinear M1 and mRNA3 production. Aberrant M2 splicing resulted from splice-site selection rather than a general defect in the splicing process. The C55T substitution significantly reduced both M2 mRNA and protein levels regardless of the virus subtype. Consequently, herboxidiene treatment dramatically decreased both the H1N1 and H3N2 virus titers. However, a lower M2 expression only attenuated H1N1 virus replication and in vivo pathogenicity. This attenuated phenotype was restored by M replacement of H3N2 M in a chimeric H1N1 virus, despite low M2 levels.

Conclusions

The discrepancy in M2-dependence emphasizes the importance of M2 in human influenza A virus pathogenicity, which leads to subtype-specific evolution. Our findings provide insights into virus adaptation processes in humans and highlights splicing regulation as a potential antiviral target.
Structure-function analysis of CYP719As involved in methylenedioxy bridge-formation in the biosynthesis of benzylisoquinoline alkaloids and its de novo production
Authors: Liu Xiuyu , Jiao Xiang , Cheng Yatian , Ma Ying , Bu Junling , Jin Baolong , Li Qishuang , Hu Zhimin , Tang Jinfu , Lai Changjiangsheng , Wang Jian , Cui Guanghong , Chen Yun , Guo Juan , Huang Luqi
Published: February 2023

Benzylisoquinoline alkaloids (BIAs) are a type of secondary metabolite with clinical application value. (S)-stylopine is a special BIA which contains methylenedioxy bridge structures. CYP719As could catalyze the methylenedioxy bridge-formation on the A or D rings of protoberberine alkaloids, while displaying significant substrate regiospecificity. To explore the substrate preference of CYP719As, we cloned and identified five CyCYP719A candidates from Corydalis yanhusuo. Two CyCYP719As (CyCYP719A39 and CyCYP719A42) with high catalytic efficiency for the methylenedioxy bridge-formation on the D or A rings were characterized, respectively. The residues (Leu 294 for CyCYP719A42 and Asp 289 for CyCYP719A39) were identified as the key to controlling the regioselectivity of CYP719As affecting the methylenedioxy bridge-formation on the A or D rings by homology modeling and mutation analysis. Furthermore, for de novo production of BIAs, CyCYP719A39, CyCYP719A42, and their mutants were introduced into the (S)-scoulerine-producing yeast to produce 32 mg/L (S)-stylopine. These results lay a foundation for understanding the structure-function relationship of CYP719A-mediated methylenedioxy bridge-formation and provide yeast strains for the BIAs production by synthetic biology.
Molecular sensitization pattern to house dust mites is formed from the first years of life and includes group 1, 2, Der p 23, Der p 5, Der p 7 and Der p 21 allergens
Authors: Yuriev Serhii , Rodinkova Victoria , Mokin Vitalii , Varchuk Ilona , Sharikadze Olena , Marushko Yuriy , Halushko Bohdan , Kurchenko Andrii
Published: February 2023

Background

As the process and nature of developing sensitivity to house dust mites (HDMs) remain not fully studied, our goal was to establish the pattern, nature and timeframe of house dust mite (HDM) sensitization development in patients in Ukraine as well as the period when treatment of such patients would be most effective.

Methods

The data of the multiplex allergy test Alex2 was collected from 20,033 patients. To determine age specifics of sensitization, descriptive statistics were used. Bayesian Network analysis was used to build probabilistic patterns of individual sensitization.

Results

Patients from Ukraine were most often sensitized to HDM allergens of group 1 (Der p 1, Der f 1) and group 2 (Der p 2, Der f 2) as well as to Der p 23 (55%). A considerable sensitivity to Der p 5, Der p 7 and Der p 21 allergens was also observed. The overall nature of sensitization to HDM allergens among the population of Ukraine is formed within the first year of life. By this time, there is a pronounced sensitization to HDM allergens of groups 1 and 2 as well as to Der p 23. Significance of sensitization to Der p 5, Der p 7 and Der p 21 allergens grows starting from the age of 3–6. Bayesian Network data analysis indicated the leading role of sensitization to Der p 1 and Der f 2. While developing the sensitivity to group 5 allergens, the leading role may belong to Der p 21 allergen.

Conclusion

The results obtained indicate the importance of determining the sensitization profile using the multi-component approach. A more detailed study of the optimal age for AIT prescription is required as the pattern of sensitization to HDMs is formed during the first year of life.
All-in-one smart dressing for simultaneous angiogenesis and neural regeneration
Authors: Yuan Tiejun , Tan Minhong , Xu Yang , Xiao Qiyao , Wang Hui , Wu Chen , Li Fulun , Peng Lihua
Published: February 2023

Wound repair, along with skin appendage regeneration, is challenged by insufficient angiogenesis and neural regeneration. Therefore, promoting both proangiogenic and neuro-regenerative therapeutic effects is essential for effective wound repair. However, most therapeutic systems apply these strategies separately or ineffectively. This study investigates the performance of an all-in-one smart dressing (ASD) that integrates angiogenic functional materials and multiple biological factors within a light crosslinked hydrogel, forming a multi-functional dressing capable of facilitating simultaneous micro-vascularization and neural regeneration. The ASD uses a zeolite-imidazolate framework 67 with anchored vanadium oxide (VO2@ZIF-67) that allows for the on-demand release of Co2+ with fluctuations in pH at the wound site to stimulate angiogenesis. It can simultaneously release CXCL12, ligustroflavone, and ginsenoside Rg1 in a sustained manner to enhance the recruitment of endogenous mesenchymal stem cells, inhibit senescence, and induce neural differentiation to achieve in situ nerve regeneration. The ASD can stimulate rapid angiogenesis and nerve regeneration within 17 days through multiple angiogenic and neuro-regenerative cues within one dressing. This study provides a proof-of-concept for integrating functional nanomaterials and multiple complementary drugs within a smart dressing for simultaneous angiogenesis and neural regeneration.
“I feel like marijuana is the only drug that wouldn’t kill me”: perceptions of cannabis use in previously incarcerated Black men who have sex with other men
Authors: Flores Rey , Kerman Jared , Schneider John , Harawa Nina
Published: February 2023

Background

Fragmented state laws have impacted cannabis uptake and perceptions in the USA. Little research has explored the attitudes, beliefs, and social network influences of young Black men who have sex with men (BMSM) who have experienced incarceration and use cannabis. While problematic cannabis use is not well defined and understudied, scholars have found that a person’s social network can mediate problematic substance use and reduce recidivism rates by providing both tangible and emotional support. This analysis examines how social networks contribute to cannabis perceptions and use among BMSM with criminal legal system involvement in Chicago, IL, and Houston TX.

Methods

Researchers conducted interviews with 25 cis gender Black men informed by life course theory, with a focus on the role of social networks, incarceration, and other life experiences in substance use. All interviews were audio-recorded, de-identified, and transcribed; participants were compensated $50. A deductive-inductive thematic analysis was used to analyze all qualitative data collected.

Results

Twelve BMSM in Chicago and 13 BMSM in Houston (M = 26.6 years old, SD = 3.7) were interviewed. A majority identified as gay (56%), with 12 participants (48%) reporting having a high school diploma or equivalent; their average age of first substance use was 15.2 (SD = 2.9). Participants perceived cannabis usage to be categorically distinct from other intoxicating substance usage, with many describing it as not harmful and potentially beneficial. Three themes shaped their choices and attitudes regarding cannabis and “hard” drugs—social networks, need fulfillment, and knowledge of risk.

Conclusion

Participant descriptions of cannabis use emphasize their drug-use behavior as being produced by agent decision-making and risk assessment. Future work should expand on how these decisions are made, and how social networks can be leveraged to encourage non-harmful drug consumption behaviors.
Crk proteins activate the Rap1 guanine nucleotide exchange factor C3G by segregated adaptor-dependent and -independent mechanisms
Authors: Rodríguez-Blázquez Antonio , Carabias Arturo , Morán-Vaquero Alba , de Cima Sergio , Luque-Ortega Juan R. , Alfonso Carlos , Schuck Peter , Manso José Antonio , Macedo-Ribeiro Sandra , Guerrero Carmen , de Pereda José M.
Published: February 2023

Background

C3G is a guanine nucleotide exchange factor (GEF) that activates Rap1 to promote cell adhesion. Resting C3G is autoinhibited and the GEF activity is released by stimuli that signal through tyrosine kinases. C3G is activated by tyrosine phosphorylation and interaction with Crk adaptor proteins, whose expression is elevated in multiple human cancers. However, the molecular details of C3G activation and the interplay between phosphorylation and Crk interaction are poorly understood.

Methods

We combined biochemical, biophysical, and cell biology approaches to elucidate the mechanisms of C3G activation. Binding of Crk adaptor proteins to four proline-rich motifs (P1 to P4) in C3G was characterized in vitro using isothermal titration calorimetry and sedimentation velocity, and in Jurkat and HEK293T cells by affinity pull-down assays. The nucleotide exchange activity of C3G over Rap1 was measured using nucleotide-dissociation kinetic assays. Jurkat cells were also used to analyze C3G translocation to the plasma membrane and the C3G-dependent activation of Rap1 upon ligation of T cell receptors.

Results

CrkL interacts through its SH3N domain with sites P1 and P2 of inactive C3G in vitro and in Jurkat and HEK293T cells, and these sites are necessary to recruit C3G to the plasma membrane. However, direct stimulation of the GEF activity requires binding of Crk proteins to the P3 and P4 sites. P3 is occluded in resting C3G and is essential for activation, while P4 contributes secondarily towards complete stimulation. Tyrosine phosphorylation of C3G alone causes marginal activation. Instead, phosphorylation primes C3G lowering the concentration of Crk proteins required for activation and increasing the maximum activity. Unexpectedly, optimal activation also requires the interaction of CrkL-SH2 domain with phosphorylated C3G.

Conclusion

Our study revealed that phosphorylation of C3G by Src and Crk-binding form a two-factor mechanism that ensures tight control of C3G activation. Additionally, the simultaneous SH2 and SH3N interaction of CrkL with C3G, required for the activation, reveals a novel adaptor-independent function of Crk proteins relevant to understanding their role in physiological signaling and their deregulation in diseases.