bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebrospinal fluid cytokine levels are associated with macrophage infiltration into tumor tissues of glioma patients
Authors: Kemmerer Constanze L. , Schittenhelm Jens , Dubois Evelyn , Neumann Laura , Häsler Lisa M. , Lambert Marius , Renovanz Mirjam , Kaeser Stephan A. , Tabatabai Ghazaleh , Ziemann Ulf , Naumann Ulrike , Kowarik Markus C.
Published: October 2021

Background

Diffuse gliomas are the most common malignant tumors of the central nervous system with poor treatment efficacy. Infiltration of immune cells into tumors during immunosurveillance is observed in multiple tumor entities and often associated with a favorable outcome. The aim of this study was to evaluate the infiltration of immune cells in gliomas and their association with cerebrospinal fluid (CSF) cytokine concentrations.

Methods

We applied immunohistochemistry in tumor tissue sections of 18 high-grade glioma (HGG) patients (4 anaplastic astrocytoma, IDH-wildtype WHO-III; 14 glioblastomas (GBM), IDH-wildtype WHO-IV) in order to assess and quantify leucocytes (CD45) and macrophages (CD68, CD163) within the tumor core, infiltration zone and perivascular spaces. In addition, we quantified the concentrations of 30 cytokines in the same patients’ CSF and in 14 non-inflammatory controls.

Results

We observed a significantly higher percentage of CD68+macrophages (21–27%) in all examined tumor areas when compared to CD45+leucocytes (ca. 3–7%); CD163+cell infiltration was between 5 and 15%. Compared to the tumor core, significantly more macrophages and leucocytes were detectable within the perivascular area. The brain parenchyma showing a lower tumor cell density seems to be less infiltrated by macrophages. Interleukin (IL)-7 was significantly downregulated in CSF of GBM patients compared to controls. Additionally, CD68+macrophage infiltrates showed significant correlations with the expression of eotaxin, interferon-γ, IL-1β, IL-2, IL-10, IL-13, IL-16 and vascular endothelial growth factor.

Conclusions

Our findings suggest that the infiltration of lymphocytes is generally low in HGG, and does not correlate with cytokine concentrations in the CSF. In contrast, macrophage infiltrates in HGG are associated with CSF cytokine changes that possibly shape the tumor microenvironment. Although results point towards an escape from immunosurveillance or even exploitation of immune cells by HGG, further studies are necessary to decipher the exact role of the immune system in these tumors.
A randomized phase III study of short-course radiotherapy combined with Temozolomide in elderly patients with newly diagnosed glioblastoma; Japan clinical oncology group study JCOG1910 (AgedGlio-PIII)
Authors: Arakawa Yoshiki , Sasaki Keita , Mineharu Yohei , Uto Megumi , Mizowaki Takashi , Mizusawa Junki , Sekino Yuta , Ono Tomohiro , Aoyama Hidefumi , Satomi Kaishi , Ichimura Koichi , Kinoshita Manabu , Ohno Makoto , Ito Yoshinori , Nishikawa Ryo , Fukuda Haruhiko , Nishimura Yasumasa , Narita Yoshitaka ,   Brain Tumor Study Group and Radiation Therapy Study Group of the Japan Clinical Oncology Group
Published: October 2021

Background

The current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy with temozolomide. In recent studies, 40 Gy in 15 fractions vs. 60 Gy in 30 fractions, 34 Gy in 10 fractions vs. 60 Gy in 30 fractions, and 40 Gy in 15 fractions vs. 25 Gy in 5 fractions have been reported as non-inferior. The addition of temozolomide increased the survival benefit of radiotherapy with 40 Gy in 15 fractions. However, the optimal regimen for radiotherapy plus concomitant temozolomide remains unresolved.

Methods

This multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant (150 mg/m2/day, 5 days) and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant (75 mg/m2/day, every day from first to last day of radiation) and adjuvant temozolomide in terms of overall survival (OS) in elderly patients with newly diagnosed glioblastoma. A total of 270 patients will be accrued from 51 Japanese institutions in 4 years and follow-up will last 2 years. Patients 71 years of age or older, or 71–75 years old with resection of less than 90% of the contrast-enhanced region, will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, and proportion of health-related quality of life preservation. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in April 2020. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in August 2020.

Discussion

If the primary endpoint is met, short-course radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma.

Trial registration

Registry number: jRCTs031200099.

Date of Registration: 27/Aug/2020. Date of First Participant Enrollment: 4/Sep/2020.
Adolescents’ physical activity and sedentary behaviour in Indonesia during the COVID-19 pandemic: a qualitative study of mothers’ perspectives
Authors: Andriyani Fitria Dwi , Biddle Stuart J. H. , De Cocker Katrien
Published: October 2021

Background

Socio-behavioural adaptations during the COVID-19 pandemic may have significantly affected adolescents’ lifestyle. This study aimed to explore possible reasons affecting changes in physical activity and sedentary behaviour in Indonesian adolescents during the pandemic based on mothers’ perspectives.

Methods

We recruited parents (n = 20) from the Yogyakarta region of Indonesia (July–August 2020) using purposive and snowball sampling. Individual interviews were audio-recorded, transcribed verbatim and anonymised. Data were imported into NVivo software for a reflexive thematic analysis.

Results

The interviews lasted between 38 and 113 min (M = 65 min). Participants’ age ranged between 36 and 54 years (M = 42.6 years). Participants’ children ranged in age from 12 to 15 years (M = 13.7 years, female: 9, male: 11). Themes related to changes in physical activity during the pandemic were 1) self-determination and enjoyment, 2) supports from others, and 3) physical activity facilities and equipment. Themes related to changes in sedentary behaviour during the pandemic included 1) educational demands, 2) psychological effects due to the pandemic, 3) devices and internet availability, 4) parental control, and 5) social facilitators.

Conclusions

During the pandemic, mothers perceived their children to be less active and using more screen-based devices, either for educational or recreational purposes, compared to before. The present themes might be useful when developing interventions and policies promoting physical activity and reducing sedentary behaviour in adolescents. Interventions could, for example, consider increasing parents’ and adolescents’ awareness on current activity guidelines, providing education on healthier recreational screen time, and involving parents, peers, and teachers. Increasing the accessibility of physical activity facilities and equipment, making use of adolescents’ favourite program and social media for interventions, and providing activities that are fun and enjoyable may also important.
Oral health assessment in a sample of displaced people as a result of the war in Syria in Damascus city: results of non-profit initiative
Authors: Kazwini Rudwan , Kasem Tarek , Alhuda Noor Ewaz Ali , Albarshah Marwah , Subeh Dania , Alhaffar M. H. D. Bahaa Aldin
Published: October 2021

Background

War on Syria extended for a long time and resulted in significant impacts on various aspects, one of these aspects was displaced people crisis, and thus its impact on complete neglecting of oral health despite of its importance and impacts on the general health. This study aims to assess the oral health of the displaced Syria sample as a result of the war on Syria.

Methods

The sample included 118 patients of displaced families from different regions and cities to shelters in Damascus city, and the study included 118 control samples from the Faculty of Dentistry, Damascus University. The non-profit initiative team included 20 dentists of all dental specialties. Oral health was assessed using DMFT index. Data were analyzed using SPSS V.22 in comparison with the gender of the patients, age groups, and socioeconomic status. Finally, the number of the treatment provided by the non-profit initiative was collected and presented in the study.

Results

No significant differences found in the DMFT index between children and adults (P = 0.750), DMFT value ranged between (0 and 11) with a mean value (2.4). The total DMFT value for adults was (2.77), while for children (2.12). Also, no statistical difference was found between males and females (P = 0.688). While the control group had an average DMFT value of (2.37), the difference between the displaced and control samples was not significant. Over 200 dental treatments were provided by the team.

Conclusion

This study concluded that the DMFT value is high among the displaced people as one of the consequences of the war on Syria, however, no significant difference was found when the results of the displaced sample was compared to a control sample.
First trimester exposure to ambient gaseous air pollutants and risk of orofacial clefts: a case–control study in Changsha, China
Authors: Jiang Wen , Xie Wanqin , Ni Bin , Zhou Haiyan , Liu Zhiyu , Li Xingli
Published: October 2021

Background

A growing body of studies have investigated the association between air pollution exposure during early pregnancy and the risk of orofacial clefts, but these studies put more emphasis on particulate matter and reported inconsistent results, while research on the independent effects of gaseous air pollutants on orofacial clefts has been quite inadequate, especially in China.

Methods

A case–control study was conducted in Changsha, China from 2015 to 2018. A total of 446 cases and 4460 controls were included in the study. Daily concentrations of CO, NO2, SO2, O3, PM2.5 and PM10 during the first trimester of pregnancy were assigned to each subject using the nearest monitoring station method. Multivariate logistic regression models were applied to evaluate the associations of monthly average exposure to gaseous air pollutants with orofacial clefts and its subtypes before and after adjusting for particulate matter. Variance inflation factors (VIFs) were used to determine if the effects of gaseous air pollutants could be independent of particulate matter.

Results

Increase in CO, NO2 and SO2 significantly increased the risk of cleft lip with or without cleft palate (CL/P) in all months during the first trimester of pregnancy, with aORs ranging from 1.39 to 1.48, from 1.35 to 1.61 and from 1.22 to 1.35, respectively. The risk of cleft palate only (CPO) increased with increasing NO2 exposure levels in the first trimester of pregnancy, with aORs ranging from 1.60 to 1.66. These effects sustained and even exacerbated after adjusting for particulate matter. No significant effect of O3 was observed.

Conclusions

Our study suggested that maternal exposure to CO, NO2, and SO2 during the first trimester of pregnancy might contribute to the development of orofacial clefts, and the associations were potentially independent of particulate matter.
The cultural and structural influences that ‘hide’ information from women diagnosed with breast cancer in Ghana: an ethnography
Authors: Agyemang Linda Serwaa , Foster Claire , McLean Chris , Fenlon Deborah , Wagland Richard
Published: October 2021

Background

Socio-cultural factors may influence the uptake of breast cancer treatments.
This study aimed to explore these socio-cultural influences on treatment decision-making for women in Ghana.

Method

An ethnographic approach was adopted. Observation was conducted of women newly diagnosed with breast cancer, nominated relatives, nurses and doctors at a breast clinic in Ghana. Semi-structured interviews followed participant observation. Thematic analysis was employed.

Findings

Over 16 weeks (July 2017–November 2017), 31 participants were observed and 29 took part in semi-structured interviews. Three overarching themes were identified: (1) unequal power relationships; (2) Language barriers and (3) structural constraints. Following a breast cancer diagnosis, essential information necessary for treatment decision making is ‘hidden’ from women due to an unequal patient-provider relationship. Patients acknowledged cultural behaviours of deference to experts. Doctors deliberately misrepresented treatment information to women to encourage them to undergo surgical treatment. Structural issues such as the lack of privacy during consultations hindered quality patient engagement with decision-making. High treatment costs and the lack of resources to assist women with fertility after treatment impeded open discussions around these issues. Language barriers included a lack of terms in the local Twi language to explain cancer and its treatment. There was also an absence of appropriate information materials.

Conclusion

Findings highlight the need for health professionals to be aware of the socio-cultural factors that limit access to quality information which is needed for informed treatment decision making. Policies that aim to provide adequate logistics; increase staffing levels; improve staff cultural awareness training and remove financial barriers are recommended.
An economic evaluation of an intervention to increase demand for medical male circumcision among men aged 25–49 years in South Africa
Authors: Holmes M. , Mukora R. , Mudzengi D. , Charalambous S. , Chetty-Makkan C. M. , Kisbey-Green H. , Maraisane M. , Grund J.
Published: October 2021

Background

Studies estimate that circumcising men between the ages of 20–30 years who have exhibited previous risky sexual behaviour could reduce overall HIV prevalence. Demand creation strategies for medical male circumcision (MMC) targeting men in this age group may significantly impact these prevalence rates.

Objectives

The objective of this study is to evaluate the cost-effectiveness and cost-benefit of an implementation science, pre-post study designed to increase the uptake of male circumcision for ages 25–49 at a fixed MMC clinic located in Gauteng Province, South Africa.

Methods

A health care provider perspective was utilised to collect all costs. Costs were compared between the standard care scenario of routine outreach strategies and a full intervention strategy. Cost-effectiveness was measured as cost per mature man enrolled and cost per mature man circumcised. A cost-benefit analysis was employed by using the Bernoulli model to estimate the cases of HIV averted due to medical male circumcision (MMC), and subsequently translated to averted medical costs.

Results

In the 2015 intervention, the cost of the intervention was $9445 for 722 men. The total HIV treatment costs averted due to the intervention were $542,491 from a public care model and $378,073 from a private care model. The benefit-cost ratio was 57.44 for the public care model and 40.03 for the private care model. The net savings of the intervention were $533,046 or $368,628 - depending on treatment in a public or private setting.

Conclusions

The intervention was cost-effective compared to similar MMC demand interventions and led to statistically significant cost savings per individual enrolled.
A feasibility study to assess non-clinical community health workers’ capacity to use simplified protocols and tools to treat severe acute malnutrition in Niger state Nigeria
Authors: Adesoro Olatunde , Oresanya Olusola , Counihan Helen , Hamade Prudence , Eguavon Dare , Emebo Chika , Marron Bethany , Kozuki Naoko , Isah Amina , Gimba Patrick , Isokpunwu Chris Osa , Maxwell Kolawole , Tibenderana James K.
Published: October 2021

Background

Severe acute malnutrition (SAM) is a major determinant of childhood mortality and morbidity. Although integrated community case management (iCCM) of childhood illnesses is a strategy for increasing access to life-saving treatment, malnutrition is not properly addressed in the guidelines. This study aimed to determine whether non-clinical Community Health Workers (called Community-Oriented Resource Persons, CORPs) implementing iCCM could use simplified tools to treat uncomplicated SAM.

Methods

The study used a sequential multi-method design and was conducted between July 2017 and May 2018. Sixty CORPs already providing iCCM services were trained and deployed in their communities with the target of enrolling 290 SAM cases. Competency of CORPs to treat and the treatment outcomes of enrolled children were documented. SAM cases with MUAC of 9 cm to < 11.5 cm without medical complications were treated for up to 12 weeks. Full recovery was at MUAC≥12.5 cm for two consecutive weeks. Supervision and quantitative data capturing were done weekly while qualitative data were collected after the intervention.

Results

CORPs scored 93.1% on first assessment and increment of 0.11 (95% CI, 0.05–0.18) points per additional supervision conducted. The cure rate from SAM to full recovery, excluding referrals from the denominator in line with the standard for reporting SAM recovery rates, was 73.5% and the median length of treatment was 7 weeks. SAM cases enrolled at 9 cm to < 10.25 cm MUAC had 31% less likelihood of recovery compared to those enrolled at 10.25 cm to < 11.5 cm. CORPs were not burdened by the integration of SAM into iCCM and felt motivated by children’s recovery. Operational challenges like bad terrains for supervision, supply chain management and referrals were reported by supervisors, while Government funding was identified as key for sustainability.

Conclusion

The study demonstrated that with training and supportive supervision, CORPs in Nigeria can treat SAM among under-fives, and refer complicated cases using simplified protocols as part of an iCCM programme. This approach seemed acceptable to all stakeholders, however, the effect of the extra workload of integrating SAM into iCCM on the quality of care provided by the CORPs should be assessed further.
Primary care registration of the mental health needs of patients treated at outpatient specialized services: results from a medium-sized city in Brazil
Authors: dos Santos Treichel Carlos Alberto , Bakolis Ioannis , Onocko-Campos Rosana Teresa
Published: October 2021

Background

Although matrix support seeks to promote integrating Primary Care with specialized mental health services in Brazil, little is known about the quantitative impact of this strategy on sharing cases between different levels of care. The aim of this study was to investigate the prevalence and factors associated with Primary Care registration of the mental health needs of patients treated at outpatient specialized services in a medium-sized city in Brazil with recent implementation of matrix support.

Methods

This is a document-based cross-sectional study conducted through an analysis of 1198 patients’ medical records. Crude and adjusted associations with the outcome were explored using logistic regression.

Results

The prevalence of cases registered in Primary Care was 40% (n = 479). Evidence was found for associations between the outcome and the patients being over 30 years old, and referral by emergency or hospital services. There was conversely an inverse association between the outcome and status as a patient from the Outpatient Clinic or from the Psychosocial Care Center for psychoactive substance misuse.

Conclusions

Even with the provision of mechanisms for network integration, such as matrix support, our results suggest that more groundwork is necessary to ensure that sharing cases between Primary Care and specialized services is effective.
Prognostic impact of tertiary lymphoid structures in breast cancer prognosis: a systematic review and meta-analysis
Authors: Zhang Na-Na , Qu Feng-Jin , Liu Hao , Li Zhu-Jun , Zhang Yu-Chi , Han Xuan , Zhu Zi-Yu , Lv Yi
Published: October 2021

Background

Tertiary lymphoid structures (TLSs), organizationally resemble lymph nodes, are frequently present in breast cancer (BCa). It is usually, but not always, associated with a positive prognosis or immunotherapy response in cancer patients. This meta-analysis was performed to assess the prognostic and clinical impact of TLSs in BCa.

Methods

We conducted a systematic search in PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and WanFang Database to obtain eligible research data up to May 30, 2021. This meta-analysis is focusing on the studies evaluated the prognostic value of TLSs and the associated clinicopathologic indicators, related gene expression and survival. STATA software 16.0 software was used to assess the prognostic significance and clinical impact of TLSs.

Results

Nine studies involved with 2281 cases were incorporated in this meta-analysis, in which four of them evaluated the prognostic value of TLSs. There are 6 studies assessed the relationship of TLSs and 4 studies investigated the clinicopathologic parameters as well as the key gene expression, respectively. The results showed the presence of TLSs were predicting a better OS (HR = 0.61, 95% CI: 0.51–0.73, p < 0.001) and DFS (HR = 0.40, 95% CI: 0.17–0.93, p < 0.001) of BCa patients. It also revealed that the presence of TLSs was significantly correlated with tumor differentiation (p < 0.001), pTNM stage (p < 0.001), lymph node metastasis (p < 0.001), and TILs density (p < 0.001) of BCa, and the expression of Her2 (p < 0.001), ER (p < 0.001), PR (p < 0.001) and Ki67 (p = 0.009) of the tumor cell.

Conclusion

Our results indicated that high levels of TLSs could predict a favorable prognosis for BCa. Moreover, the TLSs were significantly correlated with the clinicopathological indicators and the critical gene expression of BCa, indicating its potential clinical impact on BCa patients.
Neurotransmitter-stimulated neuron-derived sEVs have opposite effects on amyloid β-induced neuronal damage
Authors: Dou Yunxiao , Xie Junchao , Tan Yan , Zhang Min , Zhao Yanxin , Liu Xueyuan
Published: October 2021

The ratio of excitatory to inhibitory neurotransmitters is essential for maintaining the firing patterns of neural networks, and is strictly regulated within individual neurons and brain regions. Excitatory to inhibitory (E/I) imbalance has been shown to participate in the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Glutamate excitotoxicity and GABAergic neuron dysfunction appear to be key components of the neuronal cell death that takes place in AD. Since extracellular vesicles (EVs) are now explored as an important vehicle in transmitting signals between cells, we hypothesized that the function of neuron-derived small EVs (sEVs) might be regulated by the status of neurotransmitter balance and that sEVs might affect amyloid β (Aβ) toxicity on neurons. This study aimed to reveal the effects of sEVs from unbalanced neurotransmitter-stimulated neurons on Aβ-induced toxicity. We demonstrated the opposite effects of the two groups of sEVs isolated from neurons stimulated by glutamate or GABA on Aβ toxicity in vivo and in vitro. The sEVs released from GABA-treated neurons alleviated Aβ-induced damage, while those released from glutamate-treated neurons aggravated Aβ toxicity. Furthermore, we compared the microRNA (miRNA) composition of sEVs isolated from glutamate/GABA/PBS-treated neurons. Our results showed that glutamate and GABA oppositely regulated miR-132 levels in sEVs, resulting in the opposite destiny of recipient cells challenged with Aβ. Our results indicated that manipulating the function of sEVs by different neurotransmitters may reveal the mechanisms underlying the pathogenesis of AD and provide a promising strategy for AD treatment.
Effect of the spatial–temporal specific theca cell Cyp17 overexpression on the reproductive phenotype of the novel TC17 mouse
Authors: Secchi Christian , Belli Martina , Harrison Tracy N. H. , Swift Joseph , Ko CheMyong , Duleba Antoni J. , Stupack Dwayne , Chang R. Jeffrey , Shimasaki Shunichi
Published: October 2021

Background

In the ovarian follicle, the Theca Cells (TCs) have two main functions: preserving morphological integrity and, importantly, secreting steroid androgen hormones. TCs express the essential enzyme 17α-hydroxylase/17,20-desmolase (CYP17), which permits the conversion of pregnenolone and progesterone into androgens. Dysregulation of CYP17 enzyme activity due to an intrinsic ovarian defect is hypothesized to be a cause of hyperandrogenism in women. Androgen excess is observed in women with polycystic ovary syndrome (PCOS) resulting from excess endogenous androgen production, and in transgender males undergoing exogenous testosterone therapy after female sex assignment at birth. However, the molecular and morphological effects of Cyp17 overexpression and androgen excess on folliculogenesis is unknown.

Methods

In this work, seeking a comprehensive profiling of the local outcomes of the androgen excess in the ovary, we generated a transgenic mouse model (TC17) with doxycycline (Dox)-induced Cyp17 overexpression in a local and temporal manner. TC17 mice were obtained by a combination of the Tet-dependent expression system and the Cre/LoxP gene control system.

Results

Ovaries of Dox-treated TC17 mice overexpressed Cyp17 specifically in TCs, inducing high testosterone levels. Surprisingly, TC17 ovarian morphology resembled the human ovarian features of testosterone-treated transgender men (partially impaired folliculogenesis, hypertrophic or luteinized stromal cells, atretic follicles, and collapsed clusters). We additionally assessed TC17 fertility denoting a perturbation of the normal reproductive functions (e.g., low pregnancy rate and numbers of pups per litter). Finally, RNAseq analysis permitted us to identify dysregulated genes (Lhcgr, Fshr, Runx1) and pathways (Extra Cellular Matrix and Steroid Synthesis).

Conclusions

Our novel mouse model is a versatile tool to provide innovative insights into study the effects of Cyp17 overexpression and hyperandrogenism in the ovary.
Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia
Authors: Hoyer-Kimura Christina , Konhilas John P. , Mansour Heidi M. , Polt Robin , Doyle Kristian P. , Billheimer Dean , Hay Meredith
Published: October 2021

Background

Decreased cerebral blood flow and systemic inflammation during heart failure (HF) increase the risk for vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer disease-related dementias (ADRD). We previously demonstrated that PNA5, a novel glycosylated angiotensin 1–7 (Ang-(1–7)) Mas receptor (MasR) agonist peptide, is an effective therapy to rescue cognitive impairment in our preclinical model of VCID. Neurofilament light (NfL) protein concentration is correlated with cognitive impairment and elevated in neurodegenerative diseases, hypoxic brain injury, and cardiac disease. The goal of the present study was to determine (1) if treatment with Ang-(1–7)/MasR agonists can rescue cognitive impairment and decrease VCID-induced increases in NfL levels as compared to HF-saline treated mice and, (2) if NfL levels correlate with measures of cognitive function and brain cytokines in our VCID model.

Methods

VCID was induced in C57BL/6 male mice via myocardial infarction (MI). At 5 weeks post-MI, mice were treated with daily subcutaneous injections for 24 days, 5 weeks after MI, with PNA5 or angiotensin 1–7 (500 microg/kg/day or 50 microg/kg/day) or saline (n = 15/group). Following the 24-day treatment protocol, cognitive function was assessed using the Novel Object Recognition (NOR) test. Cardiac function was measured by echocardiography and plasma concentrations of NfL were quantified using a Quanterix Simoa assay. Brain and circulating cytokine levels were determined with a MILLIPLEX MAP Mouse High Sensitivity Multiplex Immunoassay. Treatment groups were compared via ANOVA, significance was set at p < 0.05.

Results

Treatment with Ang-(1–7)/MasR agonists reversed VCID-induced cognitive impairment and significantly decreased NfL levels in our mouse model of VCID as compared to HF-saline treated mice. Further, NfL levels were significantly negatively correlated with cognitive scores and the concentrations of multiple pleiotropic cytokines in the brain.

Conclusions

These data show that treatment with Ang-(1–7)/MasR agonists rescues cognitive impairment and decreases plasma NfL relative to HF-saline-treated animals in our VCID mouse model. Further, levels of NfL are significantly negatively correlated with cognitive function and with several brain cytokine concentrations. Based on these preclinical findings, we propose that circulating NfL might be a candidate for a prognostic biomarker for VCID and may also serve as a pharmacodynamic/response biomarker for therapeutic target engagement.
Functional role of brain-engrafted macrophages against brain injuries
Authors: Feng Xi , Frias Elma S. , Paladini Maria S. , Chen David , Boosalis Zoe , Becker McKenna , Gupta Sonali , Liu Sharon , Gupta Nalin , Rosi Susanna
Published: October 2021

Background

Brain-resident microglia have a distinct origin compared to macrophages in other organs. Under physiological conditions, microglia are maintained by self-renewal from the local pool, independent of hematopoietic progenitors. Pharmacological depletion of microglia during whole-brain radiotherapy prevents synaptic loss and long-term recognition memory deficits. However, the origin or repopulated cells and the mechanisms behind these protective effects are unknown.

Methods

CD45low/int/CD11b+ cells from naïve brains, irradiated brains, PLX5622-treated brains and PLX5622 + whole-brain radiotherapy-treated brains were FACS sorted and sequenced for transcriptomic comparisons. Bone marrow chimeras were used to trace the origin and long-term morphology of repopulated cells after PLX5622 and whole-brain radiotherapy. FACS analyses of intrinsic and exotic synaptic compartments were used to measure phagocytic activities of microglia and repopulated cells. In addition, concussive brain injuries were given to PLX5622 and brain-irradiated mice to study the potential protective functions of repopulated cells after PLX5622 + whole-brain radiotherapy.

Results

After a combination of whole-brain radiotherapy and microglia depletion, repopulated cells are brain-engrafted macrophages that originate from circulating monocytes. Comparisons of transcriptomes reveal that brain-engrafted macrophages have an intermediate phenotype that resembles both monocytes and embryonic microglia. In addition, brain-engrafted macrophages display reduced phagocytic activity for synaptic compartments compared to microglia from normal brains in response to a secondary concussive brain injury. Importantly, replacement of microglia by brain-engrafted macrophages spare mice from whole-brain radiotherapy-induced long-term cognitive deficits, and prevent concussive injury-induced memory loss.

Conclusions

Brain-engrafted macrophages prevent radiation- and concussion-induced brain injuries and cognitive deficits.
Testing the effect of an integrated-intervention to promote access to sexual and reproductive healthcare and rights among women with disabilities in Ghana: a quasi-experimental study protocol
Authors: Ganle John Kuumuori , Ofori Charlotte , Dery Samuel
Published: October 2021

Background

There is evidence that women with disabilities (WWDs) experience the most difficulty accessing and using sexual and reproductive health and rights (SRHRs) services and information worldwide. However, there are currently no workable interventions to reach WWDs with essential SRHR services. This study aims to test the effect of an integrated health facility and individual-level intervention on access to SRHRs information and services among sexually active WWDs aged 15–49 years in Ghana.

Methods

A quasi-experimental study design with four arms will be implemented in four districts in the Northern region of Ghana to test the effect of three inter-related interventions. The inventions are (1) capacity building in disability-centred SRHRs information and service delivery for healthcare providers, (2) support for WWDs to access disability-unfriendly healthcare infrastructure, and (3) one-on-one regular SRHRs education, information provision, and referral. The first two interventions are at the health-facility level while the third one is at the individual/family level. The first arm of the experiment will expose eligible WWDs to all three interventions. In the second arm, WWDs will be exposed to only the two-health facility-level interventions. The third arm will expose WWDs to only the individual level intervention. The forth arm will constitute the control group. A total of 680 (170 in each arm) sexually active women with physical disability and visual impairments will take part in the study over a period of 12 months. To assess the effect of the interventions on key study outcomes (i.e. awareness about, and use of modern contraceptive, ANC attendance, and skilled delivery among parous women), pre- and post-intervention surveys will be conducted. Difference-in-Difference analysis will be used to examine the effect of each intervention in comparison to the control group, while controlling for confounders. Cost-effectiveness analyses will also be conducted on the three-intervention arms vis a vis changes in key outcome measures to identify which of the three interventions is likely to yield greater impact with lower costs.

Discussion

Lack of access to SRHRs information and services for WWDs is not only a violation of their right to appropriate and quality SRH care but could also undermine efforts to achieve equitable healthcare access as envisaged under SDG 3. This research is expected to generate evidence to inform local health programmes to increase access to SRHRs among WWDs by strengthening local health system capacity to provide disability-sensitive SRHRs services.

Trial registration Name of the registry: Pan African Clinical Trials Registry (PACTR). Trial ID: 14591. Date of registration: 02/01/2020. URL of trial registry record: https://pactr.samrc.ac.za/Researcher/TrialRegister.aspx?TrialID=14591
Granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α in combination is a useful diagnostic biomarker to distinguish familial Mediterranean fever from sepsis
Authors: Koga Tomohiro , Furukawa Kaori , Migita Kiyoshi , Morimoto Shimpei , Shimizu Toshimasa , Fukui Shoichi , Umeda Masataka , Endo Yushiro , Sumiyoshi Remi , Kawashiri Shin-ya , Iwamoto Naoki , Ichinose Kunihiro , Tamai Mami , Origuchi Tomoki , Maeda Takahiro , Yachie Akihiro , Kawakami Atsushi
Published: October 2021

Objective

To identify potential biomarkers to distinguish familial Mediterranean fever (FMF) from sepsis.

Method

We recruited 28 patients diagnosed with typical FMF (according to the Tel Hashomer criteria), 22 patients with sepsis, and 118 age-matched controls. Serum levels of 40 cytokines were analyzed using multi-suspension cytokine array. We performed a cluster analysis of each cytokine in the FMF and sepsis groups in order to identify specific molecular networks. Multivariate classification (random forest analysis) and logistic regression analysis were used to rank the cytokines by importance and determine specific biomarkers for distinguishing FMF from sepsis.

Results

Fifteen of the 40 cytokines were found to be suitable for further analysis. Levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor 2, vascular endothelial growth factor, macrophage inflammatory protein-1b, and interleukin-17 were significantly elevated, whereas tumor necrosis factor-α (TNF-α) was significantly lower in patients with FMF compared with those with sepsis. Cytokine clustering patterns differed between the two groups. Multivariate classification followed by logistic regression analysis revealed that measurement of both GM-CSF and TNF-α could distinguish FMF from sepsis with high accuracy (cut-off values for GM-CSF = 8.3 pg/mL; TNF-α = 16.3 pg/mL; sensitivity, 92.9%; specificity, 94.4%; accuracy, 93.4%).

Conclusion

Determination of GM-CSF and TNF-α levels in combination may represent a biomarker for the differential diagnosis of FMF from sepsis, based on measurement of multiple cytokines.
Generalized fixed point results of rational type contractions in partially ordered metric spaces
Authors: Seshagiri Rao N. , Kalyani K.
Published: October 2021

Objectives

We investigated the existence and uniqueness of a fixed point for the mapping satisfying generalized rational type contraction conditions in metric space endowed with partial order. Suitable examples are presented to justify the results obtained.

Result

Some new fixed point results have been obtained for a mapping fulfilling generalized contractions. The uniqueness of the fixed point is also the part of the study based on an ordered relation. One example is given for a result which is not valid in the usual metric space.
Label-free separation of neuroblastoma patient-derived xenograft (PDX) cells from hematopoietic progenitor cell products by acoustophoresis
Authors: Olm Franziska , Panse Lena , Dykes Josefina H. , Bexell Daniel , Laurell Thomas , Scheding Stefan
Published: October 2021

Background

Graft-contaminating tumor cells correlate with inferior outcome in high-risk neuroblastoma patients undergoing hematopoietic stem cell transplantation and can contribute to relapse. Motivated by the potential therapeutic benefit of tumor cell removal as well as the high prognostic and diagnostic value of isolated circulating tumor cells from stem cell grafts, we established a label-free acoustophoresis-based microfluidic technology for neuroblastoma enrichment and removal from peripheral blood progenitor cell (PBPC) products.

Methods

Neuroblastoma patient-derived xenograft (PDX) cells were spiked into PBPC apheresis samples as a clinically relevant model system. Cells were separated by ultrasound in an acoustophoresis microchip and analyzed for recovery, purity and function using flow cytometry, quantitative real-time PCR and cell culture.

Results

PDX cells and PBPCs showed distinct size distributions, which is an important parameter for efficient acoustic separation. Acoustic cell separation did not affect neuroblastoma cell growth. Acoustophoresis allowed to effectively separate PDX cells from spiked PBPC products. When PBPCs were spiked with 10% neuroblastoma cells, recoveries of up to 98% were achieved for PDX cells while more than 90% of CD34+ stem and progenitor cells were retained in the graft. At clinically relevant tumor cell contamination rates (0.1 and 0.01% PDX cells in PBPCs), neuroblastoma cells were depleted by more than 2-log as indicated by RT-PCR analysis of PHOX2B, TH and DDC genes, while > 85% of CD34+ cells could be retained in the graft.

Conclusion

These results demonstrate the potential use of label-free acoustophoresis for PBPC processing and its potential to develop label-free, non-contact tumor cell enrichment and purging procedures for future clinical use.
Short-duration dynamic [18F]DCFPyL PET and CT perfusion imaging to localize dominant intraprostatic lesions in prostate cancer: validation against digital histopathology and comparison to [18F]DCFPyL PET/MR at 120 minutes
Authors: Yang Dae-Myoung , Alfano Ryan , Bauman Glenn , Thiessen Jonathan D. , Chin Joseph , Pautler Stephen , Moussa Madeleine , Gomez Jose A. , Rachinsky Irina , Gaed Mena , Chung Kevin J. , Ward Aaron , Lee Ting-Yim
Published: October 2021

Purpose

Localized prostate cancer (PCa) in patients is characterized by a dominant focus in the gland (dominant intraprostatic lesion, DIL). Accurate DIL identification may enable more accurate diagnosis and therapy through more precise targeting of biopsy, radiotherapy and focal ablative therapies. The goal of this study is to validate the performance of [18F]DCFPyL PET and CT perfusion (CTP) for detecting and localizing DIL against digital histopathological images.

Methods

Multi-modality image sets: in vivo T2-weighted (T2w)-MRI, 22-min dynamic [18F]DCFPyL PET/CT, CTP, and 2-h post-injection PET/MR were acquired in patients prior to radical prostatectomy. The explanted gland with implanted fiducial markers was imaged with T2w-MRI. All images were co-registered to the pathologist-annotated digital images of whole-mount mid-gland histology sections using fiducial markers and anatomical landmarks. Regions of interest encompassing DIL and non-DIL tissue were drawn on the digital histopathological images and superimposed on PET and CTP parametric maps. Logistic regression with backward elimination of parameters was used to select the most sensitive parameter set to distinguish DIL from non-DIL voxels. Leave-one-patient-out cross-validation was performed to determine diagnostic performance.

Results

[18F]DCFPyL PET and CTP parametric maps of 15 patients were analyzed. SUVLate and a model combining Ki and k4 of [18F]DCFPyL achieved the most accurate performance distinguishing DIL from non-DIL voxels. Both detection models achieved an AUC of 0.90 and an error rate of < 10%. Compared to digital histopathology, the detected DILs had a mean dice similarity coefficient of 0.8 for the Ki and k4 model and 0.7 for SUVLate.

Conclusions

We have validated using co-registered digital histopathological images that parameters from kinetic analysis of 22-min dynamic [18F]DCFPyL PET can accurately localize DILs in PCa for targeting of biopsy, radiotherapy, and focal ablative therapies. Short-duration dynamic [18F]DCFPyL PET was not inferior to SUVLate in this diagnostic task.

Clinical trial registration number: NCT04009174 (ClinicalTrials.gov).
Charting the complexity of the activated sludge microbiome through a hybrid sequencing strategy
Authors: Liu Lei , Wang Yulin , Yang Yu , Wang Depeng , Cheng Suk Hang , Zheng Chunmiao , Zhang Tong
Published: October 2021

Background

Long-read sequencing has shown its tremendous potential to address genome assembly challenges, e.g., achieving the first telomere-to-telomere assembly of a gapless human chromosome. However, many issues remain unresolved when leveraging error-prone long reads to characterize high-complexity metagenomes, for instance, complete/high-quality genome reconstruction from highly complex systems.

Results

Here, we developed an iterative haplotype-resolved hierarchical clustering-based hybrid assembly (HCBHA) approach that capitalizes on a hybrid (error-prone long reads and high-accuracy short reads) sequencing strategy to reconstruct (near-) complete genomes from highly complex metagenomes. Using the HCBHA approach, we first phase short and long reads from the highly complex metagenomic dataset into different candidate bacterial haplotypes, then perform hybrid assembly of each bacterial genome individually. We reconstructed 557 metagenome-assembled genomes (MAGs) with an average N50 of 574 Kb from a deeply sequenced, highly complex activated sludge (AS) metagenome. These high-contiguity MAGs contained 14 closed genomes and 111 high-quality (HQ) MAGs including full-length rRNA operons, which accounted for 61.1% of the microbial community. Leveraging the near-complete genomes, we also profiled the metabolic potential of the AS microbiome and identified 2153 biosynthetic gene clusters (BGCs) encoded within the recovered AS MAGs.

Conclusion

Our results established the feasibility of an iterative haplotype-resolved HCBHA approach to reconstruct (near-) complete genomes from highly complex ecosystems, providing new insights into “complete metagenomics”. The retrieved high-contiguity MAGs illustrated that various biosynthetic gene clusters (BGCs) were harbored in the AS microbiome. The high diversity of BGCs highlights the potential to discover new natural products biosynthesized by the AS microbial community, aside from the traditional function (e.g., organic carbon and nitrogen removal) in wastewater treatment.
Externalizing your eating disorder: a qualitative interview study
Authors: Voswinkel Marthe M. , Rijkers Cleo , van Delden Johannes J. M. , van Elburg Annemarie A.
Published: October 2021

Background

Anorexia nervosa (AN) is a psychiatric disorder with an ego-syntonic nature, causing many patients to perceive their AN as part of their personal identity. Therefore, an important part of treatment is the externalization of the eating disorder, in order to help patients to perceive AN as an external influence. Studies on patient experiences of externalization in treatment for AN are sadly missing. The aims of this study were to investigate, first, patients’ perspectives on the relation between identity and anorexia nervosa (AN) and second, their experiences of an externalizing approach during treatment.

Method

A qualitative interview study was conducted including fourteen patients with AN in either Family Based Treatment, the Maudsley Model for Anorexia Nervosa Treatment for Adults, Specialist Supportive Clinical Management-Severe Enduring or Cognitive Behavioural Therapy-Enhanced.

Results

There are important differences in participants’ perceptions on how AN is related to identity. AN was perceived as part of identity, as alien or as a different side of the self. Patients’ experiences towards an externalizing approach were ambivalent. Externalization was considered helpful, whilst also evoking a negative response. Participants reported feeling as if all their behaviour was referred to as part of AN, which elicited feelings of not being taken seriously or being wrongfully accused of being dishonest.

Conclusions

First, there is considerable variation in the perceived relation between AN and identity. Second, an externalizing approach within treatment may lead to so called epistemic injustice. Awareness of these two facts is of importance for clinicians and the therapeutic relationship because that will help them to refrain from actions that can be perceived as epistemic injustice.
Recurrence eigenvalues of movements from brain signals
Authors: Pham Tuan D.
Published: October 2021

The ability to characterize muscle activities or skilled movements controlled by signals from neurons in the motor cortex of the brain has many useful implications, ranging from biomedical perspectives to brain–computer interfaces. This paper presents the method of recurrence eigenvalues for differentiating moving patterns in non-mammalian and human models. The non-mammalian models of Caenorhabditis elegans have been studied for gaining insights into behavioral genetics and discovery of human disease genes. Systematic probing of the movement of these worms is known to be useful for these purposes. Study of dynamics of normal and mutant worms is important in behavioral genetic and neuroscience. However, methods for quantifying complexity of worm movement using time series are still not well explored. Neurodegenerative diseases adversely affect gait and mobility. There is a need to accurately quantify gait dynamics of these diseases and differentiate them from the healthy control to better understand their pathophysiology that may lead to more effective therapeutic interventions. This paper attempts to explore the potential application of the method for determining the largest eigenvalues of convolutional fuzzy recurrence plots of time series for measuring the complexity of moving patterns of Caenorhabditis elegans and neurodegenerative disease subjects. Results obtained from analyses demonstrate that the largest recurrence eigenvalues can differentiate phenotypes of behavioral dynamics between wild type and mutant strains of Caenorhabditis elegans; and walking patterns among healthy control subjects and patients with Parkinson’s disease, Huntington’s disease, or amyotrophic lateral sclerosis.