bluuebunny/crossref_metadata_2025 huggingface dataset:
ABBV-176, a PRLR antibody drug conjugate with a potent DNA-damaging PBD cytotoxin and enhanced activity with PARP inhibition
Authors: Anderson Mark G. , Zhang Qian , Rodriguez Luis E. , Hecquet Claudie M. , Donawho Cherrie K. , Ansell Peter J. , Reilly Edward B.
Published: June 2021

Background

Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations.

Methods

We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models.

Results

In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage.

Conclusions

Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.
Early combined rehabilitation intervention to improve the short-term prognosis of premature infants
Authors: Liu Yang , Li Zheng-feng , Zhong Yun-huan , Zhao Zhi-hui , Deng Wen-xin , Chen Ling-ling , Liu Bei-bei , Du Tao-jun , Zhang Yong
Published: June 2021

Background

To explore the clinical effect of early combined rehabilitation intervention on premature infants in the neonatal intensive care unit (NICU).

Methods

Premature infants with gestational ages less than 32 weeks or birth weights less than 1500 g were included in the present study.The participants were divided into the intervention group and control group. All infants received the current routine treatment based on the clinical guidelines, and the intervention group was additionally treated by visual and auditory stimulation, oral motor function, respiratory function and neurodevelopmental training. The following clinical outcomes were compared: durations of oxygen supplementation and indwelling gastric tube use; incidences of retinopathy of prematurity (ROP) and neonatal necrotizing enterocolitis (NEC); Sliverman scores; incidences of bronchopulmonary dysplasia (BPD) and intraventricular haemorrhage; days of hospitalization; and neurodevelopmental outcomes. Datas were analysed using the following statistical tests: the chi-square test, the independent samples or paired t test, repeated measures ANOVA, and the Wilcoxon rank sum test.

Results

Compared with those in the control group, premature infants in the intervention group had shorter durations of oxygen supplementation and indwelling gastric tube use, fewer hospitalization days and lower incidences of ROP, BPD, and NEC.The intervention group had lower Sliverman scores and higher Ballard neuromuscular scores than the control group.

Conclusion

Early combined rehabilitation intervention can improve the short-term clinical outcomes of premature infants.
Associations between the working experiences at frontline of COVID-19 pandemic and mental health of Korean public health doctors
Authors: Han Sangyoon , Choi Sejin , Cho Seung Hyun , Lee Joonhyuk , Yun Je-Yeon
Published: June 2021

Background

Demographic, work environmental, and psychosocial features are associated with mental health of healthcare professionals at pandemic frontline. The current study aimed to find predictors of mental health for public health doctors from working experiences at frontline of COVID-19 pandemic.

Methods

With first-come and first-served manner, 350 public health doctors with experiences of work at COVID-19 frontline participated online survey on August 2020. Mental health was defined using the total scores of the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7, the Perceived Stress Scale, and the Stanford Presenteeism Scale-6. Multivariate logistic regression models of mental health with lowest Akaike Information Criterion were determined among all combinations of working environments, perceived threats and satisfaction at frontline, and demographics that were significant (P < 0.05) in the univariate logistic regression.

Results

Perceived distress, lowered self-efficacy at work, anxiety, and depressive mood were reported by 45.7, 34.6, 11.4, and 15.1% of respondents, respectively. Predictors of poor mental health found in the multivariate logistic regression analyses were environmental (insufficient personal protective equipment, workplace of screening center, prolonged workhours) and psychosocial (fear of infection and death, social stigma and rejection) aspects of working experiences at frontline. Satisfaction of monetary compensation and proactive coping (acceptance and willingness to volunteer at frontline) were predictive of better mental health.

Conclusions

Sufficient supply of personal protective equipment and training on infection prevention at frontline, proper workhours and satisfactory monetary compensation, and psychological supports are required for better mental health of public health doctors at frontline of COVID-19 pandemic.
Understanding measures of racial discrimination and microaggressions among American Indian and Alaska Native college students in the Southwest United States
Authors: Greenfield Brenna L. , Elm Jessica H. L. , Hallgren Kevin A.
Published: June 2021

Background

Racial discrimination, including microaggressions, contributes to health inequities, yet research on discrimination and microaggressions has focused on single measures without adequate psychometric evaluation. To address this gap, we examined the psychometric performance of three discrimination/microaggression measures among American Indian and Alaska Native (AI/AN) college students in a large Southwestern city.

Methods

Students (N = 347; 65% female; ages 18–65) completed the revised-Everyday Discrimination Scale, Microaggressions Distress Scale, and Experiences of Discrimination measure. The psychometric performance of these measures was evaluated using item response theory and confirmatory factor analyses. Associations of these measures with age, gender, household income, substance use, and self-rated physical health were examined.

Results

Discrimination and microaggression items varied from infrequently to almost universally endorsed and each measure was unidimensional and moderately correlated with the other two measures. Most items contributed information about the overall severity of discrimination and collectively provided information across a continuum from everyday microaggressions to physical assault. Greater exposure to discrimination on each measure had small but significant associations with more substance use, lower income, and poorer self-rated physical health. The Experiences of Discrimination measure included more severe forms of discrimination, while the revised-Everyday Discrimination Scale and the Microaggressions Distress Scale represented a wider range of severity.

Conclusions

In clinical practice, these measures can index varying levels of discrimination for AI/ANs, particularly for those in higher educational settings. This study also informs the measurement of racial discrimination and microaggressions more broadly.
Systematic review of studies investigating ventilator associated pneumonia diagnostics in intensive care
Authors: Al-Omari Basem , McMeekin Peter , Allen A. Joy , Akram Ahsan R. , Graziadio Sara , Suklan Jana , Jones William S. , Lendrem B. Clare , Winter Amanda , Cullinan Milo , Gray Joanne , Dhaliwal Kevin , Walsh Timothy S. , Craven Thomas H.
Published: June 2021

Background

Ventilator-associated pneumonia (VAP) is an important diagnosis in critical care. VAP research is complicated by the lack of agreed diagnostic criteria and reference standard test criteria. Our aim was to review which reference standard tests are used to evaluate novel index tests for suspected VAP.

Methods

We conducted a comprehensive search using electronic databases and hand reference checks. The Cochrane Library, MEDLINE, CINHAL, EMBASE, and web of science were searched from 2008 until November 2018. All terms related to VAP diagnostics in the intensive treatment unit were used to conduct the search. We adopted a checklist from the critical appraisal skills programme checklist for diagnostic studies to assess the quality of the included studies.

Results

We identified 2441 records, of which 178 were selected for full-text review. Following methodological examination and quality assessment, 44 studies were included in narrative data synthesis. Thirty-two (72.7%) studies utilised a sole microbiological reference standard; the remaining 12 studies utilised a composite reference standard, nine of which included a mandatory microbiological criterion. Histopathological criteria were optional in four studies but mandatory in none.

Conclusions

Nearly all reference standards for VAP used in diagnostic test research required some microbiological confirmation of infection, with BAL culture being the most common reference standard used.
A case of tamoxifen-induced hypertriglyceridemia monitoring the changes in lipoprotein fractions over time
Authors: Isobe Hayato , Shimoda Masashi , Kan Yuki , Tatsumi Fuminori , Katakura Yukino , Kimura Tomohiko , Obata Atsushi , Kohara Kenji , Nakanishi Shuhei , Mune Tomoatsu , Kaku Kohei , Kaneto Hideaki
Published: June 2021

Background

Tamoxifen, which is one of the selective estrogen receptor modulators (SERMs), can bring out life-threatening complication, e.g. hypertriglyceridemia-induced acute pancreatitis, although it is rare. We precisely report changes in lipoprotein metabolism before and after tamoxifen discontinuation because there have been few reports of it.

Case presentation

47-year-old premenopausal woman with dyslipidemia, type 2 diabetes, nonalcoholic fatty liver disease and chronic kidney disease was prescribed tamoxifen as adjuvant therapy after operation of breast cancer. She experienced severe tamoxifen-induced hypertriglyceridemia several months after dosing tamoxifen. Before cessation of tamoxifen, lipoprotein fraction test revealed marked stagnation of VLDL and IDL metabolisms, resulting in severe hypertriglyceridemia (serum triglyceride level was 1881 mg/dL). Seven days after tamoxifen withdrawal, lipoprotein fraction test showed that the metabolisms of endogenous lipoproteins were changed drastically.

Conclusions

From these results, we confirmed that tamoxifen certainly changes lipoprotein metabolism through suppression of post-heparin lipolytic activity. It is very important to evaluate the balance between benefit and risk before dosing tamoxifen and survey lipid profiles constantly during treatment to avoid life-threatening complication when prescription of tamoxifen is planned.
The societal cost and economic impact of surgical care on patients’ households in rural Uganda; a mixed method study
Authors: Nwanna–Nzewunwa Obieze , Oke Rasheedat , Agwang Esther , Ajiko Mary-Margaret , Yoon Christopher , Carvalho Melissa , Kirya Fred , Marseille Elliot , Dicker Rochelle A.
Published: June 2021

Background

The epidemiology and cost of surgical care delivery in low-and middle-income countries (LMICs) is poorly understood. This study characterizes the cost of surgical care, rate of catastrophic medical expenditure and medical impoverishment, and impact of surgical hospitalization on patients’ households at Soroti Regional Referral Hospital (SRRH), Uganda.

Methods

We prospectively collected demographic, clinical, and cost data from all surgical inpatients and caregivers at SRRH between February 2018 and January 2019. We conducted and thematically analyzed qualitative interviews to discern the impact of hospitalization on patients’ households. We employed the chi-square, t-test, ANOVA, and Bonferroni tests and built regression models to identify predictors of societal cost of surgical care. Out of pocket spending (OOPS) and catastrophic expenses were determined.

Results

We encountered 546 patients, mostly male (62%) peasant farmers (42%), at a median age of 22 years; and 615 caregivers, typically married (87%), female (69%), at a median age of 35 years. Femur fractures (20.4%), soft tissue infections (12.3%), and non-femur fractures (11.9%) were commonest. The total societal cost of surgical care was USD 147,378 with femur fractures (USD 47,879), intestinal obstruction (USD 18,737) and non-femur fractures (USD 10,212) as the leading contributors. Procedures (40%) and supplies (12%) were the largest components of societal cost. About 29% of patients suffered catastrophic expenses and 31% were medically impoverished.

Conclusion

Despite free care, surgical conditions cause catastrophic expenses and impoverishment in Uganda. Femur fracture is the most expensive surgical condition due to prolonged hospitalization associated with traction immobilization and lack of treatment modalities with shorter hospitalization.
Occurrence and potentially zoonotic genotypes of Enterocytozoon bieneusi in wild rhesus macaques (Macaca mulatta) living in Nanwan Monkey Island, Hainan, China: a public health concern
Authors: Zhao Wei , Zhou Huan-Huan , Ren Guang-Xu , Qiang Yu , Huang Hui-Cong , Lu Gang , Tan Feng
Published: June 2021

Background

Enterocytozoon bieneusi, a microsporidian species, is a zoonotic pathogen found in both humans and animals. Here, we determined the prevalence, explored the different genotypes ofE. bieneusiin wild rhesus macaques (Macaca mulatta) (Hainan Island of China), and assessed their zoonotic potential.

Methods

We collected 173 fecal specimens from wild rhesus macaques living in Nanwan Monkey Island, Hainan, China. Subsequently, we identified and genotypedE. bieneusiusing nested PCR analysis amplification of the internal transcribed spacer region (ITS) of the rRNA gene. Lastly, a neighbor-joining tree was built based on gene sequences from the ITS region ofE.bieneusi.

Results

Of the 173 specimens from wild rhesus macaques, 26 (15%) were infected withE. bieneusi. We identified six genotypes ofE. bieneusi, of which five were known: PigEBITS7 (n = 20), D (n = 2), Type IV (n = 1), Peru6 (n = 1), Henan-III (n = 1), and a novel genotype: HNM-IX (n = 1). From the phylogenetic analysis, the six genotypes identified here were all clustered into zoonotic group 1.

Conclusion

This study is the first report to detectE. bieneusiinfection in wild rhesus macaques from Hainan, China. Human-pathogenic genotypes D, Henan-III, Peru6, PigEbITS7, and Type IV in the wild rhesus macaques support these animals infected withE. bieneusihave a public health significance.
Overexpression of DDIT4 and TPTEP1 are associated with metastasis and advanced stages in colorectal cancer patients: a study utilizing bioinformatics prediction and experimental validation
Authors: Fattahi Fahimeh , Kiani Jafar , Alemrajabi Mahdi , Soroush Ahmadreza , Naseri Marzieh , Najafi Mohammad , Madjd Zahra
Published: June 2021

Background

Various diagnostic and prognostic tools exist in colorectal cancer (CRC) due to multiple genetic and epigenetic alterations causing the disease. Today, the expression of RNAs is being used as prognostic markers for cancer.

Methods

In the current study, various dysregulated RNAs in CRC were identified via bioinformatics prediction. Expression of several of these RNAs were measured by RT-qPCR in 48 tissues from CRC patients as well as in colorectal cancer stem cell-enriched spheroids derived from the HT-29 cell line. The relationships between the expression levels of these RNAs and clinicopathological features were analyzed.

Results

Our bioinformatics analysis determined 11 key mRNAs, 9 hub miRNAs, and 18 lncRNAs which among them 2 coding RNA genes including DDIT4 and SULF1 as well as 3 non-coding RNA genes including TPTEP1, miR-181d-5p, and miR-148b-3p were selected for the further investigations. Expression of DDIT4, TPTEP1, and miR-181d-5p showed significantly increased levels while SULF1 and miR-148b-3p showed decreased levels in CRC tissues compared to the adjacent normal tissues. Positive relationships between DDIT4, SULF1, and TPTEP1 expression and metastasis and advanced stages of CRC were observed. Additionally, our results showed significant correlations between expression of TPTEP1 with DDIT4 and SULF1.

Conclusions

Our findings demonstrated increased expression levels of DDIT4 and TPTEP1 in CRC were associated with more aggressive tumor behavior and more advanced stages of the disease. The positive correlations between TPTEP1 as non-coding RNA and both DDIT4 and SULF1 suggest a regulatory effect of TPTEP1 on these genes.
Care-seeking behaviour and socio-economic burden associated with uncomplicated malaria in the Democratic Republic of Congo
Authors: Kayiba Nadine Kalenda , Yobi Doudou Malekita , Devleesschauwer Brecht , Mvumbi Dieudonné Makaba , Kabututu Pius Zakayi , Likwela Joris Losimba , Kalindula Lydie Azama , DeMol Patrick , Hayette Marie-Pierre , Mvumbi Georges Lelo , Lusamba Paul Dikassa , Beutels Philippe , Rosas-Aguirre Angel , Speybroeck Niko
Published: June 2021

Background

This study aimed to estimate the socio-economic costs of uncomplicated malaria and to explore health care-seeking behaviours that are likely to influence these costs in the Democratic Republic of Congo (DRC), a country ranked worldwide as the second most affected by malaria.

Methods

In 2017, a cross-sectional survey included patients with uncomplicated malaria in 64 healthcare facilities from 10 sentinel sites of the National Malaria Control Programme (NMCP) in the DRC. A standard questionnaire was used to assess health care-seeking behaviours of patients. Health-related quality of life (HRQL) and disutility weights (DW) of illness were evaluated by using the EuroQol Group’s descriptive system (EQ-5D-3L) and its visual analogue scale (EQ VAS). Malaria costs were estimated from a patient’s perspective. Probabilistic sensitivity analyses (PSA) evaluated the uncertainty around the cost estimates. Generalized regression models were fitted to assess the effect of potential predictive factors on the time lost and the DW during illness.

Results

In total, 1080 patients (age: 13.1 ± 14 years; M/F ratio: 1.1) were included. The average total costs amounted to US$ 36.3 [95% CI 35.5–37.2] per malaria episode, including US$ 16.7 [95% CI 16.3–17.1] as direct costs and US$ 19.6 [95% CI 18.9–20.3] indirect costs. During care seeking, economically active patients and their relatives lost respectively 3.3 ± 1.8 and 3.4 ± 2.1 working days. This time loss occurred mostly at the pre-hospital stage and was the parameter associated the most with the uncertainty around malaria cost estimates. Patients self-rated an average 0.36 ± 0.2 DW and an average 0.62 ± 0.3 EQ-5D index score per episode. A lack of health insurance coverage (896 out of 1080; 82.9%) incurred substantially higher costs, lower quality of life, and heavier DW while leading to longer time lost during illness. Residing in rural areas incurred a disproportionally higher socioeconomic burden of uncomplicated malaria with longer time lost due to illness and limited access to health insurance mechanisms.

Conclusion

Uncomplicated malaria is associated with high economic costs of care in the DRC. Efforts to reduce the cost-of-illness should target time lost at the pre-hospital stage and social disparities in the population, while reinforcing measures for malaria control in the country.
MicroRNA-30a-5p promotes differentiation in neonatal mouse spermatogonial stem cells (SSCs)
Authors: Khanehzad Maryam , Nourashrafeddin Seyed Mehdi , Abolhassani Farid , Kazemzadeh Shokoofeh , Madadi Soheila , Shiri Elham , Khanlari Parastoo , Khosravizadeh Zahra , Hedayatpour Azim
Published: June 2021

Background

The importance of spermatogonial stem cells (SSCs) in spermatogenesis is crucial and intrinsic factors and extrinsic signals mediate fate decisions of SSCs. Among endogenous regulators, microRNAs (miRNAs) play critical role in spermatogenesis. However, the mechanisms which individual miRNAs regulate self- renewal and differentiation of SSCs are unknown. The aim of this study was to investigate effects of miRNA-30a-5p inhibitor on fate determinations of SSCs.

Methods

SSCs were isolated from testes of neonate mice (3–6 days old) and their purities were performed by flow cytometry with ID4 and Thy1 markers. Cultured cells were transfected with miRNA- 30a-5p inhibitor. Evaluation of the proliferation (GFRA1, PLZF and ID4) and differentiation (C-Kit & STRA8) markers of SSCs were accomplished by immunocytochemistry and western blot 48 h after transfection.

Results

Based on the results of flow cytometry with ID4 and Thy1 markers, percentage of purity of SSCs was about 84.3 and 97.4 % respectively. It was found that expression of differentiation markers after transfection was significantly higher in miRNA-30a- 5p inhibitor group compared to other groups. The results of proliferation markers evaluation also showed decrease of GFRA1, PLZF and ID4 protein in SSCs transfected with miRNA-30a-5p inhibitor compared to the other groups.

Conclusions

It can be concluded that inhibition of miRNA-30a-5p by overexpression of differentiation markers promotes differentiation of Spermatogonial Stem Cells.
HSF1 promotes endometriosis development and glycolysis by up-regulating PFKFB3 expression
Authors: Wang Yixin , Xiu Jing , Yang Tingting , Ren Chune , Yu Zhenhai
Published: June 2021

Background

Endometriosis is a chronic hormonal inflammatory disease characterized by the presence of endometrial tissue outside the uterus. Endometriosis often causes infertility, which brings physical and mental pain to patients and their families.

Methods

We examined the functions of heat shock factor 1 (HSF1) in endometriosis development through cell count assay, cell-scratch assay and clone formation experiments. We used quantitative real-time PCR (qRT-PCR) and Western blot (WB) to detect HSF1 expression. Glucose and lactate levels were determined using a glucose (GO) assay kit and a lactate assay kit. Furthermore, we used a HSF1 inhibitor-KRIBB11 to establish a mouse model of endometriosis.

Results

Our data demonstrated that HSF1 promoted endometriosis development. Interestingly, HSF1 enhanced glycolysis via up-regulating PFKFB3 expression in endometriosis cells, which was a key glycolysis enzyme. Consistently, the HSF1 inhibitor KRIBB11 could abrogate endometriosis progression in vivo and in vitro.

Conclusions

Findings indicate that HSF1 plays an important role in endometriosis development, which might become a new target for the treatment of endometriosis.

Electronic supplementary material

Supplementary data are available.
Increased risk of pulmonary and extrapulmonary tuberculosis infection in patients with polycystic kidney disease: a nationwide population-based study with propensity score-matching analysis
Authors: Chiu Ting-Fang , Yu Tung-Min , Chiu Chih-Wei , Lee Brian K. , Lan Tsuo-Hung , Li Chi-Yuan , Lin Mei-Chen , Kao Chia-Hung
Published: June 2021

Background

Polycystic kidney disease (PKD) is a common renal disorder affecting approximately 1 in 1000 live births. Tuberculosis (TB) is an infectious disease worldwide. This study investigated the risk of TB infection in patients with PKD.

Methods

A nationwide population-based cohort study was performed using Taiwan’s National Health Insurance Research Database. We used patients’ hospitalization files for the entire analysis during 2000–2012. As per diagnosis, we divided patients into PKD and non-PKD cohorts and the major outcome was TB infection.

Results

A total of 13,540 participants with 6770 patients in each cohort were enrolled. The PKD cohort had a higher risk of TB infection than did the non-PKD cohort after adjusting for age, sex, and comorbidities (adjusted hazard ratio (aHR) = 1.91, 95% confidence interval [CI] = 1.51–2.43). When classifying by sites of pulmonary TB (PTB) and extrapulmonary TB (EPTB), the PKD cohort demonstrated a significantly higher risk of EPTB (aHR = 2.44, 95% CI = 1.46–4.08) as well as a risk of PTB (aHR = 1.69, 95% CI = 1.29–2.22). When stratified by the presence or absence of a comorbidity, high TB infection risk was noted in the PKD patients without any comorbidity (HR = 2.69, 95% CI = 1.69–4.30).

Conclusions

Taken together, our findings suggest that PKD is associated with a 1.91-fold increased risk of TB infection. Medical professionls should maintain a high index of suspicion in daily practice for patients with PKD, particularly those with EPTB infection.
Simple rapid in vitro screening method for SARS-CoV-2 anti-virals that identifies potential cytomorbidity-associated false positives
Authors: Yan Kexin , Rawle Daniel J. , Le Thuy T. , Suhrbier Andreas
Published: June 2021

Background

The international SARS-CoV-2 pandemic has resulted in an urgent need to identify new anti-viral drugs for treatment of COVID-19. The initial step to identifying potential candidates usually involves in vitro screening that includes standard cytotoxicity controls. Under-appreciated is that viable, but stressed or otherwise compromised cells, can also have a reduced capacity to replicate virus. A refinement proposed herein for in vitro drug screening thus includes a simple growth assay to identify drug concentrations that cause cellular stress or “cytomorbidity”, as distinct from cytotoxicity or loss of viability.

Methods

A simple rapid bioassay is presented for antiviral drug screening using Vero E6 cells and inhibition of SARS-CoV-2 induced cytopathic effects (CPE) measured using crystal violet staining. We use high cell density for cytotoxicity assays, and low cell density for cytomorbidity assays.

Results

The assay clearly illustrated the anti-viral activity of remdesivir, a drug known to inhibit SARS-CoV-2 replication. In contrast, nitazoxanide, oleuropein, cyclosporine A and ribavirin all showed no ability to inhibit SARS-CoV-2 CPE. Hydroxychloroquine, cyclohexamide, didemnin B, γ-mangostin and linoleic acid were all able to inhibit viral CPE at concentrations that did not induce cytotoxicity. However, these drugs inhibited CPE at concentrations that induced cytomorbidity, indicating non-specific anti-viral activity.

Conclusions

We describe the methodology for a simple in vitro drug screening assay that identifies potential anti-viral drugs via their ability to inhibit SARS-CoV-2-induced CPE. The additional growth assay illustrated how several drugs display anti-viral activity at concentrations that induce cytomorbidity. For instance, hydroxychloroquine showed anti-viral activity at concentrations that slow cell growth, arguing that its purported in vitro anti-viral activity arises from non-specific impairment of cellular activities. The cytomorbidity assay can therefore rapidly exclude potential false positives.
Panoramic prediction equations to estimate implant- to-mandibular canal dimensions in the mandibular posterior region: implications for dental implant treatment
Authors: Bertram Annika , Eckert Alexander W. , Kolk Andreas , Emshoff Rüdiger
Published: June 2021

Background

To develop and cross-validate site-specific panoramic radiography (PAN) analysis prediction equations of implant-to-mandibular canal dimensions (IMCD) in mandibular regions posterior to the mental foramen, and to help determine in which instances CBCT technology will be a justified adjunct in clinical practice.

Methods

IMCD by PAN (Pan-D) from implant site-specific regions (first premolar, second premolar, first molar, and second molar sites) were collected from 40- to 70-year-old adolescents. They were randomly assigned to validation (n = 144) and cross-validation (n = 148) groups. The cone-beam computed tomography (CBCT) technique was used as the criterion method for the estimation of IMCD (CBCT-D). The PAN analysis equations were developed using stepwise multiple regression analysis and cross-validated using the Bland–Altman approach.

Results

There was a significant relationship between PAN-D and CBCT-D for both validation (R2 = 57.8 %;p < .001) and cross-validation groups (R2 = 52.5 %;p < .001). Root means-squared error (RMSE) and pure error (PE) were highest for the first molar (RMSE = 1.116 mm, PE = 1.01 mm) and the second molar region (RMSE = 1.162 mm, PE = 1.11 mm).

Conclusions

PAN-D has the potential to be developed as an indirect measure of IMCD. However, the findings suggest to exclude scoring of the first and second molars when assessing IMCD via PAN. Use of CBCT may be justified for all IMCD estimations in the first and second molars regions.

Trial registration

This study has been registered and approved by the Ethics Committee of the Martin-Luther University, Halle, Germany (2020-034).
Abstaining from symptomatic implants of modified tension band wiring by nonabsorbable suture fixation for transverse patella fractures
Authors: Jirangkul Puripun , Kosiyatrakul Arkaphat
Published: June 2021

Background

Modified tension band fixation has become commonly used for transverse patella fractures. The conventional stainless steel wire provides sufficient stability but may be associated with complications.

Objective

The study aimed to evaluate the effectiveness of a new modified tension band fixation technique for transverse patella fractures using a nonabsorbable suture.

Material and methods

We present the result of a prospective series using a nonabsorbable suture (FiberWire) for transverse patella fractures. The mean follow-up period totaled 12 months. A total of 16 patients were evaluated by radiographic and clinical review. The postoperative clinical evaluation employed Lysholm and Böstman scores.

Result

All clinical results on follow-up were good to excellent. Minimal intra-articular joint stepping and further fracture displacement were recorded. No patient needed re-operation, and functional outcomes of the knee were satisfactory. No significant differences were found between the injured and contralateral knee range of motion. No symptomatic implants and skin complications were noted, and all fractures were completed heal within 15 weeks.

Conclusion

FiberWire provided sufficient stability and reduced postoperative complications. The results proved appropriate, and the technique has merit, as it obviates the need for re-operation.
Comparison of lateral entry and crossed entry pinning for pediatric supracondylar humeral fractures: a meta-analysis of randomized controlled trials
Authors: Zhao Huaguo , Xu Song , Liu Guanyi , Zhao Jingyu , Wu Shandong , Peng Linrui
Published: June 2021

Background

Closed reduction and pinning entry fixation have been proposed as treatment strategies for displaced supracondylar humeral fractures (SCHFs) in children. However, controversy exists regarding the selection of the appropriate procedure. Hence, this meta-analysis was conducted to compare the effect of lateral and crossed pin fixation for pediatric SCHFs, providing a reference for clinical treatment.

Methods

Online databases were systematically searched for randomized controlled trials (RCTs) comparing lateral pinning entry and crossed pinning entry for children with SCHFs. The primary endpoints were iatrogenic ulnar nerve injuries, complications, and radiographic and functional outcomes.

Results

Our results showed that iatrogenic ulnar nerve injuries occurred more commonly in the crossed pinning entry group than in the lateral pinning entry group (RR = 4.41, 95% CI 1.97–9.86, P < 0.05). However, its risk between the crossed pinning with mini-open incisions group and the lateral pinning entry group was not significantly different (RR = 1.58, 95% CI 0.008–29.57, P = 0.76). The loss of reduction risk was higher in the lateral pinning entry group than in the crossed pinning entry group (RR = 0.66; 95% CI 0.49–0.89, P < 0.05). There were no significant differences in the carry angle, Baumann angle, Flynn scores, infections, and other complications between these two groups.

Conclusions

The crossed pinning entry with mini-open incision technique reduced the loss of reduction risk, and the risk of iatrogenic ulnar nerve injury was lower than in the lateral pinning entry group. The crossed pinning entry with mini-open incision technique is an effective therapeutic strategy for managing displaced supracondylar humeral fractures in children.
Using four decades of FDA orphan drug designations to describe trends in rare disease drug development: substantial growth seen in development of drugs for rare oncologic, neurologic, and pediatric-onset diseases
Authors: Miller Kathleen L. , Fermaglich Lewis J. , Maynard Janet
Published: June 2021

Background

Orphan drug designations are a useful proxy to investigate trends in rare disease drug development. Drug developers must receive a designation before they are eligible for the economic incentives of the Orphan Drug Act in the United States. We created a database of all orphan drugs designated between 1983 and 2019 that included numerous drug characteristics, including therapeutic area. In addition, we constructed a “broad disease” categorization of designations as an alternative to therapeutic area, based on disease etiology and age of onset rather than organ system. By looking at the pattern of orphan drug designations over the past four decades, this analysis studied the impact of the evolving rare disease drug development landscape and considers the future of rare disease therapies over the coming decades.

Results

Between 1983 and 2019, a total of 5099 drugs and biologics received orphan drug designation. Designations more than doubled between the 1980s and 1990s, almost doubled between the 1990s and 2000s, and almost tripled in number between the 2000s and 2010s. The top three therapeutic areas represented in the orphan drug designations were: oncology (1910, 37%), neurology (674, 13%), and infectious diseases (436, 9%). The broad disease categorization found that the proportion of designations for pediatric-onset diseases has increased in the most recent decade to 27%.

Conclusions

Analysis of the last four decades of orphan drug designation indicates seismic shifts have occurred in the rare disease drug development space. The number of designations granted more than quadrupled between the 1990s and 2010s. While these substantial increases led to growth in the absolute number of designations within all therapeutic areas (bar one) and broad disease categories, the relative proportions have seen considerable change over time. In the most recent decade, there have been notable increases in the proportion of drugs in oncology, pediatric-onset diseases, and neurologic disorders. The dramatic rise in overall orphan designations over the past four decades suggests we may continue to see an upward trajectory in designations leading to an increased number of approvals for drugs and biologics designed specifically for diagnosing, preventing, and treating rare diseases in the coming decades.
Chromosome-level genome assembly of a regenerable maize inbred line A188
Authors: Lin Guifang , He Cheng , Zheng Jun , Koo Dal-Hoe , Le Ha , Zheng Huakun , Tamang Tej Man , Lin Jinguang , Liu Yan , Zhao Mingxia , Hao Yangfan , McFraland Frank , Wang Bo , Qin Yang , Tang Haibao , McCarty Donald R. , Wei Hairong , Cho Myeong-Je , Park Sunghun , Kaeppler Heidi , Kaeppler Shawn M. , Liu Yunjun , Springer Nathan , Schnable Patrick S. , Wang Guoying , White Frank F. , Liu Sanzhen
Published: June 2021

Background

The maize inbred line A188 is an attractive model for elucidation of gene function and improvement due to its high embryogenic capacity and many contrasting traits to the first maize reference genome, B73, and other elite lines. The lack of a genome assembly of A188 limits its use as a model for functional studies.

Results

Here, we present a chromosome-level genome assembly of A188 using long reads and optical maps. Comparison of A188 with B73 using both whole-genome alignments and read depths from sequencing reads identify approximately 1.1 Gb of syntenic sequences as well as extensive structural variation, including a 1.8-Mb duplication containing the Gametophyte factor1 locus for unilateral cross-incompatibility, and six inversions of 0.7 Mb or greater. Increased copy number of carotenoid cleavage dioxygenase 1 (ccd1) in A188 is associated with elevated expression during seed development. Highccd1expression in seeds together with low expression of yellow endosperm 1 (y1) reduces carotenoid accumulation, accounting for the white seed phenotype of A188. Furthermore, transcriptome and epigenome analyses reveal enhanced expression of defense pathways and altered DNA methylation patterns of the embryonic callus.

Conclusions

The A188 genome assembly provides a high-resolution sequence for a complex genome species and a foundational resource for analyses of genome variation and gene function in maize. The genome, in comparison to B73, contains extensive intra-species structural variations and other genetic differences. Expression and network analyses identify discrete profiles for embryonic callus and other tissues.
TBP and SNAP50 transcription factors bind specifically to the Pr77 promoter sequence from trypanosomatid non-LTR retrotransposons
Authors: Macías Francisco , Afonso-Lehmann Raquel , Carreira Patricia E. , Thomas M. Carmen
Published: June 2021

Background

Trypanosomatid genomes are colonized by active and inactive mobile DNA elements, such as LINE, SINE-like, SIDER and DIRE retrotransposons. These elements all share a 77-nucleotide-long sequence at their 5′ ends, known as Pr77, which activates transcription, thereby generating abundant unspliced and translatable transcripts. However, transcription factors that mediates this process have still not been reported.

Methods

TATA-binding protein (TBP) and small nuclear RNA-activating protein 50 kDa (SNAP50) recombinant proteins and specific antibodies raised against them were generated. Protein capture assay, electrophoretic mobility-shift assays (EMSA) and EMSA competition assays carried out using these proteins and nuclear proteins of the parasite together to specific DNA sequences used as probes allowed detecting direct interaction of these transcription factors to Pr77 sequence.

Results

This study identified TBP and SNAP50 as part of the DNA-protein complex formed by the Pr77 promoter sequence and nuclear proteins of Trypanosoma cruzi. TBP establishes direct and specific contact with the Pr77 sequence, where the DPE and DPE downstream regions are docking sites with preferential binding. TBP binds cooperatively (Hill coefficient = 1.67) to Pr77 and to both strands of the Pr77 sequence, while the conformation of this highly structured sequence is not involved in TBP binding. Direct binding of SNAP50 to the Pr77 sequence is weak and may be mediated by protein–protein interactions through other trypanosomatid nuclear proteins.

Conclusions

Identification of the transcription factors that mediate Pr77 transcription may help to elucidate how these retrotransposons are mobilized within the trypanosomatid genomes and their roles in gene regulation processes in this human parasite.

Graphical Abstract
Management of patellofemoral joint osteoarthritis using biomechanical device therapy: a systematic review with meta-analysis
Authors: Callaghan Michael J. , Palmer Elizabeth , O’Neill Terence
Published: June 2021

Background

Current clinical guidelines recommend conservative management including non-pharmacologic therapy prior to considering surgery for knee OA. There is a paucity of clinical trials investigating the use of biomechanical device therapies on those with patellofemoral joint osteoarthritis (PFJOA). The aim was to systematically review the effectiveness of biomechanical devices (bracing, taping, and footwear) in the management of symptomatic PFJOA.

Method

The Cochrane, PEDro, MEDLINE, CINAHL, AMED and EMBASE electronic databases were search from inception to October 31, 2020. Included studies were randomised controlled or clinical trials studying any form of biomechanical device therapy in the management of PFJOA in the English language. Studies included in the search were quality-appraised using the PEDro scoring system.

Result

Eleven studies were identified which included assessment of either patellar taping, or foot orthotics, knee bracing or combined physiotherapy treatments. Trial quality ranged from ‘poor’ through ‘fair’ to ‘good’. For patellar bracing, pooled analysis of two good quality randomised controlled trials showed no overall significant improvement on a visual analogue scale (VAS) (random effects (RE) standardised mean difference (SMD) = −0.42 (95%CI −1.12 to +0.29).

Pooled data from the same two studies showed a non-significant improvement in favour of bracing assessed by the KOOS/WOMAC (RE SMD = −0.18 (95%CI −0.66 to +0.31). Two studies of ‘fair’ and ‘good’ quality applying patellar tape showed a significant reduction in pain immediately after application and after 4 days. A randomised trial of a foot orthotic showed a non-significant improvement in pain after 6 weeks with a between groups adjusted mean difference for maximum VAS of 21.9 mm (95% CI − 2.1 to 46.0) and 8.1 (95% CI− 6.9 to 23.1) for KOOS pain. A multimodal physiotherapy intervention (which included taping in two studies) showed a pooled significant improvement in VAS (SMD = −0.4; (95% CI −0.71 to −0.09) at 3 months compared to controls.

Conclusion

There is some good quality evidence that a combined physiotherapy approach significantly reduces short-term pain in those with PFJOA. Long-term effects of all interventions are still unknown, which indicates the need for further research to determine the longer term impact of all biomechanical devices on outcomes in symptomatic PFJOA.
A survey of methodologies on causal inference methods in meta-analyses of randomized controlled trials
Authors: Markozannes Georgios , Vourli Georgia , Ntzani Evangelia
Published: June 2021

Background

Meta-analyses of randomized controlled trials (RCTs) have been considered as the highest level of evidence in the pyramid of the evidence-based medicine. However, the causal interpretation of such results is seldom studied.

Methods

We systematically searched for methodologies pertaining to the implementation of a causally explicit framework for meta-analysis of randomized controlled trials and discussed the interpretation and scientific relevance of such causal estimands. We performed a systematic search in four databases to identify relevant methodologies, supplemented with hand-search. We included methodologies that described causality under counterfactuals and potential outcomes framework.

Results

We only identified three efforts explicitly describing a causal framework on meta-analysis of RCTs. Two approaches required individual participant data, while for the last one, only summary data were required. All three approaches presented a sufficient framework under which a meta-analytical estimate is identifiable and estimable. However, several conceptual limitations remain, mainly in regard to the data generation process under which the selected RCTs rise.

Conclusions

We undertook a review of methodologies on causal inference methods in meta-analyses. Although all identified methodologies provide valid causal estimates, there are limitations in the assumptions regarding the data generation process and sampling of the potential RCTs to be included in the meta-analysis which pose challenges to the interpretation and scientific relevance of the identified causal effects. Despite both causal inference and meta-analysis being extensively studied in the literature, limited effort exists of combining those two frameworks.
Perennial forage legume cultivation and their above-ground mass management methods for weed suppression in arable organic cropping systems
Authors: Arlauskienė Aušra , Jablonskytė-Raščė Danutė , Šarūnaitė Lina , Toleikienė Monika , Masilionytė Laura , Gecaitė Viktorija , Kadžiulienė Žydrė
Published: June 2021

Background

In organic crop farms, growing crop yields are limited by insufficient nitrogen supply to plants and crop weediness. In such farms, legume swards are proposed as a service crop to improve nitrogen cycling. However, a positive effect of nitrogen is not only on cereals but also on weeds. In crop rotation, legume swards can stimulate the competition of cereals using the above-ground mass of legume to control the spread of weeds.

The effects of the following methods for weeds control were analyzed: (i) forage legumes (Trifolium pratenseL. andT. repens) undersown in cereals, (ii) forage legumes (T. pratense L., Medicago sativaL.) and their mixture with festulolium (x Festuliolium) and their above-ground mass management methods, and (iii) plant-based fertilizers (red clover above-ground mass fermented and composted).

Results

Oat with red clover undersown reduced weediness more than red clover monocrops, pea, and their mixture with oats. Incorporated undersown white clover mass increased spring barley competitiveness with weeds. When growing legume swards for a longer period of time (green fallow), red clover and their mixture with festulolium are the most suitable for this purpose. The lowest weed dry weight (average 34%, compared with the removal from the field) was obtained while using the mixed management. The cultivation of cereals after forage legumes and their mixtures with festulolium (as a preceding crop) increases its grain yield and competitive ability against weeds. Fermented red clover and fermented pea and spring wheat mixture mass, as a manure, did not increase weediness.

Conclusions

It was concluded that the effectiveness of the perennial forage legumes is determined by the uses of the above-ground mass: soil cover, mulching, application of green manure, and intensity of mass mineralization. Type of activity of forage legumes on weeds were competition for environmental resources, disruption/promotion of germination, destruction of above-ground mass, reduction of the amount of matured seeds, creation of a physical barrier (mulch), and increase of competitiveness of cereals. Growing forage legumes in pure crops usually leads to a loss of marketable production.

Graphic abstract