This paper proposes the design of combination opioid–adrenergic tethered compounds to enhance efficacy and specificity, lower dosage, increase duration of activity, decrease side effects, and reduce risk of developing tolerance and/or addiction. Combinations of adrenergic and opioid drugs are sometimes used to improve analgesia, decrease opioid doses required to achieve analgesia, and to prolong the duration of analgesia. Recent mechanistic research suggests that these enhanced functions result from an allosteric adrenergic binding site on opioid receptors and, conversely, an allosteric opioid binding site on adrenergic receptors. Dual occupancy of the receptors maintains the receptors in their high affinity, most active states; drops the concentration of ligand required for full activity; and prevents downregulation and internalization of the receptors, thus inhibiting tolerance to the drugs. Activation of both opioid and adrenergic receptors also enhances heterodimerization of the receptors, additionally improving each drug’s efficacy. Tethering adrenergic drugs to opioids could produce new drug candidates with highly desirable features. Constraints—such as the locations of the opioid binding sites on adrenergic receptors and adrenergic binding sites on opioid receptors, length of tethers that must govern the design of such novel compounds, and types of tethers—are described and examples of possible structures provided. This paper focuses on the observation that combinations of adrenergic and opioid drugs often display significantly enhanced activity that involves improved efficacy at lower drug dosages, increased duration of drug activity, and prevention of the development of tolerance. The mechanisms underlying this enhancement are reviewed and ways in which the enhancement mechanisms may provide the basis for the development of new classes of tethered bitopic drugs with biased activity and fewer side effects are addressed.Opioids are analgesics often used to control pain perioperatively and postoperatively, as adjuncts to improve anesthesia during operations, and occasionally as stand-alone anesthetics ,2. They Various combinations of opioids and adrenergics demonstrate synergistic antinociceptive activity ,15,16,17The α-2-adrenoceptor agonists epinephrine, clonidine, guanfacine, and dexmedetomidine inhibit the development of tolerance to morphine and other opioids ,36,37,38Adrenergic antagonists can also potentiate opioid activity : opioid In sum, α- and β-adrenergic agonists and antagonists can combine with opioid drugs to produce enhanced analgesia and to maintain it, sparing further opioid use, and together prevent the development of opioid tolerance  that are activated by binding an appropriate ligand into their highly specific orthosteric binding site. Orthosteric ligand binding results in a conformational change in the receptor that allows an intracellular guanine nucleotide-binding protein (G protein) to exchange a guanine diphosphate (GDP) for a guanine triphosphate (GTP), the GTP then permitting one of the G protein subunits to dissociate and act as an intracellular second messenger to activate downstream functions. The dissociation of the G protein also activates the phosphorylation of the remaining subunits by G protein-coupled receptor kinases (GRKs), which results in the internalization of the receptor, and thus the downregulation of receptor activity. Repeated or continuous stimulation of GPCR results in tolerance to the ligand as a result of this downregulation so that increasing concentrations of drug are needed to produce the previous effect . GPCR are also well-known to have both extracellular and intracellular allosteric binding sites that can enhance receptor function by locking the receptor into its high affinity state in the presence of its orthosteric ligand or that can impair receptor function by interfering with ligand binding or activation . As noteEvidence of opioid binding to adrenergic receptors and of adrenergic drugs to opioid receptors comes from diverse types of experiments. Opioid drugs have been demonstrated to bind to adrenergic receptors. Indirect evidence of such binding comes from studies showing that morphine, naltrexone, and naloxone inhibited the binding of [3H]clonidine and [3H]-epinephrine to α 2-adrenoceptors in their high-affinity state . SimilarSimilarly, epinephrine binds directly to the MOR enhancing morphine binding ,86. OtheEvidence from binding studies demonstrates that the extracellular binding sites on both the adrenergic and opioid receptors share, to some extent, affinity for both opioids and adrenergic drugs ,86,87,89One of the most important aspects of mutual opioid–adrenergic allosteric enhancement of each other’s receptors is that this enhancement can be performed by antagonists  as well as agonists , which argues against the enhancement resulting solely or even mainly from second-messenger crosstalk between the receptors or activation of both opioid and adrenergic receptors concurrently (though both mechanisms may nonetheless contribute to enhancement effects). Reference to the previous section demonstrates that such antagonist-induced enhancement has been documented in some clinical studies and it is worth emphasizing here that it has been very well established in experimental settings. For example, a series of studies have demonstrated that naloxone, an opioid antagonist, can enhance epinephrine and isoproterenol activity on both cardiac and smooth muscle preparations by mechanisms that do not involve the opioid receptor ,101,102.One of the explicit assumptions of this review is therefore that allosteric binding sites for adrenergic compounds exist on the extracellular side of the orthosteric opioid binding site  as imputHaving established that adrenergic-opioid enhancement can be mediated by allosteric mechanisms activated by antagonists as well as agonists, it is important to stress that hetero-oligomerization of opioid and adrenergic receptors has been well-established and also plays an important role in mediating cross-talk between these receptors  59,115,,117. ThuSome studies  suggestBitopic compounds that increase GPCR receptor selectivity by linking a compound that binds to the orthosteric site with another that binds to the allosteric site have previously been designed and tested successfully .Since at least two mechanisms exist by which opioids and adrenergic drugs enhance each other, one being through an allosteric mechanism and the other through hetero-oligomerization, it follows that there are at least two different ways of designing heterobitopic compounds to exploit these mechanisms. Consider the allosteric mechanism first.Tethered opioid–adrenergic bitopic allosteric modulators will take advantage of the proximity of the orthosteric and allosteric binding sites that are present in both the opioid and adrenergic receptors . BecauseHeterobitopic tethered inhibitors or antagonists for opioid and adrenergic receptors are also possible. Indeed, the bitopic approach to drug design originated in Portoghese’s synthesis of bivalent compounds with improved naltrexamine antagonism for opioid receptors ,142, whiAdditionally, mixed function heterobitopic compounds may be designed that potentially have a series of novel functional possibilities. For example, since opioid antagonists enhance adrenergic receptor activity (see above), tethering an opioid antagonist to an adrenergic agonist should result in enhanced antagonism of the opioid receptor but enhanced adrenergic receptor activity. Such a drug might be useful, for example, in the treatment of hypotension, negative inotropic and chronotropic effects, as well as a decrease in baroreceptor reflex responses due to an opioid overdose. Alternatively, since opioid agonists enhance adrenergic antagonist activity (see above), tethering an opioid agonist to an adrenergic antagonist may result in an opioid with enhanced agonist activity as well as enhanced adrenergic antagonist activity. Such a drug might be useful in maximizing opioid-induced analgesia while minimizing adrenergic side-effects, such as increases in heart rate and blood pressure. It must be emphasized that one benefit that can be expected for all possible tethered combinations of agonist and antagonists just described is a significant decrease in the concentration of drug required to achieve a clinical outcome along with greater specificity of action and therefore a decrease in unwanted side-effects . As Vauq“Bivalent ligands often display high affinity/avidity for and long residence time at their target. The [mechanism] responsible is the synergy that emanates from the simultaneous binding of their two pharmacophores to their respective target sites…. The first binding event prompts the still free pharmacophore to stay into ‘forced proximity’ of its target site, such lanes can be looked into by the equations that also apply to induced fit binding mechanisms. Interestingly, the simplest equations apply when bivalency goes along with a large gain in avidity. The overall bivalent ligand association and dissociation will be swifter than via each lane apart, but it is the lane that allows the fastest bidirectional ‘transit’ between the free and the fully bound target that is chiefly solicited. The bivalent ligand’s residence time is governed not only by the stability of the fully bound complex but also by the ability of freshly dissociated pharmacophores to successfully rebind.”He goes on to point out that thermodynamic “simulations reveal that positive cooperativity exacerbates these phenomena, whereas negative cooperativity curtails them,” so that both agonistic and antagonistic activity are significantly increased  (see alsNotably, the increases in agonist or antagonist activity just described can be expected whether the bivalent compound works within a receptor at orthosteric and enhancement binding sites, across orthosteric sites on dimerized receptors, or through some combination of both . While tMixed agonist–antagonist bitopic compounds have also been explored and provide models for opioid agonist–adrenergic antagonist or opioid antagonist–adrenergic agonist tethered compounds ,149,150.Another example of a dimerization-enhancing bitopic, tethered drug is provided by Peng et al. , who desTo summarize, extensive experimental and clinical data demonstrate that combinations of opioids and adrenergic drugs often result in enhance opioid activity characterized by a significant decrease in the amount of opioid required to attain analgesia and antinociception; such combinations increase the duration of opioid activity, inhibit development of tolerance and, in some cases, have been demonstrated to reverse acute tolerance. One drawback of these combinations is that they often have broad systemic effects and can activate multiple receptor subtypes. The present paper suggests that better specificity, increased activity, and decreased side-effects may be achieved by tethering the adrenergic and opioid components of such mixtures. Surprisingly, no examples of such tethered adrenergic-opioid compounds have been found in the literature. Moreover, while many adrenergic-opioid drug mixtures have been explored that may provide the basis for deriving such novel tethered compounds, many possible combinations of opioids and adrenergic drugs have not yet been explored, and certainly not in any systematic way, leaving a very large set of possible new drug entities.


The adenoma detection rate is the constant subject of research and the main marker of quality in bowel cancer screening. However, by improving the quality of endoscopy via artificial intelligence methods, all polyps, including those with the potential for malignancy, can be removed, thereby reducing interval colorectal cancer rates. As such, the removal of all polyps may become the best marker of endoscopy quality. Thus, we present a viewpoint on integrating the computer-aided detection (CADe) of polyps with high-accuracy, real-time colonoscopy to challenge quality improvements in the performance of colonoscopy. Colonoscopy for bowel cancer screening involving the integration of a deep learning methodology  has been assessed in an effort to increase the adenoma detection rate. In this viewpoint, a few studies are described, and their results show that CADe systems are able to increase screening sensitivity. The detection of adenomatous polyps, which are associated with a potential risk of progression to colorectal cancer, and their removal are expected to reduce cancer incidence and mortality rates. However, so far, artificial intelligence methods do not increase the detection of cancer or large adenomatous polyps but contribute to the detection of small precancerous polyps. Adenomatous polyps are associated with a potential risk of progression to colorectal cancer (CRC). The adenoma detection rate (ADR) is regarded as an important marker of the quality of inspection in colonoscopy. The identification and removal of adenomatous polyps are considered to be important in CRC prevention ,2. More Repici et al  have preIn Repici et al’s  study, 6A real-time automatic detection system that uses deep neural networks was trialed in Italy, and it achieved a high ADR  . HoweverRecently, a Chinese cross-sectional study  reportedThe six experienced endoscopists in the Repici et al  study haThe endoscopists’ withdrawal techniques did not meet the criteria for aspirational withdrawal time ≥10 minutes) that are present in the European Society for Gastroenterology guidelines 0 minutes. There iEndoscopists’ withdrawal techniques and specified right colon withdrawal times correlate with higher levels of polyp detection . TherefoThe adenoma miss rate varies among endoscopists who achieve the same ADRs, and a significant difference in adenoma miss rates has been reported even among endoscopists who achieve high ADRs . A reducFurther studies are required to determine whether AI is of benefit to endoscopists who are more experienced than those in Repici et al’s  study. OSo far, we know that AI methods do not increase the detection of large adenomas or cancer. The contribution of small adenomas, which have been increasingly detected via AI-assisted colonoscopy, to future CRC risk is debatable.


Childhood absence epilepsy (CAE) is a common pediatric generalized epileptic syndrome. Although it is traditionally considered as a benign self-limited condition, the apparent benign nature of this syndrome has been revaluated in recent years. This is mainly due to the increasing evidence that children with CAE can present invalidating neuropsychological comorbidities that will affect them up to adulthood. Moreover, a percentage of affected children can develop drug-resistant forms of CAE. The purpose of this review is to summarize the most recent studies and new concepts concerning CAE treatment, in particular concerning drug-resistant forms of CAE. A Pubmed search was undertaken to identify all articles concerning management and treatment of CAE, including articles written between 1979 and 2021. Traditional anticonvulsant therapy of CAE that is still in use is based on three antiepileptic drugs: ethosuximide which is the drug of choice, followed by valproic acid and lamotrigine. In the case of first line treatment failure, after two monotherapies it is usual to start a bi-therapy. In the case of absence seizures that are refractory to traditional treatment, other antiepileptic drugs may be introduced such as levetiracetam, topiramate and zonisamide. Childhood absence epilepsy (CAE) is a common pediatric generalized epileptic syndrome that affects between 10% to 17% of all school-aged children diagnosed with new onset epilepsy . These eThe first descriptions of CAE date back to the last century in German medical literature and in 1916 Sauer presented the term pyknolepsy, from the Greek word piknoz (πικνός), meaning “very frequent or grouped”, to describe absence seizures with daily recurrences . The typRecent studies have also shown a possible association of absence seizures and other epileptic syndromes such as idiopathic occipital epilepsy, Gastaut idiopathic occipital epilepsy , West syMost of the molecular-genetic studies on CAE have failed to precisely identify its genetic pathways that could be particularly useful for precision therapy . HoweverAlthough CAE is traditionally considered a benign self-limited epilepsy syndrome, data from the multicenter Childhood Absence Epilepsy Study Group have led to the review of this notion ,16. DuriIn particular, attention deficits are observed in about 1/3 of the patients and there is an increased risk of cognitive disorders . In lighCAE diagnosis is often straightforward and highly suspected in school-aged children who present with brief multiple daily episodes of staring without memory of the event or ability of caretakers to interrupt the episodes . EpisodeDiagnosis is then confirmed by a routine electroencephalography (EEG) before beginning treatment and to diagnose CAE, only typical absences have to be registered. The presence of other types of seizures  rules out a diagnosis of CAE. On EEG the typical findings are a bilaterally symmetrical and synchronous discharge of 3-Hz spike wave complexes with an abrupt start and ending ; the bacTraditional prophylactic anticonvulsant therapy of CAE is based on three antiepileptic drugs: ethosuximide (ETX), valproic acid (VPA) and lamotrigine (LTG)  and in pThe purpose of this review is to summarize the most recent studies and new concepts concerning CAE treatment, to highlight areas of consensus as well as areas of uncertainty concerning this “not so benign” common childhood epileptic syndrome. In particular, the objective of this paper is to provide an updated overview of the current knowledge concerning CAE treatment. We hope this paper is of easy access to health-care providers dealing with CAE patients. We focalize our attention on the treatment of refractory CAE also underlining that current knowledge concerning these forms is extremely scarce and that further studies are needed in this direction given the “not so benign nature” of this disease. We sincerely hope this paper will be helpful in the development of CAE treatment guidelines.This article provides an updated overview of the principal therapeutic options for childhood absence epilepsy. A thorough Pubmed search indexed for MEDLINE, Pubmed and EMBASE was undertaken to identify articles concerning management and treatment of CAE, including articles written between 1979 and September 2021. The main keywords used were: childhood absence epilepsy treatment, along with absence seizures, epilepsy treatment, antiepileptic drugs and resistant epilepsy. In particular, a non-systematic identification through Pubmed, MEDLINE, and EMBASE was performed and around 300 papers were initially screened for information relevant to this review. Forty-four of these papers were then selected according to the following inclusion criteria: available full text in either English or French, focus on CAE treatment in the pediatric population and the latest (in the last 10 years) published papers were preferred over previously conducted studies. Original articles, metanalysis, guidelines and systematic reviews along with narrative reviews were preferred over case reports. Publications containing data that were not relevant for the purpose of our review were excluded from our search.The list of references of all the relevant articles was also studied to include all relevant scientific papers connected with the subject and this led to the inclusion of another 27 articles for a total of 71 articles.The date of our last search was September 2021. p = 0.35) and higher than those of LTG compared to the other two drugs . However, post treatment attention disfunction was more frequent in patients treated with VPA rather than ETX  and patients treated with VPA also presented problems related to weight gain in the following months, causing discontinuation of therapy. ETX was therefore considered the drug of choice as initial therapy for CAE [In the last 10 years, various studies have been carried out to compare the different molecules proposed for CAE treatment. However, there are very few randomized trials in literature to guide treatment strategies for CAE. Glauser et al. in 2010  performe for CAE . This wa for CAE  who demo for CAE .Ethosuximide (2-ethyl-2-methyl-succinamide) is the drug of choice for classical CAE with simple absence seizures as it does not suppress focal onset or generalized tonic-clonic seizures . Its mecOne of the greatest concerns for pediatric neurologists is to differentiate classic isolated CAE from other forms presenting also with generalized tonic–clonic seizures. This is one of the prevailing reasons to start child treatment with either VPA or LTG as first line treatment, instead of ETX . ValproiLamotrigine acts through blockage of voltage-dependent sodium channels; it also stabilizes presynaptic membranes and inhibits the release of excitatory neurotransmitters, especially glutammate and aspartate . As we hThe failure of an antiepileptic treatment or any worsening of symptoms during treatment has to alert the pediatric neurologist among other things, to reconsider the etiologic diagnosis of the epileptic syndrome. If the diagnosis of CAE is confirmed, after the failure of two monotherapies, in particular if ETX has been used as a first line or second line monotherapy , it is uAn increased efficacy has been demonstrated when ETX and VPA are combined because VPA can decrease the clearance of ETX . The assAmong older antiepileptic drugs, clobazam, clonazepam and acetazolamide have been traditionally used as second-line therapy for CAE or as adjunctive agents ,49. OverA small Italian multicenter, prospective, long-term, open-label treatment study published in 2008 enrolled 21 patients with typical absence seizures to undergo treatment with Levetiracetam (LEV) in monotherapy . The basTopiramate (TPM) acts through ion-channel blockade as well as enhancing GABA-ergic inhibitory synaptic transmission and inhibiting excitatory pathways . An openZonisamide (ZSN) acts by inhibiting carbonic anhydrase and by blocking T-type calcium channels as well as voltage-sensitive sodium channels . Data reThe pharmaco-resistance of up to 30% of treated children with CAE and the detection of neuropsychiatric conditions on follow up, along with the adverse effects reported for many of the current antiepileptic drugs, require scientific research to focus on novel treatments . Recent The clinical course of children with CAE varies and basically includes three possible scenarios: terminal remission ≥ 12 months (occurring in about 65–82% of patients), persistent refractory CAE (occurring in about 11% of patients) and a change in epilepsy syndrome (about 15% of patients) . There aCAE is a common and easily diagnosable pediatric epileptic syndrome whose initial treatment of choice remains ethosuximide, followed by valproic acid in the case of treatment failure. There are few studies concerning the pharmacological-resistant forms and the possible neuropsychological implications of affected children.Childhood absence epilepsy should not be considered so “benign” and future studies are certainly needed to address and prevent the later psychosocial comorbidities associated with this disease, along with the not so rare eventuality of a possible resistance to traditional therapy.


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment or cure. ALS is characterized by the death of lower motor neurons (LMNs) in the spinal cord and upper motor neurons (UMNs) in the brain and their networks. Since the lower motor neurons are under the control of UMN and the networks, cortical degeneration may play a vital role in the pathophysiology of ALS. These changes that are not apparent on routine imaging with CT scans or MRI brain can be identified using modalities such as diffusion tensor imaging, functional MRI, arterial spin labelling (ASL), electroencephalogram (EEG), magnetoencephalogram (MEG), functional near-infrared spectroscopy (fNIRS), and positron emission tomography (PET) scan. They can help us generate a representation of brain networks and connectivity that can be visualized and parsed out to characterize and quantify the underlying pathophysiology in ALS. In addition, network analysis using graph measures provides a novel way of understanding the complex network changes occurring in the brain. These have the potential to become biomarker for the diagnosis and treatment of ALS. This article is a systematic review and overview of the various connectivity and network-based studies in ALS. Amyotrophic lateral sclerosis has an incidence of around 3/100,000. No definite etiology has been determined even though various genetic and environmental factors have been attributed . These aThe pattern of disease onset and rapidity of spread are highly variable. Progression ultimately results in respiratory failure and death, despite artificial means of life support. ALS is part of a spectrum of motor neuron disorders that includes frontotemporal dementia, primary lateral sclerosis, progressive muscular atrophy, and progressive bulbar palsy.Due to the lack of biomarkers, it is often difficult to diagnose ALS in the early stages of the disease. Misdiagnosis is very common, and patients often go through various expensive and invasive tests before the condition declares itself. Even if diagnosed early, there are too few treatment options if any and that too only in prolonging life for a few months. The lack of biomarkers poses a big hurdle in monitoring response to novel treatments in ALS research.The role of imaging findings as potential biomarkers gains importance in this scenario. Many structural and functional imaging studies have been performed over the years to assess their utility in ALS. There are no validated measures for clinical use yet. Newer studies using brain connectivity and network analysis look at the brain from a broader perspective as a connected network and have the potential to generate biomarkers for ALS. This article highlights the advances in imaging and electrophysiologic techniques to diagnose, assess severity, and predict the progression of ALS based on connectivity parameters and brain network analysis.This article is a literature review of brain connectivity and network analysis studies in ALS . Search The article also provides a primer on routine and specialized imaging in ALS, connectivity analysis, and generation and interpretation of networks using graph measures.Routine imaging studies done as part of clinical workup in ALS include CT scan and MRIs. The utility of the CT scan is limited to identifying focal or global atrophy of the brain and ruling out other pathologies or space-occupying lesions. MRI sequences used for clinical purposes include T1 and T2 weighted sequences, diffusion, and FLAIR images. Rarely, hyperintensities on FLAIR sequences are seen over the motor cortex in ALS patients that at times can be symmetric . While uThere are over 100 billion neurons in the brain that are interconnected through trillions of networks. Such levels of complexity are not measurable by histology or the current level of technology. Instead, imaging techniques such as fMRI, DTI, PET scan, and fNIRS and electrophysiologic techniques such as EEG and MEG can help us generate macroscale representations of these neuronal networks. With advances in imaging techniques, machine learning techniques, and large-scale studies such as the Human Connectome Project, it may become possible for us to define these connections in finer details.Several brain connectivity studies have been done in ALS with some important and promising findings. However, results have varied and at times contradicted functional connectivity studies. Most studies in ALS have been multimodal with structural studies using high-resolution anatomical MRI and diffusion imaging for white matter tracts and functional connectivity studies using fMRI, EEG, PET, fNIRS, and MEG. The two most commonly used techniques are diffusion imaging and fMRI, which will be described further.Connectivity studies can be based on structural or functional connectivity. Structural connectivity defines the anatomical connectivity between different regions of the brain. Typically, white matter tracts are defined using diffusion tensor imaging. Anatomical correlates can also be done using anatomical images and surface- or voxel-based techniques. Functional connectivity on the other hand establishes the electrophysiologic or metabolic functional correlates between different regions of the brain. EEG, PET scan, and time series correlates of fMRI data are used for this purpose.Diffusion imaging captures the spatial diffusion of water molecules along the axonal white matter tracts in different spatial directions assuming a Gaussian distribution. Tensor-based analysis along white matter tracts can provide us fiber direction, axial, radial, and mean diffusivity as well as fractional anisotropy (FA). If the integrity of the myelin sheath is preserved, the fractional anisotropy and axial diffusivity are high, while the radial diffusivity is low. FA is reduced in conditions such as ALS where there is axonal degeneration.Tractography, by fiber propagation, can generate a visual representation of white matter tracts that can then be further quantified. Deterministic tractography and probabilistic tractography are the two common techniques for generating the tracts. Deterministic tractography uses a set number of seed regions and parameters for propagation in a local fiber direction until a threshold is met for termination. Probabilistic tractography on the other hand takes into consideration propagation in any random direction. Both techniques have pros and cons. Newer techniques such as Q-space imaging may further improve the tracking of fiber bundles bypassing tissue edema and crossing fibers that are limitations of traditional DTI  12, 13], 1312, 1Once tracts are identified, network models can be generated for white matter connectivity. Tract disruptions in ALS are expected in the corticospinal tracts and corpus callosum, but a variety of other non-motor tracts and networks can be affected. Tract-based spatial statistics (TBSS) studies have shown reduced fiber density and reduced mean diffusivity along several white matter tracts in ALS –19.Diffusion tensor imaging studies have consistently shown reduced fractional anisotropy of the corticospinal as well as non-motor tracts for both sporadic and familial ALS . Large sFunctional MRI (fMRI) measures the changes in regional blood flow during resting or task activation. It uses the blood-oxygen-level-dependent (BOLD) contrast. As regional metabolism causes a shift from oxyhemoglobin to deoxyhemoglobin, there is a change in magnetization properties of blood that can be assessed using MRI. This can be a surrogate for local metabolism and neurovascular coupling . It can Graph theory is a concept that is being increasingly applied to analyze complex brain networks . This coNetworks consist of nodes and edges. Edges can have directions (directed or undirected) and densities (weighted or unweighted). A simple binary unweighted, undirected graph architecture and various measures are depicted in the graph shown in 3Brain networks can be created if we parcellate regions of brains into nodes and their connection as edges. Nodes could be anatomical regions, sites of electrode placement, or regions of interest and the “edges” derived from white matter tracts, electrical, hemodynamic, or metabolic connections or time series correlates connecting those nodes. High-resolution structural MRI images are generally used for nodes. Brain regions can be segmented into gray and white matters and then parcelled into distinct regions using anatomical atlases. Various atlases are available that can subdivide the cortical and subcortical regions anywhere from tens to as high as thousands of nodes.Edges are generated from structural or functional connectivity parameters. Functional connectivity is generally assessed using fMRI time-series data from one region that correlates with other regions in terms of BOLD activity. This could be resting or dynamic. Structural connections are usually derived from diffusion imaging. The diffusion images are corrected for susceptibility and eddy current distortions. White matter edges can be generated using tractography techniques as described earlier.Once the nodes and edges are defined, networks can be generated and a variety of graph measures are then applied to understand the brain architecture and its disruptions . NetworkClustering coefficient is the fraction of triangles around a node and is equivalent to the fraction of the node's neighbors that are neighbors of each other. It is a measure of nodes clustering together. Transitivity measures the probability that the adjacent nodes of a particular node are connected and is closely related to the clustering coefficient. It is calculated as a ratio of the observed number of closed triangles and the maximum possible number of closed triangles in the graph. High transitivity and low path lengths are characteristics of a small-world network. Diameter of a graph refers to the distance towards the maximally eccentric node and radius refers to the minimum eccentricity. The efficiency of a network refers to interconnectedness in a graph network. It can be global or regional. Global efficiency is inversely related to the path length in a network. Assortativity is a measure of similar nodes to be connected. Rich club coefficients refer to well-connected nodes that connect to each other.There are some complex graph measures as shown in . ClusterBrain connectivity studies have utility in analyzing the anatomical and functional derangement in ALS . They haStructural connectivity studies have unequivocally shown reduced fractional anisotropy along the motor and non-motor tracts –34. The In contrast to structural connectivity studies, functional connectivity studies have shown differing results with some studies showing lowered and others showing increased functional connectivity in ALS, whether it be sporadic or genetic –43. The Despite several different studies, the functional connectivity changes in ALS remain complex and poorly defined. More longitudinal studies are needed to understand the evolution of functional connectivity disruption in ALS.Few studies have looked at network disruption in ALS using graph theory. These were mostly done using structural MRI (sMRI), fMRI, and DTI. Few EEG, MEG, and fNIRS studies have also been conducted.Analysis of graph metrics using global measures in C9ORF mutation carriers showed lower global network density than healthy controls . The meaLarger studies using high-resolution T1 weighted anatomical images and structural covariance networks showed significant increases in path length, clustering coefficient, small-world index, and local efficiency in ALS patients. At the same time, there was a significant decrease in global efficiency at several network densities in ALS patients compared to controls. Modularity was higher in ALS patients for several network densities. The modularity increase indicates fragmentation of brain architecture into more tightly clustered modules with poor intermodal communication in ALS patients. Changes were also noted in regional networks and network hubs. Higher functional connectivity strength hubs were seen in ALS patients compared to healthy controls . Nodal bSignificantly different networks connecting various regions of the brain have been found in ALS patients. Such findings are important to identify heterogeneously progressing vulnerable networks in ALS. Structural network analysis of these deranged networks showed reduced local and global efficiency in ALS patients compared to controls , 77. FunElectrophysiologic studies have also been useful in identifying the functional connectivity and network parameters in ALS patients. EEG data in ALS patients showed an increased spectral density of alpha bands. Clustering coefficients in alpha and gamma bands were increased in all regions of the scalp. Overall connectivity was increased in ALS patients with increased assortativity in the alpha band . RestingWe studied differences in global structural and functional connectivity patterns between eight ALS patients and eight age-matched healthy control data from online sources in a pilot connectivity in ALS (CoALS) study . Global Brain connectivity and network analysis provide us with a novel and non-invasive approach to trace the progression of highly complex structural and functional derangements in ALS. Connectivity and network measures have shown correlation with disease progression and severity. While structural studies have unequivocally shown degrading connectivity and network architecture, functional studies have differed. These differences could be related to evolutionary changes occurring in a nonuniform pattern similar to the clinical presentation of ALS. More longitudinal studies are necessary to clarify this process.The studies done so far have indicated a “traffic-jam” type pattern in the brain of ALS patients, where structural “road” networks are disrupted with an increase in functional connectedness or “traffic.” This functional interconnectedness and hyperexcitability seem to increase with the disease progression . WhetherAs we become more proficient in characterizing the underlying network changes with more standardized methodologies and automated analysis, we may be able to further characterize the intricate changes occurring in various stages of ALS , 82. VulMultimodal brain MRI findings using DTI and fMRI have already been proposed to have biomarker value for diagnosis and stratification in ALS . Adding


Systematic reviews appraise and synthesize the results from a body of literature. In healthcare, systematic reviews are also used to develop clinical practice guidelines. An increasingly common concern among systematic reviews is that they may unknowingly capture studies published in “predatory” journals and that these studies will be included in summary estimates and impact results, guidelines, and ultimately, clinical care.There is currently no agreed-upon guidance that exists for how best to manage articles from predatory journals that meet the inclusion criteria for a systematic review. We describe a set of actions that authors of systematic reviews can consider when handling articles published in predatory journals: (1) detail methods for addressing predatory journal articles a priori in a study protocol, (2) determine whether included studies are published in open access journals and if they are listed in the directory of open access journals, and (3) conduct a sensitivity analysis with predatory papers excluded from the synthesis.Encountering eligible articles published in presumed predatory journals when conducting a review is an increasingly common threat. Developing appropriate methods to account for eligible research published in predatory journals is needed to decrease the potential negative impact of predatory journals on healthcare. Systematic reviews are intended to critically appraise and synthesize the results of entire bodies of literature. In healthcare, they may be used in the development of clinical practice guidelines. The utility of systematic reviews, however, depends on the quality of the included studies . An emerTo the unacquainted, predatory journals are “entities that prioritize self-interest at the expense of scholarship and are characterized by false or misleading information, deviation from best editorial and publication practices, a lack of transparency, and/or the use of aggressive and indiscriminate solicitation practices” . Predaton = 13) were registered. Being unable to retrieve these articles due to a lack of indexing in common databases, or choosing to disregard these trials solely due to being published in a predatory journal may impact the conclusions drawn during a systematic review and does not fulfill the goal of a systematic review in providing a comprehensive overview of all eligible studies. The counterpoint to this is that availability of findings in predatory journals also poses a threat, since this could result in unvetted research being used, and in the case of systematic reviews, potentially then integrated into clinical decision making. A recent study reported that articles in suspected predatory journals received fewer citations than those in legitimate journals. The authors concluded that the average predatory journal article has very little effect on the research of others and has limited readership [Research published in predatory journals is often difficult to retrieve through database searches as these journals are indexed less commonly than traditional journals, suggesting that when legitimate quality research gets published in predatory journals, patient participation in research, use of animals in research, and funds used for the research including paying APCs, may be wasteful. The quality of articles published in predatory journals has been studied in a sample of 1907 biomedical studies in presumed predatory journals [adership . We disaadership  and 2)  n = 13) adership , 13. Theadership , 14.https://osf.io/w9azr/?view_only=0658ab3734414562a6f0eeeee506371f) for this review was developed by an experienced medical information specialist (BS) in consultation with the review team. The MEDLINE strategy was peer reviewed using the PRESS guideline. The search did not have any language restrictions; however, eligible articles had to be published in English or French. A total of 71 RCTs were eligible for inclusion in the review. When piloting the risk of bias assessments, two reviewers noticed one trial that stood out as being particularly poorly reported [Two of us (DBR and BS) recently conducted a systematic review and network meta-analysis aimed to compare the effectiveness of psychosocial therapies among people receiving opioid agonist treatment . The seareported . This stWe reviewed the website of the journal that published the low-quality trial  and the We suspect our experience encountering presumed predatory journals during the conduct of a systematic review is increasingly common. This begs the question: what actions should systematic review teams take to deal with presumed predatory journal articles? We know of no applicable formal guidance. In Table Planning to search for, address, and include articles in potentially predatory journals prior to beginning a systematic review is important to minimize bias. The preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) is a checklist intended to facilitate the preparation and reporting of a robust protocol for systematic reviews. PRISMA-P includes items related to search strategy, data collection, and risk of bias . Updates


Despite access to a vast arsenal of anticancer agents, many fail to realise their full therapeutic potential in clinical practice. One key determinant of this is the evolution of multifaceted resistance mechanisms within the tumour that may either pre-exist or develop during the course of therapy. This is particularly evident in pancreatic cancer, where limited responses to treatment underlie dismal survival rates, highlighting the urgent need for new therapeutic approaches. Here, we discuss the major features of pancreatic tumours that contribute to therapy resistance, and how they may be alleviated through exploitation of the mounting and exciting promise of nanomedicines; a unique collection of nanoscale platforms with tunable and multifunctional capabilities that have already elicited a widespread impact on cancer management.The development of drug resistance remains one of the greatest clinical oncology challenges that can radically dampen the prospect of achieving complete and durable tumour control. Efforts to mitigate drug resistance are therefore of utmost importance, and nanotechnology is rapidly emerging for its potential to overcome such issues. Studies have showcased the ability of nanomedicines to bypass drug efflux pumps, counteract immune suppression, serve as radioenhancers, correct metabolic disturbances and elicit numerous other effects that collectively alleviate various mechanisms of tumour resistance. Much of this progress can be attributed to the remarkable benefits that nanoparticles offer as drug delivery vehicles, such as improvements in pharmacokinetics, protection against degradation and spatiotemporally controlled release kinetics. These attributes provide scope for precision targeting of drugs to tumours that can enhance sensitivity to treatment and have formed the basis for the successful clinical translation of multiple nanoformulations to date. In this review, we focus on the longstanding reputation of pancreatic cancer as one of the most difficult-to-treat malignancies where resistance plays a dominant role in therapy failure. We outline the mechanisms that contribute to the treatment-refractory nature of these tumours, and how they may be effectively addressed by harnessing the unique capabilities of nanomedicines. Moreover, we include a brief perspective on the likely future direction of nanotechnology in pancreatic cancer, discussing how efforts to develop multidrug formulations will guide the field further towards a therapeutic solution for these highly intractable tumours. Pancreatic cancer (PaCa) is a highly aggressive malignancy that is almost universally fatal. Of the various types of pancreatic tumours, the majority are classified as ductal adenocarcinomas that originate in the enzyme-producing exocrine tissues ,2. The pIn the strive to address this need, nanomedicine is rapidly gaining traction as a leading approach with much potential to reform the management of PaCa ,14,15,16Efforts to develop nanoparticles have largely concentrated on oncology indications, where they have demonstrated much promise in tumour imaging, diagnosis and treatment ,20,21. INanoparticles possess a number of desirable attributes that have led to their extensive application throughout the field of oncology. One of the primary motives for the use of nanoparticles in cancer therapy stems from their exceptional utility as drug delivery vehicles ,31. ManyDrug delivery to tumours can also be enhanced using nanoparticles ,46, whicOther benefits can be derived from the diverse materials used to fabricate nanoparticles. Phospholipids show excellent biocompatibility and biodegradability and can be readily assembled into liposomal vesicles with high drug-loading capacity, which constitute the bulk of clinically approved nanomedicines to date. While metallic nanoparticles can provide useful contrast enhancement for imaging and diagnostic purposes, they are also highly valued as therapeutics due to their unique thermal ,79,80,81primary or acquired mechanisms of resistance, respectively. In the following sections, we outline several resistance traits of pancreatic tumours that predispose patients to therapy failure and discuss how these can be effectively surmounted through use of nanotechnology. While radioresistance is a common feature of PaCa and there are nano-based strategies to tackle this issue, it is beyond the scope of this current article and discussed in more detail elsewhere [Pancreatic tumours are renowned for their intractable response to many therapeutic interventions, including molecularly targeted agents, chemotherapy and radiotherapy. The processes that contribute to the treatment-refractory nature of PaCa are multifactorial, involving both intrinsic features of the tumour cell population, together with extrinsic factors from the surrounding microenvironment ,87,88. Tlsewhere ,90,91. Insufficient drug uptake and/or enhanced drug efflux represent two of the most common chemoresistance mechanisms in PaCa that can particularly impact upon frontline therapy with gemcitabine. As a hydrophilic molecule, gemcitabine does not readily diffuse across the lipid bilayer of cell membranes and is thus dependent on the presence of nucleoside transporters for intracellular entry. These include members of the solute carrier (SLC) superfamily, such as the human concentrative nucleoside transporters (hCNT) and the human equilibrative nucleoside transporters (hENT), with reports suggesting that hENT1 is primarily responsible for gemcitabine uptake ,93,94. HAs with uptake transporters, alterations in the expression and activity of transmembrane efflux pumps can contribute to chemoresistance. Cellular drug expulsion is predominantly mediated by the adenosine triphosphate-binding cassette (ABC) superfamily, encompassing members such as P-glycoprotein, multidrug resistance proteins and breast cancer resistance protein . These pNanoparticles have also been exploited as carriers for therapeutics that can modulate the expression and activity of membrane transporters ,107. ManUnlike other ‘hot’ tumour types such as melanoma and lung carcinoma, PaCa is renowned for its ‘cold’ immune contexture that markedly impairs response to revolutionary immuno-oncology (IO) therapies such as checkpoint inhibitors. This characteristic largely results from the low mutational burden and limited neoantigen expression of pancreatic tumours and is further exacerbated by the immunosuppressive actions of resident stromal cells, as discussed in subsequent sections. Efforts to stimulate tumour immunity include the application of chemotherapeutics that are known inducers of immunogenic cell death (ICD) . For exaA defining feature of PaCa is the development of an extensive fibrotic stroma, known as desmoplasia, which can account for up to 90% of the total tumour mass  Figure . This miPancreatic tumours are often poorly perfused due to their inherent hypovascularity, which forms a major impediment to drug delivery. This challenge is exacerbated by dense deposits of ECM and unchecked growth of tumour cells in a compact tissue space, creating overwhelming stresses and compressive forces that render much of the vasculature non-functional due to collapse. Moreover, plasma leakage from hyperpermeable vessels is not effectively drained by the dysfunctional tumour lymphatics, leading to further increases in interstitial pressure. Together, these abnormalities contribute to treatment resistance by hindering multiple aspects of drug transport, such as delivery into the tumour, extravasation across the endothelium and passage through the interstitium .Attempts to counteract this pathophysiology include strategies aimed at disrupting the stroma to provide a window of opportunity for enhanced drug penetrance ,129,130.Despite these promising preclinical observations, stromal depletion has yielded disappointing outcomes in PaCa patients, and has now become highly contentious following conflicting evidence that it can enhance tumour aggressiveness and metastatic dissemination ,149,150.Other efforts to overcome the physical barriers posed by the PaCa microenvironment have focused on targeting the vasculature to restore vessel patency and intratumoral drug perfusion ,153. AltEven if physical hurdles can be overcome, therapeutics often encounter further resistance arising from the complex and dynamic biological interplay between stromal elements and the neoplastic epithelium. Key players in this respect are the cell subsets that populate the stroma, comprising fibroblasts as discussed previously, as well as immune cells from both lymphoid and myeloid lineages for example. Much progress has been made in unravelling the molecular cross-talk and communication channels that exist between these cells, which has highlighted their pivotal involvement in tumour progression and resistance to therapy . In partIn addition to their role in driving desmoplasia, fibroblasts can contribute to therapy resistance by dampening immune surveillance in the pancreatic tumour microenvironment. One of the key mechanisms by which they achieve this is via secretion of the CXCL12 chemokine, which facilitates immune evasion by blocking T cell trafficking to the vicinity of tumour cells . To inteStromal macrophages have also received considerable attention, given their unique functional plasticity that is highly amenable to therapeutic manipulation ,164. DurOther cell populations present within the pancreatic tumour stroma include myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Despite being of relatively low abundance, these cells can disproportionately contribute to drug resistance via diverse mechanisms that converge in tumour immune escape, such as induction of T cell anergy, M2 skewing of macrophages and suppression of dendritic cell activity ,186. DirCSCs comprise a small pool of pluripotent cells within tumours that are characterised by their unique ability to self-renew and give rise to differentiated progeny. These cells exhibit a remarkably resistant phenotype that can withstand multiple modes of treatment, and their persistence within tumours is believed to sustain malignant growth that eventually results in more aggressive and metastatic relapse. As such, CSCs have been proposed as major drivers of oncogenesis and are considered crucial targets if durable tumour control is to be achieved. Progress in targeting CSCs has been aided by the development of nanomedicines that interfere with CSC biology ,192,193.Tumours exhibit a range of physiologic alterations compared to normal tissue, such as a reduction in extracellular pH that renders the microenvironment mildly acidic. This largely results from metabolic adaptations of cancer cells, which show an enhanced propensity to fuel their energy demands through aerobic glycolysis to yield the acidic end product lactate (termed the ‘Warburg effect’). One of the major repercussions of microenvironmental acidification is a reduction in cellular drug influx that can lead to therapy resistance. Weakly basic drugs, which account for a sizeable proportion of all anticancer agents, are particularly affected as they become protonated under acidic conditions to an ionised form that does not readily diffuse across the cell membrane. Clear scope therefore exists for the use of nanoparticle vectors that can shield entrapped cargo from the acidic milieu and provide a route of intracellular entry. In many instances, these have been engineered with ‘smart’ features that take advantage of tumour acidosis to achieve spatiotemporal control over drug delivery. For example, studies by Han et al. showed that surface functionalisation of gemcitabine-loaded nanoparticles with a pH-responsive peptide could markedly improve their binding affinity to tumour cells . This reOxygen deprivation is a further hallmark that commonly distinguishes tumour, from normal, tissue. This characteristic is prominent in PaCa, where hypovascularity together with stroma-mediated compression of existing vasculature create barriers to blood flow that reduce oxygenation. It is well established that hypoxic conditions give rise to many of the major mechanisms of drug resistance, such as anti-apoptotic signalling, immune suppression and induction of EMT ,214. ResOf the drugs used for PaCa therapy, gemcitabine is particularly vulnerable to metabolic processes that contribute to the emergence of resistance ,229. WhiA further obstacle associated with gemcitabine therapy is the requirement for intracellular processing of the drug to a pharmacologically active conformation. This involves a series of phosphorylation events mediated by several enzymes whose expression is often dysregulated in PaCa. Hence, multiple opportunities exist for insufficient drug processing, leading to chemoresistance. In particular, monophosphorylation of gemcitabine by deoxycytidine kinase (dCK) is regarded as the critical rate-limiting step towards production of the bioactive triphosphate metabolite . Given tRewiring of amino acid metabolism in PaCa can also induce resistance to many IO therapies by exerting suppressive effects upon antitumour immunity. Enhanced tryptophan catabolism represents a classic example of metabolic reprogramming in PaCa, which mainly results from overexpression of indoleamine 2,3-dioxygenase-1 (IDO1) that catalyses the breakdown of this essential amino acid to kynurenine. In turn, local tryptophan depletion, combined with accumulating levels of metabolites, leads to a dampening of both innate and adaptive antitumour responses ,241. EffThere is an ever-increasing emphasis on multivalency in the development of new therapies as many targets require receptor clustering to achieve sufficient agonism and aid internalisation. Indeed, receptor clustering has been suggested, as this is a way cells may regulate their response to certain stimuli and potentially develop resistance ,247. NanReceptor-targeted nanoparticles can also enable novel immunotherapy strategies. Perica et al. used iron dextran nanoparticles that could activate a T cell receptor (TCR) in T cells via a magnetic field, generating proliferating T cells that recognised a grafted tumour and blocked its development in vivo . In a diPerhaps the best examples of therapeutics that have taken advantage of multivalency have been antibodies and recombinant proteins targeting death receptor 5 (DR5). The endogenous ligand of DR5, Tumour Necrosis Factor α-related apoptosis-inducing ligand (TRAIL), exists in both membrane bound and soluble forms in nature with the former being much more potent than the latter. Multiple formats of monovalent or bivalent death receptor targeting therapies have gone to clinical trial but failed to produce adequate benefit to warrant use in the clinic . Recent Chemoresistance can result from the overexpression of antiapoptotic proteins within the DR5 pathway, such as Fas-associated death domain (FADD)-like IL-1b-converting enzyme-inhibitory protein (FLIP) . FLIP isB cell lymphoma 2 (Bcl-2) and myeloid cell leukaemia (Mcl-1) are antiapoptotic members of the Bcl-2 family of proteins that bind to their proapoptotic family members, thereby preventing mitochondrial outer membrane permeabilisation (MOMP), the release of cytochrome c and second mitochondrial activator of caspase (SMAC) . The antAs one of the most difficult-to-treat malignancies with a survival rate that has scarcely improved over several decades, the identification of new therapeutic strategies for PaCa remains a leading priority. The application of nanomedicine represents a significant step towards realising this goal, which has proven capability to overcome mechanisms of resistance that ultimately lead to therapy failure and relapse in PaCa patients. Efforts in this area to date have resulted in two clinically approved nanomedicines for PaCa therapy, with numerous others demonstrating promise at various stages of development. One commonality across many of these platforms is their containment of a sole chemotherapeutic payload, such as paclitaxel and irinotecan in the case of Abraxane and Onivyde, respectively, which will be subject to much adaptation moving forwards. Initiatives to co-load multiple cargoes within a single nanoparticle platform are expected to gather pace, to overcome issues with current combination regimens in the clinic and also allow for the simultaneous and aggressive targeting of multiple aspects of PaCa pathophysiology. This will be greatly facilitated by the breadth of core materials now available for nanoparticle construction, and hybrid compositions may soon take precedence to enable packaging of drugs with disparate structural and physicochemical properties. However, although the formulation of multidrug nanoparticles offers clear benefits, these are partially offset by the inherent complexity of the final product and the need for extensive optimisation to achieve precise ratiometric control over drug loading. A key consideration will be to ensure that manufacturing practices for these nanoparticles provide a sufficient degree of homogeneity and reproducibility, to satisfy regulatory requirements and expedite their clinical translation. Another important objective of future work will involve payload diversification. While conventional chemotherapies will continue to hold a fundamental role in treatment, other payloads will be increasingly explored in line with our evolving understanding of PaCa biology and the processes that contribute to resistance. Leading candidates in this respect will include agents with immunostimulatory properties, driven by the unprecedented success of IO approaches such as checkpoint inhibition that have revolutionised cancer care in recent years. Moreover, attention must also be centred on the development of appropriate preclinical models in which to test these nanoformulations. Recent modelling advances include those based on 3D organoids and humanised mice that can recapitulate many features of PaCa, and continued innovation in this area will assist the translation of novel nanoformulations to the clinic. Collectively, these efforts will establish a rich pipeline of therapeutic nanomedicines that, with time, could lead to a radical transformation in the outlook for PaCa patients.


Social circumstances in which people live and work impact the population’s mental health. We aimed to synthesise evidence identifying effective interventions and policies that influence the social determinants of mental health at national or scaled population level. We searched five databases  between Jan 1st 2000 and July 23rd 2019 to identify systematic reviews of population-level interventions or policies addressing a recognised social determinant of mental health and collected mental health outcomes. There were no restrictions on country, sub-population or age. A narrative overview of results is provided. Quality assessment was conducted using Assessment of Multiple Systematic Reviews (AMSTAR 2). This study was registered on PROSPERO (CRD42019140198).We identified 20 reviews for inclusion. Most reviews were of low or critically low quality. Primary studies were mostly observational and from higher income settings. Higher quality evidence indicates more generous welfare benefits may reduce socioeconomic inequalities in mental health outcomes. Lower quality evidence suggests unemployment insurance, warm housing interventions, neighbourhood renewal, paid parental leave, gender equality policies, community-based parenting programmes, and less restrictive migration policies are associated with improved mental health outcomes. Low quality evidence suggests restriction of access to lethal means and multi-component suicide prevention programmes are associated with reduced suicide risk.This umbrella review has identified a small and overall low-quality evidence base for population level interventions addressing the social determinants of mental health. There are significant gaps in the evidence base for key policy areas, which limit ability of national policymakers to understand how to effectively improve population mental health.The online version contains supplementary material available at 10.1186/s12889-021-12145-1. Recent policy priorities in global mental health have focused on closing the treatment gap: improving the proportion of individuals experiencing a mental health problem who are able to access effective psychiatric treatments locally , 2. ThisThe current global mental health action plan  also priThere is now good evidence that various social determinants are associated with poor mental health outcomes. Socioeconomic factors such as poverty , 7, (un)Many of these determinants were identified in a recent review of reviews  of the sWe undertook this umbrella review to identify the best available evidence for national or population level policies or interventions that improve population mental health and wellbeing by addressing the social determinants of mental health.Umbrella reviews provide a transparent and rigorous approach, using systematic review methodology, to locate, appraise and summarise the highest quality evidence from published systematic reviews on a topic . The proWe systematically searched several databases (Cochrane Library (Wiley), Global Health (Ovid), MEDLINE (Ovid), EMBASE (Ovid) and PsycINFO (Ovid) using search strategies developed by a Senior Information Scientist   criteriaReviews were included if they reported national/population level policies or initiatives that had been evaluated at that scale (larger regions/provinces were included if the population was over a million). We placed no restrictions on age, country or sub-population. All sectors that incorporated a social determinant of mental health as recognised by World Health Organisation (WHO)  were incEndNote reference management software  was usedA data extraction form , all of which were of critically low quality.Length of maternity leave and whether the leave was paid or not was examined by three reviews  42] [43 [4342]  reportedBorrell et al.  found evSeven reviews of mixed quality  looked at economic interventions.Two high quality reviews looked at conditional benefits such as tax credits and parental benefits tied to employment as examples of welfare to work policies , 47; andLucas et al.  in a higTwo critically low quality reviews , 50 lookMcAllister et al. , in a reOne review of critically low quality assessed the impact of privatisation of public sector utilities . Only thOne critically low quality review looked at the provision of mixed income housing  and tenant-based rental assistance programmes (subsidised housing for poorer families to live in more affluent neighbourhoods) . AnalysiAnother review of moderate quality focused on housing interventions . It founOne review of low quality looked at entry and integration policies for migrants to high income countries . PolicieFive reviews of critically low quality looked at national level suicide prevention programmes and included interventions to improve education and awareness, implement screening for those at risk and restrict access to means –61.Gunnell et al.  concludeZalsman et al.  found goThere were lower rates of suicide when restricting detoxifying domestic gas (19–33% in UK and Switzerland), when restricting access to barbiturates ; and mixed effects related to restricting gun access across a range of countries, with greater impact in high risk populations. Mann et al.  reviewedTorok et al.  and ZalsZalsman et al.  report tMann et al. , revieweZechmeister et al.  simulateZalsman et al.  concludeKato et al.,   in a revIn this literature review, we found a broad, but generally low quality evidence base for interventions that address social determinants of mental health at the national or population level. Review level evidence was found across demographic, economic, neighbourhood, environmental, and social/cultural domains of social determinants of mental health as set out by Lund et al. , howeverThere are very few high quality reviews on the impacts of tackling the social determinants on mental health outcomes . The majThere are several specific findings from this umbrella review.First, we found high quality evidence to suggest that more generous welfare benefits may reduce socioeconomic inequalities in mental health outcomes, with evidence to the contrary, showing that austerity measures are likely to have detrimental impacts on mental health.Second, a wide range of lower quality evidence suggests that social policies were associated with improved mental health outcomes. These included more generous unemployment insurance (which benefits both the employed and unemployed), warmth focused housing interventions, neighbourhood renewal, paid parental leave, gender equality policies, community based parenting programmes, and less restrictive migration policies. Restriction of access to lethal means and multilevel awareness and education programmes were associated with reduced suicide risk.Third, there was high quality evidence that found no evidence of effect of conditional welfare-to work benefits on adult mental health outcomes. This may be because of the stress induced by the conditions attached to qualify for support or the benefits themselves being too small or restricted to improve material or psychological conditions of poverty. There was also no evidence of effect on child mental health outcomes.Despite using several search terms, we found very little evidence on social, cultural and community based interventions, delivered at population level and their impact on mental health apart from those linked to suicide prevention. It is possible that these interventions, whilst widely used are under-evaluated or not evaluated specifically for mental health outcomes at a population level.We address a critical gap in the literature, by examining the systematic review evidence base around the impacts of gender equality policies on women’s mental health. This review found that evidence in this area was concentrated in high income countries, with little evidence found outside of US and Europe.The findings of this review are in keeping with the WHO recommendations on national level action on social determinants of health , 65 whicIn the current context of the COVID-19 pandemic as well as numerous current natural disasters, violence and conflict, many linked to climate change, the need for national level intervention to address environmental determinants of mental health is clear, and the gap in literature on this specific domain is concerning.We found little evidence for interventions in the neighbourhood domain, with warmth related housing interventions showing some promise. This is at odds with international policy recommendations for action to promote access to employment, health care, housing, and education to improve mental health outcomes , 64, 65.Whilst the quality of Kato et al’s  review wThe WHO recommends nations should have suicide prevention policies in place . This reThe WHO European health equity framework  also higFinally, there is a case to align approaches to tackling social determinants of mental and physical health, given recent literature detailing psychosocial pathways by which social determinants impact on both physical and mental health . Bambra Our focus on national/population level interventions, may have excluded relevant interventions occurring at lower than national level. Future reviews should focus on local or community level interventions which address social determinants of mental health with potential to scale at population level.While we used a recognised tool to assess quality of reviews, the AMSTAR 2 may not be most appropriate for complex public health interventions. Review tools such as the AMSTAR 2, developed in relation to healthcare research, are conceptually framed and weighted towards a hierarchy of evidence that prefers RCT and meta-analytic synthesis and assumes that they are possible. A rigorous and well considered public heath systematic review that contains different forms of evidence may struggle to score highly on this criterion.Refining the search to systematic review level evidence only, may also have missed individual studies with good evidence that have not yet been synthesized at review level. We relied on variable methods used in the included systematic reviews for appraisal of quality and synthesis of primary studies.There are methodological challenges associated with evaluating social interventions delivered at population scale and which can be distal to the mental health outcome, forming complex pathways to impact.Methods employed in primary research studies limit the strength of findings. Quasi-experimental and observational studies have limited power to explain causality but were commonly used; likely due to the scale of intervention, population of interest, ethical considerations, policy governance  or availability of data. Bias was introduced in many studies by sub-optimal measurement (such as reliance upon retrospective self report) of mental health and intervention related factors, and not including all relevant populations in the dataset.To enhance the strength of future review level findings, primary evaluations of mental health policies and interventions should be planned in advance, before implementation of new policies/interventions, to include robust measurement of mental health status longitudinally with samples that are representative of diverse populations. Where experimental designs are not employed, observational studies can employ analytical methods designed to overcome methodological limitations. One approach is to create control groups within one population dataset, for instance employing a difference-in-differences analysis to compare impacts of policies on different subgroups of the population . AnotherFidelity is difficult to achieve as most of these interventions are implemented in varied and broad contexts, and are influenced during implementation by multiple contextual factors, many of which are not easily measured. A key example of implementation related factors is the conditionality of welfare interventions (an aspect of implementation rather than core component of the intervention) as potentially mitigating mental health benefits of increased income . Renahy Authors of included reviews highlighted that future studies should take implementation and contextual factors into account during design and analysis to enable more comprehensive evaluation. This could include a priori identification of likely relevant implementation or contextual factors which can be collected and subsequent sub-group, sensitivity or effect mediation/moderation/interaction analyses carried out as appropriate. Other methodologies can enable investigation of context-related clustering without measuring factors directly. Multilevel analyses of cross sectional or longitudinal data allow measurement of change across individuals and the wider social contexts in which they live, including analysis of cross level interactions and associations, and variation of effect for target population and the wider population . In ecolClarity on mechanistic pathways can help understand how these interventions work most effectively and what is needed to support this in implementation, but evaluation designs often do not incorporate this. None of the included reviews collected outcomes at points along the proposed mechanistic pathway, and it is unclear if this was done in primary evaluations. The mechanistic pathways set out in Fig. This umbrella review has identified a small and overall low quality evidence base for national level interventions addressing the social determinants of mental health.The most robust evidence base centred on welfare and employment support, which national policymakers should consider for implementation. Other national level interventions that are indicated in this review for policy consideration are gender equity policy, less restrictive migration policy, restricting means/ multi-component campaigns for preventing suicide and at scale delivery of community parenting interventions.There is a need for better quality primary research and improved reporting in systematic reviews that focus on impacts of conditional benefits, neighbourhood renewal or mixed income housing on mental health. No systematic review level evidence was found relating to national strategies for violence reduction, addressing environmental hazards, community services, age and ethnicity inclusive policies and their impact on mental health. There is a wider evidence base of locally evaluated interventions that may be scaled but it is important for these to be evaluated to assess effectiveness when implemented at national/population level.Additional file 1. Search strategy used in OVID MedlineAdditional file 2. AMSTAR 2 checklist tool.Additional file 3. Data extraction toolAdditional file 4. Excluded studies at full text screening stage (with reason)Additional file 5. Summary table of included studies.


Recent evidence indicates that brain somatic mutations contribute to several NDDs, in particular malformations of cortical development. While advances in sequencing technologies have enabled the detection of these somatic mutations, the mechanisms by which they alter brain development and function are not well understood due to limited model systems that recapitulate these events. Human brain organoids have emerged as powerful models to study the early developmental events of the human brain. Brain organoids capture the developmental progression of the human brain and contain human-enriched progenitor cell types. Advances in human stem cell and genome engineering provide an opportunity to model NDD-associated somatic mutations in brain organoids. These organoids can be tracked throughout development to understand the impact of somatic mutations on early human brain development and function. In this review, we discuss recent evidence that somatic mutations occur in the developing human brain, that they can lead to NDDs, and discuss how they could be modeled using human brain organoids.Neurodevelopmental disorders (NDDs) are a collection of diseases with early life onset that often present with developmental delay, cognitive deficits, and behavioral conditions. In some cases, severe outcomes such as brain malformations and intractable epilepsy can occur. The mutations underlying NDDs may be inherited or  Neurodevelopmental disorders (NDDs) impact brain development and function resulting in a range of neurological and psychiatric manifestations. These can include epilepsy, intellectual disability, autism spectrum disorder (ASD), and other behavioral, cognitive, and affective disorders , RNA processing , protein synthesis , and protein degradation . Mutations in genes encoding proteins important for neuronal excitability and synaptic transmission are also frequently found in NDDs including ASD, epileptic encephalopathy, and intellectual disability  or induced pluripotent (hiPSC) stem cells (collectively hPSCs) can be differentiated into various types of neurons and glia. n Paşca, . The forIn this mini-review, we discuss the utility of hBO models for studying brain somatic mutations during development, which can directly cause certain NDDs and may be an important contributor to many other neuropsychiatric disorders  per year over the lifespan of an individual , or loss-of-function mutations in negative regulators   and ganglionic eminence (GE) organoids called “assembloids” were generated from healthy and Timothy Syndrome patient-derived iPSCs to study defects in interneuron migration  and mutant progenitor cells expressing different fluorescent reporters . With thin utero electroporation was used to deliver Cre to a small population of c/-Tsc1 cortical progenitors during embryonic development, resulting in the formation of a focal region of dysplastic cells. More recently, a similar approach was used in c/-TSC2 hBOs with lentivirus-mediated delivery of Cre to conditionally delete TSC2 from a small population (~1–5%) of neural progenitors early in development (Blair et al., Another strategy for modeling a somatic mutation is to use Cre recombinase to induce a conditional mutation in developing hBOs . This caDelivering Cre to hBOs with a virus allows temporal control over the conditional mutation by modulating the timing of Cre expression, thereby generating mutant progenitors or post-mitotic cells at different stages of development . DiffereUnderstanding the cellular and molecular mechanisms of human brain development has been greatly challenged by limited access to developing human brain tissue. While model organisms are instrumental for studying the fundamentals of neural development, circuit function, and behavioral control, these models cannot capture aspects of human-specific development that may be important for understanding human brain function. hBO models of the human brain offer a step towards achieving the ambitious goal of modeling the complex development of the human brain in a dish. Combining the knowledge gained from patient genetics with hBO technology offers a platform for testing how altering the expression of disease-associated genes impacts cellular signaling, development, and neuronal activity in the context of human neural development. Modeling somatic mutations in hBOs will provide a new system for testing how these mutations cause brain malformations, how different mutations and their time of onset can change the cellular composition of the developing brain, and how cells harboring somatic mutations contribute to the altered function of the surrounding brain circuitry.HB conceived the idea for the review. BD wrote the initial draft. BD and HB edited the manuscript and designed the figures. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.