BACKGROUND:Practice on fasting prior to extubation in critically ill patients is variable. Efficacy of fasting in reducing gastric volume has not been well established. The primary objective of this study was to assess the effect of 4 h of fasting on prevalence of empty stomach using gastric ultrasonography in critically ill subjects who are fasted for extubation. The secondary objectives were to evaluate the change in gastric volumes during 4 h of fasting and to determine factors associated with empty stomach after fasting.METHODS:This was a single-center, prospective, observational study on adult ICU subjects who were enterally fed for at least 6 h continuously and mechanically ventilated. Gastric ultrasound was performed immediately prior to commencement of fasting, after 4 h of fasting, and after nasogastric (NG) aspiration after 4 h of fasting. An empty stomach was defined as a gastric volume ≤ 1.5 mL/kg.RESULTS:Forty subjects were recruited, and 38 (95%) had images suitable for analysis. The prevalence of empty stomach increased after 4 h of fasting (25 [65.8%] vs 31 [81.6%], P = .041) and after 4 h of fasting with NG aspiration (25 [65.8%] vs 34 [89.5%], P = .008). There was a significant difference in median (interquartile range) gastric volume per body weight between before fasting and 4 h after fasting (1.0 [0.5–1.8] mL/kg vs 0.4 [0.2–1.0] mL/kg, P < .001). No patient factors were associated with higher prevalence of empty stomach after 4 h of fasting.CONCLUSIONS:Most mechanically ventilated subjects had empty stomachs prior to fasting for extubation. Fasting for 4 h further increased the prevalence of empty stomach at extubation to > 80%.

BACKGROUND:Beneficial effects of breathing at FIO2 < 0.21 on disease outcomes have been reported in previous preclinical and clinical studies. However, the safety and intra-hospital feasibility of breathing hypoxic gas for 5 d have not been established. In this study, we examined the physiologic effects of breathing a gas mixture with FIO2 as low as 0.11 in 5 healthy volunteers.METHODS:All 5 subjects completed the study, spending 5 consecutive days in a hypoxic tent, where the ambient oxygen level was lowered in a stepwise manner over 5 d, from FIO2 of 0.16 on the first day to FIO2 of 0.11 on the fifth day of the study. All the subjects returned to an environment at room air on the sixth day. The subjects' SpO2, heart rate, and breathing frequency were continuously recorded, along with daily blood sampling, neurologic evaluations, transthoracic echocardiography, and mental status assessments.RESULTS:Breathing hypoxia concentration dependently caused profound physiologic changes, including decreased SpO2 and increased heart rate. At FIO2 of 0.14, the mean SpO2 was 92%; at FIO2 of 0.13, the mean SpO2 was 93%; at FIO2 of 0.12, the mean SpO2 was 88%; at FIO2 of 0.11, the mean SpO2 was 85%; and, finally, at an FIO2 of 0.21, the mean SpO2 was 98%. These changes were accompanied by increased erythropoietin levels and reticulocyte counts in blood. All 5 subjects concluded the study with no adverse events. No subjects exhibited signs of mental status changes or pulmonary hypertension.CONCLUSIONS:Results of the current physiologic study suggests that, within a hospital setting, delivering FIO2 as low as 0.11 is feasible and safe in healthy subjects, and provides the foundation for future studies in which therapeutic effects of hypoxia breathing are tested.

BACKGROUND:Training in mechanical ventilation is a key goal in critical care fellowship education. Web-based simulators offer a cost-effective and readily available alternative to traditional on-site simulators. However, it is unclear how effective they are as teaching tools. In this study, we evaluated the test scores of fellows who underwent mechanical ventilation training by using a web-based simulator compared with fellows who used an on-site simulator during a mechanical ventilation course.METHODS:This was a nonrandomized controlled trial conducted as part of a mechanical ventilation course that involved 70 first-year critical care fellows. The course was identical except for the simulation technology used. One group of instructors used a traditional on-site simulator, the ASL 5000 Lung Solution (n = 39). The second group was instructed in using a web-based simulator, VentSim (n = 31). Each fellow completed a pre-course test and a post-course test by using a validated, case-based ventilator waveform examination that consisted of 5 questions with a total possible score of 100. The primary outcome was a comparison of the mean scores on the posttest between the 2 groups. The study was designed as a non-inferiority trial with a predetermined margin of 10 points.RESULTS:There was no significant difference in the mean ± SD pretest scores between the web-based and the on-site groups (21.1 ± 12.6 and 26.9 ± 13.6 respectively; P = .11). The mean ± SD posttest scores were 45.6 ± 25.0 for the web-based simulator and 43.4 ± 16.5 for on-site simulator (mean difference 2.2; one-sided 95% CI –7.0 to ∞; Pnon-inferiority = .02 [non-inferiority confirmed]). Changes in mean ± SD scores (posttest – pretest) were 25.9 ± 20.9 for the web-based simulator and 16.5 ± 15.9 for the on-site simulator (mean difference 9.4, one-sided 95% CI 0.9 to ∞; Pnon-inferiority < .001 [non-inferiority confirmed]).CONCLUSIONS:In the education of first-year critical care fellows on mechanical ventilation waveform analysis, a web-based mechanical ventilation simulator was non-inferior to a traditional on-site mechanical ventilation simulator.

Memory formation is contingent on molecular and structural changes in neurons in response to learning stimuli—a process known as neuronal plasticity. The initiation step of mRNA translation is a gatekeeper of long-term memory by controlling the production of plasticity-related proteins in the brain. The mechanistic target of rapamycin complex 1 (mTORC1) controls mRNA translation, mainly through phosphorylation of the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and ribosomal protein S6 kinases (S6Ks). mTORC1 signaling decreases throughout brain development, starting from the early postnatal period. Here, we discovered that in mice, the age-dependent decrease in mTORC1 signaling occurs selectively in excitatory but not inhibitory neurons. Using a gene conditional knockout (cKO) strategy, we demonstrate that either up- or downregulating the mTORC1-4E-BP2 axis in GAD65 inhibitory interneurons, but not excitatory neurons, results in long-term object recognition and object location memory deficits. Our data indicate that the mTORC1 pathway in inhibitory but not excitatory neurons plays a key role in memory formation.

Introduction

Exacerbation of COPD complicated by respiratory acidaemia is the commonest indication for noninvasive ventilation (NIV). The NIV outcomes (NIVO) score offers the best estimate of survival for those ventilated. Unfortunately, two-thirds of cases of COPD are unrecognised, and patients may present without COPD having been confirmed by spirometry.

Background

Exacerbations of noncystic fibrosis bronchiectasis (bronchiectasis) are associated with reduced health-related quality of life and increased mortality, likelihood of hospitalisation and lung function decline. This study investigated patient clinical characteristics associated with exacerbation frequency.

Background

The real-world consequences of a Philips Respironics recall for positive airway pressure (PAP) devices distributed between 2009 and 2021 are unknown.

Exercise significantly alters human physiological functions, such as increasing cardiac output and muscle blood flow and decreasing glomerular filtration rate (GFR) and liver blood flow, thereby altering the absorption, distribution, metabolism, and excretion of drugs. In this study, we aimed to establish a database of human physiological parameters during exercise and to construct equations for the relationship between changes in each physiological parameter and exercise intensity, including cardiac output, organ blood flow (e.g., muscle blood flow and kidney blood flow), oxygen uptake, plasma pH and GFR, etc. The polynomial equation P = a_iHRⁱ was used for illustrating the relationship between the physiological parameters (P) and heart rate (HR), which served as an index of exercise intensity. The pharmacokinetics of midazolam, quinidine, digoxin, and lidocaine during exercise were predicted by a whole-body physiologically based pharmacokinetic (WB-PBPK) model and the developed database of physiological parameters following administration to 100 virtual subjects. The WB-PBPK model simulation results showed that most of the observed plasma drug concentrations fell within the 5^th–95^th percentiles of the simulations, and the estimated peak concentrations (C_max) and area under the curve (AUC) of drugs were also within 0.5–2.0 folds of observations. Sensitivity analysis showed that exercise intensity, exercise duration, medication time, and alterations in physiological parameters significantly affected drug pharmacokinetics and the net effect depending on drug characteristics and exercise conditions. In conclusion, the pharmacokinetics of drugs during exercise could be quantitatively predicted using the developed WB-PBPK model and database of physiological parameters.

Pregnane X receptor (PXR) belongs to the nuclear receptor superfamily that plays a crucial role in hepatic physiologic and pathologic conditions. Phase separation is a process in which biomacromolecules aggregate and condense into a dense phase as liquid condensates and coexist with a dilute phase, contributing to various cellular and biologic functions. Until now, whether PXR could undergo phase separation remains unclear. This study aimed to investigate whether PXR undergoes phase separation. Analysis of the intrinsically disordered regions (IDRs) using algorithm tools indicated a low propensity of PXR to undergo phase separation. Experimental assays such as hyperosmotic stress, agonist treatment, and optoDroplets assay demonstrated the absence of phase separation for PXR. OptoDroplets assay revealed the inability of the fusion protein of Cry2 with PXR to form condensates upon blue light stimulation. Moreover, phase separation of PXR did not occur even though the mRNA and protein expression levels of PXR target, cytochrome P450 3A4, changed after sorbitol treatment. In conclusion, for the first time, these findings suggested that exogenous PXR does not undergo phase separation following activation or under hyperosmotic stress in nucleus of cells.

Protein abundance data of drug-metabolizing enzymes and transporters (DMETs) are useful for scaling in vitro and animal data to humans for accurate prediction and interpretation of drug clearance and toxicity. Targeted DMET proteomics that relies on synthetic stable isotope-labeled surrogate peptides as calibrators is routinely used for the quantification of selected proteins; however, the technique is limited to the quantification of a small number of proteins. Although the global proteomics-based total protein approach (TPA) is emerging as a better alternative for large-scale protein quantification, the conventional TPA does not consider differential sequence coverage by identifying unique peptides across proteins. Here, we optimized the TPA approach by correcting protein abundance data by the sequence coverage, which was applied to quantify 54 DMETs for characterization of 1) differential tissue DMET abundance in the human liver, kidney, and intestine, and 2) interindividual variability of DMET proteins in individual intestinal samples (n = 13). Uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7), microsomal glutathione S-transferases (MGST1, MGST2, and MGST3) carboxylesterase 2 (CES2), and multidrug resistance-associated protein 2 (MRP2) were expressed in all three tissues, whereas, as expected, four cytochrome P450s (CYP3A4, CYP3A5, CYP2C9, and CYP4F2), UGT1A1, UGT2B17, CES1, flavin-containing monooxygenase 5, MRP3, and P-glycoprotein were present in the liver and intestine. The top three DMET proteins in individual tissues were: CES1>CYP2E1>UGT2B7 (liver), CES2>UGT2B17>CYP3A4 (intestine), and MGST1>UGT1A6>MGST2 (kidney). CYP3A4, CYP3A5, UGT2B17, CES2, and MGST2 showed high interindividual variability in the intestine. These data are relevant for enhancing in vitro to in vivo extrapolation of drug absorption and disposition and can be used to enhance the accuracy of physiologically based pharmacokinetic prediction of systemic and tissue concentration of drugs.

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ABSTRACTToxicological emergencies present a significant health challenge in Nepal. Despite the high burden, the country has inadequate formal toxicology training, medical toxicology expertise, and adequate poison control infrastructure. In recognition of this need, the Nepal Poison Information Center (PIC) was established as a collaborative effort involving local and international partners. Through a comprehensive partnership framework, the Nepal PIC provides 24 hours a day, 7 days a week expert guidance to health care workers, conducts educational webinars, and engages in research. Initial data from the pilot phase indicate successful consultation delivery. Challenges include bureaucratic hurdles and the need for sustainable funding. Despite these challenges, the Nepal PIC demonstrates early feasibility and potential for expansion into a comprehensive toxicology center, contributing to the advancement of clinical toxicology in Nepal. Long-term sustainability relies on governmental support and continued advocacy efforts.

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro–in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited.

Despite a significant decrease in the number of prescriptions for opioids, the opioid crisis continues, fueled in large part by the availability of the phenylpiperidine mu opioid receptor (MOR) agonist fentanyl. In contrast, the number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically, with gabapentinoids commonly detected in opioid overdose victims. Although gabapentinoids can decrease the potency of the opioid receptor antagonist naloxone to reverse heroin-induced hypoventilation in male rats, the specificity and nature of interaction between gabapentinoids and MOR agonists and any potential sex difference in those interactions are not well characterized. Gabapentinoids were studied in female and male rats discriminating fentanyl (0.0032 mg/kg, i.p.) or cocaine (3.2 mg/kg, i.p.). Alone, neither gabapentin nor pregabalin significantly increased fentanyl- or cocaine-appropriate responding. In rats discriminating fentanyl, each gabapentinoid dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the left, whereas naloxone dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the right. Each gabapentinoid (100 mg/kg) significantly decreased the potency of naloxone to antagonize the discriminative stimulus effect of fentanyl or heroin. In contrast, each gabapentinoid dose-dependently shifted the cocaine and d-methamphetamine discrimination dose-effect functions to the right. There were no significant sex differences in this study. These results suggest that gabapentinoids impact the misuse of opioids, the co-use of opioids and stimulant drugs, and the increasing number of overdose deaths in individuals using opioids, stimulant drugs, and gabapentinoids in mixtures.

Endocannabinoids, which are present throughout the central nervous system (CNS), can activate cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n = 56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120 mg) were compared with placebo and nabilone (3 and 6 mg). The primary endpoint was the peak effect (E_max) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. Lenabasum was safe and well tolerated. Compared with placebo, a 20-mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120 mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3 mg and 6 mg, a medication currently approved by the US Food and Drug Administration (FDA). At a target therapeutic dose (20 mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120 mg) did elicit subjective ratings of Drug Liking compared with placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared with 3 mg and 6 mg nabilone, lenabasum does have abuse potential and should be used cautiously in clinical settings.

The aim of this study was to validate a previously developed deep learning model in 5 independent clinical trials. The predictive performance of this model was compared with the international prognostic index (IPI) and 2 models incorporating radiomic PET/CT features (clinical PET and PET models). Methods: In total, 1,132 diffuse large B-cell lymphoma patients were included: 296 for training and 836 for external validation. The primary outcome was 2-y time to progression. The deep learning model was trained on maximum-intensity projections from PET/CT scans. The clinical PET model included metabolic tumor volume, maximum distance from the bulkiest lesion to another lesion, SUV_peak, age, and performance status. The PET model included metabolic tumor volume, maximum distance from the bulkiest lesion to another lesion, and SUV_peak. Model performance was assessed using the area under the curve (AUC) and Kaplan–Meier curves. Results: The IPI yielded an AUC of 0.60 on all external data. The deep learning model yielded a significantly higher AUC of 0.66 (P < 0.01). For each individual clinical trial, the model was consistently better than IPI. Radiomic model AUCs remained higher for all clinical trials. The deep learning and clinical PET models showed equivalent performance (AUC, 0.69; P > 0.05). The PET model yielded the highest AUC of all models (AUC, 0.71; P < 0.05). Conclusion: The deep learning model predicted outcome in all trials with a higher performance than IPI and better survival curve separation. This model can predict treatment outcome in diffuse large B-cell lymphoma without tumor delineation but at the cost of a lower prognostic performance than with radiomics.

The class F of G protein-coupled receptors (GPCRs) consists of 10 Frizzleds (FZD_1–10) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched. The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first-class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation, and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to the rapid development of our knowledge about structure-function relationships, providing a great starting point for drug development. Despite the progress, questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems.

BACKGROUND AND PURPOSE:

Patients with brain tumors have high intersubject variation in putative language regions, which may limit the utility of straightforward application of healthy subject brain atlases in clinical scenarios. The purpose of this study was to develop a probabilistic functional brain atlas that consolidates language functional activations of sentence completion and Silent Word Generation language paradigms using a large sample of patients with brain tumors.

BACKGROUND AND PURPOSE:

Angioplasty and stent placement have been described as a bailout technique in individuals with failed thrombectomy. We aimed to investigate Stent retriever AssIsted Lysis (SAIL) with tirofiban before angioplasty and stent placement.

BACKGROUND AND PURPOSE:

Reocclusion after treatment is a concern in endovascular therapy for isolated intracranial atherothrombotic stroke-related large-vessel occlusion (AT-LVO). However, the optimal endovascular therapy technique for AT-LVO has not yet been investigated. This study evaluated the optimal endovascular therapy technique for AT-LVO in a real-world setting.

BACKGROUND AND PURPOSE:

Vertebrobasilar artery stent placement (VBS) is potentially effective in preventing recurrent posterior circulation strokes; however, the incidences of in-stent restenosis and stented-territory ischemic events based on the location of stent placement have rarely been investigated. We aimed to investigate the characteristics and prognosis of VBS between intracranial and extracranial.

BACKGROUND AND PURPOSE:

Alterations of the basilar artery (BA) anatomy have been suggested as a possible MRA feature of Fabry disease (FD). Nonetheless, no information about their clinical or pathophysiologic correlates is available, limiting our comprehension of the real impact of vessel remodeling in FD.

BACKGROUND AND PURPOSE:

Intracranial vessel wall imaging is technically challenging to implement, given the simultaneous requirements of high spatial resolution, excellent blood and CSF signal suppression, and clinically acceptable gradient times. Herein, we present our preliminary findings on the evaluation of a deep learning–optimized sequence using T1-weighted imaging.

Sleep is a fundamental feature of life for virtually all multicellular animals, but many questions remain about how sleep is regulated by circadian rhythms, homeostatic sleep drive that builds up with wakefulness, and modifying factors such as hunger or social interactions, as well as about the biological functions of sleep. Substantial headway has been made in the study of both circadian rhythms and sleep in the fruit fly Drosophila melanogaster, much of it through studies of individual fly activity using Drosophila activity monitors (DAMs). Here, we describe approaches for the activation of specific neurons of interest using optogenetics (involving genetic modifications that allow for light-based neuronal activation) and thermogenetics (involving genetic modifications that allow for temperature-based neuronal activation) so that researchers can evaluate the roles of those neurons in controlling rest and activity behavior. In this protocol, we describe how to set up a rig for simultaneous optogenetic or thermogenetic stimulation and activity monitoring for analysis of sleep and circadian rhythms in Drosophila, how to raise appropriate flies, and how to perform the experiment. This protocol will allow researchers to assess the causative role in the regulation of sleep and activity rhythms of any genetically tractable subset of cells.

BackgroundDuring the COVID-19 pandemic, global trends of reduced healthcare-seeking behaviour were observed. This raises concerns about the consequences of healthcare avoidance for population health.AimTo determine the association between healthcare avoidance during the early stages of the COVID-19 pandemic and all-cause mortality.Design and settingThis was a 32-month follow-up within the population-based Rotterdam Study, after sending a COVID-19 questionnaire at the onset of the pandemic in April 2020 to all communty dwelling participants (n = 6241/8732, response rate 71.5%).MethodCox proportional hazards models assessed the risk of all-cause mortality among respondents who avoided health care because of the COVID-19 pandemic. Mortality status was collected through municipality registries and medical records.ResultsOf 5656 respondents, one-fifth avoided health care because of the COVID-19 pandemic (n = 1143). Compared with non-avoiders, those who avoided health care more often reported symptoms of depression (n = 357, 31.2% versus n = 554, 12.3%) and anxiety (n = 340, 29.7% versus n = 549, 12.2%), and more often rated their health as poor to fair (n = 336, 29.4% versus n = 457, 10.1%) . Those who avoided health care had an increased adjusted risk of all-cause mortality (hazard ratio [HR] 1.30, 95% confidence interval [CI] = 1.01 to 1.67), which remained nearly identical after adjustment for history of any non-communicable disease (HR 1.20, 95% CI = 0.93 to 1.54). However, this association attenuated after additional adjustment for mental and physical self-perceived health factors (HR 0.93, 95% CI = 0.71 to 1.20).ConclusionThis study found an increased risk of all-cause mortality among individuals who avoided health care during COVID-19. These individuals were characterised by poor mental and physical self-perceived health. Therefore, interventions should be targeted to these vulnerable individuals to safeguard their access to primary and specialist care to limit health disparities, inside and beyond healthcare crises.

PURPOSE

HIV pre-exposure prophylaxis (PrEP) may increase rates of bacterial sexually transmitted infections (STIs) among gay, bisexual, and other men who have sex with men (GBM) through risk compensation (eg, an increase in condomless sex or number of partners); however, longitudinal studies exploring the time-dependent nature of PrEP uptake and bacterial STIs are limited. We used marginal structural models to estimate the effect of PrEP uptake on STI incidence.

Trump seems to have just two options.

David Parker, TBA’s founder, chief ideologist and chief executive, tweeted “Veni, vedi, vici” last night. Just remember, Caesar said it first, and it sounded like “Weenie, Weedy, Weakie.”

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Video game workers face challenges from employers in their efforts to unionize in Canada.

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Deepfakes can be close to indistinguishable from authentic video, and are now being used to perpetrate gender based abuse.

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U.S.-backed Syrian Democratic Forces announced Tuesday that they had captured the city of Raqqa from Islamic State militants.

“Everything is finished in Raqqa, our forces have taken full control of Raqqa,” SDF spokesman Talal Sello told AFP. A formal declaration would be announced after operations to clear any remaining sleeper cells and to remove landmines in the city were completed, Sello added.

The move is a major setback for the Islamic State which considered Raqqa the de-facto capital of its self-declared caliphate. It comes on the third anniversary of the global effort to defeat ISIS.

Raqqa was the first provincial capital to fall from government control in March 2013 after it was captured by a rebel army. The army included both Syrian opposition groups and more hard line  parties including al-Nusra and the Islamic State.

A civilian government  that was established in the city divided two months later, and less than a year later ISIS recaptured Raqqa and named the the capital of their caliphate.

About 900 civilians have been killed since the the start of the five-month operation, including 570 people in coalition air raids, according to the Syrian Network for Human Rights. The Britain-based Syrian Observatory for Human Rights put the civilian death toll at 1,130 people. American journalist James Foley was beheaded in the mountains south of the city.

SDF fighters pulled down the Islamic State’s black flag from the city’s National Hospital near the city’s stadium, according to a Reuters report.

Special presidential envoy for the Global Coalition to Defeat ISIS Brett McGurk said in August that the U.S. would attempt to perform a “stabilization” in Raqqa — including demining, removing rubble from major pathways to allow trucks and equipment through, and “basic electricity, sewage, water, the basic essentials to allow populations to come back to their home.”

It is not clear when the 300,000 civilians who have fled Raqqa since April during the operation will be able to return.

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HARI SREENIVASAN: But first: The de facto capital of the Islamic State, Raqqa, in Syria fell yesterday to U.S.-backed forces.

However, the largest city the militants once held was Mosul in Iraq. They were ousted from it in July after a brutal 10-month-long fight that killed thousands.

Now a new major task: finding and destroying the ISIS mines, booby-traps and bombs that litter the city.

Special correspondent Marcia Biggs reports from Iraq.

MARCIA BIGGS, Special Correspondent: It was once a center of learning for over 6,000 students of technology, agriculture, and medicine.

Today, Mosul Technical Institute’s classrooms are burnt to the ground, laboratories reduced to rubble, and books charred and shredded. It’s one of the city’s five universities ravaged by the Islamic State and the battle to oust it.

Now that the battle is over, a new danger looms, the trail of land mines and booby-traps left by ISIS.

So this is the wire, and this is where it was buried.

CHRISTIAN, Team Leader, Janus Global Operations: Yes, they would cut the asphalt, and then they lay the wire in and put the main charge here.

MARCIA BIGGS: We spent the day with Christian, a team leader from Janus Global, a security and risk management firm hired by the U.S. government to sweep and clear major areas of unexploded ordnance and mines.

He’s not allowed to show his face or use his last name, for security reasons.

CHRISTIAN: There’s actually two more on that road before we get to the target building that have to be excavated and/or rendered safe.

MARCIA BIGGS: So, the first building you have to clear, you have got to get rid of the IEDs on the road to that building?

CHRISTIAN: Yes.

MARCIA BIGGS: It’s a long process.

CHRISTIAN: It is, but that’s what makes it interesting.

MARCIA BIGGS: The United States has sunk $30 million this year into clearing former ISIS territories all over Northern Iraq. Under this program, Janus has already cleared 727 buildings, removing 3,000 IEDs, which they say ISIS was producing on assembly lines at an industrial scale.

But State Department officials and experts say the number of unexploded ordnance in Mosul itself is unprecedented.

What’s your first line of attack, in terms of trying to clear Mosul?

CHRISTIAN: Our priority is more the community, rather than the individual, you know, infrastructure. You have got schools, power, sewer, water, so that the area can accept people back into it. And then, once this stabilization phase is over, we can move into the individual homes, so that they can be safer.

MARCIA BIGGS: Clearing Mosul is a process that they say could take years, even decades. So Janus is training local Iraqis to do the job, sending them out as a front-line search team, then investigating and removing any suspicious items themselves.

CHRISTIAN: We’re not going to be here the whole time, so when we — it’s our time to leave, they will have the capacity built from us, and the mentoring we have done, so that they can do it on their own.

MARCIA BIGGS: How are they doing?

CHRISTIAN: They’re — a lot of them are very apt to learn. They’re quick. They’re smart.

MARCIA BIGGS: Fawzi al Nabdi is the team leader for the Iraqi local partner. He’s cleared mines all over Iraq for the last six years.

CHRISTIAN: What you got?

FAWZI AL NABDI, Team Leader, Al Fahad Company (through interpreter): We are ready for this, because it’s my job and I love it. The Americans are here to complete our work and to help us. They have greater experience than we do. If we find any mines, we have to stop and they will investigate it and make a plan to remove it.

MARCIA BIGGS: But he says Mosul is the biggest project he has ever seen, and we’re told it could take at least a month to just get the campus cleared of mines. Only then can they start cleaning it up, so that students can resume classes, this itself a huge task.

ISIS fighters closed the university back in 2014, and used it as a military base. As coalition forces pounded ISIS targets, this seat of higher learning became a battleground.

Ghassan Alubaidy is the institute’s dean.

GHASSAN ALUBAIDY, Dean, Mosul Technical Institute (through interpreter): ISIS used our university to manufacture mines and bombs. For this reason, it was the target of airstrikes in the beginning. They struck the institute nine times, and they struck our workshops, too. Now we can’t use them.

MARCIA BIGGS: The former commander of coalition forces in Iraq, Lieutenant General Stephen Townsend, recently listed 81 locations where bombs were dropped, but had not yet exploded.

Facilities used to make weapons were often on the list of high-value targets for the coalition. So now those places are twice as likely to contain dangerous items.

So, this was once a workshop for electrical engineering students. You can still see the lab tables here. It was hit by an airstrike in 2015. Afterwards, members of the university staff found bomb-making instructions among the rubble. This was likely an ISIS bomb-making factory, and judging by the crater, a high-value target.

Despite the damage, Dean Alubaidy says he will hold classes this fall in alternate buildings, until the campus is ready. He’s expecting registration to be in the thousands, students who lost three years of education during the fighting and don’t want to lose another one.

GHASSAN ALUBAIDY (through interpreter): On our Facebook pages, we found a great number of students posting that they were full of encouragement to come back. For us, it was unbelievable. We couldn’t imagine it, to see how many students wanted to start again, how they were dreaming of the first day of classes, when they could sit in front of teachers again and start to live their lives again.

MARCIA BIGGS: Next door, Mosul University has already started classes. Students even volunteered to help in the cleanup.

But across the river, West Mosul was the site of ISIS’ last stand and bore the brunt of the battle. It’s densely packed Old City, with its flattened buildings, is a challenge for mine-sweeping.

FAWZI AL-NABDI (through interpreter): Most of the homes here were full of mines. And just here in front of us, a man with two kids came back to his home, and when he opened the door, the bomb killed him and his kids.

MARCIA BIGGS: Ahmed Younes fled back in early July with only the clothes on his back. Residents have been virtually banned from returning to his neighborhood on the outskirts of the Old City, but Ahmed said he got special permission, in order to retrieve some personal items.

AHMED YOUNES, Local Resident (through interpreter): We came on our own. We got permission to come, but they are not responsible if anything happens to us.

MARCIA BIGGS: Right now, there is no plan to begin clearing the Old City or even to determine how many mines there are. It is still out of bounds to anyone but the Iraqi security forces.

So the Janus team is focusing on progress in the rest of the city, building by building, bomb by bomb.

CHRISTIAN: Whoever made this device had a set goal. And to allow him to win, people get hurt. So you kind of compete against him to be better than him to take it out before it can do any harm.

MARCIA BIGGS: So, you feel like you’re winning the battle against ISIS?

CHRISTIAN: Yes, one IED at a time.

MARCIA BIGGS: For the PBS NewsHour, I’m Marcia Biggs in Mosul, Iraq.

HARI SREENIVASAN: Tune in later.

Frontline’s latest film, “Mosul,” was on the ground filming the fight as it unfolded street by street and house by house. That’s tonight on PBS.

The post The battle for Mosul is over, but this hidden ISIS danger could lurk for years appeared first on PBS NewsHour.

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