Molecular diversity in isocitrate dehydrogenase-wild-type glioblastoma.

In the dynamic landscape of glioblastoma, the 2021 World Health Organization Classification of Central Nervous System tumours endeavoured to establish biological homogeneity, yet isocitrate dehydrogenase-wild-type (IDH-wt) glioblastoma persists as a tapestry of clinical and molecular diversity. Intertumoural heterogeneity in IDH-wt glioblastoma presents a formidable challenge in treatment strategies. Recent strides in genetics and molecular biology have enhanced diagnostic precision, revealing distinct subtypes and invasive patterns that influence survival in patients with IDH-wt glioblastoma. Genetic and molecular biomarkers, such as the overexpression of neurofibromin 1, phosphatase and tensin homolog and/or cyclin-dependent kinase inhibitor 2A, along with specific immune cell abundance and neurotransmitters, correlate with favourable outcomes. Conversely, increased expression of epidermal growth factor receptor tyrosine kinase, platelet-derived growth factor receptor alpha and/or vascular endothelial growth factor receptor, coupled with the prevalence of glioma stem cells, tumour-associated myeloid cells, regulatory T cells and exhausted effector cells, signifies an unfavourable prognosis. The methylation status of O6-methylguanine-DNA methyltransferase and the influence of microenvironmental factors and neurotransmitters further shape treatment responses. Understanding intertumoural heterogeneity is complemented by insights into intratumoural dynamics and cellular interactions within the tumour microenvironment. Glioma stem cells and immune cell composition significantly impact progression and outcomes, emphasizing the need for personalized therapies targeting pro-tumoural signalling pathways and resistance mechanisms. A successful glioblastoma management demands biomarker identification, combination therapies and a nuanced approach considering intratumoural variability. These advancements herald a transformative era in glioblastoma comprehension and treatment.

Incidence and Risk Factors of Surgical Site Infection After Cranial Surgery for Patients with Brain Tumors: A Systematic Review and Meta-analysis.

BACKGROUND: Surgical site infections after craniotomy (SSI-CRANs) are a serious adverse event given the proximity of the wound to the central nervous system. SSI-CRANs are associated with substantial patient morbidity and mortality. Despite the importance and recognition of this event in other surgical fields, there is a paucity of evidence in the neurosurgical literature devoted to SSI-CRAN specifically in patients after brain tumor surgery. METHODS: Systematic searches of Medline, Embase, and Cochrane Central were undertaken. The primary outcome was the incidence of SSI-CRAN at 30 and 90 days. Secondary outcomes were risk factors for SSI-CRAN. RESULTS: Thirty-seven studies reporting 91,907 patients with brain tumors who underwent cranial surgery were included in the meta-analysis. Pooled incidence of SSI-CRAN at 30 and 90 days was 4.03% (95% CI: 2.94%-5.28%, I2 = 97.3) and 6.17% (95% CI: 3.16%-10.07%, I2 = 97.3), respectively. Specifically, incidence of SSI-CRAN following surgery for posterior fossa tumors was the highest at 9.67% (95% CI: 5.98%-14.09%, I2 = 75.5). Overall pooled incidence of readmission within 30 days and reoperation due to SSI-CRAN were 13.9% (95% CI: 12.5%-15.5%, I2 = 0.0) and 16.3% (95% CI: 5.4%-31.3%, I2 = 72.9), respectively. Risk factors for SSI-CRAN included reintervention (risk ratio [RR] 1.58, 95% CI: 1.22-2.04, I2 = 0.0), previous radiotherapy (RR 1.69, 95% CI: 1.20-2.38, I2 = 0.0), longer duration of operation (mean difference 64.18, 95% CI: 3.96-124.40 minutes, I2 = 90.3) and cerebrospinal fluid (CSF) leaks (RR 14.26, 95% CI: 2.14-94.90, I2 = 73.2). CONCLUSIONS: SSI-CRAN affects up to 1 in 14 patients with brain tumors. High-risk groups include those with reintervention, previous radiotherapy, longer duration of operation, and CSF leaks. Further prospective studies should focus on bundles of care that will reduce SSI-CRAN.

Brain tumour microstructure is associated with post-surgical cognition.

Brain tumour microstructure is potentially predictive of changes following treatment to cognitive functions subserved by the functional networks in which they are embedded. To test this hypothesis, intra-tumoural microstructure was quantified from diffusion-weighted MRI to identify which tumour subregions (if any) had a greater impact on participants' cognitive recovery after surgical resection. Additionally, we studied the role of tumour microstructure in the functional interaction between the tumour and the rest of the brain. Sixteen patients (22-56 years, 7 females) with brain tumours located in or near speech-eloquent areas of the brain were included in the analyses. Two different approaches were adopted for tumour segmentation from a multishell diffusion MRI acquisition: the first used a two-dimensional four group partition of feature space, whilst the second used data-driven clustering with Gaussian mixture modelling. For each approach, we assessed the capability of tumour microstructure to predict participants' cognitive outcomes after surgery and the strength of association between the BOLD signal of individual tumour subregions and the global BOLD signal. With both methodologies, the volumes of partially overlapped subregions within the tumour significantly predicted cognitive decline in verbal skills after surgery. We also found that these particular subregions were among those that showed greater functional interaction with the unaffected cortex. Our results indicate that tumour microstructure measured by MRI multishell diffusion is associated with cognitive recovery after surgery.

Tumour-infiltrated cortex participates in large-scale cognitive circuits.

The extent to which tumour-infiltrated brain tissue contributes to cognitive function remains unclear. We tested the hypothesis that cortical tissue infiltrated by diffuse gliomas participates in large-scale cognitive circuits using a unique combination of intracranial electrocorticography (ECoG) and resting-state functional magnetic resonance (fMRI) imaging in four patients. We also assessed the relationship between functional connectivity with tumour-infiltrated tissue and long-term cognitive outcomes in a larger, overlapping cohort of 17 patients. We observed significant task-related high gamma (70-250 Hz) power modulations in tumour-infiltrated cortex in response to increased cognitive effort (i.e., switch counting compared to simple counting), implying preserved functionality of neoplastic tissue for complex tasks probing executive function. We found that tumour locations corresponding to task-responsive electrodes exhibited functional connectivity patterns that significantly co-localised with canonical brain networks implicated in executive function. Specifically, we discovered that tumour-infiltrated cortex with larger task-related high gamma power modulations tended to be more functionally connected to the dorsal attention network (DAN). Finally, we demonstrated that tumour-DAN connectivity is evident across a larger cohort of patients with gliomas and that it relates to long-term postsurgical outcomes in goal-directed attention. Overall, this study contributes convergent fMRI-ECoG evidence that tumour-infiltrated cortex participates in large-scale neurocognitive circuits that support executive function in health. These findings underscore the potential clinical utility of mapping large-scale connectivity of tumour-infiltrated tissue in the care of patients with diffuse gliomas.

Variation in postoperative outcomes of patients with intracranial tumors: insights from a prospective international cohort study during the COVID-19 pandemic.

BACKGROUND: This study assessed the international variation in surgical neuro-oncology practice and 30-day outcomes of patients who had surgery for an intracranial tumor during the COVID-19 pandemic. METHODS: We prospectively included adults aged ≥18 years who underwent surgery for a malignant or benign intracranial tumor across 55 international hospitals from 26 countries. Each participating hospital recorded cases for 3 consecutive months from the start of the pandemic. We categorized patients' location by World Bank income groups (high [HIC], upper-middle [UMIC], and low- and lower-middle [LLMIC]). Main outcomes were a change from routine management, SARS-CoV-2 infection, and 30-day mortality. We used a Bayesian multilevel logistic regression stratified by hospitals and adjusted for key confounders to estimate the association between income groups and mortality. RESULTS: Among 1016 patients, the number of patients in each income group was 765 (75.3%) in HIC, 142 (14.0%) in UMIC, and 109 (10.7%) in LLMIC. The management of 200 (19.8%) patients changed from usual care, most commonly delayed surgery. Within 30 days after surgery, 14 (1.4%) patients had a COVID-19 diagnosis and 39 (3.8%) patients died. In the multivariable model, LLMIC was associated with increased mortality (odds ratio 2.83, 95% credible interval 1.37-5.74) compared to HIC. CONCLUSIONS: The first wave of the pandemic had a significant impact on surgical decision-making. While the incidence of SARS-CoV-2 infection within 30 days after surgery was low, there was a disparity in mortality between countries and this warrants further examination to identify any modifiable factors.

Is Xenopus laevis introduction linked with Ranavirus incursion, persistence and spread in Chile?

Ranaviruses have been associated with amphibian, fish and reptile mortality events worldwide and with amphibian population declines in parts of Europe. Xenopus laevis is a widespread invasive amphibian species in Chile. Recently, Frog virus 3 (FV3), the type species of the Ranavirus genus, was detected in two wild populations of this frog near Santiago in Chile, however, the extent of ranavirus infection in this country remains unknown. To obtain more information about the origin of ranavirus in Chile, its distribution, species affected, and the role of invasive amphibians and freshwater fish in the epidemiology of ranavirus, a surveillance study comprising wild and farmed amphibians and wild fish over a large latitudinal gradient (2,500 km) was carried out in 2015-2017. In total, 1,752 amphibians and 496 fish were tested using a ranavirus-specific qPCR assay, and positive samples were analyzed for virus characterization through whole genome sequencing of viral DNA obtained from infected tissue. Ranavirus was detected at low viral loads in nine of 1,011 X. laevis from four populations in central Chile. No other amphibian or fish species tested were positive for ranavirus, suggesting ranavirus is not threatening native Chilean species yet. Phylogenetic analysis of partial ranavirus sequences showed 100% similarity with FV3. Our results show a restricted range of ranavirus infection in central Chile, coinciding with X. laevis presence, and suggest that FV3 may have entered the country through infected X. laevis, which appears to act as a competent reservoir host, and may contribute to the spread the virus locally as it invades new areas, and globally through the pet trade.

A Prospective Study of Longitudinal Risks of Cognitive Deficit for People Undergoing Glioblastoma Surgery Using a Tablet Computer Cognition Testing Battery: Towards Personalized Understanding of Risks to Cognitive Function.

Glioblastoma and the surgery to remove it pose high risks to the cognitive function of patients. Little reliable data exist about these risks, especially postoperatively before radiotherapy. We hypothesized that cognitive deficit risks detected before surgery will be exacerbated by surgery in patients with glioblastoma undergoing maximal treatment regimens. We used longitudinal electronic cognitive testing perioperatively to perform a prospective, longitudinal, observational study of 49 participants with glioblastoma undergoing surgery. Before surgery (A1), the participant risk of deficit in 5/6 cognitive domains was increased compared to normative data. Of these, the risks to Attention (OR = 31.19), Memory (OR = 97.38), and Perception (OR = 213.75) were markedly increased. These risks significantly increased in the early period after surgery (A2) when patients were discharged home or seen in the clinic to discuss histology results. For participants tested at 4-6 weeks after surgery (A3) before starting radiotherapy, there was evidence of risk reduction towards A1. The observed risks of cognitive deficit were independent of patient-specific, tumour-specific, and surgery-specific co-variates. These results reveal a timeframe of natural recovery in the first 4-6 weeks after surgery based on personalized deficit profiles for each participant. Future research in this period could investigate personalized rehabilitation tools to aid the recovery process found.

High gamma activity distinguishes frontal cognitive control regions from adjacent cortical networks.

Though the lateral frontal cortex is broadly implicated in cognitive control, functional MRI (fMRI) studies suggest fine-grained distinctions within this region. To examine this question electrophysiologically, we placed electrodes on the lateral frontal cortex in patients undergoing awake craniotomy for tumor resection. Patients performed verbal tasks with a manipulation of attentional switching, a canonical control demand. Power in the high gamma range (70-250 Hz) distinguished electrodes based on their location within a high-resolution fMRI network parcellation of the frontal lobe. Electrodes within the canonical fronto-parietal control network showed increased power in the switching condition, a result absent in electrodes within default mode, language and somato-motor networks. High gamma results contrasted with spatially distributed power decreases in the beta range (12-30 Hz). These results confirm the importance of fine-scale functional distinctions within the human frontal lobe, and pave the way for increased precision of functional mapping in tumor surgeries.

Myeloid cell interferon secretion restricts Zika flavivirus infection of developing and malignant human neural progenitor cells.

Zika virus (ZIKV) can infect human developing brain (HDB) progenitors resulting in epidemic microcephaly, whereas analogous cellular tropism offers treatment potential for the adult brain cancer, glioblastoma (GBM). We compared productive ZIKV infection in HDB and GBM primary tissue explants that both contain SOX2+ neural progenitors. Strikingly, although the HDB proved uniformly vulnerable to ZIKV infection, GBM was more refractory, and this correlated with an innate immune expression signature. Indeed, GBM-derived CD11b+ microglia/macrophages were necessary and sufficient to protect progenitors against ZIKV infection in a non-cell autonomous manner. Using SOX2+ GBM cell lines, we found that CD11b+-conditioned medium containing type 1 interferon beta (IFNß) promoted progenitor resistance to ZIKV, whereas inhibition of JAK1/2 signaling restored productive infection. Additionally, CD11b+ conditioned medium, and IFNß treatment rendered HDB progenitor lines and explants refractory to ZIKV. These findings provide insight into neuroprotection for HDB progenitors as well as enhanced GBM oncolytic therapies.

Imaging Glioblastoma Metabolism by Using Hyperpolarized [1-13C]Pyruvate Demonstrates Heterogeneity in Lactate Labeling: A Proof of Principle Study.

Purpose To evaluate glioblastoma (GBM) metabolism by using hyperpolarized carbon 13 (13C) MRI to monitor the exchange of the hyperpolarized 13C label between injected [1-13C]pyruvate and tumor lactate and bicarbonate. Materials and Methods In this prospective study, seven treatment-naive patients (age [mean ± SD], 60 years ± 11; five men) with GBM were imaged at 3 T by using a dual-tuned 13C-hydrogen 1 head coil. Hyperpolarized [1-13C]pyruvate was injected, and signal was acquired by using a dynamic MRI spiral sequence. Metabolism was assessed within the tumor, in the normal-appearing brain parenchyma (NABP), and in healthy volunteers by using paired or unpaired t tests and a Wilcoxon signed rank test. The Spearman ρ correlation coefficient was used to correlate metabolite labeling with lactate dehydrogenase A (LDH-A) expression and some immunohistochemical markers. The Benjamini-Hochberg procedure was used to correct for multiple comparisons. Results The bicarbonate-to-pyruvate (BP) ratio was lower in the tumor than in the contralateral NABP (P < .01). The tumor lactate-to-pyruvate (LP) ratio was not different from that in the NABP (P = .38). The LP and BP ratios in the NABP were higher than those observed previously in healthy volunteers (P < .05). Tumor lactate and bicarbonate signal intensities were strongly correlated with the pyruvate signal intensity (ρ = 0.92, P < .001, and ρ = 0.66, P < .001, respectively), and the LP ratio was weakly correlated with LDH-A expression in biopsy samples (ρ = 0.43, P = .04). Conclusion Hyperpolarized 13C MRI demonstrated variation in lactate labeling in GBM, both within and between tumors. In contrast, bicarbonate labeling was consistently lower in tumors than in the surrounding NABP. Keywords: Hyperpolarized 13C MRI, Glioblastoma, Metabolism, Cancer, MRI, Neuro-oncology Supplemental material is available for this article. Published under a CC BY 4.0 license.

Assessment of neuropsychological function in brain tumor treatment: a comparison of traditional neuropsychological assessment with app-based cognitive screening.

BACKGROUND: Gliomas are typically considered to cause relatively few neurological impairments. However, cognitive difficulties can arise, for example during treatment, with potential detrimental effects on quality of life. Accurate, reproducible, and accessible cognitive assessment is therefore vital in understanding the effects of both tumor and treatments. Our aim is to compare traditional neuropsychological assessment with an app-based cognitive screening tool in patients with glioma before and after surgical resection. Our hypotheses were that cognitive impairments would be apparent, even in a young and high functioning cohort, and that app-based cognitive screening would complement traditional neuropsychological assessment. METHODS: Seventeen patients with diffuse gliomas completed a traditional neuropsychological assessment and an app-based touchscreen tablet assessment pre- and post-operatively. The app assessment was also conducted at 3- and 12-month follow-up. Impairment rates, mean performance, and pre- and post-operative changes were compared using standardized Z-scores. RESULTS: Approximately 2-3 h of traditional assessment indicated an average of 2.88 cognitive impairments per patient, while the 30-min screen indicated 1.18. As might be expected, traditional assessment using multiple items across the difficulty range proved more sensitive than brief screening measures in areas such as memory and attention. However, the capacity of the screening app to capture reaction times enhanced its sensitivity, relative to traditional assessment, in the area of non-verbal function. Where there was overlap between the two assessments, for example digit span tasks, the results were broadly equivalent. CONCLUSIONS: Cognitive impairments were common in this sample and app-based screening complemented traditional neuropsychological assessment. Implications for clinical assessment and follow-up are discussed.

Tumour treating fields in glioblastoma: is the treatment tolerable, effective, and practical in UK patients?

BACKGROUND: Tumour Treating Fields (TTF) in combination with standard therapy, prolongs survival in patients with glioblastoma (GBM). The aim of the current study was to assess the feasibility of integrating TTF into a standard UK neuro-oncology service with a focus on patient tolerability, compliance, and treatment delivery. METHODS: A prospective study was performed of UK patients with IDH 1 Wild Type, MGMT Unmethylated GBM treated with TTF, in conjunction with conventional therapy. Patient compliance data, device-specific tolerability questions, and an evaluation of disease progression and survival were collected. Monthly quality of life (QoL) questionnaires (EORTC QLQ-C30 with BN-20) examined the trend of global health, psychosocial function, and symptom progression. RESULTS: Nine patients were enrolled with a median age of 47 (seven males; two females). Overall, compliance with TTF was 89% (range 16-97%). Only one patient failed to comply with treatment. Patients tolerated the device with minimal side effects. Eight patients described mild to moderate skin irritation, whilst all patients were keen to recommend the device to other patients (100%). Most patients found the weight and size of the device to be its biggest drawback (72%). Progression-free survival was 5.5 months and median overall survival was 14.9 months. CONCLUSIONS: TTF was well-tolerated amongst a small cohort of UK patients, who were able to comply with treatment without any significant complication. QoL questionnaires showed no sustained deterioration in global health, physical and emotional function until the final months of life when the disease burden was greatest.

Climate warming triggers the emergence of native viruses in Iberian amphibians.

The number of epizootics in amphibian populations caused by viruses of the genus Ranavirus is increasing worldwide. Yet, causes for pathogen emergence are poorly understood. Here, we confirmed that the Common midwife toad virus (CMTV) and Frog virus 3 (FV3) are responsible for mass mortalities in Iberia since the late 1980s. Our results illustrate the Iberian Peninsula as a diversity hotspot for the highly virulent CMTV. Although this pattern of diversity in Europe is consistent with spread by natural dispersal, the exact origin of the emergence of CMTV remains uncertain. Nevertheless, our data allow hypothesizing that the Iberian Peninsula might harbor the ancestral population of CMTVs that could have spread into the rest of Europe. In addition, we found that climate warming could be triggering the CMTV outbreaks, supporting its endemic status in the Iberian Peninsula.

Memory recovery in relation to default mode network impairment and neurite density during brain tumor treatment.

OBJECTIVE: The aim of this study was to test brain tumor interactions with brain networks, thereby identifying protective features and risk factors for memory recovery after resection. METHODS: Seventeen patients with diffuse nonenhancing glioma (ages 22-56 years) underwent longitudinal MRI before and after surgery, and during a 12-month recovery period (47 MRI scans in total after exclusion). After each scanning session, a battery of memory tests was performed using a tablet-based screening tool, including free verbal memory, overall verbal memory, episodic memory, orientation, forward digit span, and backward digit span. Using structural MRI and neurite orientation dispersion and density imaging (NODDI) derived from diffusion-weighted images, the authors estimated lesion overlap and neurite density, respectively, with brain networks derived from normative data in healthy participants (somatomotor, dorsal attention, ventral attention, frontoparietal, and default mode network [DMN]). Linear mixed-effect models (LMMs) that regressed out the effect of age, gender, tumor grade, type of treatment, total lesion volume, and total neurite density were used to test the potential longitudinal associations between imaging markers and memory recovery. RESULTS: Memory recovery was not significantly associated with either the tumor location based on traditional lobe classification or the type of treatment received by patients (i.e., surgery alone or surgery with adjuvant chemoradiotherapy). Nonlocal effects of tumors were evident on neurite density, which was reduced not only within the tumor but also beyond the tumor boundary. In contrast, high preoperative neurite density outside the tumor but within the DMN was associated with better memory recovery (LMM, p value after false discovery rate correction [Pfdr] < 10-3). Furthermore, postoperative and follow-up neurite density within the DMN and frontoparietal network were also associated with memory recovery (LMM, Pfdr = 0.014 and Pfdr = 0.001, respectively). Preoperative tumor and postoperative lesion overlap with the DMN showed a significant negative association with memory recovery (LMM, Pfdr = 0.002 and Pfdr < 10-4, respectively). CONCLUSIONS: Imaging biomarkers of cognitive recovery and decline can be identified using NODDI and resting-state networks. Brain tumors and their corresponding treatment affecting brain networks that are fundamental for memory functioning such as the DMN can have a major impact on patients' memory recovery.

BOLD Coupling between Lesioned and Healthy Brain Is Associated with Glioma Patients' Recovery.

Predicting functional outcomes after surgery and early adjuvant treatment is difficult due to the complex, extended, interlocking brain networks that underpin cognition. The aim of this study was to test glioma functional interactions with the rest of the brain, thereby identifying the risk factors of cognitive recovery or deterioration. Seventeen patients with diffuse non-enhancing glioma (aged 22-56 years) were longitudinally MRI scanned and cognitively assessed before and after surgery and during a 12-month recovery period (55 MRI scans in total after exclusions). We initially found, and then replicated in an independent dataset, that the spatial correlation pattern between regional and global BOLD signals (also known as global signal topography) was associated with tumour occurrence. We then estimated the coupling between the BOLD signal from within the tumour and the signal extracted from different brain tissues. We observed that the normative global signal topography is reorganised in glioma patients during the recovery period. Moreover, we found that the BOLD signal within the tumour and lesioned brain was coupled with the global signal and that this coupling was associated with cognitive recovery. Nevertheless, patients did not show any apparent disruption of functional connectivity within canonical functional networks. Understanding how tumour infiltration and coupling are related to patients' recovery represents a major step forward in prognostic development.

An Evaluation of the Tolerability and Feasibility of Combining 5-Amino-Levulinic Acid (5-ALA) with BCNU Wafers in the Surgical Management of Primary Glioblastoma.

Background Glioblastoma (GBM) is the commonest primary malignant brain tumour in adults and effective treatment options are limited. Combining local chemotherapy with enhanced surgical resection using 5-aminolevulinic acid (5-ALA) could improve outcomes. Here we assess the safety and feasibility of combining BCNU wafers with 5-ALA-guided surgery. Methods We conducted a multicentre feasibility study of 5-ALA with BCNU wafers followed by standard-of-care chemoradiotherapy (chemoRT) in patients with suspected GBM. Patients judged suitable for radical resection were administered 5-ALA pre-operatively and BCNU wafers at the end resection. Post-operative treatment continued as per routine clinical practice. The primary objective was to establish if combining 5-ALA and BCNU wafers is safe without compromising patients from receiving standard chemoRT. Results Seventy-two patients were recruited, sixty-four (88.9%) received BCNU wafer implants, and fifty-nine (81.9%) patients remained eligible following formal histological diagnosis. Seven (11.9%) eligible patients suffered surgical complications but only two (3.4%) were not able to begin chemoRT, four (6.8%) additional patients did not begin chemoRT within 6 weeks of surgery due to surgical complications. Eleven (18.6%) patients did not begin chemoRT for other reasons (other toxicity (n = 3), death (n = 3), lost to follow-up/withdrew (n = 3), clinical decision (n = 1), poor performance status (n = 1)). Median progression-free survival was 8.7 months (95% CI: 6.4-9.8) and median overall survival was 14.7 months (95% CI: 11.7-16.8). Conclusions Combining BCNU wafers with 5-ALA-guided surgery in newly diagnosed GBM patients is both feasible and tolerable in terms of surgical morbidity and overall toxicity. Any potential therapeutic benefit for the sequential use of 5-ALA and BCNU with chemoRT requires further investigation with improved local delivery technologies.

Long-Term Monitoring of Amphibian Populations of a National Park in Northern Spain Reveals Negative Persisting Effects of Ranavirus, but Not Batrachochytrium dendrobatidis.

Amphibians are the most highly threatened vertebrates, and emerging pathogens are a serious threat to their conservation. Amphibian chytrid fungi and the viruses of the Ranavirus genus are causing disease outbreaks worldwide, including in protected areas such as National Parks. However, we lack information about their effect over amphibian populations in the long-term, and sometimes these mortality episodes are considered as transient events without serious consequences over longer time-spans. Here, we relate the occurrence of both pathogens with the population trends of 24 amphibian populations at 15 sites across a national Park in northern Spain over a 14-year period. Just one out 24 populations presents a positive population trend being free of both pathogens, while seven populations exposed to one or two pathogens experienced strong declines during the study period. The rest of the study populations (16) remain stable, and these tend to be of species that are not susceptible to the pathogen present or are free of pathogens. Our study is consistent with infectious diseases playing an important role in dictating amphibian population trends and emphasizes the need to adopt measures to control these pathogens in nature. We highlight that sites housing species carrying Ranavirus seems to have experienced more severe population-level effects compared to those with the amphibian chytrid fungus, and that ranaviruses could be just as, or more important, other more high-profile amphibian emerging pathogens.

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease.

CovidNeuroOnc: A UK multicenter, prospective cohort study of the impact of the COVID-19 pandemic on the neuro-oncology service.

BACKGROUND: The COVID-19 pandemic has profoundly affected cancer services. Our objective was to determine the effect of the COVID-19 pandemic on decision making and the resulting outcomes for patients with newly diagnosed or recurrent intracranial tumors. METHODS: We performed a multicenter prospective study of all adult patients discussed in weekly neuro-oncology and skull base multidisciplinary team meetings who had a newly diagnosed or recurrent intracranial (excluding pituitary) tumor between 01 April and 31 May 2020. All patients had at least 30-day follow-up data. Descriptive statistical reporting was used. RESULTS: There were 1357 referrals for newly diagnosed or recurrent intracranial tumors across 15 neuro-oncology centers. Of centers with all intracranial tumors, a change in initial management was reported in 8.6% of cases (n = 104/1210). Decisions to change the management plan reduced over time from a peak of 19% referrals at the start of the study to 0% by the end of the study period. Changes in management were reported in 16% (n = 75/466) of cases previously recommended for surgery and 28% of cases previously recommended for chemotherapy (n = 20/72). The reported SARS-CoV-2 infection rate was similar in surgical and non-surgical patients (2.6% vs. 2.4%, P > .9). CONCLUSIONS: Disruption to neuro-oncology services in the UK caused by the COVID-19 pandemic was most marked in the first month, affecting all diagnoses. Patients considered for chemotherapy were most affected. In those recommended surgical treatment this was successfully completed. Longer-term outcome data will evaluate oncological treatments received by these patients and overall survival.

Host contribution to parasite persistence is consistent between parasites and over time, but varies spatially.

Most parasites and pathogens infect multiple hosts, but a great deal of variation exists in the role of those hosts in persistence of infection. Understanding which hosts are most important in maintaining parasites can provide a clearer target for infection control. Recently developed empirical and theoretical approaches provide a way to quantify the relative contribution of hosts within a community and place them in a multi-host framework to better direct control efforts. Amphibians provide a framework for better understanding multi-host-multi-parasite dynamics. Two well-studied amphibian parasites, Batrachochytrium dendrobatidis (Bd) and Ranavirus, infect multiple host species and exhibit a great deal of heterogeneity in how they affect hosts. We used these two parasites and a community of five amphibian species to investigate the relative importance of hosts in parasite persistence, and how any patterns varied spatially and temporally. At two sites (Lake Ercina and Lake Lloroza in the Picos de Europa National Park, Spain) we collected data on the prevalence and shedding rate of parasite infection for both Bd and Ranavirus, and the abundance of each species' life stages. We used these data to parameterize a recently developed modeling framework, which was used to quantify the relative contribution of each host to the community reproductive number, R0 . By comparing each host-category over time and between sites we were able to identify consistencies in which host was responsible for the maintenance of these two parasites. Within a site one species consistently contributed the most to the persistence of both parasites. This consistency did not transfer between sites, the maintenance host species being different for each. At one site (Ercina), life stages of the common midwife toad, Alytes obstetricans, acted as the maintenance host for both Bd and Ranavirus. In contrast, at the second site, Lloroza, the alpine newt, Ichthyosaura alpestris, fulfilled that role. A single host species was responsible for infection persistence of both parasites at each lake. Attempts to control the infection levels and impacts of multiple parasites can benefit from a community epidemiology approach, and provide clarity on which hosts are the foci of mitigation efforts. However, at a small spatial scale, the target host may vary according to the physical qualities of those sites and the demographics of the host community.