Neurons in the central nervous system are among the most metabolically active cells in the body, characterized by high oxygen consumption utilizing glucose both aerobically and anaerobically. Neurons have an abundance of mitochondria which generate adequate ATP to keep up with the high metabolic demand. One consequence of the oxidative phosphorylation mechanism of ATP synthesis, is the generation of reactive oxygen species which produces cellular injury as well as damage to mitochondria. Mitochondria respond to injury by fusion which serves to ameliorate the damage through genetic complementation. Mitochondria also undergo fission to meet an increased energy demand. Loss of mitochondria is also compensated by increased biogenesis to generate new mitochondria. Damaged mitochondria are removed by mitophagy, an autophagic process, in which damaged mitochondria are surrounded by a membrane to form an autophagosome which ultimately fuses with the lysosome resulting in degradation of faulty mitochondria. Dysregulation of mitophagy has been reported in several central nervous system disorders, including, Alzheimer’s disease and Parkinson’s disease. Recent studies point to aberrant mitophagy in ocular neurodegenerative disorders which could be an important contributor to the disease etiology/pathology. This review article highlights some of the recent findings that point to dysregulation of mitophagy and it’s underlying mechanisms in ocular neurodegenerative diseases, including, glaucoma, age-related macular degeneration and diabetic retinopathy. High-energy electrons extracted from these compounds travel down the electron transport chain along a sequence of electron carriers with a decrease in free energy. During this electron transport, the electron carriers alternate between reduced (as they accept electrons) and oxidized state (as they donate electrons), ultimately culminating in the transfer of the electrons to molecular oxygen, which is the final acceptor of electrons in the electron transport chain. The downhill transport of electrons along the electron transport chain is coupled to the uphill pumping of protons across the inner mitochondrial membrane into the intermembrane space, creating a proton gradient across the inner membrane. The enzyme ATP synthase then harnesses the energy inherent in the electrochemical proton gradient across the inner mitochondrial membrane to generate ATP through chemiosmotic coupling.Mitochondria are the power grid of eukaryotic cells producing ATP, the primary energy currency of the cell, which power various biosynthetic and metabolic activities in the cell. Within the mitochondria, the inner membrane is thrown into multiple folds called cristae which greatly increase its surface area and enable the accumulation of several 1,000 copies of components of the electron transport chain (complex I to complex IV). The oxidation of metabolic fuels such as glucose and fatty acid is coupled to the reduction of NAD•O2− + H2O2 → •OH + OH− + O2. Superoxides could react nitric oxide to produce the highly reactive peroxynitrite which could have both beneficial and detrimental effects. For instance, neutrophils and macrophages generate peroxynitrite and utilize it for a host-defense response to kill bacterial invading bacteria. However, production of peroxynitrite could be a contributor to ischemia–reperfusion injury in various tissues such as the myocardium and the retina  is the best-characterized member of the Atg8 family, which is conjugated with phosphatidyl ethanolamine by Atg7 (E1-like) and Atg3 (E2-like) producing an autophagosome-associated LC3-II. Thus, LC3-positive vesicles, can be considered to be completed autophagosomes , voltage-dependent anion-selective channel protein (VDAC), and dynamin-1-like protein . In healthy mitochondria, having an intact mitochondrial transmembrane potential, PINK1 is imported to the inner mitochondrial membrane, where it is cleaved by a protease called rhomboid protease presenilin-associated-rhomboid-like (PARL) and subsequently degraded in the proteasome. Following oxidative stress and other cellular stressors, such as the elevation of intracellular Can DRP-1; . These un DRP-1; . Subsequn DRP-1; .In receptor-mediated mitophagy, proteins in the outer mitochondrial membrane including, BNIP3, NIX/BNIP3L, FUNDC1, FKBP8, and Bcl2L13 that contain an LC3-interacting domain directly bind to LC3, allowing the direct recruitment of the phagophore to damaged mitochondria in a parkin-independent manner . AdditioLoss of mitochondria could be compensated by the increased mitochondrial biogenesis characterized by growth and division of existing mitochondria. Mitochondrial biogenesis occurs in response to an increased energy demand as well as developmental signals and various environmental stresses. In humans, only 1% of mitochondrial proteins are encoded by the mitochondrial genome; the remaining 99% of mitochondrial proteins are encoded in the nuclear genome. While the majority of the mitochondrial proteins are translated in the cytoplasm and imported into the mitochondria, some the mitochondrial proteins are synthesized within the mitochondria utilizing mitochondrial ribosomes, the mechanistic details are still being elucidated . Many ofThe involvement of mitochondrial dynamics and mitophagy has garnered increasing attention in the past decade, particularly in neurodegenerative diseases. This review will focus on mitophagy in three ocular neurodegenerative diseases: glaucoma, age-related macular degeneration and diabetic retinopathy . InsightGlaucoma is an age-related neurodegenerative disease of the eye, and is a leading cause of blindness in the developed world, with 3 million patients in the United States and nearly 80 million patients worldwide . The cauOxidative stress could have damaging effects on the mitochondria and produce a decline in mitochondrial potential. Studies in several animal models of glaucoma have consistently shown that elevations in intraocular pressure have increased mitochondrial fission, increased expression of pro-apoptotic peptides, disrupted small molecule metabolism, and reduced respiratory capacity . As discWhile mitochondria have been known to contribute to glaucoma for several years, examining mitophagy in glaucoma has gained considerable attention recently. In one of the earliest findings, Interestingly, Some studies have found an increase in mitophagy in animal models of glaucoma. One study using MitoQC mice demonstrated increased mitophagy in mice following optic nerve crush . Being aAMD is a common ocular neurodegenerative disease in older adults with approximately 18 million patients in the United States and nearly 200 million s worldwide . The disRetinal pigment epithelial cells (RPE), are a supporting monolayer of epithelial cells posterior photoreceptor outer segment (POS), which forms connections with the Bruch’s membrane and plays a major role in maintaining cell homeostasis by scavenging oxygen free radicals, enabling photoreceptor renewal by phagocytosis of POS, which depend on choriocapillaris function and a supply of nutrients . Age andCorroborative findings from several groups have shown that mitochondrial dysfunction and increased oxidative stress are the major causes of atrophic AMD (dry AMD), a subset of AMD. Studies by .−/− mice following intravitreal injections of carbonyl cyanide m-chlorophenyl hydrazone (CCCP) to induce mitophagy or following inhibition of the lysosomal protease activity by intraperitonial administration of leupeptin. In the ARPE-19 cells, following siRNA mediated knockdown of pink1, the authors found evidence of dysfunctional mitochondria that was detected by a decline in various mitochondrial parameters, including, mitochondrial respiration, maximal respiration, spare respiratory capacity and ATP production , autoxidative glycosylation, metabolic stress resulting from changes in energy metabolism, alterations in sorbitol pathway activity, changes in the level of inflammatory mediators and the status of antioxidant defense systems, and localized tissue damage resulting from hypoxia and ischemic reperfusion injury . DiabeteSeveral findings point to mitochondrial injury and a compromise of mitophagy in animal models of diabetes. For instance, Apart from fusion, mitochondrial fission has also been implicated as a contributor to the pathological changes in diabetic retinopathy. Drp1 induces excessive mitochondrial fission, which could result in mitochondrial injury; hence, mitophagy plays a crucial role in clearing damaged mitochondria. In retinal endothelial cells, high glucose results in mitochondrial dysfunction via mitochondrial Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission . The autIn another study, Drp1 was highly expressed in the retinal tissues of DR rats and HG-treated RECs. Drp1 knockdown attenuated HG-mediated increase of reactive oxygen species (ROS) levels and apoptosis in RECs . MoreoveFor instance, Some studies have utilized agents to enhance mitophagy and generate cytoprotective effects. For example, oral administration of a novel saponin, Notoginsenoside R1  for 12 weeks attenuated retinal vascular degeneration, prevented the reduction of retinal thickness, and improved retinal function in db/db mice . NGR1 prThe precise etiological mechanisms by which hyperglycemia contributes to diabetic retinopathy are not entirely understood. Based on several findings, it is clear that oxidative stress, mitochondrial dysfunction, and mitochondrial injury are essential contributors to the pathogenesis of diabetic retinopathy. Recent findings about a decline in mitophagy in cell culture studies and rodent models of diabetic retinopathy bring up possibilities of developing novel treatment strategies to promote mitochondrial protection and enhance bioenergetics.Several methods have been used to study mitophagy in these retinopathies. Several studies used western blots or immunohistochemistry to detect the expression levels of key proteins involved in mitophagy . The relin vivo. The development of autophagy reporter mice has created new opportunities to understand the dynamics of mitophagy in-vivo fluorescent probes has revolutionized the study of mitophagy, the gold standard for visualizing mitophagy continues to be transmission electron microscopy (TEM). TEM allows for the direct visualization of subcellular structures, but it has several disadvantages. TEM is expensive, the preparations are time consuming, and requires great skill. Unlike other tissues where a small biopsy can be sent for TEM, the best results require the fixation of the whole eye, leaving no sample left for other assays (While the advent of r assays . The conr assays . Howeverr assays . This mar assays . As techThe precise role of mitophagy in ocular neurodegeneration is still being actively investigated; however, an abundance of data suggests that a decline in mitophagy could be a contributor to neurodegenerative effects. There are also findings that suggest an increase in mitophagy in some animal models of ocular neurodegeneration. Most studies have used immunohistochemical labeling for various markers of mitochondria, autophagosomes, and lysosomes to make conclusion about mitophagic flux. There is a need for more dynamic assays to figure out the spatiotemporal changes in mitophagic flux in various pathologies. The key steps responsible for oxidative stress-mediated damage of mitochondria and the cellular events leading to a decline in mitophagy are not entirely understood. Unraveling these pathways will facilitate an in-depth understanding of the mitophagic mechanisms and help develop therapeutic targets to quell neurodegeneration in various neurodegenerative disorders.CB: Conceptualization, Visualization, Writing – original draft, Writing – review & editing. BK: Conceptualization, Validation, Writing – original draft, Writing – review & editing. DS: Conceptualization, Funding acquisition, Validation, Writing – original draft, Writing – review & editing. RK: Conceptualization, Funding acquisition, Supervision, Validation, Writing – original draft, Writing – review & editing.


The requirement to change position whilst under general anaesthesia may expose patients to significant risks. We devised and implemented a concise and comprehensive patient positioning safety tool with the aim of reducing risks and improving patient safety during position changes under anaesthesia. Optimal patient positioning during neurosurgical procedures is essential in ensuring adequate surgical access to pathological lesions and optimal intracranial pressure and cerebral blood flow to facilitate safe surgical resection. Depending on the site of the lesion and the surgical approach, patients may need to be placed in either the supine, lateral, prone or sitting positions. Anaesthesia is usually induced with the patient in the supine position, and after induction of general anaesthesia, the patient is then moved into the required position for surgery.Changing position whilst under general anaesthesia may expose patients to many potential risks including, but not limited to, physical injury, interruption of essential monitoring, airway compromise, haemodynamic instability, impairment of ventilation and dislodgement of intravascular access and haemodynamic monitoring lines. Serious adverse effects on pulmonary physiology may occur, including a reduction in functional residual capacity and ventilation-perfusion mismatch leading to hypoxaemia.Adverse haemodynamic effects, including reduced venous return, increased intra-thoracic pressure and reduced systemic vascular resistance, may result in significant hypotension, which could potentially compromise organ perfusion resulting in serious complications and adverse patient outcomes. These effects are more likely to be exaggerated in those with pre-existing comorbidities such as obesity and chronic cardiac and pulmonary disease. According to the anaesthesia closed claims project spanning from 2000 to 2014, it has been revealed that spine surgery claims accounted for more than 10% of the total claims. Furthermore, some of these claims were linked with severe permanent disability, mainly resulting from nerve and eye injuries.2Reduce risk and improve patient safety during changes of patient position under general anaesthesia.Develop a new practical educational tool for working anaesthesia and neurosurgery staff to ensure safe and confident clinical practice when managing patient position changes under anaesthesia.After observation of existing operating team practices for several weeks, we identified key patient safety risks and key times of most significant risk during patient position changes under anaesthesia in our neurosurgical operating rooms. We then devised new pre- and post-position change safety checklists and introduced a brief safety pause to facilitate their completion.CHOPP check” CHange-Of-Patient-Position under anaesthesia Checklist.To enhance user-friendliness, we developed the acronym “before and b) after achange of patient position under anaesthesia. It focuses on four key domains of potential patient risks: haemodynamic stability, adequacy of ventilation, patient head-to-toe check and equipment function. Important considerations in design were that CHOPP-check is:CHOPP-check comprises safety checks at two-time points: a) Comprehensive: Incorporates a check on all patient safety risks we had identified during our period of observation of position changes.User-friendly: a) can be completed in 1-2 minutes and b) works with the ergonomics of the operating room and can be completed from a single standing position with only the patient “head-to-toe” check requiring movement around the operating room.Has the potential for application: To other surgical specialities for any procedure which requires a patient position change under anaesthesia.Staff education was delivered to an initial pilot group. Laminated checklists were created and displayed in prominent locations at key sites. Practice on-site drills, in addition to on-site simulation training of key operating room staff, were undertaken prior to roll-out.CHOPP-check’ roll-out, staff surveys were undertaken to assess users’ perception of usefulness and impact on risk reduction. 80% of the respondents found CHOPP check to be user-friendly and supported its implementation. About 70% of CHOPP checks performed identified potential patient safety issues. Common issues identified were traction with potential or actual disconnection of monitoring cables and vascular access lines during position changes. Less frequently, more serious, potential airway incidents were identified. Support was high amongst surgical and anaesthesia staff for the implementation of this new safety tool.After the ‘CHOPP-check is a new patient safety tool that focuses staff attention on potential hazards at times of increased risk during patient position changes under anaesthesia. It provides a concise and practical tool to guide operating theatre staff during position changes and enhances their ability to reduce risk and improve patient safety. It has the potential for application to other surgical and non-surgical specialities in which procedures require changes of patient position under anaesthesia.KH and SL: Initial write-up.MM and IL: Final write-up.All authors reviewed the manuscript before submission.


Staphylococcus aureus and Escherichia coli, two prototypical Gram-positive and Gram-negative pathogens, respectively.The fast and global spread of bacterial resistance to currently available antibiotics results in a great and urgent need for alternative antibacterial agents and therapeutic strategies. Recent studies on the application of nanomaterials as antimicrobial agents have demonstrated their potential for the management of infectious diseases. Among the diverse palette of nanomaterials currently used in biomedical applications, carbon nanotubes (CNTs) have gained massive interest given their many valuable properties, such as high thermal and electrical conductivity, tensile strength, flexibility convenient aspect ratio, and low fabrication costs. All these features are augmented by facile conjugation with functional groups. CNTs are currently available in many configurations, with two main categories being single-walled and multi-walled CNTs, depending on the number of rolled-up single-layer carbon atoms sheets making up the nanostructure. Both classes have been identified over the past years as promising antibacterial agents but the current level of understanding of their efficiency still harbors many pending questions. This mini-review surveys recent progress on the topic of antibacterial effects of CNTs and examines the proposed mechanisms of action(s) of different CNT typologies, placing the main focus on past studies addressing the antibacterial activity on  E. coli and S. aureus bacterial cells.Main effects of SWCNTs and MWCNTs on  While most species are beneficial for supporting current life on Earth, a small number are pathogenic and can cause disease to humans and animals. Many pathogenic microorganisms, especially those circulating in healthcare settings, have developed resistance to most of the available antibiotics and can cause severe infections accounting for tens of millions of deaths annually across the globe.9 Other factors contributing to the emergence of drug-resistant strains are thoroughly discussed in the recent review of Larsson et al.10 Recently, nanomaterials emerged as important tools in the fight against multidrug-resistant (MDR) bacteria.11 These materials can be used as “nano-weapons” that can act individually or in synergism with antimicrobial compounds against bacteria. This synergism holds valuable intrinsic potential for the development of next-generation, all-in-one agents, that can combat both drug-susceptible and MDR strains. The most common mechanism of action of nanomaterials relies on their interaction with the cellular envelope of bacteria, causing its destabilization and ultimately cell death, even for highly resistant species.12 Currently, among the most studied nanomaterials proposed as alternative antibacterial agents, metal-based nanoparticles (NPs), graphene-based nanomaterials, and carbon dots have extensively been demonstrated to have significant antibacterial properties .The great genetic adaptability, intrinsic bacterial resistance genes, and the selective pressure exerted by the massive use of antibiotics are responsible for the appearance, transfer, and spread of antibiotic resistance genes and bearing strains.14 listed as a priority by the World Health Organization. Among them, silver-based NPs represent maybe the most effective antibacterial agents in this class, while NPs carrying other metals  have been observed to exert variable bactericidal activities.14Given their size and selectivity for bacteria, metal-based nanoparticles (NPs) have proved to be highly effective against the pathogens15Graphene-based nanomaterials have been developed for many purposes spanning from the promotion of bacteria proliferation to microbial inhibition. These materials have been used as growth promoting agents of bacteria to accelerate interspecies electron transfer during anaerobic metabolism. On the other hand, graphene-based materials with antibacterial properties have been synthesized to prevent biofilm formation on membranes for water treatment, medical equipment, and tissue engineering scaffolds.13Carbon dots, constituted by small carbon nanoparticle cores with adsorbed surface passivation molecules, are generally nontoxic. However, with their effective light-harvesting properties over a very broad spectral range from UV to near-IR, carbon dots have exhibited strong photodynamic antibacterial effects.16–19 depending on the targeted application and the employed synthesis protocols. CNTs originate from graphene sheets, whose layers appear as a rolled-up, continuous, hexagonal-like mesh structure, with the carbon molecules positioned at the apexes of the hexagonal structures  have also been demonstrated as highly efficient antibacterial agents over the past years. CNTs are cylinder-shaped allotropic forms of carbon, with diameters of several nanometres and lengths ranging from nanometres to tens of centimetres,ructures . CNTs wiructures , while mures  and Escherichia coli (E. coli), which have profiled over the past years as two prototypical Gram-positive and Gram-negative models. S. aureus is a Gram-positive bacterium, which causes a variety of mild to extremely severe infections, that is widely acknowledged as an important source for the spread of many antibiotic resistance genes worldwide.28E. coli is a species that is responsible for diverse pathological conditions with health hazards ranging from mild to severe,29,30 with drug-resistant E. coli strains posing a significant global threat.31,32 While antibiotic drugs remain the gold-standard in the fight against bacterial infections, the use of various nanomaterials as alternative solutions has been thoroughly explored in past studies.33,34 Most of these studies concluded that Gram-negative species are more resistant to membrane damages caused by nanomaterials than Gram-positive bacteria, given additional protection provided by their outer membrane.35 CNTs were as well considered in these past efforts, having been shown to be highly capable of severly damaging the cellular envelope  leading to leakage of cytoplasmatic content and consequent cell death.36Due to their great adaptabilityvia covalent and non-covalent bonds. In many cases, such strategies were found useful to reduce the dose of CNTs, and to achieve higher therapeutic efficacy compared to antibacterial solutions building on pristine CNTs. Overall, we consider this review to be a useful resource for those interested to get acquainted with the topic of antibacterial CNTs, and for peers interested in a glimpse on the current state-of-the-art.While important work that has significantly contributed to the current level of understanding of the interactions taking place between CNTs and bacteria is also presented as background in the next section, we place the main emphasis on discussing selected works published in the past five years, that illustrate various facets on the use of SWCNTs and MWCNTs in antimicrobial applications. Considering that the use of these materials in their pristine form is known to present a series of limitations linked to aspects such as chemical inertness, hydrophobic character, poor adhesion during interaction with the cell wall, and instability in aqueous solution, we also focus our attention on SWCNTs and MWCTNs whose antibacterial properties were enhanced by the addition of functional groups 24 Many studies have attributed the antibacterial properties of SWCNTs to a wide range of potential mechanisms including metabolic alteration or inhibition,37 oxidative stress,38 and physical piercing damage to the cell envelope.39 Work performed to date has also shown that the antibacterial activity of CNTs can be influenced by: (i) structural properties , (ii) concentration; (iii) buffer solution in which SWCNTs are solved; (iv) exposure time to SWCNTs, or (v) the number of collisions and extent of the impact forces occurring between the SWCNTs and the bacterial cells.36 With respect to the latter, in a landmark study reported by Kang et al.,1 it has been proposed that cell envelope damage, resulting from direct physical contact between bacteria and SWCNTs, represents in fact the major cause of bacterial death. The authors showed that SWCNTs exhibit stronger antibacterial activity than MWCNTs against E. coli K12, speculating that this probably relates to their smaller diameter size that facilitates partitioning and partial penetration into the cell envelope. However, the relationship between SWCNTs length and antimicrobial effects remains controversial: Aslan et al.40 demonstrated that the use of shorter SWCNTs caused additional damage to the surfaces of E. coli cells, which they hypothesized to be most likely related to the increased chances for interaction between the SWCNTs open ends and the targeted microorganisms. On the other hand, Yang and co-workers41 found that longer SWCNTs have stronger antimicrobial activity against the pathogenic bacterium Salmonella typhimurium due to their improved aggregation capability with bacterial cells, in a study that discussed as well limitations of short SWCNTs to bind to bacterial cells. With respect to other physical properties, Chen et al.,42 addressing in their work a broad-spectrum of CNTs, proposed that rigid and thin SWCNTs are more effective in terms of cell wall and membrane piercing of round-shaped bacteria than MWCNTs. An open debate still exists on what is the optimal CNT configuration for achieving the most efficient antibacterial effect.Despite convincing evidence reported to date on the antibacterial role of SWCNTs, a defined mechanism of action has not been univocally demonstrated so far.S. aureus and E. coli strains.Next, we discuss several relevant works, placing main focus on those published over the past five years, in which the antibacterial effects of SWCNTs, either in pristine form, or conjugated with other nanomaterials, or antibiotics, were discussed with respect to their activity on et al.43 investigated the antibacterial effects against S. aureus of pristine SWCNTs in comparison with nanodiamond graphene (ND) and graphene oxide (GO), two alternative carbonaceous nanomaterials that have gained increasing attention due to their presumed better biocompatibility compared to CNTs in specific scenarios, discussed in previous works.44 The authors found that among the tested nanomaterials, pristine GO exhibited the most pronounced antibacterial effects, exhibiting a dose-dependent behaviour. SWCNTs showed activity against S. aureus, but only at high concentrations (1 and 10 mg mL−1), while pristine ND was found not only to be less toxic but also to promote bacterial growth at the highest concentration assayed (10 mg mL−1). We consider this study to be important as it shows that carbonaceous nanomaterials exhibit consistently different antibacterial effects depending on their size and geometric configuration.Among the wide palette of endeavours reporting SWCNT-based antibacterial tools, the work of Basiuk et al.39 have addressed in their study the fact that SWCNTs are usually difficult to disperse, and thus many studies focusing on their antibacterial effects use them in combination with dispersion aides. While many of these contribute themselves to the exerted bacterial stress, many times such aspects are unaccounted for. The authors discussed thus the antibacterial effects of SWCNTs when administered with five dispersant agents: sodium dodecyl sulfate (SDS), Pluronic, lysozyme, DNA, and tryptic soy broth (TSB). They observed that SDS is fatal to S. aureus regardless of the presence of SWCNTs, while the activity of Pluronic and lysozyme against S. aureus was enhanced by the presence of SWCNTs. In contrast, DNA and TSB dispersions did not have any activity regardless of the presence of SWCNTs. Overall, the work of Noor et al.39 showed that studies focused on assessing the antibacterial activity of SWCNTs need to carefully consider the synergistic interactions taking place between these nanomaterials and dispersants, which may result in different levels of stress exerted on cells compared to the case when pristine SWCNTs are used without dispersion agents.Noor et al.45 have introduced as an efficient photodynamic antimicrobial chemotherapeutic agent a nano-composite made up of SWCNTs and amine-functionalized porphyrin. They showed that upon exposure to visible light, the porphyrin conjugated nanotubes inflict damage to S. aureus bacterial cells, finally leading to their death. Field emission scanning electron microscopy (FESEM) images of the cells treated with the photoactivatable nanocomposite showed the formation of web-like structures on the affected cells, which were dependent on the light irradiation time. This study showcases that the intrinsic antibacterial effects of SWCNTs can be significantly augmented by conjugating them with photosensitisers. In a different study addressing the use of SWCNTs in combination with photo-active nanomaterials, Mohammad et al.46 coated pristine SWCNTs with Ag-doped TiO2 NPs with a size estimated to range between 7.7 and 13.53 nm, which were found to be responsible for antibacterial photocatalytic effects. These nanocomposites were tested against bacterial strains of both E. coli and S. aureus models, with the authors observing Gram-negative bacteria to be more resistant to the proposed nanocomposite compared to Gram-positive bacteria, under illumination by UV light. MWCNTs were evaluated as well in this study, providing less efficient results. The authors speculate that although MWCNTs–TiO2/Ag showed a slightly lesser toxicity against bacteria in their experiments, in specific applications, they might represent the better choice given their more reduced-fabrication costs. Additional insights on CNTs based antibacterial phototherapies can be found in the thorough review work of Wang et al.47The promising effects of pristine SWCNTs against bacterial pathogens prompted to the generation of functionalized forms of these CNTs to optimize their activity. In this body of efforts, Sah et al.48 introduced an ingenious antibacterial nanoplatform consisting of SWCNTs decorated with silver nanoparticles and coated with mesoporous silica. They showed that the outer mesoporous silica shells improve the dispersibility of SWCNTs, increasing their contact area with bacteria cell envelope, while the large number of mesopores in the silica layers act as microreactors for in situ synthesis of Ag NPs with controlled small size and uniform distribution. They compared the effects of this nanocomposite with the antibacterial properties of mesoporous silica coated SWCNTs and commercial Ag NPs, observing much stronger antibacterial performance against MDR S. aureus and E. coli strains, due to the larger extent of damage to the bacterial cell membranes, in vivo using a rat skin wound infection model, showing remarkable bacterial clearance capabilities for MDR S. aureus strains, accompanied not only by great biocompatibility but also by valuable wound healing effects, 49Considering other antibacterial routes, Zhu et al.50 proposed SWCNTs and nano-graphene oxide (NGO) as solutions for delivering the antibiotic tetracycline to a tetracycline-resistant E. coli strain. Tetracycline loaded-SWCNTs and NGOs were found to inhibit this strain, even for tetracycline amounts much lower compared to the minimum inhibitory concentration (MIC) of free tetracycline. This was attributed to the capacity of these two carbonaceous nanomaterials to transport the antibiotic into the cells and thus to circumvent the drug-resistance mechanism based on the expression of efflux pumps. SWCNTs were more efficient in delivering tetracycline compared to NGOs, which was attributed to their needle-like shape. This study consolidates the current belief that nanomaterials may represent a cornerstone for next-generation antibacterial therapies, showing that besides their intrinsic antibacterial properties, they can augment the effects of antibiotics, enabling their administration in lower doses, helping to reduce the selective pressure, and overcome antibiotic resistance.Besides past studies reporting the combination of SWCNTs with other nanomaterials to obtain more efficient therapeutic tools against bacteria, it is important to note that SWCNTs have also been successfully conjugated for this purpose with antibiotics. For example, Carver et al.51 the authors exploited for antibacterial purposes the fact that SWCNTs can be easily chemically combined with various semiconductor nanostructures such as ZnO, ZnS, SnO2, CdS or CuO. Considering the latter, they fabricated SWCNT–CuO nanocomposites by straightforward recrystallization accompanied by calcination, which resulted in heterojunctions being formed between the SWCNT surface and the CuO nanocrystals that were chemically attached to the SWCNT surface. Antimicrobial susceptibility assays demonstrated excellent bactericidal properties of the proposed material on both E. coli and S. aureus models. The authors attributed the bactericidal effects to the increased intracellular concentration of reactive oxygen species (ROS) resulted from the occurring chemical reactions, which are known to kill bacteria through cumulative oxidative stress.52,53 However, it is possible that endogenous ROS, produced by bacteria in response to membrane damage by SWCNT–CuO nanocomposites, may contribute to bacterial killing.54 Another study explicitly nominating ROS as the main antibacterial mechanism, is the work of Rugaie et al.,55 where the authors laced ZnO–Ag and ZnO–Au nanocomposites into SWCNTs to yield ZnO–Ag–SWCNTs, and ZnO–Au–SWCNTs. They showed that pre-treatment of phagocytic cells with these nano-hybrids activates these cells, enhancing phagocytosis and microbicidal activity by ROS and NADPH oxidase production. Moreover, this study demonstrated that ZnO–Ag–SWCNTs and ZnO–Au–SWCNTs nanocomposites contributed to the bactericidal activity against E. coli to a greater extent than the SWCNTs alone, In a study reported by Sapkota et al.56 functionalized pristine SWCNTs through acidic treatment for nucleation, followed by reduction of silver ions by microwave heating to produce Ag-NPs decorated SWCNTs (Ag–SWCNTs). Via a dip-dry-curing process, they coated on different cotton fabrics pristine SWCNTs, Ag-NPs and Ag–SWCNTs composites and qualitatively evaluated the antibacterial property of all coated fabrics against S. aureus and E. coli. The Ag–SWCNTs coated fabrics showed excellent antibacterial activity against both types of bacteria (the highest in the tested group), which did not significantly diminish even after many washings. This study represents an important example on the usefulness of SWCNTs-based nanocomposites to enable a next generation of fabrics that can prevent contamination/infection with bacteria, which can be especially useful in bacteria rich environments, such as hospitals.In a study addressing a different antibacterial function of SWCNTs, Kumar 57 with manyfold uses including as delivery vehicles for metallic nanoparticles, drugs, DNA aptamers, peptides, and proteins.58,59 Their intrinsic antibacterial properties are also widely acknowledged.24 Although it has been speculated that many of their cytotoxic effects in bacteria depend on multiple mechanisms, correlated with diverse factors such as amorphous carbon content, catalytic metal content, bundled conformation, length, and dispersity in aqueous media,60 the exact mechanisms behind their antibacterial modes of action are yet to be understood, mainly due to the scale at which MWCTNs–bacteria interactions take place, with many aspects unavailable to the resolution limitations of currently available characterization techniques. Similar to the mechanisms of actions acknowledged for SWCNTs, MWCNTs have been proposed to have membranolytic activities and/or to induce the production of ROS, which results in bacterial death due to massive oxidative stress.52,53,61 However, various studies proposed additional mechanisms over those of SWCNTs. For example, Mocan et al.62 suggested that the release of impurities upon MWCNT exfoliation may hold an important role in bacterial killing.MWCNTs are hollow cylindrical carbonaceous nanomaterials with walls composed of more than one sheet of graphene, with a typical diameter ranging in the order of tens of nanometres . Among oet al.,63 it was shown that double-walled CNTs (DWCNTs) and MWCNTs inhibit the growth of many different opportunistic pathogens, including S. aureus, P. aeruginosa, K. pneumoniae, and fungal strains belonging to Candida albicans. Importantly, it was shown that the evaluated CNTs selectively damage the microbial cell walls or membranes, 40 suggested that shorter CNTs are likely to induce more damage to bacteria, due to a higher chance of rupturing the envelope by the sharp ends, here it was hypothesized and partially demonstrated that longer CNTs may be more efficient as they wrap around the surface of the pathogen cell, yielding a higher surface contact area with the cell wall compared to shorter CNTs, with a proportional increase of efficacy. The authors also evaluated DWCNTs and MWCNTs dispersed by sodium dodecyl-benzenesulfonate (SDBS), which was used to improve the aqueous phase dispersion. FESEM images indicated strong interactions taking place between the SDBS-treated CNTs and the microbial cells, demonstrating also that stronger dispersion of CNTs increases their antimicrobial activity. Noteworthy, MWCNTs exhibited higher antimicrobial activity as compared to DWCNTs.In a study reported by Saleemi 1,60 thus prompting the development of various functionalization procedures to potentiate their activity. For example, Saleemi et al.64 investigated the antimicrobial role of thermoplastic polyurethane nanofibers containing various concentrations of surfactant-modified DWCNTs and MWCNTs against several Gram-positive and Gram-negative bacterial strains, including S. aureus. Different assays, such as number of viable cell count, diameter of inhibition zone, and growth curve values confirmed excellent microbicidal properties of the electrospun nanofibers.MWNCTs usually exhibit moderate antibacterial properties compared to SWCNTs,et al.,65 MWCNTs decorated with ZnO, Ag and hydroxyapatite (Hap) NPs (with NP diameters ranging from 7 to 35 nm depending on their type) were shown to have a significant antimicrobial activity and to reduce biofilm formation by cells of S. aureus, B. subtilis, P. aeruginosa, E. coli and C. albicans. Among other observed advantages, all the decorated MWCNTs were found to exhibit a better dispersion in water, compared to pristine MWCNTs. Among the evaluated MWCNT instances, the highest antimicrobial activity (in terms of the largest diameter of inhibition zone) was observed for MWCNTs decorated with ZnO and Ag NPs. The biofilm formation assay also demonstrated that these two variants exhibit inhibition of biofilm formation, consolidating the idea that antimicrobial systems building on MWCNTs and Ag and ZnO NPs are valuable solutions to be considered in the fight against resistant pathogens and biofilm associated infections. In another study discussing the effects of MWCNTs on biofilms, Abo-Neima et al.,66 showed that MWCNTs functionalized via an interaction with nitric acid were able to prevent E. coli and S. aureus biofilm formation. Furthermore, these materials were found to be capable to disrupt mature biofilms leading to their detachment. Transmission electron microscopy images revealed morphological changes that reflect the damage mechanisms. The functionalized MWCNTs were found to biologically isolate the cells from their surrounding microenvironment, contributing to the development of toxic substances and placing the cells under oxidative stress, finally leading to their death. The antimicrobial and biofilm formation resistance properties of MWCNTs were also demonstrated in the study of Madenli67et al., who studied MWCNTs blended polyethersulfone (PES) membranes, considering as model of target organisms E. coli and P. aeruginosa. Their results showed that, following the deposition of E. coli cells onto the membrane surface, no colonies were formed on composite membranes instances synthesized at particular MWCNT content levels, whereas for membranes of similar composition incubated in P. aeruginosa suspensions, consistently less biofilm formation occurred within 24 h. Importantly, the authors showed no MWCNT release during the water filtration of the composite membranes, which is important in light of potential applications for separation and purification.In a different study reported by David 47 In this context, Parasuraman et al.68 assessed an antimicrobial photodynamic therapy based on methylene blue-conjugated MWCNTs (MBCNTs) on biofilms of E. coli and S. aureus, S. aureus than in E. coli. This was found to be correlated with the fact that the binding and uptake of MBCNTs was greater in S. aureus compared to E. coli, which was consistent with previous work addressing the killing of Gram-positive and Gram-negative bacteria with nanoplatforms incorporating methylene blue.69 Another study evaluating an antibacterial photodynamic therapy based on MWCNTs has been performed by Cuadrado et al.70 They studied two magnetic nanocomposites based on GO and MWCNTs loaded with the photosensitiser menthol–zinc phthalocyanine (ZnMintPc). These were conjugated with iron magnetic nanoparticles and encapsulated in a lipophilic envelope, conferred by treatment with a biocompatible hydrogel based on N-vinylcaprolactam (VCL) and poly(ethylene glycol)diacrylate (PEGDA), used to help with the dispersion of the considered hydrophobic compounds in aqueous media. The two magnetic nanocomposites, VCL/PEGDA–MNPs–MWCNTs–ZnMintPc and VCL/PEGDA–MNPs–GO–ZnMintPc, were found to exhibit excellent photodynamic/photothermal effects under 630 nm illumination against E. coli, S. aureus  generation of ROS, (ii) physicochemical characteristics, (iii) the steric effect, and (iv) release of metal ions. ROS generation was found to be in lead over the others, with the physicochemical characteristics and the steric effect taking part of the contributing mechanisms as well. This study suggests also that GO-based nanocomposites are to be preferred over CNT-based nanocomposites, with Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) images revealing that GO-based nanocomposites exhibited better attachment to the bacterial surface, while CNT-based nanocomposites significantly aggregated to each other, diminishing thus the interaction chances with the cells. Another relevant study focused on ZnO–MWCNT nanocomposites has been reported by Shakir et al.,74 who evaluated Co doped-ZnO/MWCNTs nanocomposites synthesized by means of the sol–gel method. They evaluated various modifications occurring in the physical properties of instances synthesized under different Co doping concentrations. They observed the growth of spherical clusters over the surface of interlocking cylindrical tubes, and that the Co doped-ZnO/MWCNT hybrid nanocomposites exhibit high absorbance, and band gap narrowing upon increasing cobalt-doping concentration, which can facilitate a wide range of applications. With respect to the antibacterial effects, the authors observed high inhibition efficiency for instances synthesized under high concentrations of Co, for both S. aureus and E. coli models. Given that cobalt is known for good biocompatibility and low toxicity, the nanomaterials discussed in this study represent an interesting example on the synergy between CNTs and Co.In another relevant effort, Baeket al.75 introduced a novel nano-drug synthesized by covalent grafting of modified MWCNTs with levofloxacin (LVX). The MWCNT–LVX agent was demonstrated to be highly efficient against S. aureus strains. The novel synthetic nano-drug possessed high loading capacity and pH-sensitive release profile in vitro and in vivo, exhibiting higher bactericidal activity in a mouse S. aureus burn wound infection model compared to the stand-alone use of LVX.75Same as SWCNTs, MWCNTs can also be used in combination with conventional antibiotic drugs. For example, Hassani et al.,76 exploited the fact that ionic liquid (IL) and MWCNTs show significant synergistic effects given the occurring strong π–cation interactions.77 They developed a material based on IL-functionalized MWCNTs for hydrophobic coatings, showing their effectiveness over S. aureus (including a methicillin-resistant strain), and E. coli. By the help of atomic force microscopy (AFM) and SEM, they elucidated the mechanisms of action, in vitro. Overall, this study has great potential to favour the advent of next-generation antimicrobial surfaces with self-sterilizing abilities. Other important applications of CNTs in the context of antimicrobial surfaces are nicely presented in the recent review of Teixeira-Santos et al.78In a different type of approach, Bains et al.79 assayed different carbon-based nanomaterials and demonstrated that carboxyl-functionalized MWCNTs are endowed with a strong antibacterial potential against E. coli and S. aureus in terms of growth inhibition and alteration of membrane integrity, presenting an activity comparable to catalytic filamentous carbon with different orientations of graphene blocks, ionic carbon, and ultrafine explosive NDs.Moskvitina et al.80 In their study, the authors showed that VAMWCNTs arrays inactivate both Gram-negative (P. aeruginosa) and Gram-positive (S. aureus) bacterial cells. The mechanistic action leading to the bacterial cell death stems from the elasticity of the proposed nanostructures, exhibiting a high aspect ratio (100–3000) between their length (microns) and diameter (approximately 10 nm). The authors demonstrated that upon the adsorption of bacteria onto the nanostructured surface, the deflection and retraction of MWCNTs results in physical membrane perturbation and cell death , which was demonstrated in the landmark work of Linklater ll death . In the 23,24 , it seems improbable that bacteria strains could develop resistance to these nanomaterials. However, to what extent a selection of resistant mutants could withstand the action of CNTs remains a puzzling question, which definitely warrants the requirement of further studies on the subject. However, it is important to note that bacteria could potentially develop significant morphological changes, which could impact the antibacterial efficiency of CNTs. Indeed, it seems that there is a strong relation between antibiotic resistance and MWCNT effect on S. aureus cells. The antimicrobial efficiency of MWCNTs seems to be lower in MDR strains, as compared to antibiotic-susceptible isolates. S. aureus strains resistant to antibiotics acting on cell wall are less susceptible to both pristine and functionalized MWCNTs.83 The idea that cell wall structural modifications could interfere with the antimicrobial activity of CNTs is also supported by the work of Hassani et al.,75 discussed in the previous section, which reports different antibacterial efficiency of the MWCNTs depending on the cell wall structure of the target cells.In 84 A recent study85 showed that MWCNTs promote bacterial conjugative plasmid transfer in aqueous environment. The results of this study suggest that the presence of particular MWCNTs configurations, especially clustered, provide bacteria with novel surfaces for intense cell-to-cell interactions in biofilms and can promote bacterial horizontal gene transfer, hence potentially elevating the spread of antimicrobial resistance. This leads to the idea that results obtained in studies addressing planktonic bacteria cannot be straightforward extrapolated to applications addressing biofilms, therefore knowledge transfer between these two fields of research should be done with extreme caution.The antibacterial activity of nanomaterials in highly organized multicellular communities is also a common challenge, as bacteria in biofilms behave completely different compared to their planktonic counterparts. Microbial biofilms are more tolerant to all known antimicrobials and host defence mechanisms; therefore, the management of biofilm-associated infections is challenging.Due to the increasing number of drug-resistant bacterial strains and their high pressure on the sustainability of health system across the globe, there is an urgent need to reduce the exposure to antibiotics, which is known to favour the development of resistance mechanisms. To this end, nanomaterials have been widely explored to date as solution to replace antibiotics, or as means to enable lower antibiotic doses. In the frame of these efforts, CNTs have been found to hold important antibacterial potential. Knowledge on the mechanisms by which CNTs are capable to kill bacteria is constantly growing, together with the extent of functionalization routes that results in enhanced anti-microbial effects. In this focused review we have discussed recent progress on the use of SWCNTs and MWCNTs as the backbone of various antibacterial solutions and tools, placing main emphasis on works reported over the past five years. The discussed works showcase various ways by which SWCNTs and MWCNTs can contribute to overcoming the current crisis that humanity faces due to the emerging number of drug-resistant microorganisms. We hope that our work will inspire future research aimed at understanding in more detail the interactions taking place between CNTs and prokaryotic cells, and the advent of novel CNT-based “weapons” capable to efficiently fight drug-resistant and drug-susceptible bacteria.All authors identified relevant references and designed the structure of the manuscript. MA, ML, CC, AMH, PV and SGS wrote the initial draft. SGS, MA, ML and PV have prepared the figure artwork. ML and PV have prepared the tables. All authors read and revised the scientific content of the initial draft, and of the revised version, and helped on reorganizing text to promote clarity. SGS and PV coordinated the overall effort.There are no conflicts to declare.


Some hormonally active cancers have low survival rates, but a large proportion of their incidence remains unexplained. Endocrine disrupting chemicals may affect hormone pathways in the pathology of these cancers.To evaluate cross-sectional associations between per- and polyfluoroalkyl substances (PFAS), phenols, and parabens and self-reported previous cancer diagnoses in the National Health and Nutrition Examination Survey (NHANES).We extracted concentrations of 7 PFAS and 12 phenols/parabens and self-reported diagnoses of melanoma and cancers of the thyroid, breast, ovary, uterus, and prostate in men and women (≥20 years). Associations between previous cancer diagnoses and an interquartile range increase in exposure biomarkers were evaluated using logistic regression models adjusted for key covariates. We conceptualized race as social construct proxy of structural social factors and examined associations in non-Hispanic Black, Mexican American, and other Hispanic participants separately compared to White participants.Previous melanoma in women was associated with higher PFDE , PFNA , PFUA , BP3 , DCP25 , and DCP24 . Previous ovarian cancer was associated with higher DCP25 , BPA  and BP3 . Previous uterine cancer was associated with increased PFNA , while higher ethyl paraben was inversely associated . Various PFAS were associated with previous ovarian and uterine cancers in White women, while MPAH or BPF was associated with previous breast cancer among non-White women.Biomarkers across all exposure categories  were cross-sectionally associated with increased odds of previous melanoma diagnoses in women, and increased odds of previous ovarian cancer was associated with several phenols and parabens. Some associations differed by racial group, which is particularly impactful given the established racial disparities in distributions of exposure to these chemicals. This is the first epidemiological study to investigate exposure to phenols in relation to previous cancer diagnoses, and the first NHANES study to explore racial/ethnic disparities in associations between environmental phenol, paraben, and PFAS exposures and historical cancer diagnosis. Prostate and breast cancer are the most commonly diagnosed cancers among men and women, respectively . DespiteMany environmental toxicants have been identified as endocrine disruptors, including phenols, parabens, and per- and polyfluoroalkyl substances (PFAS). Human exposure to phenols and parabens occurs most commonly via plastic food/beverage packaging and personal care products. PFAS chemicals are found in stain resistant fabrics and flame retardant furniture, are persistent in the environment, and can bioaccumulate inside the body following exposure. Previous work has shown these chemicals to have effects on circulating concentrations of estrogens , 6, thyrThe National Health and Nutrition Examination Survey (NHANES) is a United States nation-wide biomonitoring effort which has demonstrated evidence of widespread human exposure to environmental toxicants including phenols, parabens, and PFAS . NHANES Data from NHANES was used for the present analysis. NHANES is composed of a non-institutionalized, nationally representative, sample of children and adults and is used to assess the health and nutritional status of the United States population. A flowchart depicting how we built our analytical datasets is presented in Fig. We included NHANES measures of a total of seven PFAS chemicals and 12 phenols/parabens. Five PFAS chemicals were measured in all cycles from 2005 to 2018: perfluorohexane sulfonic acid (PFHS), 2-(N-methyl-PFOSA)acetic acid (MPAH), perfluorodecanoic acid (PFDE), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUA). Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) were included from all cycles except 2013–2014. PFAS were quantified from serum samples using high performance liquid chromatography-turbo ion spray ionization-tandem mass spectrometry. Seven phenols/parabens were measured in all cycles between 2005 and 2016: bisphenol-A (BPA), benzophenone-3 (BP3), triclosan (TCS), methyl paraben (MPB), ethyl paraben (EPB), propyl paraben (PPB), and butyl paraben (BPB). Five additional phenols/parabens were measured from 2013 to 2016: bisphenol-F (BPF), bisphenol-S (BPS), triclocarban (TCC), 2,4-dichlorophenol (DCP24), and 2,5-dichlorophenol (DCP25). Phenols and parabens were quantified in urine samples using on-line solid phase extraction coupled to high performance liquid chromatography and tandem mass spectrometry.N < 10).Self-reported cancer diagnoses were obtained from the medical conditions questionnaire administered to all participants 20 years and older. Participants were first asked “Have you ever been told by a doctor or other health professional that you had cancer or a malignancy of any kind?” Those who responded yes were then asked to indicate which type of cancer it was, and they were able to indicate up to three different cancer types. We extracted data for 7 cancer types: breast, ovarian, uterine, prostate, testicular, thyroid, and melanoma. We also created a variable for combined reproductive cancers which included breast, ovarian, and uterine cancers for women and prostate and testicular cancer for men. Testicular cancer and thyroid cancer among men were excluded from regression analyses because of low case numbers  in more than 50% of samples, so these were treated as categorical variables with all concentrations below the LOD as the reference group and the remaining concentrations split between those below the median and those at or above the median of detectable values. All concentrations below the LOD were imputed with the LOD divided by the square root of two. Associations between exposure biomarkers and cancer outcomes were estimated using logistic regression. Based on the literature of potential cancer risk factors  we consip < 0.05 was considered statistically significant).To explore the possibility of race as a social construct proxy of structural social factors and an effect modifier on the associations between environmental exposures and cancer outcomes, we ran sensitivity analyses in which effect estimates were calculated among non-White racial groups separately  and compared to effects among White participants only. Models included interaction terms specific to each White/non-White pair such that the p-value of the interaction term (p-int) could be interpreted as the significance of the difference between those two groups  and breast cancer was the most frequently reported among women .Distributions of biomarker concentrations are shown in Supplementary Tables Associations between current PFAS concentrations and odds of having a previous cancer diagnosis are depicted in Fig. Associations between current phenol/paraben concentrations and odds of having a previous cancer diagnosis are depicted in Fig. Distribution of cancer outcomes by race are reported in Supplemental Table Here we have reported numerous associations between current concentrations of biomarkers of exposure to PFAS, phenol, and paraben chemicals and previous cancer diagnoses over multiple NHANES cycles. Of note, the PFAS chemicals PFDE, PFNA, and PFUA were associated with increased odds of prior melanoma diagnosis among women, but not men. Also, among women, concentrations of BPA, BP3, and two dichlorophenols were associated with greater odds of ovarian cancer. Both dichlorophenols showed positive associations with the odds of every cancer type assessed, particularly among women. Finally, greater odds of previous cancer diagnoses among White women were observed with higher PFAS exposure, while Black and Mexican American women were more likely to have a previous cancer diagnosis with increased phenol/paraben exposure.Numerous epidemiology studies have investigated potential associations between PFAS exposure and melanoma, but no notable effects have been found and most studies assessed only PFOA and PFOS exposures. Importantly, melanoma is the fifth most common cancer in the U.S. and recent estimates indicate increasing incidence in higher-income countries . While tSex-specific associations between PFAS chemicals and previous melanoma diagnosis, suggest that sex-mediated mechanisms may be at play. Previous work has shown that women are more likely than men to be diagnosed with melanoma, but metastasis and mortality rates are higher among men than women . DiffereBased on data collected from 1999 to 2015, uterine cancer was one of few cancers increasing in incidence and mortality in the United States . UterineWe observed an inverse association between PFOS exposure and odds of previous thyroid cancer diagnosis among women, while all other associations with thyroid cancer were null. To our knowledge, only one previous study has explored associations between PFAS exposure and risk of thyroid cancer. That community-based analysis found that those living in an area known to have experienced PFAS contamination of drinking water showed greater risk ratios of thyroid cancer relative to those living in unexposed control areas . AdditioOvarian cancer is the leading cause of death among gynecological cancers and is the seventh most commonly diagnosed cancer among women around the world . Black wOur results suggest that various environmental chemicals  are associated with previous diagnosis of ovarian cancer among all women. Previous work has shown that exposure to environmental toxicants can influence cells to undergo the epithelial-mesenchymal transition (EMT), a process, defined by epithelial cells losing their cell-to-cell adhesion properties and becoming migratory, that may be crucial in the transformation of benign cells into malignant cells . Upon trA previous review illustrates that BPA can regulate the expression of genes in ovarian cancer cells which act on pathways implicated in many of the key characteristics of cancer. For example, genes involved in cell proliferation can be upregulated by BPA, while other genes involved in apoptosis can be downregulated by BPA . HoweverIt is critical for future studies to understand the effects of endocrine active compound exposures on survivors of hormonally-driven cancers. Our findings highlight that across multiple tumor types, individuals with a prior cancer diagnosis have elevated body burdens of a range of toxicants. Hormonally-driven cancers are often treated with hormone therapy to reduce or alter the circulating concentrations of hormones . ExposurWe observed that various associations between environmental chemical exposures and previous cancer diagnoses were modified by race. Environmental exposures may differ by racial groups through various sources. For example, chemicals such as phthalates, phenols, and parabens may be found at higher concentrations in certain beauty products  that are marketed to Black, Asian, and Latina women . AnotherThese results highlight the need to carefully consider the use of survey regression methods based on whether the study hypothesis is aimed at obtaining results that are generalizable or specific to vulnerable populations. NHANES oversamples racial/ethnic minorities, which can be very useful when trying to evaluate rare disease states as outcomes in those populations. However, when survey regression methods are applied, the results generated are targeted at being generalizable to the entire United States population rather than being truly representative of the study population, which has the desired larger population of minority groups. Thus, if an association is observed among a minority group but null among non-Hispanic White participants, the survey regression results will be influenced towards the null to account for the oversampling of the minority group. We observed this in our analysis with PFDE exposure and odds of previous ovarian cancer. Standard regression analysis showed a non-significant positive association, but sensitivity analyses revealed that the association was observed only among non-Hispanic White participants. Accordingly, survey regression methods also resulted in a positive association. Thus, survey regression methods will generate more generalizable results, but if there are true differences in associations between racial groups, the survey regression results will be more representative of non-Hispanic White participants than of the minority groups.This analysis was subject to various limitations. First, our outcomes were previous cancer diagnoses and therefore causality cannot be determined. While we would have liked to account for the time between cancer diagnoses and biomarker measurement, this information was not available in NHANES. Further, because our exposures were measured after the cancer diagnoses occurred, reverse causation is a possibility if behavioral changes occurred. Subsequent treatment for cancer may also influence concentrations of endocrine-disrupting chemicals through altered metabolism, which may also be an important source of exposure misclassification among those with previous cancer diagnoses. Additionally, we have assumed that exposure biomarker measurements are accurate proxies of historical exposure levels, and so there is high risk for exposure misclassification. Despite this limitation, there is still utility in assessing PFAS and phenol/paraben profiles among previous cancer patients to inform prospective hypotheses in emerging cohort studies. Additionally, our results were likely subject to bias from unmeasured confounding factors such as family history of cancer or anatomical alterations such as ovariectomy and thyroidectomy. Our regression models may not have accounted for any correlations between covariates and biomarkers, possibly resulting in inflated associations. Similarly, we did not set multiple comparison thresholds, therefore some associations may be false positives. However, future prospective studies can build on our preliminary findings to perform targeted hypothesis testing on specific environmental contaminants. Another limitation includes potential outcome misclassification since previous cancer diagnosis was assessed using self-report questionnaire data. A previous study identified the validity of self-reported cancers with data from state cancer registries and while they identified fairly good accuracy (sensitivity of ≥ 0.9) for certain cancers  , future This study was also strong in a number of ways. Compared to previous studies, we leveraged NHANES data to investigate multiple classes of endocrine-disrupting chemicals to inform prioritization and hypothesis-driven investigation of environmental exposures in future prospective study designs. Additionally, our approach helps build the foundation for supervised multi-pollutant chemical mixtures analyses that intend to delineate chemical class-specific effects and potential interactions between chemicals. Multi-chemical class exposure assessment is becoming more common with technological advancements in high-throughput assays, however, these can be cost-prohibitive and time-consuming in certain contexts with limited resources. We also contribute toward reporting exploratory associations with understudied cancers in the context of endocrine-disrupting chemicals. For example, this is the first epidemiological study to assess phenols exposure in the context of previous ovarian cancer diagnosis. Further, this is the first NHANES analysis to investigate racial/ethnic disparities in associations between environmental exposures and previous cancer diagnoses. We also add to the current body of literature suggesting a role for estrogens in the onset and progression of ovarian cancer and melanoma, which could help inform future mechanistic and experimental studies as well as risk assessment and prevention efforts.In conclusion, we report various associations between exposure to environmental chemicals and previous cancer diagnoses that have not been previously explored. Several PFAS chemicals were positively associated with odds of previous melanoma diagnosis among only women, and various PFAS and phenols were positively associated with odds of previous ovarian cancer diagnosis. These findings highlight a sexually dimorphic nature of melanoma risk, as well as a potential estrogen-dependent mechanism for both cancer types. We also showed differential associations between environmental exposures and previous cancer diagnoses by racial groups, underscoring racial disparities that exist both in innate risk of cancer outcomes and in exposures to environmental toxicants. Future work in prospective cancer studies should aim to explore the roles of estrogenic chemicals and estrogen disruption in the pathology of melanoma and ovarian cancer and consider racial disparities when evaluating cancer mechanisms and risk. Findings from this study can be used to help inform and prioritize toxicants for policies surrounding greater surveillance of chemical exposures and risk assessment in communities with existing or emerging risk of environmental contamination.Reproducibility ChecklistSupplemental_Tables1-7Supplemental_Tables8–11


Bipolar disorder (BD) is often seen as a bridge between schizophrenia and depression in terms of symptomatology and etiology. Interestingly, hemispheric asymmetries as well as behavioral lateralization are shifted towards a tendency of left-side or mixed-side bias in schizophrenia whereas no shift is observed in subjects with depression. Given the role of BD with both, (hypo)manic and depressive episodes, investigating hemispheric asymmetries in subjects with BD is an interesting objective.A systematic review of studies including measures of behavioral lateralization in the form of handedness, footedness, eyedness, and language lateralization was performed resulting in 25 suitable studies.A broad variety of methods was used to assess behavioral lateralization, especially for eyedness, footedness, and language lateralization hindering the integration of results. Additionally, for hand preference, studies frequently used different cut-off scores and classification systems. Overall, studies do not support alteration in side preference in BD subjects. Studies focusing on differences in handedness demonstrate that subjects show equal rates of right- and non-right-handedness as the general population. Few studies focusing on manic episodes point towards increased left-side bias in ear and eye dominance, but the small sample sizes and conflicting results warrant further investigation.The results reinforce that some disorders, such as BD, should not be treated as a homogenous group but sub-groups should be analyzed within the patient’s population. Particularly, clinical implications resulting from neuroimaging studies highlight the need to study hemispheric asymmetries given that they may be important to consider for brain stimulation protocols. Especially in the context of the clinical neuroscience of lateralization, far less is known about BD than about either depression or schizophrenia (Mundorf and Ocklenburg Bipolar disorder (BD) is sometimes described as a bridge between the diagnostic classes of schizophrenia and depression in terms of symptomatology and etiology  to 18.1% for the broader definition of non-right-handedness, i.e., individuals favoring the left hand or use both hands equally often  right ear advantage during recovery  reported increased rates of non-right-handedness in BD compared to controls  and behavioral markers of visuospatial attention and visual perceptual asymmetries. When possible, we try to highlight the type of BD studied as well as the current episode of subjects (manic or depressive) to further disentangle potentially differential effects of BD. Finally, the review aims to provide insights into the important role of behavioral lateralization in mental disorders and to highlight the clinical implications derived from it.https://pubmed.ncbi.nlm.nih.gov/), PubPsych (https://www.pubpsych.eu/), ResearchGate (https://www.researchgate.net/), and Google Scholar (https://scholar.google.com/) were screened using the keywords: ((Handedness) OR (hand preference) OR (footedness) OR (foot use) OR (dichotic listening) OR (line bisection task) OR  OR  OR ) AND ((bipolar disorder) OR (manic depression)). Study identification was performed in multiple steps as different keyword combinations were searched separately. No automation tool was used. First, titles and abstracts were screened, and reviews and meta-analysis (n = 1) were removed, resulting in a total of n = 47 potentially relevant studies. Inclusion criteria were (i) a diagnosis of BD, (ii) articles must contain information on either handedness, footedness, dichotic listening, line bisection task or the visual half field technique, (iii) data must be given for BD subjects separately, (iv) original research article in English language. Exclusion criteria were (i) review articles, (ii) BD subjects and controls were matched for side preference, (iii) article only included right-handers, (iv) no BD subjects, (v) comorbid disorder. After the full-text screening, another n = 22 studies were removed due to inclusion and exclusion criteria leading to 25 articles included in this review. This process is presented in the flow chart following Prisma Guidelines  study by Bruder et al. , the 22 A study applying the line bisection task, a common measure of asymmetries in visuospatial attention Barnett , in 31 BIn sum, studies assessing behavioral markers of visuospatial attention and visual perceptual asymmetries point towards a poorer performance for the left visual field in BD subjects compared to controls.Several studies have focused on the objective to analyze potential differences in handedness in BD subjects. There are several established methods to assess hand preference, such as the Edinburgh Handedness Inventory (EHI) or the Annett Handedness Inventory Annett . Both thOne of the older studies investigated hand preference in 56 manic-depressive subjects and controls by asking the participants to mimic the use of ten different tools and tasks   hindering the synthesis of results. In terms of handedness, it is especially important to differentiate between mixed-handers (marked by doing some tasks with the left and some with the right hand) and ambidextrous  individuals which may not always have been the case in the included studies.Third, studies raise the question of to what proportion handedness may be linked to neurodevelopmental aspects given that some studies included adolescent subjects with BD or different ages of BD onset , nor did they assess acute manic or depressive episodes when testing the subjects. Grouping the results from individuals with a current manic episode or BD type I diagnosis with individuals with a current depressive episode or a type II BD diagnosis potentially dilutes effects that would be more pronounced in manic episodes as seen in the neuroimaging data  making it difficult to compare findings. Third, most studies had quite small sample sizes which reduces the validity of results. Fourth, not all studies analyzed the data separately for the type of BD or the current mood state. But given the results from the studies that did differentiate between BD type or current mood state, this should be set as an additional experimental variable. Consequently, conflicting results derive that warrant further investigation.Besides these aspects of the content and methods of the studies integrated in this systematic review, the used search strategy may be a further limitation, as other forms of behavioral asymmetries not explicitly mentioned in the search terms may have been overlooked.In conclusion, studies investigating handedness, footedness, eyedness, and language lateralization in subjects diagnosed with BD do not show overall alterations in behavioral preferences in BD. Few studies focusing on manic episodes point towards increased left ear and eye dominance, but the small sample sizes and conflicting results warrant further investigation. The results reinforce that some disorders, such as BD and schizophrenia, should not be treated as a homogenous group regarding neuronal alterations, but that studies need to separate sub-groups within the patient’s population such as BD type I and type II or even more precisely, based on the current mood episode of the subjects. Particularly, regarding clinical implications, results from neuroimaging studies reinforce the need to study hemispheric asymmetries given that they may be important to consider for brain stimulation protocols.


Adolescence is critical for physical and psychological growth, making healthy dietary behavior essential. Several countries face nutritional challenges due to a high prevalence of stunting in children under five, which can impact adolescent girls’ eating behavior. This systematic review aims to provide evidence on the eating behavior of adolescent girls in such countries, offering insights for stunting prevention programs.We conducted a systematic review following PRISMA guidelines and registered it in PROSPERO. We employed a comprehensive search strategy across multiple databases. Study selection involved three stages: deduplication, title/abstract screening, and full-text review, with inter-reviewer agreement assessment.The search identified 15 eligible studies from various countries, primarily utilizing cross-sectional designs. The studies focused on age ranges within adolescence and varied in sample size and assessment tools. The primary objective of these studies was to assess eating behavior, with outcomes related to dietary patterns, eating disorders, body image, and nutritional knowledge. The results revealed diverse eating behaviors among adolescent girls, including restrained eating, dieting for weight loss, craving-induced eating, and unhealthy dietary patterns. Many girls exhibited low dietary diversity, contributing to micronutrient deficiencies.To address these issues effectively, stunting prevention programs and policies should prioritize the following strategies: implementing comprehensive nutritional education programs to enhance adolescents’ knowledge of healthy eating habits and dietary diversity, providing resources and support for positive body image development to reduce the pressure for unhealthy dieting, improving access to affordable, nutrient-rich foods in both urban and rural areas, raising awareness about eating disorders and emphasizing early identification and intervention, engaging parents, caregivers, and communities in promoting healthy eating behaviors, and maintaining rigorous research and monitoring to adapt strategies based on evolving trends in adolescent eating behaviors.Adolescent girls in countries with high stunting prevalence exhibit diverse eating behaviors that can impact their nutritional status and overall health. Addressing these behaviors is essential to prevent stunting and its long-term consequences, emphasizing the importance of comprehensive strategies and support for this vulnerable population.https://www.crd.york.ac.uk/prospero/#recordDetails, identifier CRD42023389909. The high stunting rate in children under five persists worldwide. Globally, 149.2 million children under five suffered from stunting in 2020 . This nuThe UN defines adolescents as those aged between 10 and 19, comprising 1.2 billion people worldwide or approximately 16% of the global population. Most of these adolescents live in low- or middle-income countries and face various social and economic challenges. Investing in the rights and development of adolescents can contribute significantly to their full participation in society, a competitive workforce, sustainable economic growth, better governance, and more dynamic civil society. It can also accelerate progress toward achieving the Sustainable Development Goals (SDGs) set by the United Nations .Adolescents are increasingly seen as a window of opportunity with the recognition that investment in the health and wellbeing of young people is crucial for a country’s future and overall development. Evidence shows that adolescence provides a second chance to influence developmental trajectories (including cognitive growth and development), shape future habits, and compensate for some negative childhood experiences - second only to early childhood . InvestiMalnutrition, in all its forms, can have long-term detrimental effects on the development of children - and can even be passed down from generation to generation. In addition to poor cognitive performance and low work productivity, adolescent girls with anemia, for example, are more likely to give birth to low birth weight babies at risk of growth stunting . In counHealthy habits developed during adolescence, such as healthy eating and physical activity, can last a lifetime and help break the cycle of intergenerational malnutrition . HoweverThis review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . AdditioThe search strategy was determined based on research questions as well as inclusion and exclusion criteria based on the PICOS   as shownThe search strategy used in PubMed for this systematic review is designed to identify relevant studies related to adolescent girls’ eating behavior and its association with stunting. The strategy includes the following components; Participants (P): MeSH Term: “adolescent” and Keywords in Title/Abstract: “girls,” Outcome (O): MeSH Term: “feeding behavior” and Keywords in Title/Abstract: N/A (MeSH term covers the outcome), Exposure (E): Keywords: “growth disorders,” “growth,” “stunting,” “stunted.”The Boolean operators “AND” and “OR” are used to combine these components effectively. The search seeks to find studies that involve adolescents (using MeSH terms and title/abstract keywords), address eating behavior (using MeSH term), and explore the association with growth disorders, including stunting (using various keywords).The search strategy aims to be comprehensive by including both MeSH terms and additional keywords to ensure that relevant studies are captured. This approach helps in identifying a wide range of articles that match the research focus of the systematic review.The search started in the PubMed database in January 2023  .The search strategy resulted in a total of 601 potentially relevant studies. Of these, 408 studies met the inclusion criteria based on a review of the title and abstract. After reading the complete text, 393 articles were excluded because they did not meet the inclusion criteria, such as not being conducted in countries with a high prevalence of stunting or not focusing on adolescent girls. Finally, only 15 studies met the eligibility criteria and proceeded to the next stage. The screening process can be seen in The variables reviewed in the selected studies have been described in Most of the studies in this review utilized a cross-sectional design, with only one using a mixed-method explanatory design . The stuAlthough the target population of this study is adolescent girls, not all studies focus on the same age range, the adolescent period is divided into three stages: early (ages 11–14), mid (ages 15–17), and late (ages 18–21) . In thisThere is a difference in sample size among these studies, ranging from 24 subjects in the qualitative design study 20 to 4,993 subjects in the sizeable community-based study in Bangladesh. Therefore, this systematic review evaluated 9,831 participants.All studies utilize different assessment tools to evaluate changes in eating behavior targets. Four studies employed self-designed questionnaires , while tThe results of the studies generally show the presence of various eating behaviors in adolescent girls in the countries where the studies were conducted. Adolescent girls who diet to maintain body shape may avoid or skip meals to remain thin , especiaEating behavior is also related to Dietary Diversity (DD), which refers to consuming various food groups or types within a specific period. Consuming diverse foods is advantageous for obtaining a variety of macro and micronutrients and is essential for ensuring sufficient nutrient intake . The adoIrregular or disrupted eating schedules can also factor in developing unhealthy eating behaviors. Busy school schedules often cause adolescent girls to skip meals or rush through them, leading to loss of appetite or more meal skipping and irregular snacking . InadequThe Newcastle-Ottawa Quality Assessment Scale (NOS)  was utilTwo independent reviewers assessed the quality of each study, with a third reviewer assigned in case of disagreements. The final consensus is presented in During adolescence, there is a need for greater nutritional intake to support rapid growth and ensure a healthy lifestyle for teenagers. An additional study indicated that teenagers’ choices regarding their lifestyle and diet could either negatively affect their health during this transition period or contribute positively to their overall wellbeing as they become adults . In thisThe first crucial finding of this systematic review underscores the connection between eating disorders and extreme weight-loss behaviors among adolescent girls. Only four per cent of the surveyed teenage girls were diagnosed with an eating disorder using the EAT-26 measurement tool. Notably, individuals who engaged in extreme weight-loss behaviors in the past year were likelier to score higher on the EAT-26, indicating a potential risk of eating disorders . These rAdditionally, the study found that perceiving oneself as overweight was a predictor of higher total scores on the EAT-26 and a score equal to or greater than 20, often used as a cut-off point for identifying individuals at risk for an eating disorder. This finding aligns with previous research showing a correlation between perceiving oneself as overweight and experiencing eating problems during adolescence. It also suggests that individuals who perceive themselves as overweight may be more likely to engage in weight-loss behaviors . These fOur second key finding revolves around body perception and its role in the risk of developing eating disorders among adolescent girls. Notably, perceiving oneself as overweight predicted higher total scores on the EAT-26. This aligns with prior research showing a correlation between perceiving oneself as overweight and engaging in extreme weight-loss behaviors. Recognizing this relationship is crucial for targeted interventions and support.Adolescent girls commonly experience dissatisfaction with their body image and negative self-perception, affecting their eating behavior. In the study we reviewed, most participants reported skipping at least one meal per day. Among this group, some intentionally skipped meals to lose weight, commonly called dieting. When comparing the practice of dieting among all the reasons for skipping meals with the participants’ self-perception of their body shape, it was observed that those who engaged in dieting were only individuals who perceived their body shape as fat or normal, while none of those who considered themselves as thin reported dieting .In our third finding, we delve into body image’s influence on adolescent girls’ dieting behaviors. It was observed that those who engaged in dieting were exclusively individuals who perceived their body shape as fat or normal, while none of those who considered themselves thin reported dieting. This underscores the complexity of body image perceptions and their impact on adolescent dietary choices.Initially, the process of perceiving body image is believed to be narrow. Still, over time it can develop into body distortion, where there is a significant alteration in the perception of body size. This means that individuals may perceive themselves as fat even when dangerously underweight . This teOur fourth important finding highlights restrained eating (RE) behaviors among young adolescents. This vulnerability is linked to increased weight concerns, body dissatisfaction, and problematic eating behaviors. Adolescents who exhibited RE behaviors tended to eat only when hungry or craving, which contradicts previous notions. Understanding the factors contributing to craving-induced diet behavior, such as limited access to food at school, is critical for developing effective interventions.The restrained eating (RE) identified in four reviewed studies  indicateOur fifth finding sheds light on the unhealthy eating patterns prevalent during adolescence, characterized by skipped meals, increased consumption of processed and fast foods, and decreased intake of fruits and vegetables. Despite knowledge about the importance of a balanced diet, adolescents frequently indulged in junk food, indicating that factors beyond knowledge influence their dietary choices.During adolescence, characterized by rapid growth, individuals experience significant physical, psychological, hormonal, cognitive, and social changes. These transformations lead to fluctuations in the nutritional requirements, eating habits, and food preferences of the body. The eating pattern of adolescents differs from that of children. The higher academic and socio-economic pressures associated with this growth stage often result in skipped meals, an increased intake of processed and fast foods, and a decrease in the consumption of fruits and vegetables . The unhThe last crucial finding pertains to the presence of a low-diversity diet among adolescent girls, reflected in sub-optimal dietary intake and micronutrient deficiencies . This suThe dietary diversity score (DDS) is a measure that counts the number of different food groups consumed over a specific period . It reflWhile this systematic review provides valuable insights into eating behaviors among adolescent girls in countries with high stunting prevalence, it is essential to acknowledge its limitations:Limited Generalizability: The findings of this review are based on studies conducted in specific countries or regions with high stunting prevalence. As such, the generalizability of the results to a broader global context may be limited. Cultural, socioeconomic, and environmental factors that influence eating behaviors can vary significantly between regions, potentially affecting the applicability of these findings elsewhere.Variability in Study Designs: The included studies in this review may have employed diverse methodologies, assessment tools, and criteria for measuring eating behaviors. This variability in study designs could introduce heterogeneity into the review, making it challenging to draw uniform conclusions.Language Bias: The review’s search strategy may have been limited to studies published in English, which could introduce language bias. Relevant studies published in other languages may have been excluded, potentially affecting the comprehensiveness of the review.Publication Bias: There is a possibility of publication bias, where studies with statistically significant or more sensational findings are more likely to be published. This bias could skew the review’s findings, potentially overemphasizing certain aspects of eating behaviors among adolescent girls.Cross-Sectional Nature of Studies: Many of the included studies may have adopted cross-sectional designs, which provide a snapshot of eating behaviors at a specific point in time. Cross-sectional studies are limited in their ability to establish causality or track changes in eating behaviors over time.Self-Reported Data: Several studies may have relied on self-reported data from adolescents. Self-reporting can introduce recall and social desirability biases, as participants may underreport or overreport certain behaviors due to social or cultural pressures.Lack of Longitudinal Data: Longitudinal data that track eating behaviors and their consequences over an extended period are crucial for understanding trends and potential long-term effects. The absence of such longitudinal data may limit the review’s ability to explore the persistence and impact of certain eating behaviors.Limited Focus on Interventions: This review primarily describes eating behaviors rather than evaluating interventions or prevention programs. While identifying eating behaviors is valuable, a more comprehensive review might explore the effectiveness of interventions in addressing these behaviors.Evolving Nature of the Field: The field of nutrition and eating behaviors continually evolves. The review’s findings are based on studies available up to a specific date (knowledge cutoff in September 2021). Since then, new research may have emerged that could provide additional insights or alter the conclusions.Potential Biases in Included Studies: The individual studies in the review may have biases and limitations, which can propagate to the review itself. The quality and rigor of the original studies can impact the overall strength of the review’s conclusions.In conclusion, the eating behaviors of adolescent girls in countries with a high prevalence of stunting exhibit concerning patterns, including a low diversity diet, sub-optimal dietary intake, and the development of various micronutrient deficiencies. These challenges are compounded by eating disorders, such as retained and craving-induced diet, which further impact their nutritional status. These eating disorders contribute to an unhealthy relationship with food and can harm their physical and mental wellbeing. Addressing these multifaceted issues requires a comprehensive approach encompassing nutritional education, promoting balanced diets, addressing the underlying factors contributing to eating disorders, and providing appropriate support and intervention for those affected. By addressing these eating behaviors and disorders, we can strive to improve adolescent girls’ overall health and wellbeing in these countries and reduce the prevalence of stunting and its associated health consequence.The original contributions presented in this study are included in this article/supplementary material, further inquiries can be directed to the corresponding author.AS devised the project, the main conceptual ideas, the proof outline, composed the initial draft of the manuscript, and finalized the writing. AS and AB worked out almost all of the technical details in reviewing the articles. RI and AB reviewed the first draft. All authors contributed to the article and approved the submitted version.