Chronic pain has been widely recognized as a major public health problem that impacts multiple aspects of patient quality of life. Unfortunately, chronic pain is often resistant to conventional analgesics, which are further limited by their various side effects. New therapeutic strategies and targets are needed to better serve the millions of people suffering from this devastating disease. To this end, recent clinical and preclinical studies have implicated the epidermal growth factor receptor signaling pathway in chronic pain states. EGFR is one of four members of the ErbB family of receptor tyrosine kinases that have key roles in development and the progression of many cancers. EGFR functions by activating many intracellular signaling pathways following binding of various ligands to the receptor. Several of these signaling pathways, such as phosphatidylinositol 3-kinase, are known mediators of pain. EGFR inhibitors are known for their use as cancer therapeutics but given recent evidence in pilot clinical and preclinical investigations, may have clinical use for treating chronic pain. Here, we review the clinical and preclinical evidence implicating EGFR in pathological pain states and provide an overview of EGFR signaling highlighting how EGFR and its ligands drive pain hypersensitivity and interact with important pain pathways such as the opioid system. Chronic pain is an international health priority , with a Growth factors and their cognate receptors promote pain sensitization and have been identified as therapeutic targets in the treatment of neuropathic pain . These iHere, we first review the clinical and genetic evidence implicating EGFR in pain, emphasizing neuropathic pain, which has been the primary focus of recent studies. We next provide an overview of EGFR signaling, highlighting possible mechanisms by which EGFR and its ligands may influence pain hypersensitivity and modulate inflammatory mediators of pain. We propose future studies directed at better understanding the role of the EGFR family in pain signalling in order to allow evaluation of whether EGFR-related therapeutics may be repositioned for the treatment of neuropathic pain.Pain begins with the detection of noxious stimuli by specialized peripheral sensory neurons, termed nociceptors . These fD-aspartate receptors  experienced pain relief following treatment with erlotinib  in addit, were generally mild to moderate , which examined the environmental, biosocial, and genetic factors that may lead to painful temporomandibular disorders . Subsequin vivo evidence is limited to the use of animal models. Thus, these data highlight potential interactions in human tissues–specifically, between EGFR within the DRG and ligands associated with pain-associated diseases and underscore the importance of investigating the role of EGFR in chronic pain.Transcriptional profiling of macrophages from synovial fluids of patients suffering from rheumatoid arthritis (RA) and pancreatic cancer, has further implicated potential roles of the EGFR signaling pathway in pain . This waEGFR has central roles in development and in the maintenance of homeostasis in adult tissues, including the central and peripheral nervous systems, where it exerts neurotrophic actions . Ligand Depending on the cellular expression of HER2, HER3, and HER4, ligand-binding to EGFR induces receptor homo- or heterodimerization, and the activation of intrinsic tyrosine kinase domains that leads to phosphorylation of the receptor’s c-terminal cytosolic tail . These pAnimal models of pain are important and necessary to understand fundamental mechanisms of disease and to identify new therapeutic targets . VariousEGFR has been shown to mediate hypersensitivity in various animal models of pain. Systemic administration of various EGFR inhibitors  reverses complete Freund’s adjuvant (CFA)-, spared nerve injury (SNI)- and chronic constriction injury (CCI)-induced mechanical allodynia, as well as carrageenan-induced thermal hypersensitivity . SystemiThe dorsal horn, dorsal root ganglia, and trigeminal ganglia are important areas in pain modulation , and mulEGFR expression has also been detected in non-neuronal cell types, namely immune and glial cells, within the DRG and dorsal horn. Microglia, the resident macrophages of the CNS, may have key roles in the establishment and maintenance of neuropathic pain . CellulaEGFR mRNA increases in the ipsilateral DRG of male rats following SNL or CCD  as well EGFR phosphorylation at Y1068 leads to PI3K-Akt signaling, a phenomenon that may be increased within the DRG in various models of pain, including CFA and SNI . EGFR isSince EGFR may be activated directly by ligand-binding or indirectly through transactivation by other receptors, we next discuss EGFR ligands and their implicated roles in pain.ex/ex) mice have elevated mechanical thresholds and impaired sensitivity to heat and cold and the DRG of ADAM-17ex/ex mice contain fewer β-4 positive neurons, which are canonically responsive to thermal nociceptive stimuli , enhances formalin-induced nocifensive behaviors in mice with EREG administration alone being sufficient to induce heat and mechanical hypersensitivity . For comWhether EREG is the only EGFR ligand capable of inducing mechanical hypersensitivity has been addressed recently: EGF administration alone is sufficient to induce mechanical but not thermal hypersensitivity . However. However, whether TGF-α administration alone is sufficient to induce hypersensitivity remains to be investigated. Thus, whether other EGFR ligands may participate in sensitization of other contexts is as of yet unclear. Different EGFR ligands may distinctly contribute to neuropathic pain by different patterns of expression and secretion, or by distinct regulation of the magnitude or duration of EGFR signaling following ligand binding. Collectively, this diversity of EGFR ligand regulation may contribute to context-dependent action of each EGFR ligand in promoting pain sensitization, though further mechanistic studies are required to fully delineate whether this is indeed the case.Whether differences in ligand affinity may contribute to these potential differences remains to be determined. TGF-α may have potential roles in pancreatic cancer pain . HoweverDespite the complexity of EGFR ligand signaling, there has been substantial evidence to support a key role for EREG in pain signaling. Following lumbar vertebral disc herniation, EREG is released from intervertebral disks by the NP and annulus fibrosus in patients , or by NAs described above, recent evidence has demonstrated that inhibition of EREG reverses or enhances hypersensitivity in chronic or acute pain models, respectively . This suAs both EGFR and its ligands can be expressed in various immune cells relevant to pain and nociception, EREG may have roles in inflammation-driven pain. Clinical data shows increased levels of EREG in leukocytes of patients with temporomandibular disorders  and RA . Levels The inflammatory responses involved in both injury and various diseases drive the development and maintenance of neuropathic pain by promoting mechanical allodynia, neuronal hypersensitivity, and central sensitization . EGFR anin vitro stimulation with interleukin (IL)-6 and IL-17  . The var2) into phosphatidylinositol-3,4,5-trisphosphate (PIP3), are differentially expressed within the nervous system. The differential distribution of class I PI3K isoforms  within various neuron types, supportive cells and immune cells within the DRG and spinal dorsal horn has been implicated in mechanisms of pain P of pain . After 4 of pain . In cont of pain . CollectThere is also some evidence that PI3K contributes specifically to EGFR-dependent pain . PI3K inOne protein that is affected by EREG and/or PI3K activation is the transient receptor potential cation channel subfamily V member 1 (TRPV1). TRPV1 has been widely studied for its roles in thermal hyperalgesia and responds to polymodal stimuli including noxious heat and vanilloid substances such as capsaicin . AdminisThe mechanism by which NGF mediates TRPV1 upregulation has been studied in greater detail than that of EREG. In F-11 cells, a cellular model of undifferentiated sensory neurons, NGF-stimulation leads to increased cell surface TRPV1 , and inhClass I PI3K activation canonically leads to the phosphorylation and activation of Akt and although some studies suggest roles for Akt in hypersensitivity following formalin administration , others In F-11 cells, in addition to PI3K signaling leading to enhanced cell surface TRPV1, ectopic TRPV1 expression enhances NGF-stimulated PI3K-dependent Akt phosphorylation at T308 and S473, both of which are required for full activation of Akt . FurtherThe mammalian target of rapamycin (mTOR) controls cellular metabolism and many other cellular functions by incorporating diverse signals from ligand-binding to intracellular cues regarding energy and nutrient availability . In mammGiven the activation of mTORC1 downstream of PI3K-Akt signaling, this kinase may mediate some of the important pain signals driven by EGFR and/or PI3K. Consistent with this, mTORC1 inhibitors such as rapamycin  and rapamycin derivatives such as temsirolimus (CCI-779) inhibit mTORC1 and have been used in clinical trials for cancer therapy ; . AdminSimilarly, temsirolimus and rapamycin block EREG-mediated hypersensitivity in the formalin test . Hence, The family of mitogen-activated protein kinases (MAPKs) includes three major members: extracellular regulated kinase (ERK), p38 and c-jun N-terminal Kinase (JNK). Notably, EGFR signaling activates Erk in most cell types leading to proliferation and differentiation . p38 andIn terms of drug development, p38 MAPK is a novel target of cytokine-suppressive anti-inflammatory drugs due to its regulatory role in the synthesis of inflammatory intermediates . In the Recent evidence has shown that EGFR has non-canonical roles in regulating physiological processes such as inflammation, and pathophysiological functions in inflammatory pain and neuropathic pain. Though we have discussed how EGFR may regulate pain through direct ligand-induced activation of EGFR and canonical downstream signaling intermediates, EGFR also controls cellular processes indirectly through crosstalk with other plasma membrane receptors. Ligand-bound EGFR may induce the activation of another receptor or another receptor may transactivate EGFR. Here, we focus on two mechanisms by which EGFR regulates pain-generating processes through receptor crosstalk.Toll-like receptors (TLRs) have key roles in the activation of the innate immune system by detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) associated with various microbes and cellular damage, respectively . Upon biin vitro. A similar result has been reported in bone marrow derived macrophages and RAW 264.7 cells, in which inhibition of EGFR reduces LPS-stimulated IL-1β, IL-6, IL-10 and TNFα expression , which drives sensitization of peripheral nerve terminals and is a major cause of inflammatory pain , including that between EGFR and opioid receptors , has beein vitro . Similaritro (3R . Since oitro (3R . HoweverConsistent with a possible role of EGFR in modulating opioid receptor signaling, clinical case reports indicate that pharmacological inhibition of EGFR may have effects on opioid efficacy and tolerance. In the case series conducted by Kersten and colleagues, some patients were able to decrease their opioid dose significantly within days following treatment with cetuximab . In addiThe above is analogous to observations made in a rat CFA model, where inhibition of NGF-TrkA signaling reversed morphine tolerance . In the Chronic pain, particularly chronic neuropathic pain, remains a global health priority due to a paucity of effective and well tolerated therapies. Inhibitors of EGFR may exert analgesic effects in patients with neuropathic pain with minimal side effects. These empiric clinical findings are supported by various preclinical models of pain hypersensitivity. However, the use of EGFR inhibitors in neuropathic pain treatment may be cost-prohibitive, with costs per month in the thousands of dollars . AdditioThe mechanisms by which EGFR may mediate or contribute to the initiation and maintenance of neuropathic pain are likely diverse given the pleiotropic cellular functions of this receptor family. These may include both direct actions of the receptor by binding its cognate ligands and indirect actions through transactivation. Few studies have investigated the signaling mechanisms by which EREG may mediate sensitization, though it appears that similar to NGF-mediated sensitization, this mechanism requires PI3K. Thus, an outstanding and fundamental question surrounds whether RTKs have shared mechanisms by which they impact pain hypersensitivity or have distinct pathways. The latter is important as the differential contributions and molecular pathways may inform pharmacologic strategies with increased context specificity. Current evidence suggests that class I PI3K are the main contributors in neuropathic pain. Future work directed at delineating the specific roles of specific class I isoforms would be beneficial since there are a variety of pan- and isoform-specific inhibitors in clinical trial. Importantly, there are other pain mediators, such as STAT3 , that arLimitations of animal models of pain [reviewed by EGFR may influence pain directly or indirectly by controlling traffic of other pain-associated proteins, such as TRPV1 or TLR4 and opioid receptors, respectively. Given the importance of neuro-immune interactions in pain, the roles EGFR in these processes warrant further investigation. The reduced effectiveness of opioids and increased tolerance in patients with neuropathic pain remains problematic. As such, the preclinical evidence suggesting that EGFR inhibition may reverse morphine tolerance is exciting and requires further evaluation.The evidence we reviewed here positions EGFR as an important player in pathological pain states and provides the impetus for the clinical and biomedical research communities to investigate EGFR as a potential therapeutic target.


Cognitive impairment increases an individual’s risk of falls due to the role cognition plays in gait control. Older adults with dementia fall 2-3 times more than cognitively healthy older adults and there is a lack of evidence for effective fall prevention interventions for community-dwelling cognitively impaired adults. We conducted a systematic review and meta-analysis to investigate the effectiveness of fall prevention interventions in improving falls, perceived risk of falls, gait, balance, and functional mobility. We searched 7 databases for interventions involving community-dwelling adults ≥50 years with mild to moderate cognitive impairment. Reviewers screened citations, extracted data, assessed risk of bias and certainty of evidence (GRADE). We performed a meta-analysis of 509 community-dwelling adults (mean age 67.5 to 84.0 years) with mild to moderate cognitive impairment from 12 randomized controlled trails . Interventions had medium significant effects on perceived risk of falls , balance , and timed up and go test  and small significant effects on gait speed and control  with moderate certainty of evidence. There were no significant effects for falls. Sub-analysis showed that exercise and studies at low risk of bias remained significant for balance and perceived risk of falls. The effect of fall prevention interventions on falls remains unclear; exercise interventions are effective at addressing fall risk factors. However, high quality and longer studies with adequate sample sizes are needed to determine their effectiveness on falls.


HIV-associated neurocognitive disorder (HAND) is characterized by cognitive and behavioral deficits in people living with HIV. HAND is still common in patients that take antiretroviral therapies, although they tend to present with less severe symptoms. The continued prevalence of HAND in treated patients is a major therapeutic challenge, as even minor cognitive impairment decreases patient’s quality of life. Therefore, modern HAND research aims to broaden our understanding of the mechanisms that drive cognitive impairment in people with HIV and identify promising molecular pathways and targets that could be exploited therapeutically. Recent studies suggest that HAND in treated patients is at least partially induced by subtle synaptodendritic damage and disruption of neuronal networks in brain areas that mediate learning, memory, and executive functions. Although the causes of subtle neuronal dysfunction are varied, reversing synaptodendritic damage in animal models restores cognitive function and thus highlights a promising therapeutic approach. In this review, we examine evidence of synaptodendritic damage and disrupted neuronal connectivity in HAND from clinical neuroimaging and neuropathology studies and discuss studies in HAND models that define structural and functional impairment of neurotransmission. Then, we report molecular pathways, mechanisms, and comorbidities involved in this neuronal dysfunction, discuss new approaches to reverse neuronal damage, and highlight current gaps in knowledge. Continued research on the manifestation and mechanisms of synaptic injury and network dysfunction in HAND patients and experimental models will be critical if we are to develop safe and effective therapies that reverse subtle neuropathology and cognitive impairment. Human immunodeficiency virus (HIV) infection can cause cognitive, motor, and sensory deficits that are collectively termed HIV-associated neurocognitive disorders (HAND) . TypicalThe neuropathology of HAND has also been drastically changed by ART. Early in the HIV epidemic, many patients presented with encephalitis and neuronal loss, which were associated with severe forms of dementia , 9. TodaClinical studies of HAND patients are important for setting research directions, but the number of clinical samples available for analysis has declined since patients on ART now live close to a normal lifespan. However, new non-invasive neuroimaging techniques have become a useful alternative approach. Despite their focus on functional alterations, neuroimaging techniques can provide some information about structural changes and, therefore, aid investigations on the brain in virally suppressed subjects. Neuroimaging can also reveal insights about other factors relevant to the pathology, such as inflammatory markers and select pathogenic proteins , 13. TheNeuroimaging methods have allowed us to observe important aspects of HAND pathology in today’s patients, including brain volume, neuroinflammation, and functional connectivity . HoweverMagnetic resonance imaging (MRI) is often the initial step in the diagnostic approach for HAND, although to date, there is no unique neuroimaging technique capable of confirming a HAND diagnosis . PublishResting-state functional MRI can detect changes in brain connectivity in people with HIV and can help to determine how altered neuronal network activity contributes to cognitive impairment. One recent study found abnormal connectivity patterns at a global as well as a regional scale in subjects with HAND compared to age-matched controls, primarily in portions of the lateral occipital cortex and the cingulate cortex . Their rSustained subtle neuroinflammation is also thought to contribute to synaptodendritic damage and neuronal dysfunction in the ART era. Several groups have studied correlates of neuroinflammation in people with HIV, most notably using positron emission tomography (PET) imaging of translocator protein (TSPO) –31. TSPOAs non-invasive imaging approaches are increasingly necessary to understand HAND in the ART era, future neuroimaging studies are positioned to play important roles in uncovering brain region and network-level alterations in HAND patients with controlled infections.Neuropathology studies are currently necessary to confirm synaptodendritic damage and neuronal alterations in relevant brain regions. Unfortunately, most published neuropathology studies on HAND are from the pre-ART era or use clinical samples from patients with acquired immunodeficiency syndrome (AIDS), suggesting that they are not completely reflective of the current pathology . TherefoGene expression studies of human brain tissue offer an overhead view of many interconnected systems and allow measurement of synaptic and neuronal genes alongside of other genes that are thought to contribute to synaptic injury, including those related to inflammation and bioenergetics. Older studies from patients with moderate-to-severe HAND generally report an upregulated brain immune response and a downregulation of synaptic transmission . These fSeveral early neuropathology studies identified synaptodendritic damage in specific brain regions as a correlate of cognitive impairment in patients with AIDS. One of the early reports showed that neocortical dendritic and presynaptic damage was a strong correlate of neurocognitive impairment . AnotherOne mechanism that may lead to synaptodendritic damage in HAND patients is the accumulation of neurotoxic amyloid-β, especially as patients on ART become older. Studies of brain samples from HIV patients have shown altered amyloid precursor protein processing and the presence of amyloid-β plaques and oligomers –49. One Several studies suggest that neurotransmitter systems are disturbed in HAND patient samples. GABAergic markers in brain samples from HIV-infected patients with and without HAND appear to be significantly decreased in most areas of cerebral neocortex, the neostriatum, and the cerebellum . These fDysregulated inhibitory circuits may also lead to abnormal excitatory neurotransmission via the glutamate system, which has long been reported in HAND patients and models . HoweverClinical studies of HAND provide evidence that well-controlled HIV infection can still dysregulate neuronal functions in specific brain regions, suggesting a potential underlying cause of cognitive impairment in treated patients. However, it is still not entirely clear how controlled HIV infection contributes to this more subtle and region-specific neuronal dysfunction. Though some clinical studies of HAND would surely benefit from updates with treated patients, the field has expanded on insights gained from current clinical research using a variety of pre-clinical models. As discussed in the next section, these models support synaptodendritic injury as a substrate of neurocognitive impairment in HAND.In vitro and in vivo models of HAND have provided important insights into the neuropathological features of HAND that may exist in treated patients. Although these models have their own set of limitations, they allow for much more precise examination of neuronal structure and function and how specific HIV proteins and related stimuli contribute to synaptodendritic damage and alter the activity of neuronal networks. This section reviews recent findings from model systems regarding changes in synapses, dendritic spines, and electrophysiology.Excitatory synapses are commonly studied through quantification and morphometric analyses of dendritic spines, which are small protrusions along the dendrite that form the post-synaptic component of most excitatory synapses , 72. DenDifferent groups, including ours, have reported how dendritic spines may be altered in HAND by studying HIV-transgenic rats. These rats provide a similar environment to HIV-infected patients on ART, as they express viral proteins but do not produce infectious virus . The HIVSynaptic injury can also be caused by individual HIV proteins, including HIV tat and gp120. Tat is present in the cerebrospinal fluid of virally suppressed patients  and has IIIB in adult male rats decreases dendritic spine density in several cortical regions, including the medial prefrontal cortex [The HIV envelope glycoprotein gp120 can also produce dendritic spine deficits, although recently only a few studies have examined gp120 animal models—since tat is thought to have a prominent role in virally suppressed patients. However, considering that transient expression of gp120 in the first days of infection can trigger long-term events and/or neuroinflammation , the conl cortex  and the l cortex . As spinl cortex  and the l cortex .Alterations of dendritic spines and synapses are expected to be accompanied by changes in neuronal activity and connectivity. Indeed, several groups have demonstrated that the animal models discussed above display changes of neuronal activity in the same brain regions where spine deficits occur, including the prefrontal cortex, hippocampus, and striatum Table . One sucIIIB leads to dendritic spine deficits in cultured cortical neurons in a process that requires secretion of interleukin-1β (IL-1β) from co-cultured glial cells, suggesting that IL-1β is an important contributor to HIV-induced spine deficits in the cortex [IIIB increased inhibitory synapses and tonic inhibition, which also required gp120-induced secretion of IL-1β from microglia in the same cultures [In vitro models of exposure to HIV-1 proteins or related neurotoxins generally support the findings from animal models of HAND and recently have provided new insights on how HIV neurotoxins and comorbidities disrupt neuronal networks, and how neurons respond to these insults. For example, we have recently shown that exposure to gp120e cortex . Other scultures , 115. Sicultures , the shicultures , and thicultures .Several recent in vitro studies have also examined how HIV tat affects synapses and neuronal excitability either alone or with comorbid factors, and all studies in this paragraph examined the truncated tat 1–86 variant. In cultures of mouse primary neurons from the prefrontal cortex, tat treatment caused dendritic spine deficits and promoted excitotoxicity in line with studies from tat-transgenic mice, but these effects were mitigated by cannabinoid receptor 1 (CB1) agonists . Thus, CIt is also possible that ART itself contributes to synaptodendritic injury, either alone or in combination with other comorbid factors. For instance, select combinations of antiretrovirals and methamphetamine can alter expression of the presynaptic marker synaptophysin in cortical cultures, although ART compounds alone seem to minimally affect synaptophysin levels, even over a prolonged exposure . ReducedMost of the previously mentioned studies examined structural and functional changes in individual neurons of in vitro and in vivo models, but it is also possible to measure neuronal network activity in vitro using multielectrode arrays. A few reports have used multielectrode arrays to better understand how HIV neurotoxins alter activity at the network level in select types of primary neurons. One group examined rat primary hippocampal neurons and found that full-length tat 1–101 strongly suppressed neuronal activity and neuronal oscillations from 0 to 5 Hz, which was associated with attenuated spike frequency and amplitude across the culture. Additional tat treatments did not further reduce activity but did promote non-synchronous random firing. Neuronal activity was partially restored by removal of tat or in cultures with astrocytes, and in line with the previous studies suggesting tat promotes GABAergic inhibitory neurotransmission in the hippocampus, GABA receptor antagonists increased neuronal activity in tat-exposed cultures . These rTo date, most studies that examined the relationship between dendritic spines and behavior have been correlational. However, new techniques could surpass correlations and examine the downstream effects of structural and functional plasticity on the formation of new behavior. One example is activated synapse targeting photoactivatable Rac1, which allows erasure of recently activated synapses . The firIn vitro and in vivo models allow for probing the molecular mechanisms that underlie synaptodendritic damage and re-organization of neuronal networks in HAND. So far, a few major factors have been identified, including dysregulation of synaptic and extrasynaptic ion channels, inflammatory signaling pathways, altered synaptic actin remodeling, dysfunction of non-neuronal cells, and comorbid drug abuse. In this section, we will review recent studies on these players and pathways associated with HAND and how they are dysregulated by distinct stimuli.IIIB can activate these receptors through an indirect pathway, where it first promotes secretion of the cytokine IL-1β from CNS glial cells, and IL-1β binding to interleukin-1 (IL-1) receptors on hippocampal neurons leads to phosphorylation of the NR2B subunit and activation of NR2B-containing NMDA receptors [IIIB directly promoted surface expression of NMDA receptors in hippocampal neurons through a protein kinase A and C-dependent phosphorylation of NR1 C-terminal residues, and these receptors were transported to gp120-stabilized lipid structures that prevented internalization and enhanced abnormal calcium bursts [IIIB increased excitatory post-synaptic currents (EPSCs) from both NR2A and NR2B-containing NMDA receptors in male rat hippocampal slices, but gp120 had a more pronounced effect on NR2B-containing receptors [NMDA receptors are ionotropic glutamate receptors that play crucial roles in neuronal function and neurotransmission , and theeceptors . Though m bursts . As all eceptors . Importaeceptors . Gp120 meceptors , and by eceptors . In addieceptors , and theeceptors . Thus, gAdding to this complexity, evidence suggests that tat also regulates NMDA receptor functions, and tat from HIV-1 clade B may cause neurotoxicity by directly interacting with the NR1 subunit . EarlierThough brain inflammation is no longer considered a driver of cell death and apoptosis in patients on ART, chronic sub-threshold inflammation still appears to contribute to the more subtle pathology of modern HAND. For example, several studies suggest that inflammatory and synaptic systems are dysregulated in HAND models, including HIV-transgenic rats. These rats show higher markers of astrogliosis and microgliosis, dysregulation of genes associated with neurodegenerative disorders and synaptic plasticity in the hippocampus , and dysIIIB upregulates Mdm2 in cortical neurons, suggesting that both HIV proteins regulate Mdm2 [In response to the dysregulation of calcium channels and heightened vulnerability to excitotoxicity, neurons can initiate a homeostatic adaptation called synaptic scaling, which attempts to restore a balance between excitatory and inhibitory synaptic transmission. This often leads to a reduction or de-potentiation of excitatory synapses and increased inhibitory transmission in models of HAND, and several recent studies have explored the mechanisms underlying these adaptations  Fig. 2)2). One sate Mdm2 . Mdm2 ubate Mdm2 . Loss ofate Mdm2 , 154. Thate Mdm2 . Gp120 aate Mdm2 , 156, anate Mdm2 .Fig. 2MeIIIB increased inhibitory currents by enhancing the surface expression of neuronal α5 subunit-containing GABAA receptors, and these outcomes were mediated by gp120-induced secretion of IL-1β from microglia and activation of neuronal p38 mitogen-activated protein kinase [IIIB increased the number of gephyrin-labeled inhibitory synapses, which also involved IL-1β activation of p38 in addition to NMDA receptor and Src kinase-mediated protein synthesis [2+/calmodulin-dependent protein kinase II, and later required NR2B-containing NMDA receptors [The loss of dendritic spines and excitatory potential during synaptic scaling often occurs in concert with mechanisms that enhance inhibitory neurotransmission. Two recent studies have identified mechanistic insights on how this occurs in gp120-treated hippocampal neurons. In the first, a 4-h treatment with gp120n kinase . In the ynthesis . Tat expeceptors . Importaeceptors , dysregueceptors , and dececeptors . Notablyeceptors . The stu. These processes are often disrupted in neurologic disorders, including HAND [Dendritic spines are rich in actin. A balance between synaptic actin polymerization and depolymerization regulates their morphology and maintenance . These ping HAND , 161. Reing HAND . Normalling HAND , 163. Hoing HAND , suggesting HAND . Both efing HAND . Interesing HAND , suggesting HAND , indicating HAND –168. It ing HAND . These eing HAND , 170.Astrocytes regulate synaptic glutamate levels by taking up excess glutamate through synaptically localized glutamate transporters, and this process can be dysregulated by both inflammatory mediators and HIV proteins , 172. InSome ART medications may also disrupt astrocyte clearance of glutamate at therapeutic concentrations, as studies show that the protease inhibitors amprenavir and lopinavir reduce EAAT2 levels and function in primary human astrocytes . Thus, tComorbid drug abuse is common in patients with HAND, and recent studies have uncovered some of the mechanisms by which drugs of abuse contribute to synaptodendritic damage in HAND models. For example, our studies in cortical neurons showed that morphine activation of µ-opioid receptors inhibits signaling of the dendritic spine promoting chemokine receptor CXCR4 through a mechanism that required upregulation of ferritin heavy chain protein  Fig. 3)3). AlthoComorbid use of stimulant drugs may also contribute to synaptodendritic injury and altered excitability of neurons in specific brain regions. One group showed that cocaine treatment enhanced excitability and calcium spikes of layer V and VI rat medial prefrontal cortex neurons exposed to tat, and tat’s effects were blocked by the L-type calcium channel antagonist diltiazem . A folloThe drivers of HAND pathology in treated patients appear to be both complex and subtle. A few underlying themes promoted by both host and viral factors, such as cytokines, inflammatory mediators, and HIV toxins, fuel the pathology leading to CNS, vascular, and metabolic dysfunction. These insults are often exacerbated by comorbidities like substance abuse and aging as well as select ART regimens. Neurons in some brain regions can adapt to the continued presence of sub-threshold insults, but others seem more vulnerable to synaptodendritic damage and network alterations. Thus, this warrants continued exploration of the mechanisms that produce the subtle synaptodendritic damage underlying cognitive impairment in HAND.As published neuropathology studies that examined synaptic damage used brain tissue from patients with uncontrolled infections or with AIDS, we lack a complete picture of how synaptodendritic damage presents in today’s treated patients. Obtaining enough tissue for these studies to be meaningful will be challenging, as treated patients live much longer than the patients examined in older studies. In the absence of updated neuropathology studies, much of the knowledge on modern-day HAND will have to rely on advanced neuroimaging techniques. Though these techniques cannot directly measure synaptic damage in the brain and have produced conflicting results depending on the specific imaging approach, they can provide insights on macro-level brain alterations that can complement other powerful approaches like gene array studies (currently limited by brain tissue availability), and/or investigations in animal models. Moreover, investigations on neuronal network alterations in HAND can identify changes in neuronal functions in the absence of structural deficits. Thus, functional connectivity studies in HAND patients and animal models can inform examinations of how HIV infection alters brain function even when the infection is controlled. This is important, because HIV-induced changes in synaptic function may precede structural damage or adaptations in the same network. Targeting these upstream pathways could provide new approaches to reverse synaptodendritic damage and cognitive impairment in treated patients. Lending further support to this approach, several studies demonstrate that dendritic spine deficits and cognitive impairment are reversible in animal models of HAND. However, one of the major challenges in this line of study is to determine how factors that contribute to HAND work together to disrupt neuronal circuits. Another challenge will be teasing apart HIV-related alterations of network activity and the resulting neuronal adaptations at a structural and functional level. As certain brain regions appear more adaptive than others, a third challenge will be to determine what makes a brain region or neuronal network vulnerable to HIV-specific insults. Future studies that address these points will provide critical information about why HAND persists in treated patients.Finally, the known approaches to reverse dendritic spine deficits in animal models are a proof of concept, but additional research is required to translate this information into safe and effective treatments for humans. This is especially true considering previous clinical trial failures of compounds designed to target NMDA receptors . Recent


Since its discovery in 1951, chlorpromazine (CPZ) has been one of the most widely used antipsychotic medications for treating schizophrenia and other psychiatric disorders. In addition to its antipsychotic effect, many studies in the last several decades have found that CPZ has a potent antitumorigenic effect. These studies have shown that CPZ affects a number of molecular oncogenic targets through multiple pathways, including the regulation of cell cycle, cancer growth and metastasis, chemo-resistance and stemness of cancer cells. Here we review studies on molecular mechanisms of CPZ’s action on key proteins involved in cancer, including p53, YAP, Ras protein, ion channels, and MAPKs. We discuss common and overlapping signaling pathways of CPZ’s action, its cancer-type specificity, antitumorigenic effects of CPZ reported in animal models and population studies on the rate of cancer in psychiatric patients. We also discuss the potential benefits and limitations of repurposing CPZ for cancer treatment. Chlorpromazine (CPZ), a member of the thiazine-class of heterocyclic compounds known as phenothiazines, appeared in the repertoire of psychotherapeutic drugs in 1952, revolutionizing the treatment of psychiatric disorders , 4. AlthNot long after CPZ entered clinical use as an antipsychotic, it was proposed that CPZ also possessed anticancer activity. Epidemiological studies conducted in Denmark from 1957 to 1980 suggested that psychiatric patients prescribed CPZ had decreased risk of developing cancer . ImportaCPZ, first synthesized by Paul Charpentier in 1951, was initially used as an anesthetic  with an apparent permeability of 303 nm/s , 25. TheThe wide use of CPZ as an antipsychotic medication prompted studies on its effect on a wide range of cellular targets. It became clear that in addition to the neuronal receptors, CPZ also affects multiple seemingly unrelated targets and cellular processes, including inhibition of DNA synthesis , uncoupl3-thymidine incorporation into human bone marrow cells during DNA synthesis, indicating that CPZ inhibits DNA synthesis , also known as neural restrictive silencer factor (NRSF), represses neuronal gene transcription in non-neuronal cells, and regulates neuronal differentiation and gene expression  47–49].–49.47–49in-silico drug screening .–62.60–62In 2019, Yang and coworkers found that CPZ suppresses YAP signaling in MCF7 and MDA-MB-231 breast cancer cells . CPZ treMitosis is a crucial phase in the cell cycle and, therefore, is an important target for cancer therapies. Recent efforts to target mitosis for cancer treatment focus on suppressing cell division via affecting mitotic kinesins . MitoticIn 2007, Lee and coworkers showed that CPZ inhibited KSP/Eg5’s ability to hydrolyze ATP with an IC50 of 5 to 10 μM . The eff2) molecules and subsequently converts O2 to water. In mammals, CcO is composed of thirteen subunits, many of which have multiple isoforms . MA. MA83]. as Elk-1 . CDKN1 pas Elk-1 –90 and mas Elk-1 . The upras Elk-1 .While CPZ increased JNK and ERK1/2 phosphorylation in C6 cells, the same study demonstrated that CPZ decreased p38 MAPK phosphorylation in the same cell line . This suAnother kinase affected by CPZ is Akt, also known as protein kinase B, which in turn activates the mammalian target of rapamycin (mTOR). Akt/mTOR pathway regulates cell cycle and the induction of autophagy, and deficiencies in the pathway have been linked to cancer , 95. RecCalmodulin (CaM) is a multifunctional calcium-binding protein ubiquitously expressed in eukaryotic cells . CaM intCPZ is known to inhibit CaM activity by direct binding to the protein in a calcium-dependent manner  104]. I. I104]. Although several CaM inhibitors have successfully quelled cancer growth and metastasis, it is not clear if CaM inhibition by CPZ is therapeutically relevant. For instance, Zhong and coworkers reported that CPZ has antitumorigenic effect on small cell lung carcinoma (SCLC) . Howeverin vivo and in vitro studies of effects of CPZ on rat liver lysosomes suggested that at high concentrations (>100 μM) CPZ increases membrane permeability [Cellular membranes are vital for cellular integrity and contain numerous transmembrane proteins essential for cellular signaling . An effeeability . The dis18F]2-fluoro-2-deoxy-D-glucose-6-phosphate tracer and increased membrane fluidity in rat brain slices  and EAG-related gene (ERG) channels, which belong to the KCNH family of potassium selective channels –126. EAGClathrin assembly lymphoid myeloid leukemia (CALM) protein is crucial for the formation of clathrin coated vesicles for intracellular trafficking of receptor tyrosine kinases (RTKs) . MutatioIn this section we list known antitumorigenic CPZ effects in different cancers and reported/proposed cellular mechanisms . In brea50 of 13 μM, and also inhibited the cell neurosphere formation and anchorage-independent growth in soft agar [CPZ has been shown to exert antitumorigenic activity in several brain tumors. Medulloblastoma is the most common pediatric brain tumor frequently associated with overexpression of transcriptional repressor REST protein , 58. CPZoft agar . This anoft agar , 57. Thooft agar . CPZ alsoft agar .CPZ suppresses proliferation and induces apoptosis in cultured lymphoma and leukemia cells via DNA fragmentation without affecting the viability of normal lymphocytes . InhibitCPZ decreased proliferation of oral cancer cells while showing low toxicity in normal oral cell lines . This efIn summary, the antitumorigenic effect of CPZ in different cancers frequently involves common molecular/cellular targets that are known to be involved in cancer formation. At the same time, the CPZ’s diverse cellular targets and mechanisms uniquely confer the drug a multiscale antitumorigenic therapeutic potential which has not been fully harnessed yet.in vitro studies. One of the earliest studies of the effect of CPZ in vivo was conducted by Van Woert and Palmer in 1969 [in vivo studies aimed to elucidate CPZ’s anticancer potential and mechanism.Studies in animal models overwhelmingly recapitulate the antitumorigenic effect of CPZ that emerged from  in 1969 . CPZ was in 1969 . Tumor gin vitro studies, as discussed above. Therefore, future studies should further explore CPZ’s anticancer potential as a stand-alone medication, as well as in combination with existing therapies.Multiple studies further utilized mice xenograft models to investigate CPZ’s therapeutic potential for different cancer types, including sarcoma , colorecin vitro studies. Furthermore, animal xenograft studies suggest that repurposing CPZ for cancer treatment as a stand-alone medication or in combination with other cancer drugs should be well tolerated and have low adverse effects.In addition to the rodent xenograft models, CPZ’s antitumorigenic effect has also been demonstrated in zebrafish. Earlier this year, Jhou and coworkers found that CPZ treatment decreased tumor growth in zebrafish larvae grafted with oral cancer tumors . NotablyPopulation studies on the cancer rate in psychiatric patients administered antipsychotics/antidepressants, including CPZ, are somewhat limited and yielded contradictory results. Additionally, most of the studies do not specify which antipsychotic medication was administered to the patients. In a systemic literature review conducted in 2012, Fond and coworkers concluded that overall the patients with schizophrenia may be less likely to develop cancer than the general population . HoweverOne of the first relevant population studies was conducted in Denmark based on the analysis of 6168 patients with schizophrenia followed from 1957 to 1984 . The stuPerhaps the most controversial is the effect of antidepressants/antipsychotics on the rate of breast cancer. A study of 29,641 female schizophrenia patients receiving antidepressants and 59,282 non-users selected based on Taiwan Insurance Claims Data from 1998 to 2008 found that the risk of breast cancer was almost 2-fold higher in the users of antidepressants . This isAs reviewed above, CPZ has a potent anti-proliferative effect on many cancer types achieved by affecting a variety of molecular targets and cellular pathways. CPZ also has an additional benefit due to the documented sedative effect that can reduce anxiety, insomnia and other symptoms related to the mental state of cancer patients . TherefoDespite the potential for cancer treatment there are also known side-effects of CPZ that must be considered. CPZ can cause hypertension, bradycardia and ventricular arrhythmias . TherefoUnequivocally, CPZ is a potent antitumorigenic agent acting through a diverse range of molecular targets and cellular pathways. The rationale for repurposing CPZ for cancer treatment is strong. However, further studies on the molecular and cellular mechanisms of CPZ’s action, and their interdependence are necessary to attain a comprehensive understanding of CPZ’s action in cancer. More refined population studies, specifically focused on the effect of CPZ on cancer patients will also shed light on the therapeutic potential of this drug for cancer therapy. Finally, clinical studies involving dose- and treatment duration-dependence of the CPZ’s effect in cancer are necessary to evaluate a therapeutic potential of repurposing CPZ for cancer treatment.


The ongoing coronavirus disease 2019 (Covid-19) pandemic presents challenges for surgeons of all disciplines, including cardiologists. The volume of cardiac surgery cases has to comply with the mandatory constraints of healthcare capacities. The treatment of Covid-19-positive patients must also be considered. Unfortunately, no scientific evidence is available on this issue. Therefore, this study aimed to offer some consensus-based considerations, derived from available scientific papers, regarding the organization and performance of cardiac surgery against the backdrop of the Covid-19 pandemic.Key recommendations were extracted from recent literature concerning cardiac surgery.RESULTSː Reducing elective cardiac procedures should be based on frequent clinical assessment of patients on the waiting list (every one or two weeks) and the current local status of the Covid-19 pandemic. Screening tests at admission for every patient are broadly recommended. Where appropriate, alternative treatment methods can be considered, including percutaneous techniques and minimally invasive surgery, if performed by experienced cardiac surgery teams.There is little evidence on the strategies to organize cardiac surgery in the Covid-19 pandemic. Most authors agree on reducing elective operations based on patients’ clinical condition and the status of the Covid-19 pandemic. Admission screenings and the use of percutaneous or minimally invasive approaches should be preferred to reduce in-hospital stays. Global public healthcare providers are currently facing an unprecedented challenge in dealing with the coronavirus disease 2019 (Covid-19) pandemic. Readjustments in the field of cardiac surgery are critically important for several reasons: all phases of cardiac surgery  require high capacities of trained staff, operating rooms, and — crucially during the pandemic — intensive care resources. In apportioning intensive care and staff capacities, all involved sectors are forced to triage time-sensitive interventions from those that can be safely delayed, or in some cases, substituted by less complex therapy options [Given the high-speed dynamic of the Covid-19 outbreak, no scientific evidence is currently available to guide medical policymakers during this crucial period of readjustment. Therefore, clear guidelines and recommendations are urgently needed.In this literature review, we aimed to identify the best practices to manage surgical programs until reliable scientific data are available.We searched PubMed for scientific articles using the following terms: “cardiac surgery” AND “coronavirus” OR “covid-19” or “heart surgery” AND “coronavirus” OR “covid-19”. The last search was performed on the 19th of January 2021 .Identified manuscripts were then analyzed for available information on recommendations for cardiac surgeons during the Covid-19 pandemic. Proposed and discussed recommendations were pooled. The analysis did not require the use of any statistical methods. The acquired information was summarized, and key recommendations were generated.A total of 20 publications were identified containing recommendations on the handling of cardiac surgery during the Covid-19 pandemic. The recommendations can be summarized as follows:>Postponing of elective operations should be based on patients’ individual risk –13.>Triage and surgical indications should be adapted according to the local prevalence of Covid-19 and the hospital’s resources –6, 12.>A hub-and-spoke organization system with dedicated cardiac centers may be applied in the acute phase of the epidemic , 7.>The estimated time of the reduced capacity of cardiac surgery is not known –9.>Each hospital should prepare its own guidelines to suit the restrictions based on the local situation –7.Indeed, the incidence of Covid-19 vastly differs around the world, with various epicenters . Other hBased on epicenter experience following clinical strategies have been recently proposed by George at al .: PatienLeft-sided endocarditis with hemodynamic compromise or very large vegetations should be prioritized over cases that can be managed medically until resources improve. Most patients with mitral valve pathologies can also be postponed but should be aggressively managed medically and monitored closely for signs of decompensated heart failure.Patients with giant aneurysms (> 7 cm) as well as (saccular) pseudoaneurysms may be considered for urgent surgery depending on the risk of aneurysm-related death and the availability of resources. Asymptomatic patients with smaller aneurysms can have surgery delayed for 2 to 3 months. All in-patients, who cannot be discharged safely without surgical intervention  need completion of treatment .>Follow up and reevaluation of waiting elective patients should be performed every 1–2 weeks .Only regular contact with pending patients can guarantee their safety. The pandemic situation may also cause a fear of surgery, even in patients with symptomatic heart disease. High-risk patients should be prioritized to preventive strategies, including optimal antithrombotic management, medication review, and stringent monitoring . The Hea>Local extracorporeal membrane oxygenation (ECMO) protocols for both Covid-19 and non-Covid-19 patients should be developed , 10, 12.Although most patients with Covid-19 develop moderate symptoms and recover quickly, some develop severe respiratory failure and acute respiratory distress syndrome, requiring intensive medical care. High mortality is observed in patients with Covid-19 requiring mechanical ventilation. ECMO can save lives in patients with severe respiratory distress syndrome or refractory treatment of heart failure. Primarily, ECMO is widely used in cardiac surgery to treat acute cardiac failure and postcardiotomy cardiogenic shock.> Left ventricular assist device implantation should not be restricted as the treatment of choice for advanced heart failure due to the lack of healthy donor hearts for cardiac transplantation .>Staffing should be kept to a minimum , 2.>Telemedicine techniques should be widely used , 9, 10.>Home office strategy should be applied where possible , 9.>Surgical masks should be worn at any patient contact , 11.The purpose of the above recommendations is to reduce the risk of infection occurrence and spread among hospital staff.>Travel to the hospital by patients and accompanying relatives should be limited –9.>In-person clinic evaluations should be appraised –9.>All patients should be evaluated for respiratory symptoms before hospitalization , 11.>Nasal swab screening for Covid-19 has to be done the same day of admission to the hospital , 8, 11.>Elective or semi-elective cardiac surgeries should be postponed until Covid-19 virus detection results are negative .>All patients should wear surgical masks , 9, 11.Patient recommendations are intended to ensure their safety and prevent a new source of infection in the hospital.>A designated theatre and scrub room should be used for suspected or proven Covid-19 patients –12.>A preoperative Covid-19 checklist should be used for suspected and confirmed Covid-19 patients .>The number of personnel should be kept to a minimum –10, 12.>Appropriate personal protective equipment  should be used for all patients, and in the case of Covid-19-positive patients, PPE2/3 and goggles should be worn –12.General precautions are therefore recommended to prevent the spread of Covid-19 infection through isolation, protective measures, and staff reduction. Patients should be transferred directly to the operating room without stopping in the intesive care unit areas to minimize exposure for patients and staff .>Performing minimally invasive operations in experienced centers may shorten the hospital stay and usage of blood products .>Preference for percutaneous techniques instead of surgery ) , 12.>Extensive use of strategies to avoid wound infections after surgeries .Changing the surgical strategy can be beneficial for experienced teams.Selectively reduce elective cardiac surgery procedures based on continuous assessment of patients on the waiting list (every one or two weeks) and the current state of the epidemic.Perform time-sensitive operations without restrictions.Limit the presence of staff in the clinic and maximize the use of telemedicine.Perform screening tests on patients admitted to the clinic, and await results before undertaking further action.Use percutaneous techniques and minimally invasive procedures if experienced hospital staff are available (to provide benefit and reduce risk).Develop local protocols for patients with suspected or diagnosed Covid-19.Provide protective means including surgical masks for all hospital staff and patients .Participate in the treatment of Covid-19 patients using ECMO provided there are sufficient resources and experienced personnel to do so.Based on the available literature, the above recommendations can be summarized as follows:Due to the unexpected challenges of the Covid-19 pandemic, typical scientific guidelines for cardiac surgery are not available. Available publications usually reflect the opinion and experience of individual authors.The reduction or cancellation of elective heart surgery was identified as the main topic of most publications. Micelli et al. reported their experience in April 2020 and recommended the limitation of procedures to urgent operations only in the region of Lombardy . This re2 insufflation should be used with care to avoid the risk of aerosolization [Another recommendation is to favor percutaneous techniques, such as coronary stenting and TAVI , 12. In lization . Howeverlization . Finallylization .It is currently unclear whether the training of residents during the Covid-19 pandemic should continue. Stopping education in the acute phase of a pandemic is understandable, yet a break in training lasting several months would be not recommended. Therefore, the current recommendation is to minimize exposure among trainees and students, which would also reduce PPE usage (as access is still limited) [Patients admitted to the cardiac surgery department should routinely undergo screening for Covid-19, and the results should be obtained before further action is undertaken. Such action is required as the admission of Covid-19-positive patients increases the probability of Severe acute respiratory syndrome (SARS) coronavirus transmission to staff members, and quarantining such staff would entail excluding a significant proportion of the workforce. Interestingly, systematic polymerase chain reaction-based (PCR) testing was not broadly recommended by all authors –12. If aGaudino et al.  quantifiBetween March 16, 2020 and May 15, 2020, a total of 54 adult patients underwent cardiac surgery at Weill Cornell Medicine in New York beeing an epicenter of pandemics. There was one operative mortality (1.9%) associated with an acute perioperative Covid-19 infection .The Covid-19 pandemic is a new phenomenon in global healthcare. Currently, it is difficult to expect recommendations based on scientific evidence; however, in time, it will become possible to collect data on the results of cardiac surgery during a pandemic. Such data should include mortality rates among those on waitlists, the outcomes of operations, and the number of Covid-19-related deaths following cardiac surgery. Current data suggests an increase in operative mortality in waitlist patients . HoweverTo conclude, the majority of the authors reported reduced cardiac surgery activity, redeployed personnel, and curtailed educational and research activities in response to the Covid-19 pandemic. The volume reduction in cardiac surgery may not lead to enhanced non-Covid-19 mortality.


A 55-year-old woman with high myopia  and known history of Sjogren syndrome presented for routine asymptomatic hydroxychloroquine screening. No other relevant past ocular, medical, or family history was noted. Visual acuity was found to be 20/20 in both eyes (OU). Dilated fundus examination (DFE) without indentation was performed using tropicamide and phenylephrine, and ancillary testing was performed. No signs of hydroxychloroquine toxicity, Weiss ring, retinal tears, or peripheral retinal pathology were noted OU. Incidentally, the screening spectral domain optical coherence tomography (SD-OCT) revealed tenuous vitreous attachment to the optic disc OS [Figure 1A].Two hours after the screening outpatient examination, the patient experienced a new floater OS for which she subsequently presented to the ophthalmology emergency. The on-call ophthalmologist noted a Weiss ring OS without retinal tears or detachments OU. A subsequent SD-OCT scan in the left eye demonstrated a complete posterior vitreous detachment (PVD) [Figure 1B]. The patient was reassured, counselled about the warning symptoms of retinal detachment, and scheduled for a repeat DFE in one week. There is a known anatomical relationship between ciliary body contraction and anterior movement of anterior vitreous body and zonules.,3 Anterior zonule movement results in adjacent anterior movement of the vitreous parallel to the sclera at the ora serrata. While it is unclear if this force would translate to posterior vitreous movement, there is an interesting case report of vitreo-macular traction (VMT) following pilocarpine-induced miosis after mydriasis. In a computer animation-based model of accommodation, it was found that during accommodation the vitreous base is pulled forward and the posterior vitreous is pushed backward. Axially, it is during the relaxation of accommodation that the posterior lens capsule moves anteriorly followed by subsequent anterior movement of posterior vitreous causing shearing at the retinal vitreous attachments. Although our report illustrates temporal association of completion of impending PVD following DFE, the precise changes in the posterior hyaloid in response to DFE are still unclear.To the best of our knowledge, this is the first report of completion of an impending PVD following cycloplegic DFE. Accommodation-induced ciliary body contraction, anterior displacement of the lens–iris diaphragm, and axial elongation of the vitreous cavity may be more pronounced in myopic patients.Further work could be done to elucidate the relationship between accommodative state and PVD. Wide-field OCT may expand our understanding of peripheral vitreoretinal physiology.Nil.There are no conflicts of interest.