Medical staff caring for COVID-19 patients face mental stress, physical exhaustion, separation from families, stigma, and the pain of losing patients and colleagues. Many of them have acquired SARS-CoV-2 and some have died. In Africa, where the pandemic is escalating, there are major gaps in response capacity, especially in human resources and protective equipment. We examine these challenges and propose interventions to protect healthcare workers on the continent, drawing on articles identified on Medline (Pubmed) in a search on 24 March 2020. Global jostling means that supplies of personal protective equipment are limited in Africa. Even low-cost interventions such as facemasks for patients with a cough and water supplies for handwashing may be challenging, as is ‘physical distancing’ in overcrowded primary health care clinics. Without adequate protection, COVID-19 mortality may be high among healthcare workers and their family in Africa given limited critical care beds and difficulties in transporting ill healthcare workers from rural to urban care centres. Much can be done to protect healthcare workers, however. The continent has learnt invaluable lessons from Ebola and HIV control. HIV counselors and community healthcare workers are key resources, and could promote social distancing and related interventions, dispel myths, support healthcare workers, perform symptom screening and trace contacts. Staff motivation and retention may be enhanced through carefully managed risk ‘allowances’ or compensation. International support with personnel and protective equipment, especially from China, could turn the pandemic’s trajectory in Africa around. Telemedicine holds promise as it rationalises human resources and reduces patient contact and thus infection risks. Importantly, healthcare workers, using their authoritative voice, can promote effective COVID-19 policies and prioritization of their safety. Prioritizing healthcare workers for SARS-CoV-2 testing, hospital beds and targeted research, as well as ensuring that public figures and the population acknowledge the commitment of healthcare workers may help to maintain morale. Clearly there are multiple ways that international support and national commitment could help safeguard healthcare workers in Africa, essential for limiting the pandemic’s potentially devastating heath, socio-economic and security impacts on the continent. Studies were included if they presented data or commentaries on the infection risks and mental wellbeing impacts that healthcare workers face during the COVID-19 pandemic. Studies could be in any setting. We also included articles that covered the COVID-19 pandemic in Africa Iin general . We excluded articles on infection control or mental health of COVID-19 if they covered topics that were not relevant to Africa.The literature was identified in a search on Medline(Pubmed) up to 24 March and identified using the following search strategy: ((((((coronavirus) AND ("2020"[Date - Create] : "3000"[Date - Create]))) OR SARS-CoV-2) OR 2019-nCoV) OR COVID).Sustaining safe and quality care in the SARS-CoV-2 pandemic hinges on the health and mental wellbeing of frontline healthcare workers. Medical staff face exhaustion, difficult triage decisions, separation from families, stigma and the pain of losing patients and colleagues, in addition to their own risks of infection. In Italy as of 3 April 2020, around 10,000 healthcare workers have been infected and 74 have died, and many others have died in countries across the globe . IncidenIn this review we describe the infection risks and mental health challenges that healthcare workers face in the COVID-19 pandemic and propose interventions to counter these in Africa. We highlight lessons from previous disease-control efforts on the continent and draw on experiences with SARS-CoV-2 in other parts of the world. We searched Medline (Pubmed) on 24 March (see Additional File Fig. In all settings, patients who have unusual symptoms of COVID-19 or very mild general flu-like symptoms pose considerable risk to healthcare workers who may not have a high level of clinical suspicion in these patients and adopt adequate protective measures. Additionally, in the tropics, patients may present with febrile conditions related to vector-borne and other infections, but have SARS-CoV-2 coinfection. In Thailand, for example, a patient was admitted with dengue fever and also had SARS-CoV-2 and the healthcare worker responsible for care became infected .Healthcare workers – and, indeed, patients admitted to a health facility for other reasons – are particularly vulnerable to infection from ‘super-spreading events’. In one instance in Wuhan, China a large cluster of infections occurred in healthcare workers and patients . These iRisks of SARS-CoV-2 infection may be higher among professionals who work in close physical proximity to patients, such as ophthalmologists and dentists –15. AddiRisks of healthcare worker infection can be mitigated with adequate precautions within health facilities –20. PrimRisks of infection in healthcare workers appears tied to duration of shifts and hand hygiene, among other factors . Water sA range of simple low-cost interventions can reduce the likelihood of infection transmission to healthcare workers in hospitals, including facemasks for patients who have respiratory symptoms, tissues for patients, promotion of cough etiquette and hand washing, and maintenance of at least two metres distance from others. ‘Social [physical] distancing’ between patients and administrative, cleaning staff and healthcare workers may, however, be especially challenging in busy overcrowded primary health care clinics on the continent.Many governments in Africa will require support from international donors to protect frontline healthcare workers from the outset of the pandemic. The government of China has provided personnel and equipment to support COVID-19 services in many parts of the world . SupportMortality rates among healthcare workers who become infected may be especially high in many parts of Africa given the limited number of critical care beds . MoreoveOverall, much more thought is needed about the optimum use of healthcare workers in the COVID-19 response in rural parts of the continent. During the Ebola outbreak, mobile testing units moved between villages, detecting clusters of infection, quarantining those areas and building temporary treatment centres where required. Such efforts helped to target human and other resources to where it was most needed, while allowing economic activities to continue in unaffected areas. Some combination of antigen, antibody testing and symptom screening may be needed to identify affected communities who are then prioritised for COVID-19 services. Testing and later vaccinating of healthcare workers was a key strategy in the Ebola epidemic, but testing constraints and lack of a vaccine hinders that approach with the current pandemic. Serological testing which demonstrates past infection may provide major relief for healthcare workers and potentially allow people who have immunity to return to work.Caring for patients with COVID-19 disease causes considerable mental stress, resulting in high levels of anxiety and post-traumatic stress disorders, especially among nurses . These cPsychological support is key, perhaps drawing on the large numbers of HIV counsellors or retired nurses in many parts of the African continent. Formal structured interventions, however, may encounter obstacles, given the competing priorities of health staff . InformaWhile healthcare workers may accept an increased risk of infection as part of their chosen profession, they may have considerable anxiety about spreading the virus to their children, families and friends, especially those who are elderly or have chronic medical conditions, and perhaps even their pets, despite the evidence for this being limited , 38. HeaIn any biological disaster, fear and stigmatisation are heightened, and healthcare workers may be a target of the latter. Many healthcare workers in the recent Ebola and SARS epidemics experienced considerable stigmatization, loneliness and even loss of trust within their own communities , 41. In Initiatives to increase the number of healthcare workers available to meet the burden of care have included moving staff from other disciplines to medical wards, fast-tracking medical students to join the workforce, cancelling healthcare worker leave and drawing on retired healthcare workers , 47. HeaHealthcare workers in Africa face considerable challenges during the pandemic. We present 10 priority interventions to safeguard frontline healthcare workers in Africa (Table Additional file 1.


Robotic systems have fundamentally altered the landscape of functional neurosurgery. These allow automated stereotaxy with high accuracy and reliability, and are rapidly becoming a mainstay in stereotactic surgeries such as deep brain stimulation (DBS), stereoelectroencephalography (SEEG), and stereotactic laser ablation/MRI guided laser interstitial thermal therapy (MRgLITT). Robotic systems have been effectively applied to create a minimally invasive approach for diagnostics and therapeutics in the treatment of epilepsy, utilizing robots for expeditious and accurate stereotaxy for SEEG and MRgLITT. MRgLITT has been shown to approach open surgical techniques in efficacy of seizure control while minimizing collateral injury. We describe the use of robot assisted MRgLITT for a minimally invasive laser anterior temporal lobotomy, describing the approach and potential pitfalls. Goals of MRgLITT are complete ablation of the epileptogenic zone and avoiding injury to uninvolved structures. In the middle fossa these include structures such as cranial nerves in the skull base and cavernous sinus and the thalamus. These can be mitigated with careful trajectory planning and control of laser ablation intensity. Advancements in robotic and laser technology have dramatically altered the landscape of functional neurosurgery. The principal application of robotics in functional neurosurgery has been automated stereotaxy, providing a potentially expeditious workflow for cases involving multiple sequential and unrelated trajectories, as exemplified by stereoelectroencephalography (SEEG). A number of robotic stereotactic devices are currently available in North America, including the Neuromate robotic system (Renishaw), ROSA ONE Brain robotic platform (Zimmer Biomet), and Stealth Autoguide cranial robotic guidance platform (Medtronic). Robots are rapidly becoming a mainstay in surgical stereotaxy and studies have demonstrated that the accuracy of robotic guidance systems can approach that of gold-standard stereotactic frames –4.Likewise, the modern surgical application of laser technology combines a number of advancements, narrow-caliber cooled-fibers for laser interstitial thermal therapy and magnetic resonance thermography for non-invasive real-time imaging of tissue temperature, into a minimally invasive therapeutic strategy. Two commercial platforms utilizing this technology are currently available for central nervous system application in North America, NeuroBlate (Monteris) and Visualase (Medtronic). Robotic stereotaxy and laser technology can be combined as a minimally invasive therapy, providing surgeons a method to ablate tissue across a number of subspecialties including epilepsy and neuro-oncology.Laser ablation of the temporal lobe is especially challenging due to its complex shape and volume. MRgLITT has been successfully applied to ablation of the mesial temporal lobe for laser amygdalohippocampotomy, with up to 53% freedom from focal seizures impairing awareness reported after 12 months , with vaA 32-year-old right handed female presented with a 2-year history of medically refractory right temporal lobe epilepsy. Her seizures comprised 2 semiologies; the first consisted of focal seizures with déjà vu, out of body sensation and dream-like state, shortness of breath, nausea, diaphoresis, and bilateral hand paresthesia. These sometimes progress to behavioral arrest and loss of awareness. She reported post-ictal tiredness, fear and confusion. These initially occurred 2–20 times per day, however the frequency reduced to 1–3 times per month with lacosamide treatment, and followed a catamenial pattern. Her second seizure semiology consisted of generalized tonic seizures, characterized by arm extension and stiffening, lasting a few minutes, with 2 h of post-ictal confusion. These were infrequent, having occurred twice since the onset of her seizures. She has an existing diagnosis of depression and took citalopram for this. She denied specific risk factors, precipitating events, or other psychiatric comorbidities. She reported, however, that she was hospitalized with fever of unknown origin at age 19-years-old and again at 20-years-old (10–11 years prior to seizure onset). Her other medical history was unremarkable and she had not had prior epilepsy surgery or evaluation. She had failed trials of levetiracetam, oxcarbazepine, and lamotrigine. Cerebrospinal fluid and blood serology were negative for auto-antibodies. She was neurologically non-focal on examination.Long-term video scalp electroencephalography (LTvEEG) captured 10 events. Two events were characterized by whole body tremors and pelvic thrusting without electrographic correlate (and were deemed non-epileptic events). For two events she reported a dreamlike state that often occurred prior to her seizures, however these had no electrographic change. Six typical events were captured, during which she described her typical semiology of a rushing feeling, bilateral hand paresthesia and nausea; she did not exhibit behavioral arrest. During these typical events, right frontal temporal polymorphic delta and theta activity were noted, maximal in F8/T2. She underwent neuropsychological testing, which demonstrated average to above average function with mild dysfunction in both verbal and non-verbal domains. While there was a slight split favoring non-verbal performance, other areas conflicted this, including better visual naming vs. auditory naming. Therefore, her neuropsychological testing was felt to be non-lateralizing.z = −2.78) however this was felt to be discordant with her semiology and therefore of low clinical relevance during epilepsy multi-disciplinary team discussion. Ictal single-photon emission computerized tomography (SPECT) was attempted but injection of isotope was unable to be timed appropriately with a seizure. Results were therefore reported as interictal SPECT, which showed an area of hypometabolism in right inferior temporal lobe. Magnetoencephalography (MEG) demonstrated a single interictal spike in right medial basal temporal lobe. Her case was discussed in an epilepsy multi-disciplinary team meeting; given her semiology and LTvEEG findings it was reasoned that the most likely location for seizure onset was her right mesial temporal lobe. As she did not have mesial temporal sclerosis (and therefore did not meet criteria to skip invasive monitoring), it was recommended that she undergo stereoelectroencephalography (SEEG). Given mixed language dominance and potentially discordant neuropsychological memory results, she also underwent Wada testing, which unambiguously confirmed left sided support of memory and language.Her brain MRI showed no structural abnormalities . VolumetStereoelectroencephalography (SEEG) was performed targeting the right temporal lobe and related networks. Sampled locations included mesial structures , basal structures (fusiform gyrus), lateral structures , and limbic lobe associated structures . Twelve electrode arrays were placed in total, utilizing robotic assisted stereotaxy (ROSA robot), and the patient was monitored for 4-weeks. She had one typical clinical seizure  which was first detected in the contacts located in the fusiform gyrus  with sprMRgLITT was performed utilizing the ROSA stereotactic robot, at 6 trajectories encompassing the right temporal lobe. The patient's head was secured within a stereotactic frame base ring  and then affixed to the ROSA robot. Stereotactic registration was performed and the robotic articulated arm was navigated to each trajectory. In each location a twist-drill hole was made and laser bolts  were placed. Once the bolts had been placed, alignment stylets were inserted to target  and an O3 [itksnap.org  was used to ablate all six trajectories, with the intention of confluent ablation of the medial temporal structures , as well as temporal pole, basal temporal lobe, and lateral temporal lobe extending 5 cm from the temporal tip. snap.org . Total aImmediately after surgery the patient had no gross neurological deficits. By post-operative day 1, however, she was noted to have the onset of right facial weakness. This gradually progressed by post-operative day 3 to an inability to close her right eye (House Brackman grade 4). Direct thermal injury during the ablation was considered unlikely to have occurred as the laser fiber was intentionally placed 8 mm away from the middle fossa skull base, and deficit took time to develop. She underwent repeat CT that demonstrated stable post-ablation changes . She remAt 6-months after surgery, her hemifacial weakness had improved considerably to House Brackman grade 2, not visible at rest and she was able to close her right eye completely, and some residual reduced acuity of hearing with the right ear. She reported subjective headaches and insomnia but she did not find these symptoms bothersome enough to warrant further investigation. Her husband also reported multiple episodes of brief staring and unresponsiveness, and the patient denied recollection of these events, and given history of non-epileptic events, the episodes remained unconfirmed. These events occurred several times per week, without conversion to generalized seizure. Given the history of non-epileptic events, these episodes could not be discriminated from possible focal impaired awareness seizures, and lacosamide dosing was increased by her treating neurologist.At 12-months after surgery, she reported complete resolution of her hemifacial weakness, however she acknowledged subjectively reduced acuity of right-sided hearing. She was referred to otorhinolaryngology, but chose not to pursue this. She denied new memory complaints and did not submit to post-operative neuropsychological assessment. Notably, follow up history and physical examinations did not detect visual defects or complaints, although we did not pursue formal ophthalmological evaluations. She and her husband denied any further episodes of impaired awareness since the increase in lacosamide dosing and no generalized seizures since surgery.Robot-assisted MRI-guided laser interstitial thermal therapy provides a novel tool in the neurosurgeon's armamentarium for the treatment of epilepsy . In particular, the surgical techniques that we describe combine novel robotic stereotaxy with laser technology to provide a minimally invasive approach for laser temporal lobotomy. A surgical strategy that utilizes robot-assisted stereoencephalography (SEEG) and MRgLITT is particularly powerful as it combines minimally invasive intracranial diagnostics with minimally invasive therapy. LITT ablation of the mesial temporal lobe has now been reported from multiple epilepsy surgery centers in North America, and such ablations have often utilized robotic and SEEG techniques . NonetheFor patients diagnosed with MTLE, larger temporal lobe resections are associated with a greater chance of seizure freedom, presumably by eliminating occult epileptogenic tissues. The highly selective laser technique that is typically reported targets the amygdala, hippocampus, subiculum, and part of the entorhinal cortex. By contrast, open anterior temporal lobectomy generally also includes resection of the temporal pole, all of the rhinal cortices within the anterior fusiform and parahippocampal gyri, as well as anterior portions of the lateral temporal lobe, all of which may harbor occult epileptogenic tissues. Middle ground is represented by open “selective” amygdalohippocampectomy techniques which typically include much of the rhinal cortices. Thus, it comes as no surprise that despite efforts to select patients ideal for each of these procedures, overall seizure freedom rates have been reported as ~68–78% achieved by anterior temporal lobectomy in lesional cases , 11 vs. Improved patient experience with MRgLITT may also expand access to epilepsy surgery for patients fearful of open surgery. When patients are asked their opinions about epilepsy surgery beforehand, a majority (74%) expressed “anxiety of the unknown” prior to surgery, even though after surgery the vast majority (94%) reported surgery increased their independence and only a minority (19%) complained of wide-ranging psychological and neurological long-term adverse effects such as fatigue, memory, and concentration impairment . These aWe have previously described outcomes of LITT to target lesion boundaries and networks explored by SEEG . In our For trajectory planning, deliberate considerations must be made to (i) target the appropriate tissue for ablation and (ii) avoid key structures to minimize the risk of complications from off-target injury. In particular for the mesial temporal lobe, cranial nerves within the cavernous sinus, along the tentorium, and within the skull base are vulnerable to thermal injury, as well as the optic tracts and lateral geniculate nucleus (LGN) of the thalamus which overly the body of the hippocampus. This patient did incur an ipsilateral facial nerve injury, which resolved with conservative management by 6-months after surgery. Proximity to the skull base was considered during surgical planning, and the trajectory in this location was planned 8 mm away from the skull base to account for the expected diameter of the ablation. As the patient seemed to have no facial nerve palsy immediately after surgery but developed hemifacial weakness progressively over the first 3 days after surgery, this suggests that direct thermal injury during the ablation was not the cause. Given prior reports of prolonged blood brain barrier disruption following laser ablation including a published case of delayed optic neuritis , it is pWe described the application of robotic stereotaxy and MR-guided laser interstitial thermal therapy in a combined minimally invasive surgical workflow for anterior temporal lobotomy. Robot guided MRgLITT provides a number of benefits, including those associated with minimally invasive techniques such as smaller incisions and reduced length of stay, with comparable surgical efficacy. Complications remain possible with minimally invasive techniques, and must be considered and mitigated with prior knowledge and experience. Minimally invasive techniques such as MRgLITT will not entirely replace open surgical techniques, however complement existing treatments and offer alternate therapeutic strategies in selected patients. MRgLITT may also expand access to epilepsy surgery for patients who refuse open surgery.The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Emory University IRB. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.KG and JW conceptualized the manuscript. KG, AD, and JW wrote the manuscript. RH and EF provided data. All authors approved the final manuscript.JW: Medtronic-consulting, research contract , honoraria for teaching, Neuropace-consulting, research contract, honoraria for teaching, Clearpoint Neuro/MRI Interventions-consulting, AiM Medical-consulting. EF has received research support from UCB Pharma, Xenon, Eisai, and the NINDS, and consulting fees from Biogen, Supernus, SKLife Science, and the CDC. RH is involved with the Medtronic SLATE trial but receives no financial support. The remaining 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.


Cellular secretion depends on exocytosis of secretory vesicles and discharge of vesicle contents. Actin and myosin are essential for pre-fusion and post-fusion stages of exocytosis. Secretory vesicles depend on actin for transport to and attachment at the cell cortex during the pre-fusion phase. Actin coats on fused vesicles contribute to stabilization of large vesicles, active vesicle contraction and/or retrieval of excess membrane during the post-fusion phase. Myosin molecular motors complement the role of actin. Myosin V is required for vesicle trafficking and attachment to cortical actin. Myosin I and II members engage in local remodeling of cortical actin to allow vesicles to get access to the plasma membrane for membrane fusion. Myosins stabilize open fusion pores and contribute to anchoring and contraction of actin coats to facilitate vesicle content release. Actin and myosin function in secretion is regulated by a plethora of interacting regulatory lipids and proteins. Some of these processes have been first described in non-neuronal cells and reflect adaptations to exocytosis of large secretory vesicles and/or secretion of bulky vesicle cargoes. Here we collate the current knowledge and highlight the role of actomyosin during distinct phases of exocytosis in an attempt to identify unifying molecular mechanisms in non-neuronal secretory cells. Regulated secretion is a fundamental process in many different types of eukaryotic cells. In general, vesicle contents are released by exocytosis of secretory vesicles in response to an extracellular stimulus. This involves a sequence of highly regulated steps. Secretory vesicles are transported to the plasma membrane (PM), fuse with the PM and release their secretory cargo into the extracellular space. The basic principles are conserved amongst all secretory cells, mainly neurons, hematopoietic, endocrine and exocrine cells . HoweverIn particular, cytoskeletal elements such as actin and myosin have been found to play distinct roles within different types of secretory cells. Historically, it was believed that the cortical actomyosin complex beneath the PM mainly acts as a mechanical barrier to prevent “premature” fusion of secretory vesicles with the PM. This hypothesis mainly originated from early observations in neuronal and neuro-endocrine cells. The recent development in imaging technologies and the wider interest in secretion from non-neuronal cell types, however, have revealed a much wider impact of the actomyosin system on secretion. Novel molecular pathways and regulatory mechanisms of the actomyosin system have been described. It is well established now that the actin cytoskeleton provides tracks for trafficking of secretory granules towards the fusion sites ,3 and thBiogenesis of secretory vesicles typically starts in the center of the cell, within the Golgi network. Lipids and proteins destined for secretion or insertion into the PM are packed in vesicles that bud off the trans-Golgi network. The vesicles are then transported (trafficked) to the cell periphery to finally fuse with the PM. The cytoskeleton provides intracellular tracks to facilitate directional movement of secretory vesicles towards PM. In mammalian cells, microtubules serve as major tracks for long distance vesicle transport by the motor proteins kinesin and dynein. Thus microtubule organization is important for targeted delivery of secretory carriers to the cell periphery ,11. BindDrosophila larval epithelial cells [In mammalian pancreatic acinar cells  and Drosal cells , organizal cells ,15,16.MyoV is the best-known actin-associated molecular motor involved in transport of secretory vesicles towards the PM ,18. MyoVVesicle membrane proteins that can provide the connection to myosin motors are Rab GTPases. Rab proteins are a large family of small GTPases that selectively bind to different intracellular compartments involved in trafficking ,23. TradMyoV binds to secretory vesicle associated Rab indirectly via linker molecules. In endothelial cells, which secrete high molecular weight protein von Willebrand factor (vWF) from cigar-shaped secretory vesicles termed Weibel–Palade bodies (WPBs), the linker molecule between myoVa and Rab27a is the Rab effector MyRIP  ,26. MyRITogether these findings suggest that transport mediated by actin and myoV functions via a conserved set of accessory proteins. In most cases actin provides tracks for short-range transport near the cell periphery. However, the actin cytoskeleton can also provide a means for long-range trafficking. Disruption of microtubules with nocodazole had no effect on cortical granule trafficking from the cell center towards the PM in oocytes. However, when the actin network was disrupted with cytochalasin, vesicle transport was abolished, suggesting a pivotal role for actin in transport ,32. Following transport to the PM, a myoV-mediated connection between actin and secretory granules was also suggested to be important for vesicle attachment to the cell cortex .Docking and fusion of secretory vesicles with the PM require a cortical actin network and its remodeling . CorticaFormins and Arp2/3 represent the most important actin nucleators in the actin cortex. Their contribution to production of actin filaments in the cell cortex varies in different cell types and in different stages of cell division . This afDue to its density, cortical actin was long regarded as a diffusion barrier that prevents access of granules to secretory sites and traps secretory vesicles in the cortical network ,42. In nActin cortex remodeling is necessary to enable access of large secretory vesicles to the PM for fusion of vesicles with the PM. Myosin II (myoII), which is ubiquitously present in the cortical network, was suggested to play a pivotal role in this remodeling step. In NKcells, lytic granules, which contain pore forming proteins and proteases such as perforin and granzyme, are secreted at the site of immunological synapse. A recent super-resolution microscopy study showed that displacement of actin filaments created clearances in cortical actin that were sufficiently large to allow passage of lytic granules . An Arp22) levels and to activity of small GTPases of the Rho family. PIP2 regulates adhesion between the PM and cytoskeleton by affecting numerous actin-associated proteins necessary for actin crosslinking and turnover [2 and actin-binding protein phosphorylated by protein kinase C (PKC). Increased intracellular Ca2+ concentration activates PKC, which phosphorylates MARCKS and thereby induces its translocation from the PM to the cytosol. MARCKS translocation from the PM can decrease actin filament crosslinking in the cell cortex and increase PIP2 availability, which facilitates cortical actin dynamics during exocytosis [Regulation of cortical actin reorganization is often connected to changes in PM phosphatidylinositol 4,5-bisphosphate  ,96. HoweDrosophila larvae [In many secretory cells actin and myosin are specifically recruited to the surface of secretory granules following their fusion with the PM. Actin and myoII coating of fused granules had already been observed several decades ago ,105. Eara larvae  and insua larvae . All the2 diffuses from the PM into the membrane of fused vesicles in salivary glands of Drosophila [2 hydrolysis by phospholipase C, was identified as the main regulator of actin coat formation on cortical granules in Xenopus oocytes [Most studies focused on a specific set of molecules/regulators of actin coat formation and compression in different secretory cells. However, some overlap exists between individual studies and fundamental principles seem to be widely conserved. Membrane mixing seems a prerequisite for actin coat formation. Upon fusion, key signaling molecules of the PM can diffuse into the fused secretory granule membrane and act as trigger for local actin assembly (‘kiss-and-coat’) . In partosophila  and in A oocytes . Subsequ oocytes ,106,111  oocytes ,112. Nuc oocytes ,80,111 o oocytes ,95. Give oocytes . Drosophila line expressing fluorescently labelled Arp3, Arp3 was recruited to vesicles with considerable delay (~29 s) after actin coat formation [Formins have been found to be necessary for formation of actin coats within numerous secretory cells ,80,111. ormation . Arp2/3 ormation ,64, but ormation ,80.It is tempting to speculate on whether the main nucleation mechanism determines subsequent coat compression and/or stabilization. Formins mediate nucleation of unbranched, linear filaments  and acceXenopus oocytes [A role for myoII in actin coat contraction has been reported in most systems ,108,117. oocytes . Inhibit oocytes . Myo1b [ oocytes  and myo1It has also been speculated that actin polymerization alone might be sufficient to compress the exocytic vesicle ,124. RecMost likely, contraction is a result of several synergistic mechanisms, including actin polymerization/crosslinking and myosin driven contraction ,120. SynThe role of coat contraction and vesicle compression seems to be adapted to the physiological setting of secretion. For secretion of bulky, poorly soluble cargo , it is mainly to provide the force necessary to expel cargo from fused granules through a narrow fusion pore ,81,120 aXenopus laevis oocytes [Compensatory endocytosis is one of the primary mechanisms through which cells maintain their surface area after exocytosis . It is w oocytes  by an en oocytes . Exocyto oocytes .Similar observations have been made in pancreatic beta and acinar cells. Actin-coating of fused insulin granules leads to local enrichment of endocytic proteins quickly after granule fusion  and zymoIn most of the non-neuronal secretory cells where actin coat formation on exocytosed granules has been reported, compensatory endocytosis is not directly driven by actin coat dynamics. In salivary gland acinar cells, the vesicle membrane is integrated into the PM before retrieval by clathrin-independent endocytic mechanisms ,131. In It is well established that actin and myosin are central players for regulated exocytosis in non-neuronal secretory cells. From providing tracks to target secretory granules to fusion sites to actively squeezing bulky cargoes from fused vesicles and retrieving excess membrane following fusion, actin, myosin and a plethora of interacting regulatory lipids and proteins contribute to secretion. Our understanding of these interactions and molecular mechanisms is increasing. However, how this is temporarily and spatially regulated from the pre- to the post-fusion phase is still enigmatic. This is particularly so for how changes in actin polymerization/depolymerization are regulated—from a dense cortical barrier meshwork to a permissive, docking and fusion promoting gel, to a complex actin structure essential for fusion pore stabilization and post-fusion actin coating. Similarly, myosins seem to serve multiple functions, from force generation to filament crosslinking and stabilization of membranes and actin networks. All these processes are intimately intertwined. The advent of novel, super-resolution technologies promises to provide means to follow these interactions with ever increasing detail to increase our understanding of the molecular mechanism governing secretion not only in neuronal but also in non-neuronal secretory cells.


Cancer occurs when cells refuse to die and keep multiplying while concealing themselves from the adaptive immune system. Remarkably, the innate immune infiltrate  often supports cancer progression, especially at later stages of tumor development. In this regard, myeloid-derived innate cells are greatly responsible for tumor promoting-inflammation and constitute the major source of (lymph)angiogenic factors, thus creating new routes of cancer escape and mediating resistance to anti-angiogenic therapies . In mammRecently, we have identified a subset of TAMs characterized by the expression of Podoplanin (PDPN) – a glycoprotein implicated in regulating cell motility and adhesion . Up to dIn vivo, the deletion of PDPN in macrophages or the deletion of GAL8 in lymphatic vessels exerted very similar effects, namely impaired TAM-LV interactions, abridged tumor lymphangiogenesis and consequently diminished organ metastasis. The deletion of both proteins at the same time had no synergistic effects, confirming that PDPN in macrophages and GAL8 in lymphatics participate in the same molecular process which facilitates lymphangiogenesis in breast cancer.Based on these observations, we further investigated why PoEMs were found in the lymphatic space and by what means their presence aided lymphangiogenesis. In a series of Transwell migration assays we identified Galectin 8 (GAL8) as a soluble factor released by lymphatic endothelial cells (LECs) that attracted PoEMs but not Podoplanin-negative macrophages (non-PoEMs). GAL8 is a glycan-binding protein often classified as an extracellular matrix (ECM) component with properties similar to fibronectin. At large, GAL8 acts as a molecular anchor regulating cell motility and adhesion, as its binding triggers integrin-mediated signaling cascades resulting in cytoskeleton rearrangement and directional cell movement . In linein vitro and in vivo assays, summarized in In order to unveil the functional differences between PoEMs and non-PoEMs we sorted those populations from orthotopic 4T1 tumors and analyzed their transcriptomes. We found that PoEMs significantly upregulated genes related to extracellular matrix (ECM) remodeling, both in terms of matrix deposition (collagen subunits) and degradation . Unsurprisingly, ECM remodeling is of paramount importance during lymphangiogenesis, as LVs stay in direct contact with the matrix due to the incompletion of their basement membrane. Most commonly, lymphatic capillaries lay on type I collagen, whose various subunits were highly upregulated in PoEMs. Furthermore, sprouting lymphatic tip cells migrate towards growth factors, and those are liberated from the matrix due to the enzymatic activity of MMPs. Of note, ECM formation and degradation, as well as matrix stiffness, mechanically modulate the ability of cancer cells to migrate and invade LVs. Following, we confirmed the enhanced ability of PoEMs to deposit and digest various matrix components in several Finally, we translated those findings to human breast cancer. First, we found that PoEMs represented 30% of the overall TAM population also in this context, and that they were able to migrate towards lymphatic endothelium-derived GAL8, mirroring our observations in mice. Then, we assessed the localization of PoEMs in tumor samples from a unique cohort of patients with bilateral tumors, in which one tumor was LN-positive (indicating LN involvement) and the other tumor was LN-negative. Remarkably, LN-positive tumors were characterized by a significantly higher frequency of PoEMs in the perilymphatic space as compared to LN-negative tumors. Moreover, elevated numbers of perilymphatic PoEMs in those samples correlated with higher rate of distant organ metastasis.On the whole, our findings highlight an emerging concept that properties of macrophages are inherently related to specific niches they reside in. In recent years, a plenty of research has focused on TIE2-positve macrophages proximal to blood vessels (where they promote pro-angiogenic programs) . On the


In today’s society, commercial physical activity apps  are ubiquitous and hold considerable potential to increase physical activity behavior. Many commercial physical activity apps incorporate social components, in particular app-specific communities  or the capacity to connect to existing social networking platforms . There is a growing need to gain greater insights into whether commercial physical activity apps and specific components of these apps  are beneficial in facilitating physical activity.This study aimed to examine the relationship between the use of commercial physical activity apps and engagement in physical activity. The social components of commercial physical activity apps  were also explored. This involved isolating specific features  of app-specific communities and existing social networking platforms that were most valuable in facilitating physical activity.A cross-sectional web-based survey was conducted. Participants were 1432 adults  who completed measures assessing physical activity, the use of commercial physical activity apps, and engagement with app-specific communities and existing social networking platforms.Overall, 53.14% (761/1432) of the sample reported engaging with a commercial physical activity app. The most commonly used apps were Fitbit , Strava , and Garmin . The use of physical activity apps was significantly associated with physical activity. Notably, the use of app-specific communities and existing social networking platforms facilitated significantly greater engagement in physical activity. The features of app-specific communities that were most beneficial in promoting engagement in physical activity were providing encouragement to a partner, receiving encouragement from close friends and family, and engaging in competitions with members of public app-specific communities. In relation to existing social networking platforms, sharing physical activity posts predicted engagement in physical activity.The findings indicate that app-specific communities and existing social networking platforms are components of apps that are fundamental in facilitating physical activity. They further suggest that commercial physical activity apps afford high population level reach and hold great potential to promote engagement in physical activity, an important public health consideration. Physical activity confers many health benefits, including a reduced risk of cardiovascular disease, hypertension, osteoporosis, diabetes mellitus, obesity, mental illness, and premature mortality -3. DespiPhysical activity mobile apps present an innovative approach to promote engagement in physical activity due to their widespread reach, accessibility, and convenience. Recently, there has been exponential growth in the availability of commercial physical activity apps  . HoweverA growing body of research examining the content of commercial apps has identified that social features are an increasingly ubiquitous component ,8-10. ThContent analyses of commercial apps have identified that many physical activity apps also have the capacity to connect to existing social networking platforms such as Facebook or Instagram ,8-10. ThTo our knowledge, no previous study has comprehensively examined commercial physical activity apps and specifically, how the social components of these apps  may be associated with physical activity. This is important given the increasing prevalence of commercial physical activity apps together with the need to isolate components of apps that are linked to physical activity engagement. Thus, the first aim of this study was to gain a comprehensive understanding of the use of commercial physical activity apps and their relationship with physical activity. The second aim was to explore the value of app-specific communities and existing social networking platforms in facilitating physical activity. More specifically, we sought to ascertain the features of app-specific communities and existing social networking platforms that were used and how these were associated with frequency of app use and engagement in physical activity.Physical Activity and Online Social Networking. Ethical approval was obtained from the University Social and Behavioral Research Ethics Committee (protocol no. 8232). All participants provided informed consent electronically. Participants were adults, ≥18 years, and proficient in English.A web-based cross-sectional survey was conducted. Participants were recruited via the Discipline of Psychology’s web-based research participation system, paid Facebook advertising, and free advertisements placed on social networking platforms  for a study on Participants completed a web-based survey through the Qualtrics platform between February and April 2019. The survey took approximately 30 min to complete and incorporated the measures listed below in the order of presentation. As a token of appreciation, participants could enter a raffle to win 1 of 5 AUD $25 (USD $15) shopping gift vouchers.Participants were invited to report their age, gender identity, and ethnicity.Regular structured physical activity was assessed following the methods of Prichard and Tiggemann . ParticiParticipants were asked to self-report their current use of physical activity apps, defined as apps that have the capacity to track or monitor physical activity  or provide guided training or workouts. In particular, participants were asked to self-report using an open-ended response format, the name of the physical activity app they were currently using most frequently , the physical activity or sport they were using the app for, and their level of engagement with the app (number of times used per week). The apps were categorized according to their capabilities, including tracking, providing guided workouts, tracking plus providing guided workouts, or other . The types of physical activity the apps were used for were classified as all daily activities, individual activities , group-based activities , gym-based activities , or a combination of different activities .never) to 5 (very often) they engaged with specific features of the app community, such as sharing physical activity posts, liking and/or providing positive comments on others’ posts, receiving likes and/or positive comments, comparing their physical activity performance with others, and engaging in competitions. Furthermore, participants were asked to indicate the frequency that they engaged with the aforementioned features with specific members of their app community, including partners, family, close friends, peers, public app-specific community members, and work colleagues. Example items include Within the main physical activity app you are currently using, how often do you share posts relating to your physical activity performance with a partner? and Within the main physical activity app you are currently using, how often do you Like/Kudos/Cheer and/or provide positive comments on physical activity posts from close friends? As the networks within each feature were highly correlated (α=.74), a composite score was calculated for the use of each specific feature of the app community  across the different networks  while also examining the independent influence of engaging with specific networks in relation to each feature.In relation to the main physical activity app participants were currently using, they were asked to self-report their engagement with the features of the app-specific community. This included specifying how frequently on a 6-point Likert scale ranging from 0  they share physical activity posts, like and/or provide positive comments on others’ posts, receive likes and/or positive comments, and compare their physical activity performance with others’ physical activity posts on Facebook, Instagram, and Twitter (plus the option to specify other platform(s)). Example items included How often do you share physical activity posts on the following social networking platforms? and How often do you like and/or provide positive comments on physical activity posts from other people on the following social networking platforms? A composite score was calculated for the use of each specific feature  across the different social networking platforms .Participants were also asked to self-report their physical activity-related use of existing social networking platforms on measures developed for this study. Specifically, participants were asked to specify on a 6-point Likert scale how frequently (from P<.05 (2-tailed). Overall, the study variables (with the exception of app engagement) did not deviate substantially from normality based on skewness, kurtosis, or histogram examination. Therefore, parametric tests were used for all analyses, except those that included the variable app engagement for which a nonparametric test  was used.Data were analyzed using Statistical Package for the Social Sciences version 25 . Significance for all analyses was set at t tests and chi-square analyses were conducted to determine differences between app users and nonusers in age, gender identity, ethnicity, and minutes of physical activity per week. Chi-square analyses were used to identify differences in app use  based on demographics (age and gender identity). A Kruskal-Wallis test with pairwise comparisons using the Dunn-Bonferroni correction was conducted to examine the relationship between app engagement (frequency of app use per week) and physical activity.Descriptive statistics were used to generate demographic information. A series of independent samples t tests and chi-square analyses were also used to determine differences between users and nonusers of the app-specific communities and existing social networking platforms.Kruskal-Wallis tests were also conducted to examine the relationships between the use of specific features of app-specific communities and app engagement among app users. In addition, 1-way analyses of variance were performed to determine differences in engagement with features of app-specific communities based on age, capabilities of the app used, and activity the app was used for, but not for gender identity . The aforementioned analyses were repeated using specific features of existing social networking platforms. Independent samples Finally, a multiple linear regression was conducted to explore the predictors of physical activity among app users. The regression model incorporated the frequency of app usage and all features of both app-specific communities (including specific networks) and existing social networking platforms. Demographic characteristics  were incorporated as control variables.In total, 1640 individuals began the survey, 208 of whom did not complete it (a response rate of 87.3%), resulting in a final sample of 1432 participants. The sample had a mean age of 34.1 years (range 18-83 years) and comprised predominately female participants . Overall, the sample engaged in high levels of structured physical activity , and 53.14% (761/1432) reported currently engaging with a physical activity app. P=.006) across levels of app usage. Specifically, pairwise comparisons identified that participants who used the app on 6 occasions per week engaged in significantly higher levels of structured physical activity (median 491.9 min) than those who used the app on 2 occasions per week . Overall, participants who used an app 6 times per week engaged in the highest levels of structured physical activity.The greatest proportion of participants reported using their physical activity app on 7 occasions per week , followed by use on 3 occasions  and more than 7 occasions  per week. A Kruskal-Wallis Test comparing weekly physical activity duration revealed a statistically significant difference  used app-specific communities exclusively, 59.9% (456/761) used existing social networking platforms exclusively, and 22.0% (167/761) used both app-specific communities and existing social networking platforms. This did not differ significantly by age, gender identity, ethnicity, capabilities of the app used , the type of physical activity the app was used for, or frequency of app usage per week.445=2.62; P=.009; d=0.25). However, there were no significant differences between users and nonusers of the app-specific community in relation to gender identity, ethnicity, capabilities of the app used , the type of physical activity the app was used for, or app usage per week. Among participants who reported not engaging with the app-specific community , the reasons identified were privacy or security concerns, negative attitudes toward the use of the community, considered unnecessary, lack of support, beliefs regarding the nature of physical activity, disinterest in others’ physical activity performance, and use of an alternative social network. Of these, the most commonly cited reasons were that the use of the community was considered unnecessary , disinterest in others’ physical activity performance , and privacy or security concerns .Among app users, 59.0% (447/761) reported that the physical activity app they were currently using incorporated an app-specific community. Of these, 43.1% (193/447) reported engaging with the community. Participants who reported engaging with the app-specific communities predominantly used Strava , Fitbit , and Garmin . Among participants who engaged with the app-specific community (n=193), users most frequently used features that allowed the sharing of physical activity performance, providing encouragement to others’ physical activity posts , and receiving encouragement on one’s own posts. These features were most frequently reported to be used with networks that were close friends or peers. There were no significant differences in engagement with features of app-specific communities across age, levels of app usage or according to capabilities of the app used, or the activity the app was used for.672=2.9; P=.004; d=0.44). The features of existing social networking platforms that were most frequently used were providing encouragement on others’ physical activity posts, followed by receiving encouragement on one’s own physical activity posts . Notably, there were significant differences in the frequency of engagement with features of existing social networking platforms based on age, both in terms of sharing physical activity posts  and engaging in comparisons . Specifically, participants aged 18-25 years shared posts to existing social networking platforms significantly less frequently than all other age groups. In addition, participants >40 years made significantly fewer comparisons relative to all other age groups. However, there were no significant differences in the frequency of engagement with features of existing social networking platforms across the frequency of app usage or according to the capabilities of the app used, or the activity the app was used for.Among app users, 82.0% (624/761) reported using existing social networking platforms  in relation to physical activity. There were no significant differences between users and nonusers of existing social networking platforms in relation to age, gender identity, or ethnicity. Participants who used existing social networking platforms engaged in significantly more structured physical activity than those who did not (t(R2=0.426) and was significant . The following variables were significant positive predictors of structured physical activity: frequency of app use , providing encouragement to a partner , receiving encouragement from close friends  and family , engaging in competitions with members of a public app-specific community , and sharing posts to existing social networking platforms . In addition, the following variables were significant negative predictors of structured physical activity: sharing physical activity posts with a partner , providing encouragement to close friends , receiving encouragement from members of a public app-specific community , and engaging in competitions with a partner  and their value in facilitating engagement in physical activity. This study is timely, given the ubiquity of commercial physical activity apps coupled with the need to understand how specific components of these apps may be beneficial in facilitating physical activity.Overall, the findings demonstrate that the use of physical activity apps is common, with over half of the participants reporting that they currently use a physical activity app. Our findings are consistent with Krebs and Duncan , who repThis study identified that participants most commonly engaged with physical activity apps on 7 occasions per week, and in line with previous research, the frequency of app usage was significantly associated with physical activity . InteresA novel aspect of this study was its comprehensive examination of the social components  of commercial physical activity apps. Interestingly, the use of the social components of apps differed markedly, such that most app users engaged exclusively with existing social networking platforms , whereas far fewer engaged with both app-specific communities and existing social networking platforms  or app-specific communities exclusively . This is perhaps not surprising given that existing social networking platforms are immensely popular, afford widespread reach, and achieve high levels of sustained engagement . Age is Despite the differences in the usage of app-specific communities and existing social networking platforms, the social features across both were used similarly, with providing and receiving encouragement the most popular features. Interestingly, the findings also indicate that demographic characteristics may be linked to the likelihood that individuals will utilize specific features. For example, in relation to existing social networking platforms, those aged 18-25 years shared posts less frequently than all other age groups, whereas those aged >40 years engaged in comparisons less frequently relative to all other age groups. This is consistent with a recent review  of mobilNotably, the use of app-specific communities and existing social networking platforms was associated with significantly higher engagement in structured physical activity. This is a novel finding given that it suggests that the social components of apps may play a fundamental role in facilitating engagement in physical activity. This may be attributed to the unique capacity of app-specific communities and existing social networking platforms to generate social support , an impoFinally, the regression analysis revealed that the frequency of app usage was a significant predictor of structured physical activity, indicating the need to determine strategies that will facilitate app use. Interestingly, in relation to app-specific communities, providing encouragement to a partner, receiving encouragement from close friends and family, and engagement in competitions with members of public app-specific communities were positive predictors of physical activity. Conversely, sharing physical activity posts and engaging in competitions with a partner, providing encouragement to close friends, and receiving encouragement from members of public app-specific communities were negative predictors of physical activity. These findings indicate that receiving encouragement from strong ties (close friends and family) is beneficial in facilitating engagement in physical activity, whereas receiving encouragement from weak ties (public app-specific communities) is not. This is consistent with previous research showing that strong ties provide emotional support  ,24, whicThe regression analysis also showed that in relation to existing social networking platforms, sharing physical activity posts positively predicted engagement in physical activity. This is perhaps not surprising given that a recent study  found thOur findings have important implications for informing the design of future app-based interventions. They demonstrate that commercial physical activity apps, in particular, those that facilitate self-monitoring  hold great potential to promote engagement in physical activity. The convenience, accessibility, and affordability of commercial apps coupled with their capacity to facilitate physical activity highlight that future app-based interventions should harness commercial apps, as opposed to previous interventions that have predominately incorporated researcher-developed apps . The finThis study also has important implications for guiding future research. Experimental evidence is now needed to isolate the influence of the social components of apps and their associated features on physical activity. Future research should also endeavor to ascertain the mechanisms  underlying the capacity of app-specific communities and existing social networking platforms to facilitate physical activity. Finally, longitudinal research is needed to determine the value of app-specific communities and existing social networking platforms in promoting sustained app use, and thus prolonged engagement in physical activity.As with all studies, there are a number of limitations that need to be acknowledged. First, the sample consisted predominantly of white women, and the participants’ origin (country/region) was unknown. These 2 sample characteristics limit the generalizability of the findings to the population more broadly. Nevertheless, app usage rates were similar to those previously reported in a large, diverse US sample . Second,Notwithstanding these limitations, this study provides an important contribution to existing literature by comprehensively exploring the use of commercial physical activity apps and their associated social components in a large cross-sectional sample. The findings indicated that the use of commercial physical activity apps facilitates engagement in physical activity and, therefore, have great potential to disseminate scalable interventions to improve health behavior. This study also provided a nuanced insight into app-specific communities and existing social networking platforms, identifying that they are components of apps that are valuable in promoting physical activity, and should be harnessed in the development of future app-based interventions. Together, these findings highlight the importance of further examining the social components of apps and gaining an understanding of the mechanisms underlying their influence on physical activity. In so doing, this study has demonstrated that commercial physical activity apps afford high population level reach and hold great potential to facilitate engagement in physical activity. Thus, future interventions aimed at increasing physical activity should further explore commercial physical activity apps and their associated social components.


Background: The association between metformin and amiodarone-induced adverse events was examined using spontaneous adverse event database. Additionally, the association between other antidiabetic drugs and amiodarone-induced adverse events were also examined.Methods: A total of 6,153,696 reports from the first quarter of 2004 through the fourth quarter of 2015 were downloaded from the US Food and Drug Administration adverse event reporting system. Reporting odds ratio (ROR) and information component (IC) were used to detect associations between antidiabetic drugs and amiodarone-associated adverse events. Additionally, subset data analysis was performed to investigate whether the use of antidiabetic drugs further increased or decreased the risk of adverse events in patients receiving amiodarone therapy. Next, the RORs were adjusted for coadministered antidiabetic drugs using logistic regression analysis.Results: By whole dataset analysis, significant inverse associations were found between metformin and interstitial lung disease . In the subset data analysis, metformin , sulfonylureas , and dipeptidyl peptidase-4 (DPP-4) inhibitors  were inversely associated with hyperthyroidism. Additionally, metformin , sulfonylureas , and DPP-4 inhibitors  were inversely associated with interstitial lung disease. In the logistic regression analyses, DPP-4 inhibitors  and metformin  were inversely associated with amiodarone-associated hyperthyroidism and interstitial lung disease, respectively.Conclusion: Metformin is a candidate drug to reduce the risk of amiodarone-induced hyperthyroidism and interstitial lung disease. Amiodarone, a class III antiarrhythmic drug that is used for the treatment of recurrent severe ventricular arrhythmia, paroxysmal atrial tachycardia, and atrial fibrillation as well as the maintenance of sinus rhythm after cardioversion of atrial fibrillation et al. utilized a FAERS-based approach to identify a concomitantly used drug B that might mitigate the risk of adverse events associated with the use of drug A et al. reported a FAERS-based approach to determine an effective drug combination that could lower known adverse events Spontaneous adverse event databases are utilized in signal detection for potential drug-associated adverse events. The US Food and Drug Administration (FDA) adverse event reporting system (FAERS) is a large and useful database for spontaneous adverse events, which can be utilized to identify unknown drug-associated adverse events using disproportionality analysis algorithms where reporting odds ratio (ROR) and information component (IC) are widely used parameters in detecting signals for drug-associated adverse events http://www.fda.gov/Drugs/InformationOnDrugs/ucm135151.htm). The system contains all reports of adverse events reported spontaneously by healthcare professionals, manufacturers, and consumers worldwide. The database comprises seven datasets: patient demographic and administrative information , drug and biologic information , adverse events , patient outcomes , report sources , start and end dates of drug therapy , and indications for use/diagnosis . A relational database that concatenated the seven datasets by unique identification numbers for each FAERS report was built. The current study included data from the first quarter of 2004 through the fourth quarter of 2015. Reports with a common case number were identified as duplicate reports, and all duplicates were removed and excluded from all analyses. Finally, a total of 6,153,696 reports were included in the study.This retrospective study included data analysis of adverse event reports based on the FAERS, a computerized information database designed to support post-marketing safety surveillance programs for all approved drugs and therapeutic biological products. Adverse events and medication errors recorded in the FAERS database were downloaded from the FDA website (https://www.medicinescomplete.com/mc/login.ht m). Although metformin is a main target drug in the current study, we included other antidiabetic drugs for comparison . Adverse events in the FAERS were coded using the MedDRA® preferred terms (PTs), which are grouped by defined medical condition or area of interest. We identified PTs related to hyperthyroidism, hypothyroidism, interstitial lung disease, and hepatic disorder using the Standardised MedDRA® Queries (SMQ). Hepatic disorder contains nine items of SMQ: drug related hepatic disorders - comprehensive search; cholestasis and jaundice of hepatic origin; drug related hepatic disorders - severe events only; hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; hepatitis, non-infectious; liver neoplasms, benign (incl cysts and polyps); liver neoplasms, malignant and unspecified; liver-related investigations, signs and symptoms; and liver-related coagulation and bleeding disturbances. SMQs usually contain two PT categories corresponding to a “narrow” scope and a “broad” scope. The narrow and broad categories allow for the identification of cases that are highly likely to represent the condition of interest and those that would be useful when a user seeks to identify all possible cases, including some that may prove to be of little or no interest on closer inspection, respectively. In the current study, only PTs included in the narrow category were targeted.Adverse events analyzed in the current study were based on the definition provided by the Medical Dictionary for Regulatory Activities (MedDRAFor signal detection using spontaneous reports, we calculated RORs and ICs using the case/non-case method A total of 6,011, 11,286, 37,993, and 222,806 reports of hyperthyroidism, hypothyroidism, interstitial lung disease, and hepatic disorders, respectively, were identified in the FAERS. The results of disproportionality analyses were summarized in Table The subset data analyses were performed using 30,508 reports by restricting the whole dataset to patients receiving amiodarone. There were a total of 711, 568, 1,645, and 3,820 reports of hyperthyroidism, hypothyroidism, interstitial lung disease, and hepatic disorders, respectively. The results of the subset data analyses are presented in Table The current study utilizing the FAERS database revealed that amiodarone was significantly associated with increased risk of hyperthyroidism, hypothyroidism, interstitial lung disease, and hepatic disorders, which are serious amiodarone-induced adverse events that are well recognized in clinical practice, and indicated that the FAERS analysis was able to detect the risk of amiodarone-induced adverse events. In addition, our analyses also detected significant associations between certain antidiabetic drugs and adverse events Table . However2 radicals which can damage cells directly et al. reported that metformin, an adenosine monophosphate-activated protein kinase activator, attenuated the development of lung fibrosis by inhibiting transforming growth factor signaling through the suppression of NADPH oxidase and reactive oxygen species 2 radicals.We also examined whether metformin attenuated the risk of the amiodarone-associated adverse events using the subset data that were restricted to the patients who were treated with amiodarone and consequently identified a significant inverse association between metformin and interstitial lung disease, which implicated metformin as a candidate drug to attenuate the risk of amiodarone-induced interstitial lung disease. The inverse association between metformin and interstitial lung disease was also identified in the logistic regression analysis, which adjusted confounding factors including coadministered antidiabetic drugs. This result strongly suggested that metformin attenuates the risk of the amiodarone-induced interstitial lung disease. Amiodarone and its metabolites indirectly damage lung tissue by an immune response The current study also revealed that metformin was associated with a decreased risk of amiodarone-associated hyperthyroidism based on the analysis of the subset data restricted to the patients treated with amiodarone, suggesting that metformin attenuates the risk of amiodarone-induced hyperthyroidism. Meanwhile, the logistic regression analysis did not identify any inverse association between metformin and hyperthyroidism. Therefore, the association between metformin and hyperthyroidism remains unclear. Amiodarone-induced hyperthyroidism is primarily due to the direct effect of amiodarone on thyroid cells; however, excess iodide released from amiodarone may contribute to its toxicity et al. reported that reduction in mean amplitude of glycemic excursions caused by vildagliptin and sitagliptin is associated with reduction of oxidative stress and markers of systemic inflammation in type 2 diabetic patients The current study revealed that DPP-4 inhibitors are also associated with a decreased risk of amiodarone-induced hyperthyroidism in the analysis of the subset data and logistic regression analysis. Hyperglycemia is a major contributor to oxidative stress There are several inherent limitations that should be taken into account when interpreting results obtained from the FAERS database. First, not all adverse events observed in clinical settings are included in the database. Second, the FAERS database contains missing data, misspelled drug names or duplicate data. To overcome problems with data quality, we had deleted or corrected such data before conducting analysis in this study. Third, several variables were also limited in our FAERS analysis; age, sex, race, treatment duration, or drug dosage were not considered. Finally, there were some separations between the results of the subset analysis and the adjusted ROR. Various methods have been reported for detecting the signals related to the drug interaction The current study results provide evidence for metformin as a candidate drug that might attenuate the risk of hyperthyroidism and interstitial lung disease in patients treated with amiodarone. Furthermore, for interstitial lung disease, the potential beneficial effect of metformin may not be limited only to patients treated with amiodarone. As signal detection using the FAERS should not be interpreted as assuming a causal relation between drugs and clinical events, the hypotheses generated by the FAERS needs to be validated using other methods. Therefore, experimental and clinical studies are warranted to elucidate the effect of metformin on amiodarone-induced interstitial lung disease and hyperthyroidism.The current study based on the analysis of the FAERS database revealed that metformin was associated with a decreased risk of amiodarone-associated interstitial lung disease and hyperthyroidism in patients treated with amiodarone. Furthermore, the results indicated that metformin was associated with a decreased risk of interstitial lung disease in the whole dataset analysis. Overall, these findings raise the possibility of metformin as a therapeutic option to attenuate the risk of hyperthyroidism and interstitial lung disease in patients treated with amiodarone. Furthermore, for interstitial lung disease, this potentially beneficial effect of metformin may not be limited only to patients treated with amiodarone.


In the clinical study by Le Thi Bich et al., allogeneic expanded umbilical cord-derived mesenchymal stem cells (UC-MSCs) were intravenously infused to treat patients with chronic obstructive pulmonary disease (COPD). No severe or significant adverse effects were observed, while a significant improvement in COPD patients’ quality of life was reported up to 6 months. In addition, the authors argue that bone marrow-derived cells are not suitable to treat COPD based on the “failure” of 3 clinical trials . In fact, Le Thi Bich et al. and the three above-mentioned studies reported similar clinical outcomes, id est., no significant improvement in the pulmonary function of COPD patients. Therefore, since no COPD treatment involving cells either from bone marrow or umbilical cord was detrimental or provided lung regeneration in human patients, in our view, it is too early to point failures of cellular sources. Instead, it is a valuable opportunity to reflect on the poorly understood therapeutic mechanism of MSCs and the pathophysiology of COPD. In respect of cellular sources, only controlled trials with a strict comparison between different tissues might determine the suitability and efficacy of specific cell types to treat COPD. Finally, further studies are still required to determine whether and via which mechanism MSCs are able to provide structural and functional restoration of gas exchange in COPD patients. Moreover, while the authors outlined several advantages of UC-MSCs over other tissue sources, it is argued in the introduction and discussion sections that bone marrow-derived cells are not suitable to treat COPD. Le Thi Bich et al. point out that the “failure” of 3 clinical trials , which used bone marrow-derived cells for COPD treatment [In the study reported by Le Thi Bich et al., allogeneic umbilical cord-derived mesenchymal stem cells (UC-MSCs) were intravenously infused into patients with chronic obstructive pulmonary disease (COPD) . The autFirst and foremost, we share great enthusiasm regarding the reported safety on the systemic administration of allogeneic expanded UC-MSCs into a comorbid population of moderate-to-severe COPD patients. We also applaud the authors’ efforts at conducting a pilot study whose therapeutic approach lead to an improvement in COPD patients’ quality of life in 6 months. Nonetheless, our divergencies arise at discarding bone marrow-derived cells for COPD treatment due to the “failure” of previous studies.Despite being added by Le Thi Bich et al. alongside studies which worked on isolated and expanded bone marrow-derived mesenchymal stem cells (BM-MSCs), in NCT01110252, we used neither cultured nor isolated mesenchymal stem cells (MSCs). We intravenously infused autologous fresh-isolated bone marrow mononuclear cells (BMMCs) into 4 COPD patients and reported the main results in the first worldwide publication using BMMCs as a new therapeutic approach in COPD , 5. In NOver the past 70 years, extensive research on bone marrow transplantation initiated and underpinned the broader use of bone marrow-derived cells in regenerative medicine. Despite being associated with an invasive procedure, autologous and allogeneic bone marrow-derived cells have been largely investigated in lung diseases either in animal models or human patients. It is only recently, however, that stem and progenitor cells from other less invasive sources such as adipose tissue, umbilical cord, and cord blood have been isolated . More spSince no COPD treatment involving cells either from bone marrow or umbilical cord was harmful or provided evidence of lung regeneration in human patients, in our view, it is too early to point failures of specific cellular sources. Instead, it is a valuable opportunity to reflect on the poorly understood therapeutic mechanism of MSCs and the pathophysiology of COPD. Encouraging findings show that UC-MSCs exhibit stronger immunomodulatory capacity than BM-MSCs in vitro . HoweverCOPD leads to a permanent pulmonary and systemic inflammatory condition besides lung degeneration. Upon systemic infusion, MSCs are primarily hosted in the lungs due to the capillary system and associated inflammatory microenvironment. As mentioned by Le Thi Bich et al., MSCs may exert anti-inflammatory control by releasing cytokines and paracrine factors which act on lung resident immune and inflammatory cells. However, MSCs undergo clearance from the lungs after few days . It chal+ cells, which might be involved in tissue regeneration. However, G-CSF treatment did not provide an increase in CD34+ and CD133+ cells and we suggested the omission of G-CSF from future clinical studies [In an experimental elastase-induced emphysema model, two doses of MSCs enhanced anti-inflammatory control and lung repair compared to one single dose of MSCs . In COPD studies . TherefoAnother major concern refers to the quality and existence of endogenous progenitors which could be stimulated by MSCs at the lungs of COPD patients. Although the interruption of tobacco smoking stimulates mitotically quiescent cells to replenish the bronchial epithelium , it is nIn our view, the utmost caution should be exercised when designing further cell therapy clinical trials to treat COPD. In respect of cellular sources, only controlled trials with strict comparison between different tissues can determine the suitability, failure, or efficacy of specific cell types to treat COPD. Moreover, the combination of cells from different sources might be studied in order to elucidate the possibility of synergistic or additive effects. The results provided so far by cell therapy clinical trials are positive regarding safety aspects and the absence of adverse effects. Even though promising results from cell therapy-based clinical trials and animal models are encountered, several biological aspects must be investigated to elucidate the lack of functional and structural restoration of gas exchange in COPD patients. For this reason, a critical evaluation on the pathophysiology of COPD and cell therapy regimen must be considered in further randomized and controlled clinical trials.


During embryonic development, radial glial precursor cells give rise to neural lineages, and a small proportion persist in the adult mammalian brain to contribute to long-term neuroplasticity. Neural stem cells (NSCs) reside in two neurogenic niches of the adult brain, the hippocampus and the subventricular zone (SVZ). NSCs in the SVZ are endowed with the defining stem cell properties of self-renewal and multipotent differentiation, which are maintained by intrinsic cellular programs, and extrinsic cellular and niche-specific interactions. In glioblastoma, the most aggressive primary malignant brain cancer, a subpopulation of cells termed glioblastoma stem cells (GSCs) exhibit similar stem-like properties. While there is an extensive overlap between NSCs and GSCs in function, distinct genetic profiles, transcriptional programs, and external environmental cues influence their divergent behavior. This review highlights the similarities and differences between GSCs and SVZ NSCs in terms of their gene expression, regulatory molecular pathways, niche organization, metabolic programs, and current therapies designed to exploit these differences. Glioblastoma  is the most common and aggressive primary CNS malignancy in adults. The short median survival of 9–18 months in patients with GBM has been attributed to the highly invasive nature of the disease with rapid cell infiltration, frequent relapses, and therapy resistance . AnatomiLimited therapeutic options, poor survival, and the universally fatal nature of the disease have fueled research efforts to uncover novel molecular vulnerabilities within GBM. However, despite the best efforts, the discovery of novel effective treatments remains elusive. GBM tumors exhibit a large degree of intra- and inter-tumoral heterogeneity, which frequently renders majority of targeted therapies ineffective . In an aNeural stem and progenitor cells are a specialized population of multipotent cells that contribute to lifelong neural plasticity. During embryonic neurogenesis, NSCs are spatiotemporally regulated to generate multiple neural populations including neurons and glial cells . Beyond Adult NSC self-renewal and multipotency have been proposed to be regulated by various transcriptional factors. One such factor is the orphan nuclear receptor TLX, which has been shown to be an essential transcriptional regulator of NSC maintenance and proliferation in the adult brain . TranscrCell-intrinsic regulation is also maintained through epigenetic modification and chromatin remodeling. Epigenetic control has been demonstrated to be regulated by the aforementioned polycomb repressor Bmi1 by methylation of the histone tail H3K27 to promote self-renewal . SVZ-NSCEpigenetic mechanisms in SVZ-NSCs are also regulated by a network of miRNAs and non-coding RNAs, which play an additional regulatory role in adult neurogenesis. Many members of the small RNA family have been implicated in modulating neuronal differentiation by binding to the RE1-silencing transcription factor (REST), a crucial regulator of neuronal gene expression . TogetheNSC intrinsic programs are also regulated by signals from the neurogenic niche , 43. TheThe extracellular matrix is a critical component of the SVZ niche that has been identified as a regulator of NSC proliferation , 45. Unlmilieu of the SVZ niche.Molecular signals in the ECM regulating adult NSC activity can originate from multiple cell types. In assessing the cellular composition of the SVZ microenvironment, endothelial, pericyte and vascular cells, as well as immature and mature lineages of NSCs are found , 51. Mosvia canonical Wnt signaling  and blood-derived systemic signals. NSCs have direct access to the CSF which provides a rich supply of various additional mitogens such as PDGF, and morphogens including the Wnt ligands which particularly promote proliferation and self-renewal of adult NSCs ignaling . Peripheignaling , 63.NSC multipotency and stemness is also modified by endogenous and niche-derived metabolic factors. Adult NSCs are known to rely on aerobic glycolysis prior to differentiation. Changes in metabolic activity affects adult NSC differentiation and cell-fate commitment, particularly by activation of mitochondrial respiration and reactive oxygen species production . Oxygen While other niche-mediated cues such as regional identity  and posiThe cancer stem cell (CSC) hypothesis has been used as a framework describe and provide explanation for the high degree of molecular heterogeneity, cellular plasticity, and the molecular divergence of recurrent GBM. CSCs were observed to share many of the similar properties to the healthy stem cells including multipotent differentiation and self-renewal , low freWhile the precise identification of the GBM cell of origin remains elusive, two major hypotheses have been explored over the years. In one theory, GBM arises from a transformation events in differentiated astrocytes, while others have suggested that a GBM pathogenesis begins with a transformed NSC [Comprehensive review by Fan et al. ]. PrevioEarly mouse models exploring effects of genetic alterations in either NSCs or differentiated astrocytes have failed to provide definitive resolution to the cell-of-origin question. Some reports suggested that overexpression of Ras and Akt signaling in neural progenitor cells but not in more differentiated astrocytes was sufficient to induce formation of GBM-like lesions . On the Like all cancers, GBM exhibits behavioral hallmarks that distinguish it from healthy tissue . CompareEGFR) amplification is one of the most frequent mutations in GBM patients , is a critical regulator in the proliferation of normal NSCs in mice . Aberranpatients , and haspatients , its tarpatients . Even inpatients .in vitro (via fibroblast growth factor receptors (FGFRs), or be translocated directly to the cytoplasm and nucleus  play an important role in the regulation of stemness in GSCs in vitro , 119. Thin vitro . Of partin vitro  and was in vitro . The low nucleus . The tra nucleus , has bee nucleus , suggest is another important regulator of NSCs in the SVZ. When neural stem cells were identified to express PDGF-receptor-alpha (PDGFRA) in the adult mouse SVZ, supplemental PDGF alone was sufficient to induce hyperplasia with some features of GBM . These r subtype . As PDGF subtype , its inc subtype . While tAs one of the most studied tumor suppressors in cancer, TP53 has been shown to regulate a wide range of cellular functions of various cancers including GBM. As a key stem cell maintenance regulator, TP53 is expressed in proliferating cells within the SVZ and has been implicated in controlling cell division and differentiation . The keyAnother common loss of tumor suppressor in GBM is phosphatase and tensin homolog (PTEN). The role of PTEN in the regulation of mouse NSCs in SVZ is extensively reviewed in Li et al. . TogetheThe PI3K/AKT/mTOR intracellular pathway is a critical pathway for cell cycle regulation, proliferation, and it is directly antagonized by PTEN . The patSignal transducer and activator of transcription-3 (STAT3) is a transcription factor whose activity is directly regulated by PI3K/AKT/mTOR . A varieTERT  and contributes to immunosuppression by glutamate production to ensure pro-tumor survival  under stress which increases oxidative metabolism and ATP generation, by catalyzing the conversion of glutamine to glutamate and increasing α-ketoglutarate (α-KG) levels . This mesurvival . As an asurvival .via glucose and glutamine catabolism that promoted histone/DNA demethylation and maintenance of pluripotency (Glutamate can be converted to α-KG by either glutamate dehydrogenase 1 (GDH1) or transaminases such as glutamate pyruvate transaminase 2 (GPT2) and glutamate oxaloacetate transaminase 2 (GOT2) . Conversipotency . By alteipotency  DNA demeipotency . In addiipotency .in vitro experimental methods such as 3D-culture methods and cerebral organoids are becoming more prevalent  edge is the third and final major GBM niche. As a highly invasive tumor, GBMs can infiltrate into healthy brain tissue and limit the effectiveness of maximal surgical resection. To circumvent and eradicate infiltrative GSCs, patients receive whole-brain radiation therapy. However, GBM cells, and most notably GSCs, have been shown to adapt and resist the applied environmental stress of irradiation . Once exWhile understanding the similarities between GSCs and NSCs is instrumental for contextualization of gliomagenesis and underlying mechanisms driving GBM progression and therapy resistance, it is leveraging the differences between two cell populations that may offer avenues for generation of novel targeted therapies. Unlike other solid tumors, brain tumors present a unique set of challenges for development of new treatment options. First, the blood-brain-barrier (BBB), which normally protects the brain from harmful toxins, can also hinder the access of targeted therapies against GBM. Although BBB permeability can be theoretically increased through chemical modification of small molecule-based inhibitors, such approach does not expand to more precise modalities including antibody-drug conjugates (ADCs) and adoptive cell transfer therapies. In both mouse models , 217 andOne of the most widespread strategies in targeting GSCs is through identification and subsequent development of targeted therapies against cell surface markers. Several different targeting approaches have been investigated in the recent years including antibody-drug conjugates (ADCs) and chimeric antigen receptor T cells , 218. Anin vitro and in vivo pre-clinical studies, inhibiting CXCL12/CXCR4 signaling in the mouse SVZ promoted radiosensitization and reduced GBM tumor cell proliferation  contributed to article writing and editing. Figures were generated with NS is funded by Mitacs Accelerate Fellowship, SSa is generously supported by CIHR CGS-M award and SSi holds Terri Fox Program Project Grant.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.