bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional differences in general practitioners’ behaviours regarding influenza vaccination: a cross-sectional study
Authors: Arlt Jonathan , Flaegel Kristina , Goetz Katja , Steinhaeuser Jost
Published: March 2021

Background

The World Health Organization recommends vaccination rates of 75% against seasonal influenza for patients over 65 years old. In the 2013/2014 season, the German vaccination rates ranged between 14 and 65%. This study aimed to compare the attitudes, personal characteristics and vaccination behaviours of general practitioners (GPs) in regions with high and low vaccination rates in Germany.

Methods

In May 2016, a questionnaire was sent to 1594 GPs practising in 16 districts with the highest and the lowest vaccination rates in Western and Eastern Germany as described by the Central Research Institute of Ambulatory Health Care in Germany for the 2013/2014 season. Descriptive statistics and multiple regression analyses were computed to identify potential factors associated with high vaccination rates.

Results

A total response rate of 32% (515/1594 participants) was observed in the study. GPs reported their attitudes towards vaccination in general and vaccination against influenza as mostly ‘very positive’ (80%, n = 352 and 65%, n = 288, respectively). GPs practising in regions with low vaccination rates reported their attitudes towards vaccinations in general (p = 0.004) and towards influenza vaccination (p = 0.001) more negatively than their colleagues from regions with high vaccination rates. Multiple logistic regression identified an increasing influence of year-dependent changing efficiency on GPs’ influenza rates as the strongest factor for predicting GPs from highly vaccinating regions (OR = 4.31 [1.12–16.60]), followed by the patient’s vaccination refusal despite GP advice due to already receiving a vaccination from another physician (OR = 3.20 [1.89–5.43]) and vaccination information gathering through medical colleagues (OR = 2.26 [1.19–4.29]).

Conclusions

The results of this study suggest a correlation between GPs’ attitudes and regional vaccination rates. Beneath GPs’ individual attitudes, the regional attitude patterns of patients, colleagues and medical assistants surrounding those GPs seem decisive and should be integrated into future campaigns to increase vaccination rates at a regional level.
Automated detection of lung nodules and coronary artery calcium using artificial intelligence on low-dose CT scans for lung cancer screening: accuracy and prognostic value
Authors: Chamberlin Jordan , Kocher Madison R. , Waltz Jeffrey , Snoddy Madalyn , Stringer Natalie F. C. , Stephenson Joseph , Sahbaee Pooyan , Sharma Puneet , Rapaka Saikiran , Schoepf U. Joseph , Abadia Andres F. , Sperl Jonathan , Hoelzer Phillip , Mercer Megan , Somayaji Nayana , Aquino Gilberto , Burt Jeremy R.
Published: March 2021

Background

Artificial intelligence (AI) in diagnostic radiology is undergoing rapid development. Its potential utility to improve diagnostic performance for cardiopulmonary events is widely recognized, but the accuracy and precision have yet to be demonstrated in the context of current screening modalities. Here, we present findings on the performance of an AI convolutional neural network (CNN) prototype (AI-RAD Companion, Siemens Healthineers) that automatically detects pulmonary nodules and quantifies coronary artery calcium volume (CACV) on low-dose chest CT (LDCT), and compare results to expert radiologists. We also correlate AI findings with adverse cardiopulmonary outcomes in a retrospective cohort of 117 patients who underwent LDCT.

Methods

A total of 117 patients were enrolled in this study. Two CNNs were used to identify lung nodules and CACV on LDCT scans. All subjects were used for lung nodule analysis, and 96 subjects met the criteria for coronary artery calcium volume analysis. Interobserver concordance was measured using ICC and Cohen’s kappa. Multivariate logistic regression and partial least squares regression were used for outcomes analysis.

Results

Agreement of the AI findings with experts was excellent (CACV ICC = 0.904, lung nodules Cohen’s kappa = 0.846) with high sensitivity and specificity (CACV: sensitivity = .929, specificity = .960; lung nodules: sensitivity = 1, specificity = 0.708). The AI findings improved the prediction of major cardiopulmonary outcomes at 1-year follow-up including major adverse cardiac events and lung cancer (AUCMACE = 0.911, AUCLung Cancer = 0.942).

Conclusion

We conclude the AI prototype rapidly and accurately identifies significant risk factors for cardiopulmonary disease on standard screening low-dose chest CT. This information can be used to improve diagnostic ability, facilitate intervention, improve morbidity and mortality, and decrease healthcare costs. There is also potential application in countries with limited numbers of cardiothoracic radiologists.
Identification of super enhancer-associated key genes for prognosis of germinal center B-cell type diffuse large B-cell lymphoma by integrated analysis
Authors: Li Xi , Duan Yan , Hao Yuxia
Published: March 2021

Background

The pathogenesis of germinal center B-cell type diffuse large B-cell lymphoma (GCB-DLBCL) is not fully elucidated. This study aims to explore the regulation of super enhancers (SEs) on GCB-DLBCL by identifying specific SE-target gene.

Methods

Weighted gene co-expression network analysis (WGCNA) was used to screen modules associated with GCB subtype. Functional analysis was performed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. H3K27ac peaks were used to identify SEs. Overall survival analysis was performed using Kaplan–Meier curve with log-rank and Breslow test. The effect of ADNP, ANKRD28 and RTN4IP1 knockdown on Karpas 422 and SUDHL-4 cells proliferation was analyzed by CCK-8. Karpas 422 and SUDHL-4 cells were treated with bromodomain and extra-terminal domain (BET) inhibitor JQ1, and the expression of ADNP, ANKRD28 and RTN4IP1was measured by qRT-PCR.

Results

A total of 26 modules were screened in DLBCL. Turquoise module was closely related to GCB-DLBCL, and its eigengenes were mainly related to autophagy. There were 971 SEs in Karpas 422 cell and 1088 SEs in SUDHL-4 cell. Function of the nearest genes of overall SEs were related to cancer. Six SE-related genes associated with GCB-DLBCL were identified as prognostic markers. Knockdown of ADNP, ANKRD28 and RTN4IP1 inhibited the proliferation of Karpas 422 and SUDHL-4 cells. JQ1 treatment suppressed ADNP, ANKRD28 and RTN4IP1 expression in Karpas 422 and SUDHL-4 cells.

Conclusions

A total of 6 SE-related genes associated with GCB-DLBCL overall survival were identified in this study. These results will serve as a theoretical basis for further study of gene regulation and function of GCB-DLBCL.
Predictors of mortality in COPD exacerbation cases presenting to the respiratory intensive care unit
Authors: Cao Yang , Xing Zhenzhen , Long Huanyu , Huang Yilin , Zeng Ping , Janssens Jean-Paul , Guo Yanfei
Published: March 2021

Background

Studies report high in-hospital mortality of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) especially for those requiring admission to an intensive care unit. Recognizing factors associated with mortality in these patients could reduce health care costs and improve end-of-life care.

Methods

This retrospective study included AECOPD patients admitted to the respiratory intensive care unit of a tertiary hospital in Beijing from Jan 1, 2011 to Dec 31, 2018. Patients demographic characteristics, blood test results and comorbidities were extracted from the electronic medical record system and compared between survivors and non-survivors.

Results

We finally enrolled 384 AECOPD patients: 44 (11.5%) patients died in hospital and 340 (88.5%) were discharged. The most common comorbidity was respiratory failure (294 (76.6%)), followed by hypertension (214 (55.7%)), coronary heart disease (115 (29.9%)) and chronic heart failure (76 (19.8%)). Multiple logistic regression analysis revealed that independent risk factors associated with in-hospital mortality included lymphocytopenia, leukopenia, chronic heart failure and requirement for invasive mechanical ventilation.

Conclusions

The in-hospital mortality of patients with acute COPD exacerbation requiring RICU admission is high. Lymphocytes < 0.8 × 109/L, leukopenia, requirement for invasive mechanical ventilation, and chronic heart failure were identified as risk factors associated with increased mortality rates.
Molecular and morphological identification of suspected Plasmodium vivax vectors in Central and Eastern Sudan
Authors: Abdelwhab Omnia Fathelrhman , Elaagip Arwa , Albsheer Musab M. , Ahmed Ayman , Paganotti Giacomo Maria , Abdel Hamid Muzamil Mahdi
Published: March 2021

Background

In spite of the global effort to eliminate malaria, it remains the most significant vector-borne disease of humans. Plasmodium falciparum is the dominant malaria parasite in sub-Saharan Africa. However, Plasmodium vivax is becoming widely spread throughout Africa. The overuse of vector control methods has resulted in a remarkable change in the behaviour of mosquito that feeds on human as well as on vector composition. The aim of this study was to identify Anopheles mosquito species in vivax malaria endemic regions and to investigate their role in P. vivax circumsporozoite protein (Pvcsp) allele diversity.

Methods

Mosquito samples were collected from Central Sudan (Rural Khartoum and Sennar) and Eastern Sudan (New Halfa, Kassala state) using pyrethrum spray catch (PSC) and CDC light traps. Mosquitoes were identified using appropriate morphological identification keys and Anopheles gambiae complex were confirmed to species level using molecular analysis. A subset of blood-fed anopheline mosquitoes were dissected to determine the presence of natural infection of malaria parasites. In addition, the rest of the samples were investigated for the presence of Pvcsp gene using nested-PCR.

Results

A total of 1037 adult anopheline mosquitoes were collected from New Halfa (N = 467), Rural Khartoum (N = 132), and Sennar (N = 438). Morphological and molecular identification of the collected mosquitoes revealed the presence of Anopheles arabiensis (94.2%), Anopheles funestus (0.5%), and Anopheles pharoensis (5.4%). None of the dissected mosquitoes (N = 108) showed to be infected with malaria parasite. Overall P. vivax infectivity rate was 6.1% (63/1037) by Pvcsp nested PCR. Co-dominance of An. arabiensis and An. pharoensis is reported in Sennar state both being infected with P. vivax.

Conclusion

This study reported P. vivax infection among wild-caught anopheline mosquitoes in Central and Eastern Sudan. While An. arabiensis is the most abundant vector observed in all study areas, An. funestus was recorded for the first time in New Halfa, Eastern Sudan. The documented Anopheles species are implicated in Pvcsp allele diversity. Large-scale surveys are needed to identify the incriminated vectors of P. vivax malaria and determine their contribution in disease transmission dynamics.
Hindlimb unloading-induced reproductive suppression via Downregulation of hypothalamic Kiss-1 expression in adult male rats
Authors: Moustafa Amira
Published: March 2021

Background

Spaceflights-induced microgravity can alter various physiological processes in human’s body including the functional status of the reproductive system. Rodent model of tail-suspension hindlimb unloading is extensively used to stimulate the organs responses to the microgravity condition. This study explores the potential effects of hindlimb unloading on testicular functions and spermatogenesis in adult male rats and the underlying mechanism/s.

Methods

Twenty Sprague-Dawley rats were allotted into two groups: normally loaded group (control; all arms were in touch with the grid floor) and hindlimb unloaded group (HU; only the forearms were in contact with the grid floor).

Results

Following 30 days of exposure, the HU group saw a decline in body weight, testicular and epidydimal weights, and all semen parameters. The circulating concentrations of gonadotropin-releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone significantly decreased, while levels of kisspeptin, corticosterone, inhibin, prolactin and estradiol (E2) increased in the HU group. Intratesticular levels of 5α-reductase enzyme and dihydrotestosterone (DHT) were suppressed, while the levels of aromatase and kisspeptin were significantly elevated in the HU group. Hypothalamic kisspeptin (Kiss1) mRNA expression levels were downregulated while its receptors (Kiss1R) were upregulated in the HU group. On the contrary, the mRNA expression levels of testicularKiss1were upregulated whileKiss1Rwere downregulated. The pituitary mRNA expression levels ofFSHβandLHβdecreased in the HU group. The levels of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and nitric oxide (NO) concentrations, and total antioxidant capacity (TAC) were elevated while malondialdehyde (MDA) concentrations declined in the testes of HU group. The testes of the HU rats showed positive immunostaining of caspase-3, heat shock protein 70 (HSP70) and Bcl2.

Conclusions

Altogether, these results revealed an inhibitory effect of hindlimb unloading on kisspeptin signaling in the hypothalamic-pituitary-testicular axis with impaired spermatogenesis and steroidogenesis.
The effect prophylactic internal iliac artery balloon occlusion in patients with placenta previa or placental accreta spectrum: a systematic review and meta‐analysis
Authors: Nankali Anisodowleh , Salari Nader , Kazeminia Mohsen , Mohammadi Masoud , Rasoulinya Samira , Hosseinian-Far Melika
Published: March 2021

Background

Placenta previa describes a placenta that extends partially or completely over the internal cervical oss. Placenta previa is one of the leading causes of widespread postpartum hemorrhage and maternal mortality worldwide. Another cause of bleeding in pregnant women is Placenta accreta spectrum. Therefore, the aim of the present systematic review and meta-analysis is to determine the effect of prophylactic balloon occlusion of the internal iliac arteries in patients with placenta previa or placental accreta spectrum (PAS).

Methods

In this systematic review and meta-analysis, to identify and select relevant studies, the SID, MagIran, ScienceDirect, Embase, Scopus, PubMed, Web of Science, and Google Scholar databases were searched, using the keywords of internal iliac artery balloon, placenta, previa, balloon, accreta, increta and percreta, without a lower time limit and until 2020. The heterogeneity of the studies was examined using the I2index, and subsequently a random effects model was applied. Data analysis was performed within the Comprehensive Meta-Analysis software (version 2).

Results

In the review of 29 articles with a total sample size of 1140 in the control group, and 1225 in the balloon occlusion group, the mean difference between the two groups was calculated in terms of Intraoperative blood loss index (mL) and it was derived as 3.21 ± 0.38; moreover, in 15 studies with a sample size of 887 in the control group, and 760 in the balloon occlusion group, the mean difference between the two groups in terms of gestation index (weeks) was found as 2.84 ± 0.49; and also with regards to hysterectomy balloon occlusion after prophylactic closure of the iliac artery, hysterectomy (%) balloon occlusion was calculated as 8.9 %, and this, in the hysterectomy control group (%) was obtained as 31.2 %; these differences were statistically significant and showed a positive effect of the intervention (P < 0.05).

Conclusion

The results of this study show that the use of prophylactic internal iliac artery balloon occlusion in patients with placenta previa or Placenta accreta spectrum has benefits such as reduced intraoperative blood loss, reduced hysterectomy and increased gestation (weeks), which can be considered by midwives and obstetricians.
Comparative analysis of perinatal outcomes and birth defects amongst adolescent and older Ugandan mothers: evidence from a hospital-based surveillance database
Authors: Serunjogi Robert , Barlow-Mosha Linda , Mumpe-Mwanja Daniel , Williamson Dhelia , Valencia Diana , Tinker Sarah C. , Adler Michelle R. , Namale-Matovu Joyce , Kalibbala Dennis , Nankunda Jolly , Nabunya Evelyn , Birabwa-Male Doreen , Byamugisha Josaphat , Musoke Philippa
Published: March 2021

Background

Uganda has one of the highest adolescent pregnancy rates in sub-Saharan Africa. We compared the risk of adverse birth outcomes between adolescents (age 12–19 years) and mothers (age 20–34 years) in four urban hospitals.

Methods

Maternal demographics, HIV status, and birth outcomes of all live births, stillbirths, and spontaneous abortions delivered from August 2015 to December 2018 were extracted from a hospital-based birth defects surveillance database. Differences in the distributions of maternal and infant characteristics by maternal age groups were tested with Pearson’s chi-square. Adjusted odds ratios (aORs) and 95% confidence intervals (CI) were calculated using logistic regression to compare the prevalence of adverse birth outcomes among adolescents to mothers 20–34 years.

Results

A total of 100,189 births were analyzed, with 11.1% among adolescent mothers and 89.0% among older mothers. Adolescent mothers had an increased risk of preterm delivery (aOR: 1.14; CI 1.06–1.23), low birth weight (aOR: 1.46; CI 1.34–1.59), and early neonatal deaths (aOR: 1.58; CI 1.23–2.02). Newborns of adolescent mothers had an increased risk of major external birth defects (aOR: 1.33; CI 1.02–1.76), specifically, gastroschisis (aOR: 3.20; CI 1.12–9.13) compared to mothers 20–34 years. The difference between the prevalence of gastroschisis among adolescent mothers (7.3 per 10,000 births; 95% CI 3.7–14.3) was statistically significant when compared to mothers 20–34 years (1.6 per 10,000 births; 95% CI 0.9–2.6).

Conclusions

This study found that adolescent mothers had an increased risk for several adverse birth outcomes compared to mothers 20–34 years, similar to findings in the region and globally. Interventions are needed to improve birth outcomes in this vulnerable population.
Construction of a recombinant avipoxvirus expressing the env gene of Zika virus as a novel putative preventive vaccine
Authors: Zanotto Carlo , Paolini Francesca , Radaelli Antonia , De Giuli Morghen Carlo
Published: March 2021

Background

Zika virus (ZIKV) has been declared a public health emergency that requires development of an effective vaccine, as it might represent an international threat.

Methods

Here, two novel DNA-based (pVAXzenv) and fowlpox-based (FPzenv) recombinant putative vaccine candidates were constructed that contained the cPrME genes of ZIKV. The env gene inserted into the fowlpox vector was verified for correct transgene expression by Western blotting and by immunofluorescence in different cell lines. The production of virus-like particles as a result of env gene expression was also demonstrated by electron microscopy. BALB/c mice were immunosuppressed with dexamethasone and immunized following a prime–boost strategy in a heterologous protocol where pVAXzenv was followed by FPzenv, to evaluate the immunogenicity of the Env protein. The mice underwent a challenge with an epidemic ZIKV after the last boost.

Results

These data show that the ZIKV Env protein was correctly expressed in both normal human lung fibroblasts (MRC-5 cells) and green monkey kidney (Vero) cells infected with FPzenv, and that the transgene expression lasted for more than 2 weeks. After mucosal administration of FPzenv, the immunized mice showed specific and significantly higher humoral responses compared to the control mice. However, virus neutralizing antibodies were not detected using plaque reduction assays.

Conclusions

Although BALB/c mice appear to be an adequate model for ZIKV infection, as it mimics the natural mild infection in human beings, inadequate immune suppression seemed to occur by dexamethasone and different immune suppression strategies should be applied before challenge to reveal any protection of the mice.
Weighted gene co-expression network analysis to identify key modules and hub genes related to hyperlipidaemia
Authors: Liao Fu-Jun , Zheng Peng-Fei , Guan Yao-Zong , Pan Hong-Wei , Li Wei
Published: March 2021

Background

The purpose of this study was to explore the potential molecular targets of hyperlipidaemia and the related molecular mechanisms.

Methods

The microarray dataset of GSE66676 obtained from patients with hyperlipidaemia was downloaded. Weighted gene co-expression network (WGCNA) analysis was used to analyse the gene expression profile, and the royal blue module was considered to have the highest correlation. Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were implemented for the identification of genes in the royal blue module using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool (version 6.8; http://david.abcc.ncifcrf.gov). A protein–protein interaction (PPI) network was established by using the online STRING tool. Then, several hub genes were identified by the MCODE and cytoHubba plug-ins in Cytoscape software.

Results

The significant module (royal blue) identified was associated with TC, TG and non-HDL-C. GO and KEGG enrichment analyses revealed that the genes in the royal blue module were associated with carbon metabolism, steroid biosynthesis, fatty acid metabolism and biosynthesis pathways of unsaturated fatty acids. SQLE (degree = 17) was revealed as a key molecule associated with hypercholesterolaemia (HCH), and SCD was revealed as a key molecule associated with hypertriglyceridaemia (HTG). RT-qPCR analysis also confirmed the above results based on our HCH/HTG samples.

Conclusions

SQLE and SCD are related to hyperlipidaemia, and SQLE/SCD may be new targets for cholesterol-lowering or triglyceride-lowering therapy, respectively.
Management of idiopathic granulomatous mastitis in lactation: case report and review of the literature
Authors: Kornfeld Hannah W. , Mitchell Katrina B.
Published: March 2021

Background

Idiopathic Granulomatous Mastitis (IGM) is a benign chronic inflammatory breast condition that mimics two common breast disorders: breast carcinoma and breast abscess. It can form breast masses, fistulae, and fluid collections, resulting in breast disfigurement with retraction and nipple areolar complex (NAC) inversion. IGM most often presents in women of childbearing age within a few years of pregnancy, and can significantly impact lactation. Despite the prevalence of this disease, no current literature describes an approach to managing IGM during breastfeeding.

Case presentation

A 28-year-old G3P2 patient of Native American origin presented to her obstetrician at 7 months pregnant with worsening left breast swelling and redness. She underwent a mammogram, ultrasound and core needle biopsy that confirmed the diagnosis of Idiopathic Granulomatous Mastitis. During the postpartum period, she underwent intralesional triamcinolone injections of her left breast. Due to the contraindication of breastfeeding after local steroid injection, the patient stopped breastfeeding from the affected breast and continued breastfeeding unilaterally.

Conclusions

Idiopathic Granulomatous Mastitis is a challenging chronic inflammatory breast disease that affects women primarily in the reproductive years, with a higher incidence in patients of Hispanic, Native American, Middle Eastern, and African descent. Treatment of IGM during pregnancy and lactation has thus far not been addressed. We review the literature on the treatment of IGM in the non-lactating population, and propose considerations for treating breastfeeding women affected by this disease. Traditional treatment has included systemic immunosuppression and surgery, but newer literature demonstrates that intralesional injection of steroid can provide significant symptomatic relief to patients. A diagnosis of IGM does not preclude breastfeeding, though patients may experience challenges with milk production and latch on the affected breast. Individualized care should be provided, with considerations given to the following: side effects of systemic steroids, the need to wean a breast being treated with intralesional steroids, and augmentation of milk production on the unaffected breast to promote continued breastfeeding.
Clinical outcomes of extensive-stage small cell lung cancer patients treated with thoracic radiotherapy at different times and fractionations
Authors: Han Jinmin , Fu Chengrui , Li Baosheng
Published: March 2021

Objective

The purpose of this study was to assess whether thoracic radiotherapy (TRT) combined with chemotherapy (CHT) showed promising anti-tumour activity in extensive-stage small cell lung cancer (ES-SCLC), to explore practice patterns for the radiation time and dose/fractionation and to identify prognostic factors for patients who would benefit from CHT/TRT.

Methods

A total of 492 ES-SCLC patients were included from January 2010 to March 2019, 244 of whom received CHT/TRT. Propensity score matching was performed to minimize bias between the CHT/TRT and CHT-alone groups. Patients in the CHT/TRT group were categorized into four subgroups based on the number of induction CHT cycles. For effective dose fractionation calculations, we introduced the time-adjusted biological effective dose (tBED). Categorical variables were analysed with chi-square tests and Fisher’s exact tests. Kaplan–Meier curves were generated to estimate survival rates using the R-project. Multivariate prognostic analysis was performed with Cox proportional hazards models.

Results

Patients who received CHT/TRT experienced improved overall survival (OS) (18.1 vs 10.8 months), progression-free survival (PFS) (9.3 vs 6.0 months) and local recurrence-free survival (LRFS) (12.0 vs 6.6 months) before matching, with similar results after matching. In the CHT/TRT group, the median LRFS times for the groups based on the radiation time were 12.7, 12.0, 12.0, and 9.0 months, respectively. Early TRT had a tendency to prolong PFS (median 10.6 vs 9.8 vs 9.0 vs 7.7 months, respectively, p = 0.091) but not OS (median 17.6 vs 19.5 vs 17.2 vs 19.0 months, respectively, p = 0.622). Notably, patients who received TRT within 6 cycles of CHT experienced prolonged LRFS (p = 0.001). Regarding the radiation dose, patients in the high-dose group (tBED > 50 Gy) who achieved complete response and partial response (CR and PR) to systemic therapy had relatively short OS (median 27.1 vs 22.7, p = 0.026) and PFS (median 11.4 vs 11.2, p = 0.032), but the abovementioned results were not obtained after the exclusion of patients who received hyperfractionated radiotherapy (all p > 0.05).

Conclusion

CHT/TRT could improve survival for ES-SCLC patients. TRT performed within 6 cycles of CHT and hyperfractionated radiotherapy (45 Gy in 30 fractions) may be a feasible treatment scheme for ES-SCLC patients.
Standard of care versus new-wave corticosteroids in the treatment of Duchenne muscular dystrophy: Can we do better?
Authors: Kourakis Stephanie , Timpani Cara A. , Campelj Dean G. , Hafner Patricia , Gueven Nuri , Fischer Dirk , Rybalka Emma
Published: March 2021

Background

Pharmacological corticosteroid therapy is the standard of care in Duchenne Muscular Dystrophy (DMD) that aims to control symptoms and slow disease progression through potent anti-inflammatory action. However, a major concern is the significant adverse effects associated with long term-use.

Main

This review discusses the pros and cons of standard of care treatment for DMD and compares it to novel data generated with the new-wave dissociative corticosteroid, vamorolone. The current status of experimental anti-inflammatory pharmaceuticals is also reviewed, with insights regarding alternative drugs that could provide therapeutic advantage.

Conclusions

Although novel dissociative steroids may be superior substitutes to corticosteroids, other potential therapeutics should be explored. Repurposing or developing novel pharmacological therapies capable of addressing the many pathogenic features of DMD in addition to anti-inflammation could elicit greater therapeutic advantages.
Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models
Authors: Chen Ming , Chen Yunan , Huo Qingwei , Wang Lei , Tan Shuyi , Misrani Afzal , Jiang Jinxiang , Chen Jian , Chen Shiyuan , Zhang Jiawei , Tabassum Sidra , Wang Jichen , Chen Xi , Long Cheng , Yang Li
Published: March 2021

Background

Before the deposition of amyloid-beta plaques and the onset of learning memory deficits, patients with Alzheimer’s disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discriminate, and identify odors. Rodent models of AD, such as the Tg2576 and APP/PS1 mice, also display impaired olfaction, accompanied by aberrant in vivo or in vitro gamma rhythms in the olfactory pathway. However, the mechanistic relationships between the electrophysiological, biochemical and behavioral phenomena remain unclear.

Methods

To address the above issues in AD models, we conducted in vivo measurement of local field potential (LFP) with a combination of in vitro electro-olfactogram (EOG), whole-cell patch and field recordings to evaluate oscillatory and synaptic function and pharmacological regulation in the olfactory pathway, particularly in the olfactory bulb (OB). Levels of protein involved in excitation and inhibition of the OB were investigated by western blotting and fluorescence staining, while behavioral studies assessed olfaction and memory function.

Results

LFP measurements demonstrated an increase in gamma oscillations in the OB accompanied by altered olfactory behavior in both APP/PS1 and 3xTg mice at 3–5 months old, i.e. an age before the onset of plaque formation. Fewer olfactory sensory neurons (OSNs) and a reduced EOG contributed to a decrease in the excitatory responses of M/T cells, suggesting a decreased ability of M/T cells to trigger interneuron GABA release indicated by altered paired-pulse ratio (PPR), a presynaptic parameter. Postsynaptically, there was a compensatory increase in levels of GABAAR α1 and β3 subunits and subsequent higher amplitude of inhibitory responses. Strikingly, the GABA uptake inhibitor tiagabine (TGB) ameliorated abnormal gamma oscillations and levels of GABAAR subunits, suggesting a potential therapeutic strategy for early AD symptoms. These findings reveal increased gamma oscillations in the OB as a core indicator prior to onset of AD and uncover mechanisms underlying aberrant gamma activity in the OB.

Conclusions

This study suggests that the concomitant dysfunction of both olfactory behavior and gamma oscillations have important implications for early AD diagnosis: in particular, awareness of aberrant GABAergic signaling mechanisms might both aid diagnosis and suggest therapeutic strategies for olfactory damage in AD.
Experimental infection of indigenous North African goats with goatpox virus
Authors: Hamdi Jihane , Bamouh Zahra , Jazouli Mohammed , Alhyane Meryem , Safini Najet , Omari Tadlaoui Khalid , Fassi Fihri Ouafaa , El Harrak Mehdi
Published: March 2021

Background

Goatpox is a viral disease caused by infection with goatpox virus (GTPV) of the genus Capripoxvirus, Poxviridae family. Capripoxviruses cause serious disease to livestock and contribute to huge economic losses. Goatpox and sheeppox are endemic to Africa, particularly north of the Equator, the Middle East and many parts of Asia. GTPV and sheeppox virus are considered host-specific; however, both strains can cause clinical disease in either goats or sheep with more severe disease in the homologous species and mild or sub-clinical infection in the other. Goatpox has never been reported in Morocco, Algeria or Tunisia despite the huge population of goats living in proximity with sheep in those countries. To evaluate the susceptibility and pathogenicity of indigenous North African goats to GTPV infection, we experimentally inoculated eight locally bred goats with a virulent Vietnamese isolate of GTPV. Two uninfected goats were kept as controls. Clinical examination was carried out daily and blood was sampled for virology and for investigating the antibody response. After necropsy, tissues were collected and assessed for viral DNA using real-time PCR.

Results

Following the experimental infection, all inoculated goats displayed clinical signs characteristic of goatpox including varying degrees of hyperthermia, loss of appetite, inactivity and cutaneous lesions. The infection severely affected three of the infected animals while moderate to mild disease was noticed in the remaining goats. A high antibody response was developed. High viral DNA loads were detected in skin crusts and nodules, and subcutaneous tissue at the injection site with cycle threshold (Ct) values ranging from 14.6 to 22.9, while lower viral loads were found in liver and lung (Ct = 35.7 and 35.1). The results confirmed subcutaneous tropism of the virus.

Conclusion

Clinical signs of goatpox were reproduced in indigenous North African goats and confirmed a high susceptibility of the North African goat breed to GTPV infection. A clinical scoring system is proposed that can be applied in GTPV vaccine efficacy studies.
SCAMP5 mediates activity-dependent enhancement of NHE6 recruitment to synaptic vesicles during synaptic plasticity
Authors: Lee Unghwi , Ryu Seung Hyun , Chang Sunghoe
Published: March 2021

Na+(K+)/H+exchanger 6 (NHE6) on synaptic vesicle (SV) is critical for the presynaptic regulation of quantal size at the glutamatergic synapses by converting the chemical gradient (ΔpH) into membrane potential (Δψ) across the SV membrane. We recently found that NHE6 directly interacts with secretory carrier membrane protein 5 (SCAMP5), and SCAMP5-dependent recruitment of NHE6 to SVs controls the strength of synaptic transmission by modulation of quantal size of glutamate release at rest. It is, however, unknown whether NHE6 recruitment by SCAMP5 plays a role during synaptic plasticity. Here, we found that the number of NHE6-positive presynaptic boutons was significantly increased by the chemical long-term potentiation (cLTP). Since cLTP involves new synapse formation, our results indicated that NHE6 was recruited not only to the existing presynaptic boutons but also to the newly formed presynaptic boutons. Knock down of SCAMP5 completely abrogated the enhancement of NHE6 recruitment by cLTP. Interestingly, despite an increase in the number of NHE6-positive boutons by cLTP, the quantal size of glutamate release at the presynaptic terminals remained unaltered. Together with our recent results, our findings indicate that SCAMP5-dependent recruitment of NHE6 plays a critical role in manifesting presynaptic efficacy not only at rest but also during synaptic plasticity. Since both are autism candidate genes, reduced presynaptic efficacy by interfering with their interaction may underlie the molecular mechanism of synaptic dysfunction observed in autism.
Pseudohypoparathyroidism: application of the Italian common healthcare-pathway for a homogeneous clinical approach and a shared follow up
Authors: Tessaris Daniele , Bonino Elisa , Weber Giovanna , Wasniewska Malgorzata , Corica Domenico , Pitea Marco , Scirè Giuseppe , Caruso-Nicoletti Manuela , Fintini Danilo , de Sanctis Luisa
Published: March 2021

Background

Pseudohypoparathyroidism (PHP) represents a heterogeneous group of rare endocrine disorders caused by (epi) genetic abnormalities affecting the GNAS locus. It is mainly characterized by resistance to PTH and TSH, and by peculiar clinical features such as short stature, obesity, cognitive impairment, subcutaneous ossifications and brachydactyly. Delayed puberty, GHRH and calcitonin resistances have also been described. The healthcare-pathway recently proposed by the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) has provided a standardized clinical approach to these conditions. The purpose of the present study was to evaluate its application in clinical practice, and to collect data for setting future specific studies.

Methods

Through a semi-structured survey, based on the indications of the care-pathway, data on PHP clinical management were collected. The compilation of each data in the survey was read as an index of the adoption of the healthcare-pathway in clinical practice.

Results

In addition to the proposing Center, 4 Centers joined the study, thus obtaining a large collection of data on 48 PHP patients. Highest rates in the completion of data were obtained for diagnostic history, auxological measurements and subcutaneous ossifications evaluation. As expected, the availability of data for the other investigated fields was lower, coming from recent research studies. More information has been obtained on hormonal resistance classically involved in PHP (PTH, TSH, GHRH and GnRH) and on cognitive impairment, while a few data has been collected on bone mineral status, calcitonin levels and glucolipid metabolism.

Conclusions

The presented data show that the ISPED healthcare-pathway could represent a valid tool both to confirm the clinical approach to PHP patients and to allow homogeneous data collection; however, it has not yet been fully adopted. The strengthening of the network among the major Italian Endocrine Centers will contribute to improve its application in clinical practice, optimizing the follow-up of these patients and increasing knowledge on PHP.
A case report of Phelan-McDermid syndrome: preliminary results of the treatment with growth hormone therapy
Authors: Xie Rui Jin , Li Tian Xiao , Sun Chenyu , Cheng Ce , Zhao Jinlin , Xu Hua , Liu Yueying
Published: March 2021

Background

Phelan-McDermid syndrome (PMS), also known as 22q13.3 deletion syndrome, is a rare neurodevelopmental syndrome resulting from a deletion of the distal long arm of chromosome 22.

Case presentation

We report a case of a 21 months old Chinese girl presenting with global developmental delay, regression of language skills, unable to understand a few words or walk independently, insomnia, and autism-like behaviors. Copy number variation (CNV) analysis showed a heterozygous loss of SHANK3 gene in the 22q13 region, consistent with a diagnosis of PMS. After treatment with recombinant human growth hormone (rhGH), this patient had an improvement in motor skills and social behaviors. No side effects from rhGH therapy were reported.

Conclusions

This is the first report of using rhGH to treat a Chinese girl diagnosed with PMS. We speculate rhGH could be a reasonable alternative choice for PMS treatment with similar clinical outcomes in comparison to insulin-like growth factor-1(IGF-1). However, further clinical trials are needed to confirm this hypothesis.
First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models
Authors: Pairawan Seyed , Zhao Ming , Yuca Erkan , Annis Allen , Evans Kurt , Sutton David , Carvajal Luis , Ren Jian-Guo , Santiago Solimar , Guerlavais Vincent , Akcakanat Argun , Tapia Coya , Yang Fei , Bose Priya Subash Chandra , Zheng Xiaofeng , Dumbrava Ecaterina Ileana , Aivado Manuel , Meric-Bernstam Funda
Published: March 2021

Background

MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models.

Methods

Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel.

Results

ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent.

Conclusion

The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.
An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer
Authors: Stringer-Reasor Erica M. , May Jori E. , Olariu Eva , Caterinicchia Valerie , Li Yufeng , Chen Dongquan , Della Manna Deborah L. , Rocque Gabrielle B. , Vaklavas Christos , Falkson Carla I. , Nabell Lisle M. , Acosta Edward P. , Forero-Torres Andres , Yang Eddy S.
Published: March 2021

Background

Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC.

Methods

A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded.

Results

Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0–2). Fifty percent of patients were Caucasian, 45% African–American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug–drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders.

Conclusions

Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed.

Trial registration

ClinicalTrials.gov, NCT02158507. Registered on 12 September 2014
Effects of Dangguixu-san in patients with acute lateral ankle sprain: a randomized controlled trial
Authors: Kim Jae-Hong , Lee Cham-Kyul , Lee Eun-Yong , Cho Myoung-Rae , Lee Young-Su , Lee Jeong-Soon
Published: March 2021

Background

Dangguixu-san (DS), a herbal extract, is widely used in Korean medicine to treat pain and swelling caused by ankle sprain. However, there is insufficient evidence regarding the effects of DS on ankle sprains. Accordingly, we assessed the efficacy and safety of DS for the treatment of acute lateral ankle sprain (ALAS).

Methods

This study was a multicenter (two Korean hospitals), randomized, double-blind, placebo-controlled, parallel-arm clinical trial with a 1:1 allocation ratio that included a per-protocol analysis and sub-analysis based on symptom severity. Forty-eight participants (n = 28 at Semyung University Korean Medicine Hospital in Chungju;n = 20 at DongShin University Gwangju Korean Medicine Hospital) with grade I or II ALAS that occurred within 72 h before enrollment were randomized to a DS (n = 24) or placebo (n = 24) group. Both groups received acupuncture treatment once daily for 5 consecutive days and the trial medication (DS/placebo capsule) three times a day for 7 consecutive days. Primary (visual analog scale [VAS] scores for pain) and secondary (Foot and Ankle Outcome Scores [FAOS], edema, and European Quality of Life Five-Dimension-Five-Level Scale [EQ-5D-5L] scores) outcome measures were recorded at baseline (week 0), the end of the intervention (week 1), and 4 weeks after treatment completion (week 5).

Results

Forty-six participants completed the trial (n = 23 each). Changes in VAS scores, FAOS Symptom/Rigidity, and FAOS Ache from week 1 to week 5 showed significant differences between the two groups. Sub-analyses showed significant differences in changes of FAOS Ache (week 0 to week 5) and VAS scores, total FAOS, and EQ-5D-5L scores (week 1 to week 5) between the two subgroups (grade II). There were no adverse events and significant negative changes in clinical laboratory parameters in both groups.

Conclusions

Overall, the results of this study are in favor of DS combined with acupuncture and suggest that DS combined with acupuncture is a safe treatment with positive long-term effects in terms of pain reduction and symptom alleviation in patients with grade I or II ALAS.

Trial registration

Clinical Research Information ServiceKCT0002374. Registered on July 11, 2017; retrospectively registered.
Effluent solids recirculation to municipal sludge digesters enhances long-chain fatty acids degradation capacity
Authors: Shakeri Yekta Sepehr , Liu Tong , Mendes Anacleto Thuane , Axelsson Bjerg Mette , Šafarič Luka , Goux Xavier , Karlsson Anna , Björn Annika , Schnürer Anna
Published: March 2021

Background

Slow degradation kinetics of long-chain fatty acids (LCFA) and their accumulation in anaerobic digesters disrupt methanogenic activity and biogas production at high loads of waste lipids. In this study, we evaluated the effect of effluent solids recirculation on microbial LCFA (oleate) degradation capacity in continuous stirred-tank sludge digesters, with the overall aim of providing operating conditions for efficient co-digestion of waste lipids. Furthermore, the impacts of LCFA feeding frequency and sulfide on process performance and microbial community dynamics were investigated, as parameters that were previously shown to be influential on LCFA conversion to biogas.

Results

Effluent solids recirculation to municipal sludge digesters enabled biogas production of up to 78% of the theoretical potential from 1.0 g oleate l−1 day−1. In digesters without effluent recirculation, comparable conversion efficiency could only be reached at oleate loading rates up to 0.5 g l−1 day−1. Pulse feeding of oleate (supplementation of 2.0 g oleate l−1 every second day instead of 1.0 g oleate l−1 every day) did not have a substantial impact on the degree of oleate conversion to biogas in the digesters that operated with effluent recirculation, while it marginally enhanced oleate conversion to biogas in the digesters without effluent recirculation. Next-generation sequencing of 16S rRNA gene amplicons of bacteria and archaea revealed that pulse feeding resulted in prevalence of fatty acid-degrading Smithella when effluent recirculation was applied, whereas Candidatus Cloacimonas prevailed after pulse feeding of oleate in the digesters without effluent recirculation. Combined oleate pulse feeding and elevated sulfide level contributed to increased relative abundance of LCFA-degrading Syntrophomonas and enhanced conversion efficiency of oleate, but only in the digesters without effluent recirculation.

Conclusions

Effluent solids recirculation improves microbial LCFA degradation capacity, providing possibilities for co-digestion of larger amounts of waste lipids with municipal sludge.