Latent human herpesvirus 6 is reactivated in CAR T cells.

Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)1. Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4+ T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration2 or are in clinical studies3-5, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials1,6-8 and may influence the design and production of autologous and allogeneic cell therapies.

Auditory Competition and Coding of Relative Stimulus Strength across Midbrain Space Maps of Barn Owls.

The natural environment challenges the brain to prioritize the processing of salient stimuli. The barn owl, a sound localization specialist, exhibits a circuit called the midbrain stimulus selection network, dedicated to representing locations of the most salient stimulus in circumstances of concurrent stimuli. Previous competition studies using unimodal (visual) and bimodal (visual and auditory) stimuli have shown that relative strength is encoded in spike response rates. However, open questions remain concerning auditory-auditory competition on coding. To this end, we present diverse auditory competitors (concurrent flat noise and amplitude-modulated noise) and record neural responses of awake barn owls of both sexes in subsequent midbrain space maps, the external nucleus of the inferior colliculus (ICx) and optic tectum (OT). While both ICx and OT exhibit a topographic map of auditory space, OT also integrates visual input and is part of the global-inhibitory midbrain stimulus selection network. Through comparative investigation of these regions, we show that while increasing strength of a competitor sound decreases spike response rates of spatially distant neurons in both regions, relative strength determines spike train synchrony of nearby units only in the OT. Furthermore, changes in synchrony by sound competition in the OT are correlated to gamma range oscillations of local field potentials associated with input from the midbrain stimulus selection network. The results of this investigation suggest that modulations in spiking synchrony between units by gamma oscillations are an emergent coding scheme representing relative strength of concurrent stimuli, which may have relevant implications for downstream readout.

Telomere length as biomarker of nutritional therapy for prevention of type 2 diabetes mellitus development in patients with coronary heart disease: CORDIOPREV randomised controlled trial.

BACKGROUND: Telomere Length (TL), a marker of cellular aging, holds promise as a biomarker to elucidate the molecular mechanism of diabetes. This study aimed to investigate whether shorter telomeres are associated with a higher risk of type 2 diabetes mellitus (T2DM) incidence in patients with coronary heart disease; and to determine whether the most suitable dietary patterns, particularly a Mediterranean diet or a low-fat diet, can mitigate the development of diabetes in these patients after a follow-up period of five years. METHODS: The CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (CORDIOPREV study) was a single-centre, randomised clinical trial done at the Reina Sofia University Hospital in Córdoba, Spain. Patients with established coronary heart disease (aged 20-75 years) were randomly assigned in a 1:1 ratio by the Andalusian School of Public Health to receive two healthy diets. Clinical investigators were masked to treatment assignment; participants were not. Quantitative-PCR was used to assess TL measurements. FINDINGS: 1002 patients (59.5 ± 8.7 years and 82.5% men) were enrolled into Mediterranean diet (n = 502) or a low-fat diet (n = 500) groups. In this analysis, we included all 462 patients who did not have T2DM at baseline. Among them, 107 patients developed T2DM after a median of 60 months. Cox regression analyses showed that patients at risk of short telomeres (TL < percentile 20th) are more likely to experience T2DM than those at no risk of short telomeres (HR 1.65, p-value 0.023). In terms of diet, patients at high risk of short telomeres had a higher risk of T2DM incidence after consuming a low-fat diet compared to patients at no risk of short telomeres (HR 2.43, 95CI% 1.26 to 4.69, p-value 0.008), while no differences were observed in the Mediterranean diet group. CONCLUSION: Patients with shorter TL presented a higher risk of developing T2DM. This association could be mitigated with a specific dietary pattern, in our case a Mediterranean diet, to prevent T2DM in patients with coronary heart disease. TRIAL REGISTRATION: Clinicaltrials.gov number NCT00924937.

The impact of the COVID-19 pandemic on people living with HIV: a cross-sectional study in Caracas, Venezuela.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disrupted multiple health services, including human immunodeficiency virus (HIV) testing, care, and treatment services, jeopardizing the achievement of the Joint United Nations Programme on HIV/AIDS 90-90-90 global target. While there are limited studies assessing the impact of the COVID-19 pandemic on people living with HIV (PLHIV) in Latin America, there are none, to our knowledge, in Venezuela. This study aims to assess the impact of the COVID-19 pandemic among PLHIV seen at the outpatient clinic of a reference hospital in Venezuela. METHODS: We conducted a cross-sectional study among PLHIV aged 18 years and over seen at the Infectious Diseases Department of the University Hospital of Caracas, Venezuela between March 2021 and February 2022. RESULTS: A total of 238 PLHIV were included in the study. The median age was 43 (IQR 31-55) years, and the majority were male (68.9%). Most patients (88.2%, n = 210) came for routine check-ups, while 28 (11.3%) were newly diagnosed. The majority of patients (96.1%) were on antiretroviral therapy (ART), but only 67.8% had a viral load test, with almost all (95.6%) being undetectable. Among those who attended regular appointments, 11.9% reported missing at least one medical consultation, and 3.3% reported an interruption in their ART refill. More than half of the patients (55.5%) had received at least one dose of the COVID-19 vaccine, while the rest expressed hesitancy to get vaccinated. Most patients with COVID-19 vaccine hesitancy were male (65.1%), younger than 44 years (57.5%), employed (47.2%), and had been diagnosed with HIV for less than one year (33%). However, no statistically significant differences were found between vaccinated patients and those with COVID-19 vaccine hesitancy. Older age was a risk factor for missing consultations, while not having an alcoholic habit was identified as a protective factor against missing consultations. CONCLUSION: This study found that the COVID-19 pandemic had a limited impact on adherence to medical consultations and interruptions in ART among PLHIV seen at the University Hospital of Caracas, Venezuela.

Deep learning, radiomics and radiogenomics applications in the digital breast tomosynthesis: a systematic review.

BACKGROUND: Recent advancements in computing power and state-of-the-art algorithms have helped in more accessible and accurate diagnosis of numerous diseases. In addition, the development of de novo areas in imaging science, such as radiomics and radiogenomics, have been adding more to personalize healthcare to stratify patients better. These techniques associate imaging phenotypes with the related disease genes. Various imaging modalities have been used for years to diagnose breast cancer. Nonetheless, digital breast tomosynthesis (DBT), a state-of-the-art technique, has produced promising results comparatively. DBT, a 3D mammography, is replacing conventional 2D mammography rapidly. This technological advancement is key to AI algorithms for accurately interpreting medical images. OBJECTIVE AND METHODS: This paper presents a comprehensive review of deep learning (DL), radiomics and radiogenomics in breast image analysis. This review focuses on DBT, its extracted synthetic mammography (SM), and full-field digital mammography (FFDM). Furthermore, this survey provides systematic knowledge about DL, radiomics, and radiogenomics for beginners and advanced-level researchers. RESULTS: A total of 500 articles were identified, with 30 studies included as the set criteria. Parallel benchmarking of radiomics, radiogenomics, and DL models applied to the DBT images could allow clinicians and researchers alike to have greater awareness as they consider clinical deployment or development of new models. This review provides a comprehensive guide to understanding the current state of early breast cancer detection using DBT images. CONCLUSION: Using this survey, investigators with various backgrounds can easily seek interdisciplinary science and new DL, radiomics, and radiogenomics directions towards DBT.

Clinical impact of an integrated e-health system for diabetes self-management support and shared decision making (POWER2DM): a randomised controlled trial.

AIMS/HYPOTHESIS: There is a lack of e-health systems that integrate the complex variety of aspects relevant for diabetes self-management. We developed and field-tested an e-health system (POWER2DM) that integrates medical, psychological and behavioural aspects and connected wearables to support patients and healthcare professionals in shared decision making and diabetes self-management. METHODS: Participants with type 1 or type 2 diabetes (aged >18 years) from hospital outpatient diabetes clinics in the Netherlands and Spain were randomised using randomisation software to POWER2DM or usual care for 37 weeks. This RCT assessed the change in HbA1c between the POWER2DM and usual care groups at the end of the study (37 weeks) as a primary outcome measure. Participants and clinicians were not blinded to the intervention. Changes in quality of life (QoL) (WHO-5 Well-Being Index [WHO-5]), diabetes self-management (Diabetes Self-Management Questionnaire - Revised [DSMQ-R]), glycaemic profiles from continuous glucose monitoring devices, awareness of hypoglycaemia (Clarke hypoglycaemia unawareness instrument), incidence of hypoglycaemic episodes and technology acceptance were secondary outcome measures. Additionally, sub-analyses were performed for participants with type 1 and type 2 diabetes separately. RESULTS: A total of 226 participants participated in the trial (108 with type 1 diabetes; 118 with type 2 diabetes). In the POWER2DM group (n=111), HbA1c decreased from 60.6±14.7 mmol/mol (7.7±1.3%) to 56.7±12.1 mmol/mol (7.3±1.1%) (means ± SD, p<0.001), compared with no change in the usual care group (n=115) (baseline: 61.7±13.7 mmol/mol, 7.8±1.3%; end of study: 61.0±12.4 mmol/mol, 7.7±1.1%; p=0.19) (between-group difference 0.24%, p=0.008). In the sub-analyses in the POWER2DM group, HbA1c in participants with type 2 diabetes decreased from 62.3±17.3 mmol/mol (7.9±1.6%) to 54.3±11.1 mmol/mol (7.1±1.0%) (p<0.001) compared with no change in HbA1c in participants with type 1 diabetes (baseline: 58.8±11.2 mmol/mol [7.5±1.0%]; end of study: 59.2±12.7 mmol/mol [7.6±1.2%]; p=0.84). There was an increase in the time during which interstitial glucose levels were between 3.0 and 3.9 mmol/l in the POWER2DM group, but no increase in clinically relevant hypoglycaemia (interstitial glucose level below 3.0 mmol/l). QoL improved in participants with type 1 diabetes in the POWER2DM group compared with the usual care group (baseline: 15.7±3.8; end of study: 16.3±3.5; p=0.047 for between-group difference). Diabetes self-management improved in both participants with type 1 diabetes (from 7.3±1.2 to 7.7±1.2; p=0.002) and those with type 2 diabetes (from 6.5±1.3 to 6.7±1.3; p=0.003) within the POWER2DM group. The POWER2DM integrated e-health support was well accepted in daily life and no important adverse (or unexpected) effects or side effects were observed. CONCLUSIONS/INTERPRETATION: POWER2DM improves HbA1c levels compared with usual care in those with type 2 diabetes, improves QoL in those with type 1 diabetes, improves diabetes self-management in those with type 1 and type 2 diabetes, and is well accepted in daily life. TRIAL REGISTRATION: ClinicalTrials.gov NCT03588104. FUNDING: This study was funded by the European Union's Horizon 2020 Research and Innovation Programme (grant agreement number 689444).

Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial.

BACKGROUND: Mediterranean and low-fat diets are effective in the primary prevention of cardiovascular disease. We did a long-term randomised trial to compare the effects of these two diets in secondary prevention of cardiovascular disease. METHODS: The CORDIOPREV study was a single-centre, randomised clinical trial done at the Reina Sofia University Hospital in Córdoba, Spain. Patients with established coronary heart disease (aged 20-75 years) were randomly assigned in a 1:1 ratio by the Andalusian School of Public Health to receive a Mediterranean diet or a low-fat diet intervention, with a follow-up of 7 years. Clinical investigators (physicians, investigators, and clinical endpoint committee members) were masked to treatment assignment; participants were not. A team of dietitians did the dietary interventions. The primary outcome (assessed by intention to treat) was a composite of major cardiovascular events, including myocardial infarction, revascularisation, ischaemic stroke, peripheral artery disease, and cardiovascular death. This study is registered with ClinicalTrials.gov, NCT00924937. FINDINGS: From Oct 1, 2009, to Feb 28, 2012, a total of 1002 patients were enrolled, 500 (49·9%) in the low-fat diet group and 502 (50·1%) in the Mediterranean diet group. The mean age was 59·5 years (SD 8·7) and 827 (82·5%) of 1002 patients were men. The primary endpoint occurred in 198 participants: 87 in the Mediterranean diet group and 111 in the low-fat group (crude rate per 1000 person-years: 28·1 [95% CI 27·9-28·3] in the Mediterranean diet group vs 37·7 [37·5-37·9] in the low-fat group, log-rank p=0·039). Multivariable-adjusted hazard ratios (HRs) of the different models ranged from 0·719 (95% CI 0·541-0·957) to 0·753 (0·568-0·998) in favour of the Mediterranean diet. These effects were more evident in men, with primary endpoints occurring in 67 (16·2%) of 414 men in the Mediterranean diet group versus 94 (22·8%) of 413 men in the low-fat diet group (multiadjusted HR 0·669 [95% CI 0·489-0·915], log-rank p=0·013), than in 175 women for whom no difference was found between groups. INTERPRETATION: In secondary prevention, the Mediterranean diet was superior to the low-fat diet in preventing major cardiovascular events. Our results are relevant to clinical practice, supporting the use of the Mediterranean diet in secondary prevention. FUNDING: Fundacion Patrimonio Comunal Olivarero; Fundacion Centro para la Excelencia en Investigacion sobre Aceite de Oliva y Salud; local, regional, and national Spanish Governments; European Union.

Neolithic expansion and the 17q21.31 inversion in Iberia: an evolutionary approach to H2 haplotype distribution in the Near East and Europe.

The chromosomal region 17q21.31 harbors a 900 kb inversion polymorphism named after the microtubule-associated protein tau (MAPT) gene. Since no recombination occurs, two haplotypes are recognized: a directly oriented variant (H1) and an inverted variant (H2). The H2 haplotype features a distribution pattern with high frequencies in the Near East and Europe, medium levels in South Asia and North Africa, and low levels elsewhere. Studies of this genomic region are relevant owing to its likely association with numerous neurodegenerative diseases. However, the causes underlying the geographic distribution of the haplotype frequencies remain a bone of contention among researchers. With this work, we have intended to outline a plausible hypothesis on the origin of the high European H2 frequencies. To that end, we have analyzed an extensive population database (including three new Iberian populations) to explore potential clinal variations of H2 frequencies. We found a sigmoidal frequency cline with an upward trend from South Asia to Europe. The maximum value was detected in the Basques from Gipuzkoa province (0.494) with the curve's inflection point in the Near East. From our results, we suggest that the most likely scenario for high H2 frequencies in Europe would be a founding event in the Near East during the late Paleolithic or early Neolithic. Subsequently, such H2 overrepresentation would have reached Europe with the arrival of the first Neolithic farmers. The current frequencies and geographic distribution of the 17q21.31 inversion suggest that the founding events mainly affected the H2D subhaplotype.

Adherence to a Mediterranean lifestyle improves metabolic status in coronary heart disease patients: A prospective analysis from the CORDIOPREV study.

BACKGROUND AND OBJECTIVES: A Mediterranean lifestyle may prevent and mitigate cardiometabolic disorders. We explored whether adherence to a Mediterranean lifestyle was prospectively associated with the risk of metabolic syndrome (MetS) among coronary heart disease (CHD) patients. METHODS: The Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention (CORDIOPREV) study was an interventional diet study to compare a Mediterranean diet with a low-fat diet, in 1002 CHD patients. The Mediterranean lifestyle (MEDLIFE) index was used to assess adherence to a MEDLIFE at baseline, and after 5 years, in 851 participants from the CORDIOPREV study. Subjects were classified as having high (>13 points), moderate (12-13 points), and low (<12 points) adherence to the MEDLIFE. Multivariable logistic regression models were used to determine the association between MEDLIFE adherence and the risk of MetS development or reversal. RESULTS: During the 5-year follow-up, CORDIOPREV participants with high adherence to MEDLIFE had a lower risk of MetS development (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.19-0.75, p < 0.01) and a higher likelihood of reversing preexisting MetS (OR 2.08 CI 95% 1.11-3.91, p = 0.02) compared with participants in the low MEDLIFE adherence group. Each additional one-point increment in the MEDLIFE index was associated with a 24% lower risk of MetS development (OR 0.76, 95% CI 0.64-0.90, p < 0.01) and a 21% higher likelihood of reversing preexisting MetS (OR 1.21 CI 95% 1.04-1.41, p = 0.01). CONCLUSIONS: Our results showed that greater adherence to a MEDLIFE reduced the risk of subsequent MetS development and increased the likelihood of reversing preexisting MetS among patients with CHD at baseline.

Plasma lipidic fingerprint associated with type 2 diabetes in patients with coronary heart disease: CORDIOPREV study.

OBJECTIVE: We aimed to identify a lipidic profile associated with type 2 diabetes mellitus (T2DM) development in coronary heart disease (CHD) patients, to provide a new, highly sensitive model which could be used in clinical practice to identify patients at T2DM risk. METHODS: This study considered the 462 patients of the CORDIOPREV study (CHD patients) who were not diabetic at the beginning of the intervention. In total, 107 of them developed T2DM after a median follow-up of 60 months. They were diagnosed using the American Diabetes Association criteria. A novel lipidomic methodology employing liquid chromatography (LC) separation followed by HESI, and detection by mass spectrometry (MS) was used to annotate the lipids at the isomer level. The patients were then classified into a Training and a Validation Set (60-40). Next, a Random Survival Forest (RSF) was carried out to detect the lipidic isomers with the lowest prediction error, these lipids were then used to build a Lipidomic Risk (LR) score which was evaluated through a Cox. Finally, a production model combining the clinical variables of interest, and the lipidic species was carried out. RESULTS: LC-tandem MS annotated 440 lipid species. From those, the RSF identified 15 lipid species with the lowest prediction error. These lipids were combined in an LR score which showed association with the development of T2DM. The LR hazard ratio per unit standard deviation was 2.87 and 1.43, in the Training and Validation Set respectively. Likewise, patients with higher LR Score values had lower insulin sensitivity (P = 0.006) and higher liver insulin resistance (P = 0.005). The receiver operating characteristic (ROC) curve obtained by combining clinical variables and the selected lipidic isomers using a generalised lineal model had an area under the curve (AUC) of 81.3%. CONCLUSION: Our study showed the potential of comprehensive lipidomic analysis in identifying patients at risk of developing T2DM. In addition, the lipid species combined with clinical variables provided a new, highly sensitive model which can be used in clinical practice to identify patients at T2DM risk. Moreover, these results also indicate that we need to look closely at isomers to understand the role of this specific compound in T2DM development. Trials registration NCT00924937.

Artificial sweeteners and cardiovascular risk.

PURPOSE OF REVIEW: Globalization and the increase in consumption of ultra-processed foods have led to a need for greater knowledge on the health impacts of certain nutrients such as artificial sweeteners. This review aims to analyse the role of artificial sweeteners (nutritive and nonnutritive) and their impact on cardiometabolic and cardiovascular disease (CVD) risk. RECENT FINDINGS: The detrimental effects of a high-calorie, high-sugar diet have been well established. In light of this, health authorities recommend limiting sugar consumption. This has led the food industry to develop different artificial sweeteners with specific properties, such as flavour and stability (nutritive artificial sweeteners: NAS), and others aimed at limiting sugar in the diet (nonnutritive artificial sweeteners: nNAS). Likewise, recent evidence explores the influence of artificial sweeteners (NAS and nNAS) on CVD risk through risk factors such as obesity and type 2 diabetes mellitus, among others. SUMMARY: This review aims to provide an updated overview of the impact of NAS and nNAS on cardiovascular health and provide recommendations regarding their consumption.

New daily persistent headache after SARS-CoV-2 infection in Latin America: a cross-sectional study.

BACKGROUND: Persistent headache is a frequent symptom after coronavirus disease 2019 (COVID-19) and there is currently limited knowledge about its clinical spectrum and predisposing factors. A subset of patients may be experiencing new daily persistent headache (NDPH) after COVID-19, which is among the most treatment-refractory primary headache syndromes. METHODS: We conducted a cross-sectional study in Latin America to characterize individuals with persistent headache after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and to identify factors associated with NDPH. Participants over 18 years old who tested positive for SARS-CoV-2 infection and reported persistent headache among their symptoms completed an online survey that included demographics, past medical history, persistent headache clinical characteristics, and COVID-19 vaccination status. Based on participants' responses, NDPH diagnostic criteria were used to group participants into NDPH and non-NDPH groups. Participant data was summarized by descriptive statistics. Student's t and Mann-Whitney U tests were used according to the distribution of quantitative variables. For categorical variables, Pearson's chi-square and Fisher's exact tests were used according to the size of expected frequencies. Binomial logistic regression using the backward stepwise selection method was performed to identify factors associated with NDPH. RESULTS: Four hundred and twenty-one participants from 11 Latin American countries met the inclusion criteria. One in four participants met the NDPH diagnostic criteria. The mean age was 40 years, with most participants being female (82%). Over 90% of the participants reported having had mild/moderate COVID-19. Most participants had a history of headache before developing COVID-19 (58%), mainly migraine type (32%). The most predominant clinical characteristics in the NDPH group were occipital location, severe/unbearable intensity, burning character, and radiating pain (p < 0.05). A higher proportion of anxiety symptoms, sleep problems, myalgia, mental fog, paresthesia, nausea, sweating of the face or forehead, and ageusia or hypogeusia as concomitant symptoms were reported in participants with NDPH (p < 0.05). Palpebral edema as a concomitant symptom during the acute phase of COVID-19, occipital location, and burning character of the headache were risk factors associated with NDPH. CONCLUSION: This is the first study in Latin America that explored the clinical spectrum of NDPH after SARS-CoV-2 infection and its associated factors. Clinical evaluation of COVID-19 patients presenting with persistent headache should take into consideration NDPH.

Changes in quantity plant-based protein intake on type 2 diabetes remission in coronary heart disease patients: from the CORDIOPREV study.

PURPOSE: Diabetes remission is a phenomenon described in the context of drastic weight loss due to bariatric surgery or low-calorie diets. Evidence suggests that increasing the intake of plant protein could reduce the risk of type 2 diabetes. We sought for association between changes in plant protein intake in the context of 2 healthy diets without weight loss nor glucose-lowering medication, and diabetes remission in coronary heart disease patients from the CORDIOPREV study. METHODS: Newly diagnosed type 2 diabetes participants without glucose-lowering treatment were randomized to consume a Mediterranean or a low-fat diet. Type 2 diabetes remission was assessed with a median follow-up of 60 months according to the ADA recommendation. Information on patient's dietary intake was collected using food-frequency questionnaires. At first year of intervention, 177 patients were classified according to changes in plant protein consumption into those who increased or decreased its intake, in order to perform an observational analysis on the association between protein intake and diabetes remission. RESULTS: Cox regression showed that patients increasing plant protein intake were more likely to remit from diabetes than those who decreased its intake (HR = 1.71(1.05-2.77)). The remission occurred mainly at first and second year of follow-up with diminished number of patients achieving remission in the third year onwards. The increase in plant protein was associated with lower intake of animal protein, cholesterol, saturated fatty acids, and fat, and with higher intake of whole grains, fibre, carbohydrates, legumes, and tree nuts. CONCLUSION: These results support the need to increase protein intake of vegetal origin as dietary therapy to reverse type 2 diabetes in the context of healthy diets without weight loss.

Historical evaluation of the in vivo adventitious virus test and its potential for replacement with next generation sequencing (NGS).

The Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) collected historical data from 20 biopharmaceutical industry members on their experience with the in vivo adventitious virus test, the in vitro virus test, and the use of next generation sequencing (NGS) for viral safety. Over the past 20 years, only three positive in vivo adventitious virus test results were reported, and all were also detected in another concurrent assay. In more than three cases, data collected as a part of this study also found that the in vivo adventitious virus test had given a negative result for a sample that was later found to contain virus. Additionally, the in vivo adventitious virus test had experienced at least 21 false positives and had to be repeated an additional 21 times all while using more than 84,000 animals. These data support the consideration and need for alternative broad spectrum viral detection tests that are faster, more sensitive, more accurate, more specific, and more humane. NGS is one technology that may meet this need. Eighty one percent of survey respondents are either already actively using or exploring the use of NGS for viral safety. The risks and challenges of replacing in vivo adventitious virus testing with NGS are discussed. It is proposed to update the overall virus safety program for new biopharmaceutical products by replacing in vivo adventitious virus testing approaches with modern methodologies, such as NGS, that maintain or even improve the final safety of the product.

The COVID-19 Data Portal: accelerating SARS-CoV-2 and COVID-19 research through rapid open access data sharing.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic will be remembered as one of the defining events of the 21st century. The rapid global outbreak has had significant impacts on human society and is already responsible for millions of deaths. Understanding and tackling the impact of the virus has required a worldwide mobilisation and coordination of scientific research. The COVID-19 Data Portal (https://www.covid19dataportal.org/) was first released as part of the European COVID-19 Data Platform, on April 20th 2020 to facilitate rapid and open data sharing and analysis, to accelerate global SARS-CoV-2 and COVID-19 research. The COVID-19 Data Portal has fortnightly feature releases to continue to add new data types, search options, visualisations and improvements based on user feedback and research. The open datasets and intuitive suite of search, identification and download services, represent a truly FAIR (Findable, Accessible, Interoperable and Reusable) resource that enables researchers to easily identify and quickly obtain the key datasets needed for their COVID-19 research.

Barn Owl's Auditory Space Map Activity Matching Conditions for a Population Vector Readout to Drive Adaptive Sound-Localizing Behavior.

Space-specific neurons in the owl's midbrain form a neural map of auditory space, which supports sound-orienting behavior. Previous work proposed that a population vector (PV) readout of this map, implementing statistical inference, predicts the owl's sound localization behavior. This model also predicts the frontal localization bias normally observed and how sound-localizing behavior changes when the signal-to-noise ratio varies, based on the spread of activity across the map. However, the actual distribution of population activity and whether this pattern is consistent with premises of the PV readout model on a trial-by-trial basis remains unknown. To answer these questions, we investigated whether the population response profile across the midbrain map in the optic tectum of the barn owl matches these predictions using in vivo multielectrode array recordings. We found that response profiles of recorded subpopulations are sufficient for estimating the stimulus interaural time difference using responses from single trials. Furthermore, this decoder matches the expected differences in trial-by-trial variability and frontal bias between stimulus conditions of low and high signal-to-noise ratio. These results support the hypothesis that a PV readout of the midbrain map can mediate statistical inference in sound-localizing behavior of barn owls.SIGNIFICANCE STATEMENT While the tuning of single neurons in the owl's midbrain map of auditory space has been considered predictive of the highly specialized sound-localizing behavior of this species, response properties across the population remain largely unknown. For the first time, this study analyzed the spread of population responses across the map using multielectrode recordings and how it changes with signal-to-noise ratio. The observed responses support the hypothesis concerning the ability of a population vector readout to predict biases in orienting behaviors and mediate uncertainty-dependent behavioral commands. The results are of significance for understanding potential mechanisms for the implementation of optimal behavioral commands across species.

Multiomics subtyping for clinically prognostic cancer subtypes and personalized therapy: A systematic review and meta-analysis.

PURPOSE: Multiomics cancer subtyping is becoming increasingly popular for directing state-of-the-art therapeutics. However, these methods have never been systematically assessed for their ability to capture cancer prognosis for identified subtypes, which is essential to effectively treat patients. METHODS: We systematically searched PubMed, The Cancer Genome Atlas, and Pan-Cancer Atlas for multiomics cancer subtyping studies from 2010 through 2019. Studies comprising at least 50 patients and examining survival were included. Pooled Cox and logistic mixed-effects models were used to compare the ability of multiomics subtyping methods to identify clinically prognostic subtypes, and a structural equation model was used to examine causal paths underlying subtyping method and mortality. RESULTS: A total of 31 studies comprising 10,848 unique patients across 32 cancers were analyzed. Latent-variable subtyping was significantly associated with overall survival (adjusted hazard ratio, 2.81; 95% CI, 1.16-6.83; P = .023) and vital status (1 year adjusted odds ratio, 4.71; 95% CI, 1.34-16.49; P = .015; 5 year adjusted odds ratio, 7.69; 95% CI, 1.83-32.29; P = .005); latent-variable-identified subtypes had greater associations with mortality across models (adjusted hazard ratio, 1.19; 95% CI, 1.01-1.42; P = .050). Our structural equation model confirmed the path from subtyping method through multiomics subtype (߈ = 0.66; P = .048) on survival (߈ = 0.37; P = .008). CONCLUSION: Multiomics methods have different abilities to define clinically prognostic cancer subtypes, which should be considered before administration of personalized therapy; preliminary evidence suggests that latent-variable methods better identify clinically prognostic biomarkers and subtypes.

Poacic acid, a ß-1,3-glucan-binding antifungal agent, inhibits cell-wall remodeling and activates transcriptional responses regulated by the cell-wall integrity and high-osmolarity glycerol pathways in yeast.

As a result of the relatively few available antifungals and the increasing frequency of resistance to them, the development of novel antifungals is increasingly important. The plant natural product poacic acid (PA) inhibits ß-1,3-glucan synthesis in Saccharomyces cerevisiae and has antifungal activity against a wide range of plant pathogens. However, the mode of action of PA is unclear. Here, we reveal that PA specifically binds to ß-1,3-glucan, its affinity for which is ~30-fold that for chitin. Besides its effect on ß-1,3-glucan synthase activity, PA inhibited the yeast glucan-elongating activity of Gas1 and Gas2 and the chitin-glucan transglycosylase activity of Crh1. Regarding the cellular response to PA, transcriptional co-regulation was mediated by parallel activation of the cell-wall integrity (CWI) and high-osmolarity glycerol signaling pathways. Despite targeting ß-1,3-glucan remodeling, the transcriptional profiles and regulatory circuits activated by caspofungin, zymolyase, and PA differed, indicating that their effects on CWI have different mechanisms. The effects of PA on the growth of yeast strains indicated that it has a mode of action distinct from that of echinocandins, suggesting it is a unique antifungal agent.

Diverse processing underlying frequency integration in midbrain neurons of barn owls.

Emergent response properties of sensory neurons depend on circuit connectivity and somatodendritic processing. Neurons of the barn owl's external nucleus of the inferior colliculus (ICx) display emergence of spatial selectivity. These neurons use interaural time difference (ITD) as a cue for the horizontal direction of sound sources. ITD is detected by upstream brainstem neurons with narrow frequency tuning, resulting in spatially ambiguous responses. This spatial ambiguity is resolved by ICx neurons integrating inputs over frequency, a relevant processing in sound localization across species. Previous models have predicted that ICx neurons function as point neurons that linearly integrate inputs across frequency. However, the complex dendritic trees and spines of ICx neurons raises the question of whether this prediction is accurate. Data from in vivo intracellular recordings of ICx neurons were used to address this question. Results revealed diverse frequency integration properties, where some ICx neurons showed responses consistent with the point neuron hypothesis and others with nonlinear dendritic integration. Modeling showed that varied connectivity patterns and forms of dendritic processing may underlie observed ICx neurons' frequency integration processing. These results corroborate the ability of neurons with complex dendritic trees to implement diverse linear and nonlinear integration of synaptic inputs, of relevance for adaptive coding and learning, and supporting a fundamental mechanism in sound localization.

Systemic inflammation and sympathetic activation in gestational diabetes mellitus with obstructive sleep apnea.

BACKGROUND: Although some evidence suggests an association between obstructive sleep apnea (OSA) and gestational diabetes mellitus (GDM), its consequences still remain largely unknown. We sought to determine whether OSA is associated with higher inflammation and sympathetic levels in GDM, and to relate them with insulin resistance and perinatal outcomes. METHODS: OSA was identified by polysomnography and defined as an apnea-hypopnea index of ≥ 5 h-1. Plasma cytokines (TNF-α, IL-1ß, IL-6, IL-8, IL-10), metanephrine, and normetanephrine were determined by immunoassays. RESULTS: We included 17 patients with GDM and OSA and 34 without OSA. Women with GDM and OSA had higher normetanephrine concentrations [81 IQR (59-134) vs. 68 (51-81) pg/mL]. No differences in the inflammatory profile were found, while IL-1ß was higher in patients with mean nocturnal oxyhemoglobin saturation ≤ 94%. We found positive correlations between increased sympathetic activation and IL-1ß, with obstructive apneas, while time in REM showed an inverse relationship with IL-1ß and metanephrine. Furthermore, IL-10 was inversely related with time in sleep stages 1-2, and with the arousal index, and it was positively related with time in slow-wave sleep. Significant correlations were also found between IL-1ß and insulin resistance. There were no significant differences in neonatal characteristics; however, we found inverse relationships between IL-10 and birth weight (BW), and percentile of BW. CONCLUSIONS: OSA increased sympathetic activity, and IL-1ß concentration was higher in patients with GDM with lower nocturnal oxygenation, all of which were related with obstructive events, and time in REM. Moreover, IL-1ß was related with insulin resistance, and IL-10 inversely correlated with neonatal BW.