bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage
Authors: Peng Yucong , Zhuang Jianfeng , Ying Guangyu , Zeng Hanhai , Zhou Hang , Cao Yang , Chen Huaijun , Xu Chaoran , Fu Xiongjie , Xu Hangzhe , Li Jianru , Cao Shenglong , Chen Jingyin , Gu Chi , Yan Feng , Chen Gao
Published: May 2020

Background

Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH.

Methods

A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro.

Results

STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1β, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust anti-inflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro.

Conclusion

Microglial STING yielded neuroinflammation after SAH, while pharmacologic inhibition of STING could attenuate SAH-induced inflammatory injury at least partly by activating AMPK signal. These data supported the notion that STING might be a potential therapeutic target for SAH.
Intermittent peripheral exposure to lipopolysaccharide induces exploratory behavior in mice and regulates brain glial activity in obese mice
Authors: Huang Hui-Ting , Chen Po-See , Kuo Yu-Min , Tzeng Shun-Fen
Published: May 2020

Background

Consecutive peripheral immune challenges can modulate the responses of brain resident microglia to stimuli. High-fat diet (HFD) intake has been reported to stimulate the activation of astrocytes and microglia in the arcuate nucleus (ARC) of the hypothalamus in obese rodents and humans. However, it is unknown whether intermittent exposure to additional peripheral immune challenge can modify HFD-induced hypothalamic glial activation in obese individuals.

Methods

In this study, we administered 1 mg/kg LPS (or saline) by intraperitoneal (i.p.) injection to 8-week-old male mice after 1, 2, or 8 weeks of a regular diet (show) or HFD. The level of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) expression in the plasma and hypothalamic tissue was analyzed 24 h after each LPS injection. The behaviors of the animals in the four groups (the chow-saline, chow-LPS, HFD-saline, and HFD-LPS groups) were examined 5 months after exposure to chow or a HFD. Morphological examination of microglia in related brain regions was also conducted.

Results

The plasma levels and hypothalamic mRNA levels of IL-1β and TNF-α were significantly upregulated 24 h after the first injection of LPS but not after the second or third injection of LPS. Chow-LPS mice displayed increased exploratory behavior 5 months after feeding. However, this LPS-induced abnormal exploratory behavior was inhibited in HFD-fed mice. Chronic HFD feeding for 5 months induced apparent increases in the number and cell body size of microglia, mainly in the ARC, and also increased the size of microglia in the nucleus accumbens (NAc) and insula. Moreover, microglial activation in the ARC, anterior cingulate cortex (ACC), insula, and basolateral amygdala (BLA) was observed in chow-LPS mice. However, microglial activation in the analyzed brain regions was suppressed in HFD-LPS mice.

Conclusions

Altogether, the results indicate that intermittent peripheral challenge with LPS might prime microglia in the ARC and NAc to modify their response to chronic HFD feeding. Alternatively, chronic HFD feeding might mediate microglia in LPS-affected brain regions and subsequently suppress LPS-induced atypical exploratory behavior. Our findings suggest that the interaction of intermittent acute peripheral immune challenges with chronic HFD intake can drive microglia to amend the microenvironment and further modify animal behaviors in the later life.
A chart review of substance use screening and related documentation among adolescents in outpatient pediatric clinics: implications for practice
Authors: Kuhns Lisa M. , Carlino Brookley , Greeley Katie , Muldoon Abigail L. , Karnik Niranjan , Thompson Hale , Garofalo Robert , Rahmandar Maria
Published: May 2020

Background

Despite recent reductions, youth substance use continues to be a concern in the United States. Structured primary care substance use screening among adolescents is recommended, but not widely implemented. The purpose of this study was to describe the distribution and characteristics of adolescent substance use screening in outpatient clinics in a large academic medical center and assess related factors (i.e., patient age, race/ethnicity, gender, and insurance type) to inform and improve the quality of substance use screening in practice.

Methods

We abstracted a random sample of 127 records of patients aged 12–17 and coded clinical notes (e.g., converted open-ended notes to discrete values) to describe screening cases and related characteristics (e.g., which substances screened, how screened). We then analyzed descriptive patterns within the data to calculate screening rates, characteristics of screening, and used multiple logistic regression to identify related factors.

Results

Among 127 records, rates of screening by providers were 72% (each) for common substances (alcohol, marijuana, tobacco). The primary method of screening was use of clinical mnemonic cues rather than standardized screening tools. A total of 6% of patients reported substance use during screening. Older age and racial/ethnic minority status were associated with provider screening in multiple logistic regression models.

Conclusions

Despite recommendations, low rates of structured screening in primary care persist. Failure to use a standardized screening tool may contribute to low screening rates and biased screening. These findings may be used to inform implementation of standardized and structured screening in the clinical environment.

Clinical trial registration

not applicable.
High prevalence of symptomatic spinal stenosis in Norwegian adults with achondroplasia: a population-based study
Authors: Fredwall Svein O. , Steen Unni , de Vries Olga , Rustad Cecilie F. , Eggesbø Heidi Beate , Weedon-Fekjær Harald , Lidal Ingeborg B. , Savarirayan Ravi , Månum Grethe
Published: May 2020

Background

Symptomatic spinal stenosis (SSS) is a well-known medical complication in achondroplasia. The reported prevalence of SSS is 10 to 30%, an estimate based on small studies or selected populations. No population-based studies exist currently. Furthermore, the relationship between SSS and physical functioning has not been investigated in detail. The aims of this study were to describe the prevalence of SSS in Norwegian adults with achondroplasia, and to explore the impact of SSS on physical functioning.

Methods

This was a population-based study on Norwegian community-dwelling adults with genetically confirmed achondroplasia. Prevalence of SSS was defined by clinical symptoms, and confirmed by imaging or surgical reports. Physical functioning was assessed by walking capacity (6-min walk test), hand strength (Grippit), and activities of daily living (the Health Assessment Questionnaire, HAQ). Pain was assessed by pain site locations and intensity (Numeric Rating Scale, NRS).

Results

In total, 50 participants were included (27 males, 23 females). Median age was 41 years (range 16 to 87 years), 34 (68%) had SSS. The estimated median age at first symptom onset was 33 years (95% confidence interval (CI) 29 to 43 years), range 10 to 67 years. The majority had multiple spinal levels affected. The walking distance was 110 m shorter in the SSS group (95% CI − 172 to − 40 m) as compared with the non-SSS group (p < 0.01). There was no considerable difference in hand strength between the two groups. Mean HAQ scores (0–3) for walking and hygiene were significantly higher in the SSS group, reflecting more activity limitations. Mean differences were 0.9 (95% CI 0.3 to 1.4,p < 0.01) and 0.6 (95% CI 0.2 to 1.0, p < 0.01). Pain intensity (NRS 0–10) was also significantly higher in the SSS group with a mean difference of 3.2 (95% CI 0.6 to 5.6,p = 0.02).

Conclusions

SSS was highly prevalent in Norwegian adults with achondroplasia, with symptom onset at young age, and multiple spinal levels affected. The presence of SSS was associated with reduced walking distance, activity limitations, and more pain. The findings underline the importance of thorough assessment and monitoring of SSS in achondroplasia, including a formal assessment of physical functioning.
Accounting for cell type hierarchy in evaluating single cell RNA-seq clustering
Authors: Wu Zhijin , Wu Hao
Published: May 2020

Cell clustering is one of the most common routines in single cell RNA-seq data analyses, for which a number of specialized methods are available. The evaluation of these methods ignores an important biological characteristic that the structure for a population of cells is hierarchical, which could result in misleading evaluation results. In this work, we develop two new metrics that take into account the hierarchical structure of cell types. We illustrate the application of the new metrics in constructed examples as well as several real single cell datasets and show that they provide more biologically plausible results.
Personalized and graph genomes reveal missing signal in epigenomic data
Authors: Groza Cristian , Kwan Tony , Soranzo Nicole , Pastinen Tomi , Bourque Guillaume
Published: May 2020

Background

Epigenomic studies that use next generation sequencing experiments typically rely on the alignment of reads to a reference sequence. However, because of genetic diversity and the diploid nature of the human genome, we hypothesize that using a generic reference could lead to incorrectly mapped reads and bias downstream results.

Results

We show that accounting for genetic variation using a modified reference genome or a de novo assembled genome can alter histone H3K4me1 and H3K27ac ChIP-seq peak calls either by creating new personal peaks or by the loss of reference peaks. Using permissive cutoffs, modified reference genomes are found to alter approximately 1% of peak calls while de novo assembled genomes alter up to 5% of peaks. We also show statistically significant differences in the amount of reads observed in regions associated with the new, altered, and unchanged peaks. We report that short insertions and deletions (indels), followed by single nucleotide variants (SNVs), have the highest probability of modifying peak calls. We show that using a graph personalized genome represents a reasonable compromise between modified reference genomes and de novo assembled genomes. We demonstrate that altered peaks have a genomic distribution typical of other peaks.

Conclusions

Analyzing epigenomic datasets with personalized and graph genomes allows the recovery of new peaks enriched for indels and SNVs. These altered peaks are more likely to differ between individuals and, as such, could be relevant in the study of various human phenotypes.
Radiotherapy-related skin toxicity (RAREST-02): A randomized trial testing the effect of a mobile application reminding head-and-neck cancer patients to perform skin care (reminder app) on radiation dermatitis
Authors: Rades Dirk , Narvaez Carlos Andres , Doemer Claudia , Janssen Stefan , Olbrich Denise , Tvilsted Soeren , Conde-Moreno Antonio J. , Cacicedo Jon
Published: May 2020

Background

Radiotherapy of head-and-neck cancer can be associated with significant toxicities including dermatitis and oral mucositis. Severe toxicities may require interruptions of the radiation treatment associated with impairment of the patients’ prognoses. This study will investigate whether the addition of a reminder app to standard care can reduce dermatitis and oral mucositis rates during radiotherapy in these patients.

Methods

This randomized trial compares standard care supported by a reminder app (Arm A) to standard care alone (Arm B) with respect to grade ≥ 2 radiation dermatitis and oral mucositis at 60 Gy of radiotherapy, the minimum planned dose for patients receiving definitive or adjuvant radiotherapy for locally advanced head- and-neck cancer. Moreover, radiation-induced dermatitis and oral mucositis grade ≥ 3 at 60 Gy and both grade ≥ 2 and grade ≥ 3 at the end of radiation treatment (EOT) will be evaluated, as well as quality of life and pain. According to sample size calculations, 80 patients are required per arm within the full analysis set. Taking into account that 5% of patients will not qualify for full analysis set, 168 patients should be randomized. The impact of the reminder app will be considered clinically relevant, if the rates of grade ≥ 2 radiation dermatitis (primary endpoint) and oral mucositis (secondary endpoint) can be reduced by 20%.

Discussion

If the addition of a reminder app to standard care will lead to a significant reduction of radiation dermatitis and oral mucositis, it could become a helpful tool for patients with head-and-neck cancer during radiotherapy.

Trial registration

clinicaltrials.gov (NCT04110977). Registered on September 27, 2019. First patient is planned to be included in December 2019.
Analysis of responder-based endpoints: improving power through utilising continuous components
Authors: Wason James , McMenamin Martina , Dodd Susanna
Published: May 2020

Background

Clinical trials and other studies commonly assess the effectiveness of an intervention through the use of responder-based endpoints. These classify patients based on whether they meet a number of criteria which often involve continuous variables categorised as being above or below a threshold. The proportion of patients who are responders is estimated and, where relevant, compared between groups. An alternative method called the augmented binary method keeps the definition of the endpoint the same but utilises information contained within the continuous component to increase the power considerably (equivalent to increasing the sample size by > 30%). In this article we summarise the method and investigate the variety of clinical conditions that use endpoints to which it could be applied.

Methods

We reviewed a database of core outcome sets (COSs) that covered physiological and mortality trial endpoints recommended for collection in clinical trials of different disorders. We identified responder-based endpoints where the augmented binary method would be useful for increasing power.

Results

Out of the 287 COSs reviewed, we identified 67 new clinical areas where endpoints were used that would be more efficiently analysed using the augmented binary method. Clinical areas that had particularly high numbers were rheumatology (11 clinical disorders identified), non-solid tumour oncology (10 identified), neurology (9 identified) and cardiovascular (8 identified).

Conclusions

The augmented binary method can potentially provide large benefits in a vast array of clinical areas. Further methodological development is needed to account for some types of endpoints.
High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes
Authors: Oliveira Dennis , Stegmayr Carina , Heinzel Alexander , Ermert Johannes , Neumaier Bernd , Shah N. Jon , Mottaghy Felix M. , Langen Karl-Josef , Willuweit Antje
Published: May 2020

Background

Recent studies reported on high uptake of the PSMA ligands [68Ga]HBED-CC (68Ga-PSMA) and 18F-DCFPyL in cerebral gliomas. This study explores the regional uptake and cellular targets of 68Ga-PSMA and 18F-DCFPyL in three different rat glioma models.

Methods

F98, 9 L, or U87 rat gliomas were implanted into the brains of 38 rats. After 13 days of tumor growth, 68Ga-PSMA (n = 21) or 18F-DCFPyL (n = 17) was injected intravenously, and animals were sacrificed 40 min later. Five animals for each tracer and tumor model were additionally investigated by micro-PET at 20–40 min post injection. Cryosections of the tumor bearing brains were analyzed by ex vivo autoradiography and immunofluorescence staining for blood vessels, microglia, astrocytes, and presence of PSMA. Blood-brain barrier (BBB) permeability was tested by coinjection of Evans blue dye (EBD). 68Ga-PSMA uptake after restoration of BBB integrity by treatment with dexamethasone (Dex) was evaluated in four animals with U87 gliomas. Competition experiments using the PSMA-receptor inhibitor 2-(phosphonomethyl)pentane-1,5-dioic acid (PMPA) were performed for both tracers in two animals each.

Results

Autoradiography demonstrated a strong 68Ga-PSMA and 18F-DCFPyL binding in the peritumoral area and moderate binding in the center of the tumors. PMPA administration led to complete inhibition of 68Ga-PSMA and 18F-DCFPyL binding in the peritumoral region. Restoration of BBB by Dex treatment reduced EBD extravasation but 68Ga-PSMA binding remained unchanged. Expression of activated microglia (CD11b) was low in the intra- and peritumoral area but GFAP staining revealed strong activation of astrocytes in congruency to the tracer binding in the peritumoral area. All tumors were visualized in micro PET, showing a lower tumor/brain contrast with 68Ga-PSMA than with 18F-DCFPyL.

Conclusions

High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of all glioma models is presumably caused by activated astrocytes. This may represent a limitation for the clinical application of PSMA ligands in gliomas.
Trends in burden of chronic obstructive pulmonary disease in Iran, 1995–2015: findings from the global burden of disease study
Authors: Hashemi Seyed Yaser , Momenabadi Victoria , Faramarzi Ahmad , Kiani Amin
Published: May 2020

Background

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder that progresses over time, and currently it is the fourth leading cause of death across the globe. The World Health Organization (WHO) predicts that the disease will become the third leading cause of death by 2030. The present study aimed to assess the burden trends of COPD in Iran by estimating the disability-adjusted life years (DALYs) from 1995 to 2015.

Methods

Data were retrospectively collected as the Global Burden of Disease (GBD) from 1995 to 2015 and published by the Institute for Health Metrics and Evaluation. We applied DALYs, incidence and prevalence rate to report the burden of COPD in Iran. To assess the statistical significance according to trend, the Cochran-Armitage test was applied. Additionally, the t-test was used to analyze the DALYs number by gender and Onaway ANOVA by age groups at a significance level set atP < 0.05.

Results

From 1995 to 2015, there were approximately 1.1 million DALYs attributable to COPD in Iran. In both genders and at all ages, the number of DALYs increased significantly from 176,224 in 1995 to 253,618 in 2015. The incidence and prevalence rate were 76.65 and 1491.37 per 100,000 population, respectively in both genders in 2015 in Iran. It is noticeable that the number of deaths during the study years, 1995 to 2015, was 39,064. This study showed that the COPD burden was significantly different by age groups and gender.

Conclusions

COPD is still a public health problem in Iran and has an increasing trend. The majority of DALYs were due to the years of life lost as a result of premature death (YLLs), indicating that prevention and early detection, especially in the age groups of 15 to 70 years, should be considered.
Trends in response rates and respondent characteristics in five National Maternity Surveys in England during 1995–2018
Authors: Harrison Siân , Alderdice Fiona , Henderson Jane , Redshaw Maggie , Quigley Maria A.
Published: May 2020

Background

The National Perinatal Epidemiology Unit in England has conducted five National Maternity Surveys (NMS) at varying intervals since 1995. This paper aims to describe the changes in NMS response rates over time and to compare the demographic characteristics of respondents to each NMS.

Methods

This paper is based on secondary data analysis of the NMS (cross-sectional postal surveys) from 1995 to 2018. All women aged 16 years and over who gave birth in England (and Wales in 1995) during specified time periods from 1995 to 2018 were eligible to be selected. For each survey, between 3570 and 16,000 women who were 3–6 months postpartum were selected at random by the Office for National Statistics, using birth registrations. Women could participate on paper, by telephone (from 2006) or online (from 2010).

Results

The response rate to the NMS decreased from 67% in 1995 to 29% in 2018. The decline was evident across demographic groups. In all NMS, response rates were higher in women who were older (crude prevalence ratios (PR) for 16–24 years versus 30–34 years = 0.51–0.73 (across surveys)), married (crude PR for sole versus married registrants = 0.41–0.62), born in the UK (crude PR for non UK-born versus UK-born = 0.70–0.84), and living in less deprived areas (crude PR for least versus most deprived = 0.42–0.63). However, the association between each demographic characteristic and response varied across surveys, with the youngest women, women who registered the birth of the baby in their sole name, and women living in the most deprived areas becoming relatively less likely to respond over time. In multivariable analysis in 2014 and 2018, the effects of age, marital status, country of birth and level of area deprivation on response were attenuated but all four demographic characteristics remained statistically significantly associated with response.

Conclusions

Response rates to the NMS have declined significantly during the last 23 years. The demographic characteristics associated with response were consistent across surveys, but the size of the effect varied significantly, with underrepresented groups becoming relatively less likely to participate over time. It is important to find strategies to increase response rates, particularly amongst underrepresented groups, and to validate the data collected.
Health risk factors associated with pesticide use by watermelon farmers in Central region, Ghana
Authors: Miyittah Michael K. , Kwadzo Moses , Gyamfua Abigail Peprah , Dodor Daniel E.
Published: May 2020

Background

The export drive for watermelon production is huge and so is pesticide usage. However, the health and safety of the farmers, as well as threat to the environment lie in the shadow. The purpose of the study is to evaluate watermelon farmers’ knowledge and application of pesticides in the Central region of Ghana, to ascertain factors associated with the pesticides application.

Methods

A field survey of 300 farmers were conducted in six communities through questionnaire. Logistic regression model was used to describe and explain burning sensation as the response variable and the factors that likely affect appropriate pesticide usage.

Results

The results show that farmers were aware of the environmental and health impacts of pesticides use. However, their knowledge of the risks associated with pesticides is not translated into actual practice to avoid the exposure of pesticides. The farmers experienced various levels of health risks symptoms. Health risks symptoms of headache, burning sensation, fever, watering eyes, chest pains, etc., were reported. The most common symptom is burning sensation. A model capturing biosocial factors influencing predisposition to burning sensation was developed. The model revealed that knowledge to identify pests, knowledge to identify diseases and wearing coverall were the most significant factors farmers experienced to influence burning sensation.

Conclusion

Significant number of watermelon farmers’ experienced health risks symptoms. In order to minimize the health risk symptoms and environmental consequences, educational training programs must involve the farmers and retailers through strong policy intervention.
Factors affecting severe weather threat index in urban areas of Turkey and Iran
Authors: Rabbani Ghazaleh , Kardani-Yazd Neda , Mansouri Daneshvar Mohammad Reza
Published: May 2020

Background

Distinguishing dynamic variations of the climate from the physical urban indicators is a challenge to assess the factors affecting weather severity. Hence, the time-series of the severe weather threat index (SWEAT) were considered in the four urban areas of Turkey and Iran to identify its affecting factors among the climatic variables and urban indicators in 2018. The SWEAT data were obtained from the upper-air sounding database of the University of Wyoming. The climatic variables were extracted from the Asia Pacific data research center (APDRC). The spatial statistics for urban expansion were collected from global human built-up and settlement extent (HBASE) data sets. A quantitative measuring of the Pearson correlation test was used to expose the relationships between dependent index (SWEAT) and independent variables (climatic and anthropogenic).

Results

Results revealed that the high and extreme severity classes of the weather condition in the Ankara, Istanbul, Mashhad, and Tehran are estimated as 7.7% (28 days), 15.3% (56 days), 1.1% (4 days), and 4.4% (16 days), respectively. The strongest values of the annual SWEAT index, exposing the unstable and severe weather conditions, were observed for Istanbul and Ankara urban regions. This result may be corresponding to the highest values of mean annual precipitation and relative humidity in addition to the largest values of urban expansion and sprawl index. The statistical correlation tests in annual scale confirmed the effective role of climatic elements of precipitation, relative humidity, and cloudiness (R from 0.94 to 0.99) and the urban expansion indicators (R from 0.86 to 0.91) in increasing annual severe weather index of SWEAT at above 85–95% of confidence level.

Conclusions

The correlations between the urban expansion indicators and outcome SWEAT index can be strengthened by some climatic elements (e.g., precipitation, humidity, and cloudiness), revealing the mediator and magnifier task. However, the mentioned correlations can be weakened by another climatic variable (i.e., air temperature), revealing a moderator and modifier task. Ultimately, investigation of the weather severity indices (e.g., SWEAT index) could be applied to identify the local and regional evidence of climate change in the urban areas.
Genome-wide association studies of lactation yields of milk, fat, protein and somatic cell score in New Zealand dairy goats
Authors: Scholtens Megan , Jiang Andrew , Smith Ashley , Littlejohn Mathew , Lehnert Klaus , Snell Russell , Lopez-Villalobos Nicolas , Garrick Dorian , Blair Hugh
Published: May 2020

Background

Identifying associations between genetic markers and traits of economic importance will provide practical benefits for the dairy goat industry, enabling genomic prediction of the breeding value of individuals, and facilitating discovery of the underlying genes and mutations. Genome-wide association studies were implemented to detect genetic regions that are significantly associated with effects on lactation yields of milk (MY), fat (FY), protein (PY) and somatic cell score (SCS) in New Zealand dairy goats.

Methods

A total of 4,840 goats were genotyped with the Caprine 50 K SNP chip (Illumina Inc., San Diego, CA). After quality filtering, 3,732 animals and 41,989 SNPs were analysed assuming an additive linear model. Four GWAS models were performed, a single-SNP additive linear model and three multi-SNP BayesC models. For the single-SNP GWAS, SNPs were fitted individually as fixed covariates, while the BayesC models fit all SNPs simultaneously as random effects. A cluster of significant SNPs were used to define a haplotype block whose alleles were fitted as covariates in a Bayesian model. The corresponding diplotypes of the haplotype block were then fit as class variables in another Bayesian model.

Results

Across all four traits, a total of 43 genome-wide significant SNPs were detected from the SNP GWAS. At a genome-wide significance level, the single-SNP analysis identified a cluster of variants on chromosome 19 associated with MY, FY, PY, and another cluster on chromosome 29 associated with SCS. Significant SNPs mapped in introns of candidate genes (45%), in intergenic regions (36%), were 0–5 kb upstream or downstream of the closest gene (14%) or were synonymous substitutions (5%). The most significant genomic window was located on chromosome 19 explaining up to 9.6% of the phenotypic variation for MY, 8.1% for FY, 9.1% for PY and 1% for SCS.

Conclusions

The quantitative trait loci for yield traits on chromosome 19 confirms reported findings in other dairy goat populations. There is benefit to be gained from using these results for genomic selection to improve milk production in New Zealand dairy goats.
The effects of B cell depletion on immune related adverse events associated with immune checkpoint inhibition
Authors: Risbjerg Rasmus Strøm , Hansen Mie Vennize , Sørensen Anne Sofie , Kragstrup Tue Wenzel
Published: May 2020

This letter describes the potential effect of B cell depletion on immune related adverse events associated with immune checkpoint inhibition. B cell depleting agents such as rituximab reduce B cell to plasma cell differentiation and antibody production. This treatment strategy is used in several immune mediated inflammatory diseases such as rheumatoid arthritis and small vessel vasculitis. The immune related adverse events associated with immune checkpoint inhibition resemble immune mediated inflammatory diseases. Here, we report a lower incidence of hypothyroidism in a trial of combined B cell depletion and immune checkpoint inhibitor treatment compared with studies of immune checkpoint inhibitor monotherapy. This letter aims to increase awareness of the immune related adverse events associated with immune checkpoint inhibition in future clinical trials of immune checkpoint inhibition together with B cell depletion (primarily trials of B cell lymphomas). Hopefully, observations from these clinical trials can guide future treatment strategies to treat or prevent immune related adverse events associated with immune checkpoint inhibition.
Tuberculosis infection prevention and control: why we need a whole systems approach
Authors: Kielmann Karina , Karat Aaron S. , Zwama Gimenne , Colvin Christopher , Swartz Alison , Voce Anna S. , Yates Tom A. , MacGregor Hayley , McCreesh Nicky , Kallon Idriss , Vassall Anna , Govender Indira , Seeley Janet , Grant Alison D.
Published: May 2020

Infection prevention and control (IPC) measures to reduce transmission of drug-resistant and drug-sensitive tuberculosis (TB) in health facilities are well described but poorly implemented. The implementation of TB IPC has been assessed primarily through quantitative and structured approaches that treat administrative, environmental, and personal protective measures as discrete entities. We present an on-going project entitled Umoya omuhle (“good air”), conducted in two provinces of South Africa, that adopts an interdisciplinary, ‘whole systems’ approach to problem analysis and intervention development for reducing nosocomial transmission of Mycobacterium tuberculosis (Mtb) through improved IPC. We suggest that TB IPC represents a complex intervention that is delivered within a dynamic context shaped by policy guidelines, health facility space, infrastructure, organisation of care, and management culture. Methods drawn from epidemiology, anthropology, and health policy and systems research enable rich contextual analysis of how nosocomial Mtb transmission occurs, as well as opportunities to address the problem holistically. A ‘whole systems’ approach can identify leverage points within the health facility infrastructure and organisation of care that can inform the design of interventions to reduce the risk of nosocomial Mtb transmission.
Pharmacists reinventing their roles to effectively respond to COVID-19: a global report from the international pharmacists for anticoagulation care taskforce (iPACT)
Authors: Alves da Costa Filipa , Lee Vivian , Leite Silvana Nair , Murillo Maria Dolores , Menge Tom , Antoniou Sotiris
Published: May 2020

SARS-CoV2 is dramatically impacting the global population. Worldwide, pharmacists are changing their roles and being increasingly recognized for their role as essential service providers. This commentary provides some examples collected from Asia, Europe, the Americas and Africa, ranging from essential services to meet human rights basic needs, extended generalist services developed to ensure continuity of care and supply of essential medicines to the development of differentiated extended responsibilities in emergency care. All examples were collected using a network of pharmacists from 27 countries, representing various areas of pharmacy practice, education and research and outreaching to include patient advocates. Selected services illustrate good practice, capability to adapt and contribution to universal health coverage. Above all, it demonstrates the commitment and innovation of the pharmaceutical workforce in the fight against COVID-19.
A method for high-throughput screening hydrolase of lignin β-aryl ether linkage from directed evolution by glutathione (GSH) assay
Authors: Wang Jiaxi , Yan Kun , Wang Wenya , Zhou Yan
Published: May 2020

Background

Lignin’s valorization plays a critical role in refining the bioresource. Considering that the β-aryl ether linkage (β-O-4 bond) accounts for 50–70% of lignin chemical linkage between aromatic rings, the hydrolase of lignin β-aryl ether linkage, especially the β-etherase, provided a promising way for the lignin depolymerization and valorization. As a result, it is essential to develop the effective high-throughput methods for screening the mutant library of β-etherase from directed evolution.

Results

Based on the enzymatic mechanism of β-O-4 bond’s cleavage by β-etherase, the LigF was selected as the model to study high-throughput method by GSH assay for screening the mutant library of β-etherase from directed evolution. After the primary study with purified LigF and cell lysate, the GSH assay was used to screen mutant library of β-etherase. The study on screening the mutant library with about 600 colonies indicated that the selected transformants all have one or two mutated sites in the gene sequence of LigF, and the activities from GSH assay of most selected transformants were the same as their activities from HPLC assay.

Conclusions

The results from the high-throughput screening of mutant library demonstrated that GSH assay could be applied to screen β-etherase mutant from directed evolution.
Assessment of the dynamics of the Volta river estuary shorelines in Ghana
Authors: Appeaning Addo K. , Brempong E. K. , Jayson-Quashigah P. N.
Published: May 2020

Estuarine shorelines similar to marine coastlines are highly dynamic and may increase disaster risk in vulnerable communities. The situation is expected to worsen with climate change impacts and increasing anthropogenic activities such as upstream water management. This study assessed shoreline changing trends along the Volta river estuary in Ghana as well as the marine coastline using satellite imageries, orthophotos and topographic maps spanning a period of 120 years (1895, 1990, 2000, 2005 and 2015). Linear regression method in the Digital Shoreline Analysis System (DSAS) was used to determine the estuary shoreline migration trend by estimating the shorelines rate of change for the eastern and western sides of the estuary. The rates of change of the marine coastlines on the east and west of the estuary were also estimated. The results show that the eastern and western shoreline of the estuary are eroding at an average rate of about 1.94 m/yr and 0.58 m/yr respectively. The coastlines on the marine side (eastern and western) are eroding at an average rate of about 2.19 m/yr and 0.62 m/yr respectively. Relatively high rates of erosion observed on the eastern estuarine shoreline as well as the coastline could be explained by the reduced sediment supply by the Volta River due to the damming of the Volta River in Akosombo and the sea defence structures constructed to manage erosion problems. The trend is expected to increase under changing oceanographic conditions and increased subsidence in the Volta delta. Effective management approach, such as developing disaster risk reduction strategy, should be adopted to increase the resilience of the communities along the estuarine shoreline and increase their adaptive capacity to climate change hazards and disasters.
The role of labour market integration in migrants’ decisions about family reunification: a comparative study of Polish migrants in Norway, Sweden, and the UK
Authors: Ryndyk Oleksandr
Published: May 2020

With about 2.7 million nationals residing elsewhere in the European Economic Area, Poland was the second largest country of origin of all intra-European migrants in 2018. After the country’s accession to the European Union in 2004, some Polish migrants have brought abroad their families, while others continue living alone and commuting to visit their families in Poland. Based on a sample of 1153 survey respondents in three European contexts—Norway, Sweden, and the United Kingdom—this article investigates from a comparative perspective how Polish migrants’ family reunification status is related to their integration on the labour market. Results show that only in the Scandinavian labour markets, and not in the British, is migrants’ economic integration decisive for family reunification. This article argues that in contexts which offer broader employment opportunities for family migrants, who tend to be women, such as in the UK between 2004 and 2016, the lead migrant’s labour market integration may not be crucial for family reunification. The findings may be of special interest for migration policymakers in the Scandinavian countries working towards greater gender equality outcomes among its immigrant populations.
A computational outlook on neurostimulation
Authors: Capogrosso Marco , Lempka Scott F.
Published: May 2020

Efficient identification of effective neurostimulation strategies is critical due to the growing number of clinical applications and the increasing complexity of the corresponding technology. In consequence, investigators are encouraged to accelerate translational research of neurostimulation technologies and move quickly to clinical applications. However, this process is hampered by rigorous, but necessary, regulations and lack of a mechanistic understanding of the interactions between electric fields and neural circuits. Here we discuss how computational models have influenced the field of neurostimulation for pain and movement recovery, deep brain stimulation, and even device regulations. Finally, we propose our vision on how computational models will be key to accelerate clinical developments through mechanistic understanding.
Retrospective analysis of burn windows for fire and fuels management: an example from the Lake Tahoe Basin, California, USA
Authors: Striplin Randy , McAfee Stephanie A. , Safford Hugh D. , Papa Michael J.
Published: May 2020

Background

In fire-adapted ecosystems of the western USA, prescribed fire is an essential restoration and fuel reduction tool. There is general concern that, as the fire season lengthens, the window for conducting prescribed burns will contract unless management changes are made. This could occur because a number of conditions must be met before prescribed fire can be used in the field, and those are most common during the spring and autumn when the need for fire suppression response has been historically less. To assess patterns of potential prescribed burning feasibility, this study evaluated three conditions: (1) permission to burn as granted by air quality regulators; (2) weather within burn plan prescription; and (3) availability of operational and contingency resources. Our 21-year analysis (1999 to 2019) combines three independent datasets for a daily comparison of when prescribed fires could have been implemented (henceforth, burn windows) in the Lake Tahoe Basin (LTB) and analyzes seasonality, interannual variability, and trends.

Results

Burn windows were most frequent during spring, followed by autumn, with the fewest burn windows during the summer and winter. Burn windows lasting multiple days occurred infrequently. Two- to three-day burn windows did not often occur more than twice per month over the study period, and longer burn windows were very rare. Interannual variation was considerable. Finally, an abrupt increase in burn windows was detected in 2008. This was determined to be related to a methodological change by air quality regulators and not to any changes in climate or resource availability.

Conclusions

While this case study focuses on the LTB, the analysis was performed with readily available data and could be applied easily to other land management units, demonstrating a valuable method for planning and prioritizing fire and fuels management activities. This type of tool can also identify areas for research. For example, if there were unused burn windows during the winter and early spring—or they were projected to increase—research into the ecological impacts of winter and spring burning may allow managers to more confidently adapt to changing climate. Moreover, this analysis demonstrated that modest and reasonable regulatory changes can increase opportunities for prescribed burning.
Formulation and evaluation of buccal films of piroxicam co-crystals
Authors: Ammanage Anand , Rodriques Paul , Kempwade Amolkumar , Hiremath Ravindra
Published: May 2020

Background

The aim of the present study was to enhance the solubility of piroxicam (BCS class II drug) using co-crystallization technique and formulate the buccal films of selected co-crystals for improved therapeutic utilization of drug. Co-crystals of drug with various co-formers (molar ratio 1:1) were prepared by solvent evaporation method and were screened for their aqueous solubility and percent drug content. The formation of co-crystals was confirmed by FTIR, DSC and XRD. Piroxicam co-crystals loaded buccal films were prepared and evaluated for in vitro drug release, ex vivo drug permeation while safety of formulation was determined by histopathological study.

Results

The co-crystals prepared with different co-formers have proved their potential to improve the solubility of the drug. Co-crystals of piroxicam-sucralose have shown six-folds more solubility than parent drug. FTIR analysis indicated shifting in characteristics peaks of piroxicam. DSC analysis showed an extra exothermic peak and alteration in characteristic endothermic peak. The powder x-ray diffraction pattern exhibited changes in 2θvalues of intense peaks. Thus, formation of co-crystal was confirmed. Physical characters of buccal films were found to be within limits. Formulation F6 showed highest mucoadhesive strength (5617 ± 636 dynes /cm2) while formulation F2 showed highest in vitro drug release after 8 h, i.e., 94.557%. The ex vivo drug permeation of F2 was found to be 84.74%. The hisopathological study revealed that there was no damage to buccal mucosal tissue and was found to be intact.

Conclusion

The piroxicam-suralose co-crystals based mucoadhesive films of piroxicam could be a better formulation approach with improved solubility, safety, and therapeutic efficacy as compared to conventional tablets.

Graphical abstract
Significant antitumor activity for low-dose ipilimumab (IPI) with pembrolizumab (PEMBRO) immediately following progression on PD1 Ab in melanoma (MEL) in a phase II trial.
Authors: Olson Daniel , Luke Jason J. , Poklepovic Andrew Stewart , Bajaj Madhuri , Higgs Emily , Carll Timothy C. , Labadie Brian , Krausz Thomas , Zha Yuanyuan , Karrison Theodore , Lutzky Jose , Hallmeyer Sigrun , Brockstein Bruce , Sondak Vernon K. , Eroglu Zeynep , Gajewski Thomas , Khushalani Nikhil I.
Published: May 2020

10004

Background: Combination PD1 + CTLA4 antibodies (Abs) shows greater response rate (RR) versus PD1 Ab alone in MEL, but RR after initial PD1 Ab progression awaits robust investigation. CTLA4 Ab alone after PD1 Ab progression has a historical RR of 13%. We report final results of the first prospective clinical trial evaluating IPI 1mg/kg + PEMBRO immediately following progression on PD1 Ab (NCT02743819). Methods: Patients (pts) with advanced MEL, no prior CTLA4 Ab for metastatic disease, and who had progressed on PD1 Ab as immediately prior therapy (or non-CTLA4 Ab combination) were eligible. Pts received PEMBRO 200 mg + IPI 1 mg/kg Q3W for 4 doses, then PEMBRO alone for up to two years. The primary endpoint was RR by irRECIST. After 35 pts, the study met its primary endpoint with 10/22 evaluable pts achieving a response. The trial was expanded to enroll a total of 70 pts in open-label accrual to further describe the RR for this regimen in an exploratory fashion. The data analysis cutoff was January 30, 2020. Results: 67/70 accrued patients were evaluable for treatment response. Prior treatments included 60 on PD1 Ab alone and 10 on PD1 Ab-based combinations. Of these, 10 pts had progressed in the adjuvant setting. Median length of treatment on prior PD1 Ab was 4.8 months. Response assessments included 4 CR, 17 PR and 16 SD for a RR of 31% (21/67) in evaluable pts, and 30% (21/70) in all enrolled pts. 4 pts with a PR and 6 with SD had unconfirmed responses making the irRECIST response rate 25% (17/67) and 24% (17/70) among evaluable and enrolled pts, respectively. Median progression free survival (PFS) was 4.7 mo (95% CI: 2.8-8.3) and PFS at six months was 45% (95% CI: 33%-57%). 15/70 (21%) pts experienced ≥ grade 3-4 drug-related AEs, the most common being diarrhea, rash and transaminase elevation. PD-L1 positive vs negative status from historical tumor specimens did not associate with RR. Conclusions: This is the largest prospective study of IPI 1mg/kg + PEMBRO, demonstrating significant antitumor activity and tolerability in MEL post-PD1 Ab. Clinical trial information: NCT02743819.