Breast cancer accounts for approximately 25% of cancer cases and 16.5% of cancer deaths in women, and the World Health Organization predicts that the number of new cases will increase by almost 70% over the next two decades, mainly due to an ageing population. Effective diagnostic and treatment strategies are, therefore, urgently required for improving cure rates among patients since current therapeutic modalities have many limitations and side effects. Nanomedicine is evolving as a promising approach for cancer management, including breast cancer, and various types of organic and inorganic nanomaterials have been investigated for their role in breast cancer diagnosis and treatment. Following an overview on breast cancer characteristics and pathogenesis and challenges of the current treatment strategies, the therapeutic potential of biocompatible organic-based nanoparticles such as liposomes and polymeric micelles that have been tested in breast cancer models are reviewed. The efficacies of different drug delivery and targeting strategies are documented, ranging from synthetic to cell-derived nanoformulations together with a summary of the interaction of nanoparticles with externally applied energy such as radiotherapy. The clinical translation of nanoformulations for breast cancer treatment is summarized including those undergoing clinical trials. In 2020, an estimated 2.3 million new cases of breast cancer and 685,000 deaths were reported worldwide, and breast cancer was first for incidence in 159 countries and for mortality in 110 countries [The application of nanotechnology in various medical domains has grown enormously in the past decades . In thisEnormous effort has been made to characterize the molecular features underlying breast cancer formation and progression. Various possible mechanisms have been proposed for the development of breast cancer, which may occur across multiple phases of life. Carcinogenesis is a result of accumulated damage from both spontaneous and environmentally induced events that contribute to cancer development through multiple stages, beginning with the alteration of cells from a normal healthy state . At the There is ample evidence showing that numerous genetic and epigenetic alterations trigger breast tumourigenesis. Gene expression studies have distinguished several breast cancer subtypes related to oestrogen receptor (ER) expression , human epidermal growth factor 2 (HER2) expression and the basal cluster of genes. Breast cancer is, thus, divided into six subtypes , with differing clinical prognoses and responses to therapy , as depiBreast cancer can be highly heterogeneous, with tumours showing variable morphologic, phenotypic and biological features. These variations can evolve with time and in different regions of the tumour, and are categorised as interpatient heterogeneity (variations between tumours in different patients), intertumoural (variability between primary tumour and metastases) and intratumoural heterogeneity (diversity within different regions of the same tumour mass). Such heterogeneity makes the study and treatment of breast cancer difficult because tumour samples (taken as needle core biopsy) may not be representative of the whole lesion , althougAnother type of tumour heterogeneity that is seldom taken into consideration but is significant from a therapeutic perspective, mainly for metastatic deposits, is the pharmacokinetic and pharmacodynamic aspects related to tumour heterogeneity, and even small drugs exhibit heterogeneous distribution in different regions of a tumour ,12,13 anCurrent therapeutic approaches comprise local and systemic treatments, which can be used in combination or alone. The primary treatment, if the cancer has not metastasised, is surgery, to which adjuvant radiotherapy may be added. Systemic treatments include chemotherapy, immunotherapy, targeted and hormone therapy. In patients with early-stage tumours, the mainstay line of treatment is local therapy, with surgical removal of the tumour and surgical assessment of the axilla, and, if necessary, removal of axillary lymph nodes. When the breast is preserved, radiotherapy is given either during the operation (TARGIT-IORT) ,19 or asHormonal therapy uses drugs that affect how hormones stimulate the growth of cancerous cells . OestrogNumerous obstacles also account for the limitations of conventional radiation-based therapies in breast cancer. Radiotherapy can have toxic side effects such as dose heterogeneity, local discomfort and long-term exposure to healthy tissues. Many of the side effects are potentially reversible and self-limiting, but some can be irreversible and progressively worsen. Cardiac toxicity, lymphedema and pneumonitis are amongst the known side effects of radiotherapy for breast cancer, although some of these can be avoided through the use of intraoperative radiotherapy ,19,22. HThe obstacles to the success of systemic drug therapy arise for pharmaceutical, pharmacokinetic and pharmacodynamic reasons. Major limiting factors to anticancer drug delivery include low aqueous solubility, poor in vivo stability and toxicity of the drugs or the formulation agents, such as surfactants and organic co-solvents. Pharmacokinetic obstacles that hinder reaching optimum drug concentration at the target tumour site include the rapid clearance and short half-life of drug molecules. Alteration in drug cellular uptake processes by cancer cells is another issue. It has been proposed that cancer cells develop multiple mechanisms that eventually impair drug uptake by the cells, for example, changes in lipid plasma membrane composition, downregulation of the expression of drug transporters that promote drug uptake by the cell and overexpression of efflux pumps that expel drugs out of the cells such as ATP-binding cassette pumps  . FinallyThe introduction of nanotechnology to oncological research through the development of nano-based drug delivery systems and imaging agents has made a major impact as part of a field more widely known as “nanomedicine” . NanoparInvestigation of the use of nanoparticles in cancer treatment has been driven by several advantageous factors. Firstly, the solubility, stability and half-life of drugs can be improved by incorporation or attachment of the drug to the nanoparticle, thereby increasing the bioavailability of many chemotherapeutic agents. If the drug is prone to hydrolysis, for example, then its incorporation within a nanoparticle matrix can improve its stability. Secondly, the use of NPs can increase the drug accumulation in cancer tissues either via passive targeting through the enhanced permeability and retention (EPR), or active targeting by using various ligands targeted to overexpressed tumour antigens. Accordingly, NPs can enhance tumour specificity, and reduce drug levels within normal tissues and adverse side effects. In contrast to small drugs, the uptake of NPs by cells is mainly via endocytosis, which can counteract cellular drug efflux mechanisms. The versatility of nanoparticles is illustrated in their range of applications and functions. Several agents may be co-delivered in NPs for combination therapy, or where one agent is used for imaging, combined imaging and therapy. Furthermore, it is possible to control the rates of drug release from the NPs both spatially and temporally using stimuli-responsive nanoformulations. Moreover, NPs offer the possibility of co-delivery of agents that target drug resistance mechanisms  . NanoparAs well as chemotherapy, nanotechnology has substantial applications in radiotherapy, which include enhancing the delivery of radioisotopes to tumour tissues with higher specificity through passive or active targeting and by combining chemotherapy and radiotherapy in the treatment of breast cancer. In this scenario, the chemotherapy sensitises the tumour cells to radiotherapy through the radiosensitising capabilities of common chemotherapeutics such as cisplatin, doxorubicin and paclitaxel . Such apNevertheless, there remain concerns about retention of nanoparticles within the body, their clearance rate and potential toxicity, which may hamper clinical translation and regulatory approval in some cases. Nanoparticles can be prepared in different sizes, shapes and ranges of stability and drug loading capacity, but can be classified structurally into two main categories based on their composition, namely ‘organic’ and ‘inorganic’. Organic-based nanoparticles mainly encompass lipid-based and polymer-based NPs, including dendrimers. Inorganic nanoparticles include metal-based , quantum dots and silica nanoparticles . In thisWe have summarised the various types of organic-based nanoparticles that have been investigated for application in breast cancer treatment in the following section. We begin with lipid-based nanoparticles, and Among the many nanoformulations that have been investigated for the treatment of cancer in research, lipid-based nanoformulations are the most studied. There are several different types of lipid-based formulations such as liposomes, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), which are discussed in the following sections.Liposomes are spherical vesicles that can be divided into the categories of small unilamellar vesicles with a single lipid bilayer approximately 100 nm in size, and larger unilamellar and multilamellar vesicles containing multiple bilayers with sizes that can range to several hundred nm. The bilayer is typically composed of amphipathic phospholipid molecules, which enables suspension and storage in aqueous solution. Liposomes are versatile and can be used to deliver a wide range of agents of differing water solubility either within the central aqueous compartment or the lipid bilayer in the case of hydrophobic drugs, whilst conferring protection against degradation in the circulation . Owing tAmong the most frequently used chemotherapy regimens in the treatment of breast cancer are those that encompass anthracyclines, specifically doxorubicin and epirubicin (FDA-approved), and/or taxanes, specifically docetaxel and paclitaxel (FDA-approved), although in selected patients, cyclophosphamide/methotrexate/5-fluorouracil (CMF) may still be used. The addition of taxanes slightly improves the efficacy of chemotherapy, but at the expense of increased non-cardiac toxicity; most importantly, it allows the use of a lower total dose of anthracyclines by using sequential regimens. Chemotherapy regimens based on anthracyclines and taxanes are effective in reducing mortality among patients with breast cancer, but potential long-term sequelae of induced cardiotoxicity are of particular concern. As a result, a study by Franco et al. found that compared to free paclitaxel and doxorubicin, a 1:10 co-encapsulation ratio of paclitaxel and doxorubicin in liposomes decreased the cardiac toxicity profile in mice bearing 4T1 breast tumour . Papa etSolid lipid nanoparticles (SLNs) usually have a spherical shape and diameter size in the range of 50–1000 nm. They are composed of a solid lipid core matrix and stabilized by a surfactant coating. SLNs offer high drug loading, efficient drug release and high long-term stability (at room temperature and at human body temperature) and ease of scale-up for mass production . For exaNevertheless, SLNs exhibit some disadvantages as drug delivery agents, for example, a tendency for aggregation and gelation, polymorphic transition and, in certain cases, low incorporation because of the crystalline structure of the solid lipids. As a result, nanostructured lipid carriers (NLCs) were developed to address some of these drawbacks, and consist of a combination of various lipids, i.e., a solid lipid matrix incorporating a liquid lipid. Adjusting the ratio of solid to liquid lipid can enhance the solubility of drugs, thus improving the encapsulation efficiency and the rate of drug release ,86. For Sun et al., 2014, developed quercetin-loaded nanostructured lipid carriers in an attempt to overcome some well-known limitations of quercetin, such as low aqueous solubility and poor bioavailability. The entrapment efficiency reached 95%, and the extended-release of quercetin facilitated MCF-7 and MDA-MB-231 cell killing . Another® showed that the complex-loaded chitosan nanoparticles exhibited sustained release of the PTX [p < 0.05) and higher apoptosis was found in tumour cells compared to other treatment groups [PNPs are colloidal particles typically with a size of a few hundred nanometres, formulated from biodegradable natural sources such as cellulose, chitosan and Poly(L-lysine) (PLL), which is the polymerized form of lysine, or they can be synthetic polymers such as poly(caprolactone), poly (glycolic acid), polylactic acid (PLA) and Poly(lactide-co-glycolide) (PLGA). PNPs are suitable for carrying hydrophilic and hydrophobic drugs and are prepared by a variety of methods. The anti-cancer drug can be loaded onto the surface of polymeric nanoparticles through surface adsorption, chemical conjugation or encapsulation into the polymeric nanoparticle drug delivery systems. Depending on the method of drug entrapment, polymeric nanoparticles are divided into nanospheres and nanocapsules. Biodegradable polymers offer numerous benefits, for example, better drug encapsulation, higher solubility and permeability and controlled release property of chemotherapeutics agents, which takes place through degradation of the polymeric membrane. They also show remarkable biocompatibility since they are broken down into readily metabolizable polysaccharides in the body as a result of enzymatic degradation . PLGA is the PTX . In anot the PTX . Tran et the PTX . Guixia  the PTX . Xiong et groups . In anott groups .This drug delivery system is composed of amphiphilic block copolymers that self-assemble into a core–shell micellar structure. The hydrophobic core is intended for water-insoluble drugs, while the hydrophilic shell is intended for hydrophilic drug loading. In addition, core cross-linked polymer micelles exhibit high stability in circulation, thereby harnessing the EPR effect. Guo et al. studied the potential of resveratrol (RES) and docetaxel (DTX) combination using methoxylpoly(ethylene glycol)-poly  (mPEG-PDLA) copolymer micelles in MCF-7 cells. The IC50 of RES and DTX in MCF-7 cells were found to be 23.0 μg/mL and 10.4 μg/mL, respectively, whereas a lower IC50 was obtained for the combination of resveratrol and docetaxel, which was 4.8 μg/mL. RES and DTX-loaded mPEG-PDLA micelles showed prolonged release profiles, as well as enhanced cytotoxicity against MCF-7 cells. The dual drug-loaded mPEG-PDLA micelles exhibited the highest anticancer activity against MCF-7 cells compared to other treatment groups of micelles containing either the same concentration of docetaxel or resveratrol . LapatinDendrimers comprise compact and well-ordered nano-sized polymeric structures based on repetitively branched molecules or dendrons with a spherical, symmetric conformation around the particle core. Dendrimers have a well-defined size from 1–15 nm depending on the number of dendrons incorporated, and each dendron branch can incorporate active functional groups. The drug can either be encapsulated within the cavities of the dendritic polymer or be attached to functional groups via biodegradable linkers on the surface of the dendrimer. The drug can be released from the dendrimer whilst in circulation or internalised following its endocytic uptake. The well-defined, uniform, monodisperse, and highly branched symmetrical structure of dendrimers in contrast to conventional polymeric nanocarriers makes them attractive candidates for the targeted delivery of therapeutic and diagnostic agents . For exaAnother study carried out by Mei, M et al. used a combination of chemotherapy and gene therapy. 5-fluorouracil (5-FU) was conjugated to polyamidoamine dendrimers by direct encapsulation combined with anti-sense micro-RNA 21 (as-miR-21), which can selectively knock down the expression of miR-21, a tumour oncogene overexpressed in primary breast cancer cells. The codelivery of as-miR-21 significantly enhanced the cytotoxicity and chemosensitivity of 5-FU, markedly increased the apoptotic percentage of the MCF-7 cells and reduced the migration ability of tumour cells . Meng WaIn recent years, advances have been made in the design of ‘hybrid’ nanocarriers that incorporate both polymeric and liposomal structures , variousPolymeric lipid hybrid nanoparticles hold many promising applications including cancer diagnostic imaging treatment . PLNs weConventional nanocarriers are susceptible to recognition by the immune system, which leads to a short circulation half-life and uptake by the reticuloendothelial system (RES). Surface modification of the nanoparticles by polyethylene glycol (PEG) can inhibit this process, but repeated use of PEG may also stimulate the production of its specific antibody and accelerate the clearance. Accordingly, this has stimulated research into biomimetic nanoparticles that recapitulate properties of natural materials, with the aim of countering immunogenicity and improving tissue uptake. Bioengineered components employed in cell-based drug delivery systems can include either whole cells, cell membranes or extracellular vesicles (exosomes) . In the Cells can be utilized for drug delivery using several approaches, for example through the cell membrane coating of nanoparticles or codelivery of nanoparticles on cells (cellular trojan horses). Cell membrane coating technology comprises nanoparticles covered in a layer of cell membrane of various cell types such red blood cells, platelets, lymphocytes, cancer cells, stem cells and others. Owing to the presence of different proteins and carbohydrates on the membrane of various cell types, cells perform variable specific functions in the body and, therefore, the nanocarriers developed from cell-derived membranes that encapsulate drugs may incorporate some of the properties of the original cells. For example, red blood cells can escape the immune system due to the expression of CD47 on their cell membrane but have no targeting capability, while white blood cell membranes exhibit the characteristic of tumour homing . Cell meApplications of cell-derived nanoparticles in experimental breast cancer treatment are summarised in a separate section of Extracellular vesicles or exosomes are identified as membrane-bound biological nanoparticles that can be involved in intercellular signalling either in physiological or pathological conditions. EVs are generated by virtually all cell types, and are composed of various biomolecules according to their origin, e.g., membrane proteins, lipid bilayers, metabolites and nucleic acids. Membrane proteins play a role in targeting EVs to particular sites, whereas lipid bilayers aid in protecting bioactive contents from the body fluid environment and degradation by extracellular proteases and nucleases. Extracellular vesicles can dissociate from the source cells and spread through the vascular system, targeting specific cells to deliver their contents. Extracellular vesicles have attracted interest for the targeted delivery of imaging therapeutic agents due to their cell-derived origin . ExtraceTian et al. studied the delivery of doxorubicin to tumour tissue in murine MDA-MB-231 and MCF-7 models using engineered exosomes. In this study, immature dendritic cells (imDCs) were genetically modified to express lysosome-associated membrane glycoprotein 2b (Lamp2b), a well-characterized exosomal membrane protein, linked to the iRGD peptide that targets αv integrin expressed on tumour cells. The efficacy and improved therapeutic index of the iRGD-exosomes loaded with doxorubicin was demonstrated in vitro and in vivo via the specific targeting of αv integrin-expressing cells (MDA-MB-231 cells), resulting in tumour growth inhibition without noticeable toxicity . AnotherNucleic acids (DNA and RNA) are natural building blocks that enable a bottom-up self-assembly approach stemming from precise base pairing that can be exploited for the manufacture of well-defined nanostructures. The introduction of biological tags and stimuli-responsive moieties into DNA or RNA structures has enabled the exploitation of their properties beyond their natural roles and made it possible to design nanostructures for many applications, including cancer targeting and therapy . A key aAs with DNA, RNA can be used for the fabrication of nanoparticles, which can be functionalized with targeting moieties, imaging and therapeutic agents, which, in some cases, can also be composed of RNA nucleotides . In cancAs a result of their versatility and biocompatibility, proteins have gained considerable attention as templates for drug delivery nanosystems and have been used successfully for the delivery of anticancer drugs and other agents . The appAlbumin is a highly soluble, strong protein that remains stable at pH 4–9. Moreover, the selective uptake of albumin in tumour and inflamed tissues and its biocompatibility, low toxicity, biodegradability and low immunogenicity make it suitable for systemic in vivo applications. Additionally, albumin contains many functional groups that can be suitable for the binding of molecules, making it an attractive substrate for nanoparticle preparation. Moreover, tumour metastases may express albumin-binding proteins, thereby improving the uptake of the albumin-based nanoparticle . Taking Ferritin is a ubiquitous intracellular protein for storing iron. A key property of ferritin is that it can self-assemble into a cage-like nanostructure with an external diameter of 12–13 nm comprising 12 or 24 subunits, and this architectural formation of ferritin has attracted much interest in its use as a nanomaterial. Additionally, ferritin is differentially overexpressed in several types of malignant tissue including breast cancer, and it was found that L-ferritin was approximately six-fold higher in breast tumours than benign breast tissue . H-chainHigh-density lipoproteins (HDLs) and low-density lipoproteins (LDLs) are examples of lipoproteins that form through the spontaneous synergistic self-assembly of lipids combined with a type of protein known as apolipoproteins. Considering that the size of the LDL and HDL (less than 30 nm) can promote the deep penetration of lipoproteins into tumours, biocompatible lipid complexes could also be ideal candidates for cancer diagnosis and therapy. HDL has gained attention as a nanodelivery system due to its biodegradability, low immunogenicity and natural targeting ability. The hydrophobic core and phospholipid corona of HDL facilitate the incorporation of lipophilic cargoes, imaging agents and therapeutic drugs. Moreover, HDL particles can evade the reticuloendothelial system and subsequently exhibit prolonged circulation times. In a study by Gong et al., a high-density lipoprotein (sHDL) nanoparticle loaded with docetaxel (DTX) was manufactured and tested against breast cancer. The data revealed that the synthesized sHDL nanoparticles displayed a high loading efficiency of docetaxel, slow drug release profile and excellent biocompatibility. Furthermore, DTX-sHDL nanoparticles improved the uptake of docetaxel, augmented the cytotoxic effect against MCF-7 cells and reduced the toxicity to normal cells. Finally, in vivo experiments in 4T1 tumour-bearing mice showed superior tumour growth inhibition by DTX-sHDL nanoparticles than that of the free docetaxel-treated group . AnotherPeptides are attractive substrates for biocompatible and degradable nanodelivery systems and other biomedical applications such as biosensors and tissue regeneration. The self-assembling properties of peptides have been exploited for the fabrication of nanostructures of different shapes, for example nanotubes, nanofibers and hydrogels . VariousNanostructures can be designed to be multifunctional so that they can incorporate therapeutic agents, targeting ligands, imaging agents, stimuli-responsive structures, and molecules that can control the drug release profile, all within the same nanosystem. Surface functionalisation by molecules that inhibit recognition by the immune system is another important feature, and in addition to the aforementioned approach of PEGylation, a number of other strategies have been investigated such as coating with peptides or polysaccharides . In thisThe tumour microenvironment (TME) comprises cellular and non-cellular components that form the tumour’s niche. The non-cellular components include the extracellular matrix, growth factors, cytokines, chemokines, small RNAs, DNA and extracellular vesicles. Along with cancer cells, several other cell types are also present in the tumour tissue for example mesenchymal stromal cells, adipocytes, pericytes, cancer-associated fibroblasts, cancer stem cells and immune cells such as tumour-associated macrophages (TAM), T and B lymphocytes, dendritic cells (DC), neutrophils and natural killer cells (NK). The tumour microenvironment is characterized by the presence of hypoxia, acidosis and oxidative stress, and by interactions between these different cell types, which will cause modulation of the immune system, induction of angiogenesis and subsequent metastasis. Several barriers in the tumour microenvironment have been found to inhibit the diffusion of NPs through the tumour tissue, such as dense extracellular matrix, high interstitial fluid pressure and the heterogeneous permeability of blood vessels. Hence, to improve treatment efficacy, a number of new strategies that can deliver nanoparticles deep into tumours  have beeActivated cancer-associated fibroblasts and mesenchymal stromal cells secrete extracellular matrix components, cytokines and chemokines that stimulate tumour cell proliferation and drug resistance. Stromal cell proteins such as fibroblast activation protein α and extracellular matrix components (particularly extracellular matrix enzymes) can, therefore, be utilized as targets for delivery or a method for selective drug release. In order to enhance the penetration and targeting of nanoparticles, their coupling with drugs that target stromal aberrations within the tumour is one such approach that has been proposed . Ji, T eFibronectin is a glycoprotein that is abundant in the extracellular matrix and upregulated in many tumours, which can be exploited for drug targeting using antibodies and peptides. CREKA (Cys-Arg-Glu-Lys-Ala) is an example of a targeting peptide that binds to the fibrin–fibronectin complex. PEGylated liposomes containing CREKA loaded with doxorubicin elicited higher retention in murine 4T1 breast tumours but negligible binding to fibrin–fibronectin complexes in normal tissue . In the To enable tumour homing in breast cancer tumours, nanoparticles can be functionalized with general tumour-homing peptides or proteins specifically recognizing breast cancer epitopes. The tripeptide RGD is a common tumour-homing peptide found in proteins that mediate cell adhesion. This peptide is recognized and bound by integrins present in tumour cells with high affinity. It has gained much interest because it targets both breast tumour and tumour angiogenesis. Integrins are receptors abundantly expressed on cancer cells and associated blood vessels, mediating cell motility, proliferation and apoptosis. Breast cancer cells are found to express α6β4 and ανβ3 integrins, which have been associated with increased tumour size, grade and metastasis. Attaching RGD peptides to nanoparticles to target breast cancer cells for imaging and treatment purposes has been explored on multiple occasions . Cyclic Epidermal growth factor receptor (EGFR) is overexpressed in approximately 50% of triple-negative breast cancer cases. The antibody anti-EGFR Cetuximab successfully targets EGFR-overexpressing cancers, specifically in triple-negative breast cancer. For example, Roncato et al. conjugated Cetuximab to nanoparticles and nucleic acid assemblies carrying doxorubicin to selectively target triple-negative breast cancer MDA-MB-231 cells . Another2O2 in the mitochondria. Subcellular targeted nanoparticle–drug systems can be designed to have dual targeting  capability combined with triggered release of the payload [The fundamental difference between nanoformulations and free drugs is the controllable release of the cargoes in specific locations. Some drug formulations are not simply delivered to the cell interior, but require direct delivery to the subcellular site/organelle of action . This direct delivery of therapeutic agents to their site of action has the potential to amplify the therapeutic efficacy of the agent, but the sole use of cell surface biomarkers is unlikely to be sufficient to deliver drugs to particular subcellular locations/organelles . Consequ payload . A recen payload .Wang et al. described the formulation of a multifunctional micelle system (HEKM) composed of shape-altering micelles incorporating doxorubicin, a metalloproteinase (MMP-2) substrate, an optical imaging agent, a mitochondrial damage segment (KLA) and a peptide targeting the EGFR/HER2 complex that is overexpressed in certain breast tumours. Studies were carried out using SKBR-3 and MDA-MB-468 carcinomas that highly express EGFR-HER2. HEKMs initially self-assembled as nanorods in the circulation, which may aid the avoidance of uptake by the reticuloendothelial system. When HEKMs reached the tumour area, guided by binding to the EGFR-HER2 complex, the MMP-2 substrate was degraded , leading to the deformation of the nanorods into spheres, which aided deeper tumour penetration. The HEKM-mediated combination therapy elicited the highest tumour growth inhibition amongst the treated groups, consistent with improved targeting and tumour penetration . AnotherNanoparticles can be functionalized with stimuli-responsive materials, which confers new properties through altering their physicochemical behaviour in response to small external or internal stimuli and increasing the selectivity within the tumour tissue, and exhibits advantages compared to conventional systems, namely a reduction in the systemic toxic effects. These materials can be divided into intrinsic/chemical  and extrinsic/physical . In this way, stimuli-responsive nanoparticles can achieve, for example, the release of drugs in a specific tissue in response to the applied or intrinsic stimulus .Nanocarriers that are responsive to changes in pH have been commonly used as an approach for drug delivery in cancer therapy by exploiting the observation that tumours possess a lower pH (5.4 to 6.8) than adjacent normal tissue. This characteristic of tumour tissue is attributed to the high rate of glycolysis in cancer cells and excessive production of acidic compounds such as lactate. For breast cancer therapy, a variety of “smart” pH-sensitive nanocarriers have been designed. For instance, a study by Zhou et al. reported the synthesis of a multifunctional polymeric nanocarrier incorporating a targeting ligand and pH-sensitive moiety to increase the specificity and efficacy of the drug delivery system. Trastuzumab was conjugated to the nanocarriers, and encapsulation of paclitaxel and doxorubicin was achieved. In vitro experiments against breast cancer cell lines showed significantly increased uptake for trastuzumab-conjugated nanoparticles compared to non-targeted nanoparticles, and they exhibited superior therapeutic efficacy in vivo . AnotherHypoxia is commonly known to be associated with all types of solid tumours. It occurs due to overconsumption of oxygen by rapidly proliferating cells present at the periphery of the tumour, leaving only a small portion of oxygen remaining to diffuse further into the tumour centre. Hypoxia can also arise from immature and leaky tumour blood vessels and poor perfusion, and these hypoxic areas are much less susceptible to chemotherapy owing to the limited drug delivery via the microvasculature. Radiation therapy is less effective at treating hypoxic areas due to the lower generation efficiency of oxygen free radicals, which cause cytotoxic DNA damage. Nanotechnology research has, therefore, focused on exploiting this physiological condition to develop nanoparticles, which are activated only when they encounter hypoxic conditions whilst remaining inactive under normoxia . NumerouOxidative stress is usually produced by the accumulation of reactive oxygen species (ROS). There is a balance between ROS and antioxidants (redox homeostasis) in normal cells, while increased ROS levels in cancer cells reflect genomic instability, activated oncogenic signalling and metastatic potential. Cancer cells can adapt to a wide range of environmental conditions, such as persistent oxidative stress, by shifting their redox environment to a more reductive condition and overexpressing antioxidant enzymes, leading to the upregulation of several redox-sensitive pro-survival pathways. Redox-sensitive nanoparticles are designed to achieve triggered controlled release of loaded therapeutic drugs in response to intracellular redox potential. These stimuli-responsive drug delivery systems usually incorporate a disulphide linkage and are, therefore, prone to degradation by intracellular reducing molecules, primarily Glutathione (GSH). Tumour tissues exhibit a high concentration of GSH in the cytoplasm compared to healthy tissues . Li et aThermosensitive nanoparticles are materials that can be responsive to a change in temperature in a nonlinear relationship. The function of thermosensitive  drug delivery nanocarriers is to retain their loaded drug at body temperature (~37 °C) and promptly release the drug in the locally heated tumour tissue (~42 °C) corresponding to mild hyperthermia. There are several methods for inducing local hyperthermia such as focused ultrasound and electromagnetic techniques such as radiofrequency-induced hyperthermia. In the case of liposomes, the elevated temperature induces a phase transition of the lipid membrane and permeation of the encapsulated drug. For example, a thermoresponsive liposome nanocarrier loaded with doxorubicin has been evaluated using a syngeneic NDL murine breast tumour model. Complete tumour regression was elicited following cycles of liposome administration and tumour hyperthermia induced using ultrasound . The useNear-infrared (NIR) light has a wide “therapeutic window” from 700 nm to the micron range, which helps to provide deeper tissue penetration both for imaging and therapeutic applications. The development of cheap but powerful NIR laser diodes and light-emitting diodes has spurred on the development of tumour-specific optical imaging agents and photosensitisers combined with different targeted drug delivery systems. Moreover, the ability to detect and treat tumour tissues using NIR light is aided by differences between the optical absorption and scattering properties of healthy and diseased tissue volumes, which renders tumours more transparent. A study by Yildiz et al. reported the design and preparation of nanoparticles for NIR imaging and doxorubicin delivery to the MDA-MB-231 cells . In thisThe absorption of NIR light by tissue sensitised with NIR-absorbing nanoparticles or drugs can be exploited for therapeutic applications such as photothermal therapy (PTT), which can then be combined with chemotherapy using a nanocarrier containing a chemotherapeutic and sensitizer. The use of inorganic metallic nanoparticles for PTT has been widely studied, especially gold, owing to the strong optical absorption induced by the surface plasmon resonance. The application of PTT using organic biodegradable nanoparticles can generally be achieved by sensitising the nanoparticles with an NIR-absorbing dye such as indocyanine green (ICG). Several studies have been carried out where sensitised local hyperthermia induced by NIR irradiation has been exploited for enhancing chemotherapy drug delivery. For example, Su et al. (2015) formulated a thermosensitive polymeric nanoparticle integrating ICG, paclitaxel (PTX) and survivin siRNA into these nanoparticles as a triple-punch strategy against triple-negative breast cancer. The results showed that the prepared nanoparticles significantly enhanced the stability of ICG. The controlled release of paclitaxel in the tumour regions was elicited by the hyperthermia generated through NIR laser-irradiated ICG. Furthermore, the nanoparticles displayed antitumour efficacy owing to the combinatorial effects of chemotherapy, photothermal therapy and gene therapy, with minimal adverse effects .Photodynamic therapy (PDT) offers a non-thermal way to utilise red or NIR light for inducing localised necrosis after prior administration of a photosensitizing agent . The comCombining multiple chemical moieties that respond to different stimuli into the same nanoparticles should, in principle, improve the efficiency of the controlled release profile and targeting of nanocarriers. Based on this concept, Verma et al. fabricated dual temperature/pH-sensitive nanoparticles loaded with doxorubicin. The researchers reported that there was a greater release of doxorubicin in the presence of acidic pH and at high temperatures, and the cytotoxicity of the nanoformulation was tested in several breast cancer lines . AnotherIn the current clinical perspective, many of these next-generation nanoparticles have undergone clinical trials and have been approved for various indications. The clinical translation of effective nanotechnology-based inventions is rapidly evolving, and has revolutionized cancer treatment . The car2 or doxorubicin 60 mg/m2. It was shown that the overall cardiotoxicity risk was significantly reduced with Doxil (~three-fold), while both Doxil and doxorubicin were comparable regarding progression-free survival and overall survival. Doxil has been used in combination with numerous other chemotherapy drugs  and targeted therapy such as trastuzumab for advanced cancer treatment in clinical trials, where it showed good efficacy [A PEGylated liposomal formulation of doxorubicin trademarked as Doxil was the first nanoformulation approved by the FDA in 1995. In a phase III clinical trial, a sample of 22,509 female patients with metastatic breast cancer were treated with either Doxil 50 mg/mefficacy . Doxil i2) was administrated combined with cyclophosphamide (600 mg/m2) to metastatic breast cancer patients in a multicentric clinical trial, demonstrating equivalent efficacy with minimal adverse effects in comparison to free doxorubicin/cyclophosphamide combination at the same dose [Myocet is a non-PEGylated liposomal formulation of doxorubicin that exhibited a comparable antitumour effect to free doxorubicin but lower cardiotoxicity than doxorubicin in patients with metastatic breast cancer . Myocet ame dose .®-PM is an example of a PEG-coated polymeric micelle formulation of paclitaxel that has been clinically approved in Europe and South Korea for the treatment of metastatic breast cancer. This nanoformulation could deliver a paclitaxel dose higher than the conventional therapy without dose-limiting toxicity, and was able to achieve a 1.8-time longer circulation half-life compared to free paclitaxel. In a phase II clinical trial, 41 patients with metastatic cancer were treated with a Genexol-PM dose of 300 mg/m2 over a period of 3 h every 3 weeks. Based on this clinical study, the overall response rate ranged between 43.5 and 73.7%, and the average time to progression for all patients was 9 months [Caelyx is a generic example of a PEGylated liposomal formulation of doxorubicin that is approved in Europe for advanced and metastatic breast cancer. Regarding the clinical translation of polymer-based nanomedicines, Genexol9 months . AnotherAbraxane is a nanoparticle albumin-bound (nab)-paclitaxel that was approved by the FDA in 2005 to treat metastatic breast cancer. Safe administration of a much higher dose of paclitaxel  and shorter injection times have been achieved by Abraxane . AbraxanLiposomal formulations of paclitaxel such as LEP-ETU and EndoTAG-1 are being investigated for metastatic breast cancer in phase II and III clinical trials, respectively. MM-302 is an example of an antibody–drug conjugate liposomal nanoformulation comprising an HER2-targeted antibody attached to doxorubicin, which is being investigated for HER2-positive, locally advanced/metastatic breast cancer in phase III clinical trials .2. In addition to a 61.9% local response rate among patients, a combined local response rate was noticed in almost half of the cohort (46.4%), showing five durable local responses lasting more than 3 months, four complete responses and one partial response. It was also observed that patients who received the lower liposomal doxorubicin dose (40 mg/m2) exhibited a comparable response rate and a superior safety profile in comparison to those receiving the higher nanoformulation dose (50 mg/m2) [Stimuli-responsive liposome-based nanodrugs have also been investigated clinically, most commonly using thermally induced drug release, as described in 0 mg/m2) .2 for NK105 attained comparable efficacies to an 80 mg/m2 dose of paclitaxel in terms of progression-free survival (8.4 months for NK105 vs. 8.5 months for PTX), and the incidence of peripheral sensory neuropathy was 1.4% compared to 7.5% (≥Grade 3) for NK105 and paclitaxel, respectively. This indicates that NK105 was well tolerated, particularly for the peripheral sensory neuropathy profile [NK-105 is another example of a polymeric micellar formulation of paclitaxel that is currently undergoing phase III clinical trial for the treatment of recurrent breast cancer . It disp profile .In the clinical domain, it is evident that liposome and micelles remain the dominant nanoformulations; however, the advent of the clinical use of lipid nanoparticles (LNPs) for RNA vaccine delivery  and otheAs nanomedicine is continuously evolving, concerns have been raised regarding the safety and toxicological properties of nanomaterials and environmental hazards. As previously discussed, the long-term retention of nanoparticles within the body is of particular concern, which has led to increased attention being paid to biodegradable nanomaterials for the sake of improving the safety profile of nanomedicine. However, increasing attention is also being given to potential environmental hazards arising from the manufacture and use of nanomaterials. The widespread manufacture and utilization of nanomaterials have raised numerous concerns about their fate, life cycle and potential toxicity in the environment and to human health. The discharge of engineered nanomaterials into the environment is the final stage in their life cycle . NanomatThe recent advancement in molecular biology techniques and genetic sequencing analysis has improved our understanding of breast carcinogenesis and aided in the identification of various subtypes of breast cancer. This has led to substantial progress in research studies focusing on the application of nanomedicine for breast cancer diagnosis and treatment. From the literature survey of nanomedicines that are currently being evaluated, it can be observed that a myriad of nanotherapeutic approaches ranging from inorganic nanoparticles, organic nanoparticles and actively targeted nanoparticles to smart multifunctional nanocarriers are being investigated for breast cancer. This review has mainly shed light on studies that investigated the effect of biodegradable, biocompatible and biomimetic nanocarriers in breast cancer. Additionally, the ability to incorporate multiple functional moieties into the same nanodelivery system in order to enhance specific tumour targeting, the prolongation of circulation time, sustained drug release, combination therapy and tumour visualization  has revolutionized the field of nanomedicine applications in breast cancer management. Although utilizing multifunctional moieties may indeed improve the efficacy of nanocarriers, their inclusion in nano-based drug delivery systems may also lead to formulation complexity, which, in turn, may possibly lead to higher toxicity and immunogenicity, increased manufacturing cost and good manufacturing practice issues. Nevertheless, given the increasing role of combination therapy in cancer treatment, it is likely that nanodelivery systems will play an increasingly important role in the armamentarium for breast cancer treatment. Despite all these recent developments in nano-based platforms, caution must be still taken into consideration when adopting these advanced strategies for breast cancer management in clinics. Several issues should be addressed first to achieve successful translation of these nano-based platforms from bench to clinic, such as better understanding of the biological fate of nanomaterials in vivo, better appreciation of their interactions within the blood circulation and further examination of their trafficking through intracellular compartments. Nanoparticles face a long journey with many obstacles in the way to reach tumour sites. They must first evade uptake by the immune system, then bypass biological barriers in the tumour microenvironment and successfully reach their target site of action. For drugs that are borne within nanocarriers taken up via endocytosis, a key barrier to overcome is endolysosomal sequestration and the associated risk of degradation within these vesicles. Thus, developing nanoformulations that can effectively overcome all these hurdles with minimal adverse effects is of great significance, but also remains challenging. Furthermore, novel nanoformulations need to be clinically safe, sufficiently stable, cost-effective and ideally environmentally benign. Another issue that needs to be tackled is tumour heterogeneity. Given the high inter- and intra-individual heterogeneity of breast cancer, which greatly affect the therapeutic response to nanomedicines, it has become extremely important to employ biomarkers to guide patient selection and clinical trial design. These interpatient variations in breast tumour behaviour make it almost impossible to use one approach that fits all. This implies the need for tailoring a specific nanomedicine therapeutic approach for each patient. Unfortunately, at present, no biomarkers or diagnostic tests are widely available to guide the clinical translation of cancer nanomedicines. Future directions for cancer nanomedicine will involve nanobioinformatics, which brings together the science of nanotechnology with bioinformatics. Nanobioinformatics can offer new routes to finding solutions to problems involving high-throughput genomics data, complex biological systems, novel biomarker discovery and computer-aided drug design. In the longer term, such analysis could facilitate and optimise the design of drug nanocarrier systems to treat solid tumours such as breast cancer.


Borderline personality disorder (BPD) is a severe mental disorder characterized by affective, behavioral and relational instability, along with interpersonal hypersensitivity and unstable affective relationships (APA 2013). Poor interpersonal functioning could be associated with critical deficits in the ability to mentalize in these patients, together with high levels of impulsivity. Although most studies have described hypermentalization deficits among BPD patients , existing literature is still scarce on this aspect, as well as its relationship with the impulsive behavior.1) to assess specific mentalizing deficits in BPD compared to healthy controls in a complex ecological mentalization task; 2) evaluate the relationship between mentalization and impulsivity in BPD.63 patients diagnosed with borderline personality disorder and 31 control subjects were studied using the Movie for the Assessment of Social Cognition -MASC-  and the Barratt Impulsivity Scale -BIS-11- , as well as other sociodemographic and clinical factors. The clinical research study was approved by the Clinical Research Ethics Committee of the Hospital Clínico San Carlos .The results showed significant differences in the scores related to correct mentalization, hypomentalization, and non-mentalizing responses between patients and controls, with BPD patients showing worse performance. A significant negative relationship was also observed between impulsivity scores and correct mentalizing responses in BPD patients.The results showed a deficit in the ability to mentalize in BPD patients, compared to control subjects, characterized by a hypomentalization and an absence of mentalization. Likewise, this deficit in mentalization ability was related to greater impulsive behavior in patients. These results would be consistent with the hyperarousal hypothesis in BPD, which would reduce inhibitory control, causing mentalization deficits . Future studies will try to associate specific impulsive behaviors associated with the characteristics of hypomentalization and absence of mentalization observed in our results.None Declared


Glaucoma is a leading cause of irreversible blindness worldwide. While intraocular pressure (IOP) presents a major risk factor, the underlying pathophysiology still remains largely unclear. The correlation between vascular abnormalities and glaucoma has been deliberated for decades. Evidence for a role played by vascular factors in the pathogenesis of glaucomatous neurodegeneration has already been postulated. In addition, the fact that glaucoma causes both structural and functional changes to retinal blood vessels has been described. This review aims to investigate the published evidence concerning the relationship between vascular abnormalities and glaucoma, and to provide an overview of the “chicken or egg” dilemma in glaucoma. In this study, several biomarkers of glaucoma progression from a vascular perspective, including endothelin-1 (ET-1), nitric oxide, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), were identified and subsequently assessed for their potential as pharmacological intervention targets. Glaucoma is characterized by the progressive death of retinal ganglion cells (RGCs) and consequential functional impairments of the visual field . HoweverThere is a growing body of compelling evidence supporting the notion that vascular abnormalities, encompassing both vascular factors and systemic hemodynamics, play a substantial role in the complex etiology of glaucoma. The vascular theory in glaucomatous neurodegeneration postulates that diminished perfusion pressure, impaired vascular autoregulation, and disrupted neurovascular coupling serve as the underlying mechanisms. These factors collectively contribute to the progressive degeneration of the optic nerve and retinal ganglion cells in glaucoma ,4.Regarding hemodynamics, a notable association between glaucoma and systemic cardiovascular diseases, such as diabetes mellitus (DM) ,6,7, higRetinal vascular dysfunction has been reported secondary to glaucoma, indicative of a bidirectional relationship between glaucoma and retinal vascular pathology . These sThe retina is a highly metabolically active tissue that requires a constant supply of nutrients and oxygen to function properly. The blood supply of the outer retina and inner retina comes from different circulatory pathways: the central retinal artery (CRA) and the choroidal circulation, respectively. This is summarized in The vascular theory of glaucomatous neurodegeneration suggests that reduced perfusion pressure, faulty vascular autoregulation, and loss of neurovascular coupling play important roles in the relationship between vascular abnormalities and glaucomatous neurodegeneration ,31. In tThe ocular perfusion pressure (OPP) refers to the pressure necessary to propel blood through the intraocular vasculature and represents the blood flow and oxygen supplying ONH . Thus, iVascular autoregulation, commonly known as vasoreactivity, represents the intrinsic capacity of the vascular system to adapt to varying physiological conditions and meet diverse metabolic demands by maintaining stable and sufficient blood flow ,39. A reThe central nervous system exhibits highly coordinated coupling between neuronal activity and blood flow. When there is a surge in neuronal activity, it triggers an increase in blood flow to the corresponding area, which is referred to as neurovascular coupling (NVC) . NVC resThe role of systemic hemodynamics in glaucoma pathogenesis has been widely investigated. A “U-shaped” effect of BP on retinal function and structure has been revealed ,57. On tApart from BP, it also has been reported that individuals with DM have a higher incidence of developing glaucoma . AdditioIOP is the dynamic equilibrium between the production and drainage of AH ,68. The It has been demonstrated that different vascular diseases are related to increased IOP. For instance, the pericyte loss of retinal blood vessels is a recognized marker of diabetic retinopathy (DR), which provokes capillary occlusion and overexpressed VEGF , potentiSturge–Weber syndrome (SWS) is a rare, non-inherited neurovascular disorder characterized by abnormal vasculature in the brain, skin, and eye . GlaucomCarotid–cavernous fistulas (CCFs) are acquired vascular abnormalities with flow between the cavernous sinus and branches of either the external or internal carotid artery . ElevateET-1, a key regulator of vascular autoregulation ,99, has An imbalance between the vasoconstrictor ET-1 and the vasodilator nitric oxide has been observed in glaucoma, leading to endothelial dysfunction and decreased ocular blood flow . Nitric VEGF is a primary factor contributing to vascular permeability and plays a pivotal role in the process of neovascularization . In the 2+/calmodulin-dependent manner, which is essential for maintaining IOP homeostasis [Nitric oxide is generated by neuronal nitric oxide synthase and endothelial nitric oxide synthase in a Caeostasis . Neuronaeostasis ,114. Theeostasis . Ocular eostasis . Studieseostasis  or animaeostasis ,118 showMMPs are enzymes that play a role in the breakdown of extracellular matrix proteins, and are thought to contribute to the IOP change in glaucoma . The TM Together, the biomolecules VEGF, nitric oxide, and MMPs hold promise as potential biomarkers for predicting the progression of glaucoma and as targets for pharmacologic intervention.Retinal vascular dysfunction has been observed as a secondary manifestation both in individuals diagnosed with glaucoma and animal models employed to study the disease, suggesting that glaucoma may also serve as the instigator of retinal vascular abnormalities . These sA study conducted on individuals with early normal-tension glaucoma demonstrated that there were no significant differences in retinal arterial diameters compared to normal controls. This finding suggests that the narrowing of retinal arterioles observed in glaucoma patients is a consequence of the disease rather than being its underlying cause . FurtherIn a case-control study, it was discovered that individuals afflicted with unilateral acute primary angle closure glaucoma (PACG) demonstrated a significant reduction in peripapillary retinal vessel density within affected eyes, as compared to contralateral unaffected eyes . The notIn experiments conducted on cultivated mouse retinas subjected to elevated intrachamber pressure, it was observed that the expression of tight adherens junction proteins, such as zonula occludens 1 (ZO-1), occludin, and the adherens junction protein VE-cadherin in retinal vessels, underwent alterations . These fIn a mouse model of glaucoma induced by unilateral cauterization of three episcleral veins ,140, elep < 0.001). However, some studies did not find this association [Multiple studies have reported a notable association between glaucoma, specifically open-angle glaucoma, and an increased incidence of retinal vascular occlusions ,142. In ociation ,145. A mociation  reportedThe introduction of the vascular theory, as well as the hemodynamics surrounding it, has spurred a growing body of scientific investigations aimed at unraveling the intricate relationship between vascular abnormalities and the underlying pathophysiology of glaucoma. It has become increasingly apparent that vascular abnormalities are closely associated with the observed neurodegeneration in glaucoma. However, it is important to recognize that glaucoma itself can initiate retinal vascular abnormalities. Nevertheless, given the multifactorial nature of glaucoma, it is acknowledged that vascular abnormalities represent just one of many contributing factors to the neurodegenerative processes observed in this disease. In addition to determining the causality between vascular abnormalities and glaucoma, longitudinal studies are necessary to disentangle the temporal association between loss of neural structure and loss of vascularization.


A wise person avoids it” (Albert Einstein). There is no convincing evidence that any modality 100% effectively prevents nerve injury. The risk of nerve injury remains the same even with the ultrasound due to limitations in the resolution of images and inter-operator and inter-patient differences. In a nutshell, caution is required when dealing with precious nerves in the perioperative period, either during peripheral nerve blocks (PNBs), patient positioning, or surgery. Identifying pre-existing nerve injury, either due to trauma or an existing neuropathy, and preventing further nerve injury should be an important goal in providing safe regional anesthesia (RA).Multimodal monitoring is key to avoiding multifactorial nerve injuries. The use of triple guidance  during PNBs further improves the safety of RA. The ultrasound helps in real-time visualization of the nerve, needle, and drug spread; the peripheral nerve stimulator helps confirm the target nerves; and the injection pressure monitor helps avoid nerve injury. Such multimodalities can also give the confidence to administer PNB without risk of nerve injury.This article is part of the comprehensive overview of the essential understanding of peripheral nerves before blocking them. It describes various preventive measures to avoid peripheral nerve injuries while administering PNBs. It will help readers understand the importance of prevention in each step to avoid perioperative PNIs. Suffering from neurological injuries in the perioperative period is a kind of psychological trauma for the patient. Due to multifactorial origin, nerve injury can occur at any step in the perioperative period, such as during peripheral nerve block (PNB) administration, ongoing surgery, or the postoperative period. Preventing nerve injuries can be possible by eliminating all potential causes and taking precautions at every step rather than just focusing on one aspect. The ultimate goal is to provide safe and effective regional anesthesia (RA). Achieving this requires a basic understanding of the structures, equipment, modalities, and people involved. Modern RA practices facilitate providing targeted RA training, obtaining basic knowledge of the target structures and modern equipment, and creating red flags to review each step to avoid complications.The advent of ultrasound guidance (USG) in RA and various available objective monitoring techniques to avoid nerve injuries have made RA practice much safer. However, ultrasound has been implicated and proven revolutionary in RA practice, but it fails to accurately locate intrafascicular or extrafascicular needle tips. Hence, the risk of nerve injury remains the same even with the ultrasound due to limitations in the resolution of images and inter-operator and inter-patient differences. Therefore, like multimodal analgesia for multifactorial pain, multimodal monitoring may be useful in preventing peripheral nerve injuries (PNIs) of multifactorial origin.Multimodal monitoring includes using multiple objective modalities such as ultrasound, peripheral nerve stimulators (PNSs), and injection pressure monitoring techniques. Using ultrasound allows real-time visualization of the needle and local anesthetic (LA) deposition. PNS helps confirm target nerves and avoid intraneuronal injection. Injection pressure monitoring devices are designed to avoid intraneuronal injections by stopping injection at high opening pressures. So far, three injection pressure monitoring devices are commercially available: BSmart™ , NerveGuard , and SAFer Injection for Regional Anesthesia (SAFIRA™) . The NerveGuard and SAFIRA are essentially in-line pressure limiters that stop injections automatically once the pressure reaches above 15-20 pounds per square inch (psi) (>15 psi for the NerveGuard and >20 psi for the SAFIRA). The BSmart offers the advantage of using the decision-making capacity to inject at any indicated pressure. However, no convincing evidence exists that any modality is 100% effective in preventing nerve injury .This article is part of the comprehensive overview of the essential understanding of peripheral nerves before blocking them. It describes various preventive measures to avoid PNIs while administering PNBs. It will help readers understand the importance of prevention in each step to avoid perioperative PNIs.This narrative overview describes various preventive measures to avoid PNIs while administering PNBs. Related literature searches were performed using online platforms  using relevant search terms (neurons/nerve damage/nerve injuries/prevention of nerve injuries/monitoring in RA/injection pressure monitors/in-line pressure manometers/recent advances in ultrasound to prevent PNIs). Articles published in English were selected (year 2000-2023), and their reference sections were manually searched for additional information.Prevention of nerve injuriesPrevention is always better than cure. All preventive measures are very effective if implemented on all fronts Figure , i.e., bWhen administering PNB, attention can be paid to many important factors Figure  to preveThe available assistant should know the importance of intermittent aspiration during the injection and avoid high-pressure injections, felt by the tactile feel of the syringe. Various syringes and in-line connectors used during PNB can also play an important role in preventing nerve injury. The modalities such as ultrasound, PNS, and dual guidance (USG + PNS) offer their advantages in preventing nerve injuries. Most important is the monitoring during the performance of PNB. Such monitoring can be subjective, relying entirely on the subject (patient) and their symptoms (such as paresthesia/pain) or on the assistant’s tactile sense of high injection pressure while injecting the drug. Objective monitoring helps prevent intraneuronal injection by either automatically stopping the injection at high pressure or displaying the pressure at injection, prompting the anesthetist to decide on the injection. After PNB, all important precautions should be followed during the perioperative period. Patient follow-up is very important to identify, evaluate, diagnose, or explain neurological deficits, and to reassure the patient about them.Structured RA trainingMost PNB-related nerve injuries are related to needle trauma or needling technique. Acquiring needling skills during RA training is important to ensure safe RA without causing nerve injury. The entire success of ultrasound-guided RA (UGRA) depends on a triad of three distinct but interrelated skills: image acquisition, correct interpretation of the sonoanatomy, and hand-eye coordination to visualize the needle in real-time while reaching the target nerves. The needle visualization is a dynamic process that often requires constant needle manipulation with simultaneous adjustments of the ultrasound transducer. There can be an extensive learning curve when acquiring UGRA skills . Proper Needling in a living patient by inexperienced hands harbors a high potential for injury to nerves, vessels, or other vital structures. To overcome this hurdle, looking for alternative training tools that provide at least basic training in a controlled environment is important. Simulation training is one option where different scenarios can be created, and various techniques or strategies can be taught effectively without hurting any live patient. Such training was used as early as 1964 to test the acquisition of cardiopulmonary resuscitation skills with a Resusci-Anne mannequin in paramedics and laypersons . Such siMonitoring modalities during RAAvoiding nerve injuries from various sources  can be possible by anticipating such damages before their occurrence and adopting preventive and safety measures. Several techniques have been advocated to improve safety during the execution of PNBs that facilitate vigilant monitoring to avoid nerve injuries. Such monitoring can be subjective and objective based on the patient and devices Figure .Sometimes, PNB is administered to sleeping/heavily sedated/constrained patients such as pediatric, mentally incompetent, traumatically injured, and intubated patients. Sometimes, it is managed as a rescue or repeat block. In such cases, using more objective monitors than the patient’s subjective symptoms can provide greater confidence in avoiding nerve injury. Therefore, more attention should be paid to objective rather than subjective monitoring. Subjective monitoring includes paresthesia, pain on injection, or resistance during injection (syringe feel) . It is uParesthesia on injectionParesthesia refers to an abnormal painless skin sensation  distal to the block site. During PNB, the patient usually experiences electric shock-type paresthesia. Paresthesia is abnormal electrical activity in the nerve caused by nerve irritation due to the pressure of the needle or the injected solution. Therefore, it should always be interpreted as a warning sign of needle-nerve proximity -12. It hPain on injectionIntraneural placement of the injection can be exquisitely painful. Since pain is a subjective feeling, which may vary from person to person, assessing pain in terms of intensity and quality is difficult. It is sometimes difficult to differentiate between a common discomfort during LA injections (pressure paresthesia) and pain during intrafascicular injection. Various patient conditions (such as diabetes mellitus), peripheral neuropathy, premedication, and sedation can impair pain perception. There appears to be little evidence that pain on injection is sensitive or specific. Since a fraction of a milliliter is enough to cause irreversible fascicular damage, the patient’s subjective symptoms may be too late ,15.Subjective “syringe feel”While administering ultrasound-guided PNB, the anesthetist mainly focuses on handling the probe and needle while observing the ultrasound image. At the same time, another anesthetist/assistant performs the actual injection. In such a scenario, the assistant feels the actual resistance upon high opening pressure via tactile feedback, which is again prone to subjective bias. If the assistant does not stop injecting upon resistance, it can lead to neuronal damage . Such siElectrical nerve stimulationPeripheral nerve stimulation is based on the relationship between the current required to elicit a motor response and the distance between the needle tip and the nerve . A thresElectrical impedancePNS used for PNB are constant current generators. It means that despite the changing resistance offered by different tissues in the body, the same current can be generated. Such resistance to the flow of alternating current in an electrical circuit is known as electrical impedance. It depends on the water-lipid ratio of the tissues. Nerves have a higher water-to-lipid ratio than skin, muscle, fat, or bone . BecauseThe course of the needle from the extraneural to the intraneural compartment can cause a sudden increase in electrical impedance to almost double the value. Therefore, electrical impedance monitoring can detect the placement of the intraneural needle tip. However, the needle tip must be in the nerve for this to work. Such an electrical impedance measurement can also distinguish between the intravascular and intraneural placement of the needle. Tsui et al. found a near doubling of baseline electrical impedance upon intraneural insertion of the needle . HoweverUltrasonographyThe modernization of RA has paved the way for the resurgence of UGRA techniques. Modern UGRA techniques provide a real-time visual representation of the internal anatomy and help increase the nerve block success rate, accelerate the onset time, and reduce the volume and risk of complications of LA ,25. USG The advent of USG for nerve blocks has likely led to an increase in recognition of inadvertent intraneural injections, as evidenced by nerve swelling. However, it may not be an essentially effective means of preventing nerve injury. The reliability of ultrasound in keeping the needle tip extraneural depends largely on the skill of the operator and the imaging properties of the needle and tissue. Despite USG, several case reports of accidental nerve (and vascular) punctures highlight that ultrasound monitoring is not a fail-safe method of preventing neurological  complications -29.Furthermore, ultrasound resolution sometimes fails to accurately locate the intrafascicular or extrafascicular needle tip, which is the critical anatomical differentiation required to avoid nerve injury. Finally, by the time the nerve swells in the image, the damage may already have been done by the time the injection is made inside the fascicle. In order to avoid nerve injury, a hydro-dissection technique is recommended while using USG, in which small aliquots of LA are injected during the advancement of the needle toward the target nerve. Dual guidance (USG + PNS) helps reduce the risk of nerve injury by depositing LA around the confirmed nerve (by PNS response) and reducing effective LA volume. In addition, triple guidance Figures , 5  ultrasound offers planar images that require skill and frequent probe maneuvering to optimize the images generated and real-time needle tracking. Various technologies such as three-dimensional (3D) and four-dimensional (4D) USG have emerged in pursuit of better image optimization, real-time needle tracking, and visualization of drug spread. The 3D USG offers the advantage of providing the third volume dimension by providing a 360-degree dataset of the traditional 2D image. It helps get an overview of the spread of the LA around the nerve. Although 3D-USG provides additional volumetric information, it does not help in real-time needle visualization ,33.On the other hand, 4D USG can be called real-time 3D USG. It provides a multi-planar view of the sonographic image, aiding in needle tracking, catheter placement, LA spread, and visualization of adjacent structures without extensive probe movement . CurrentArtificial Intelligence in UltrasoundThe advent of assistive artificial intelligence (AI) has also touched the UGRA sector. The future prospects of this technology are currently being studied, and the possibility of reducing the occurrence of nerve injuries is one area where AI can help find solutions. The ScanNav™ Anatomy Peripheral Nerve Block  is an FDA-approved AI-based technology that generates color overlays and highlights key structures in real-time B-mode USG. It has been trained with more than 800,000 USG images ,36. By hInjection pressure monitoringInjection pressure monitoring is useful in detecting needle-nerve contact. It is highly sensitive but lacks specificity. In other words, the absence of high injection pressure effectively rules out an intrafascicular injection ,37. HighDespite a lack of paresthesia, PNBs associated with high injection pressure have been reported to result in permanent neurologic injury . As per Injection pressure is often assessed using a “syringe-hand-feel” technique, which is prone to subjective bias. Objective injection pressure monitoring is considered safe and effective due to the inability to gauge injection pressure with tactile feedback using the syringe feel technique ,21. ObjeCompressed air injection techniqueThis technique is based on Boyle’s law (pressure × volume = constant), i.e., gas or air volume and pressure have an inverse relationship at a constant temperature. It consists of a syringe (20 ml) filled with half a volume of LA (10 ml) and half a volume of air (10 ml) above it Figure . During In terms of advantages, firstly, it is a simple, more economical, and practical method that constantly keeps the LA injection pressure below the threshold level, thus minimizing the risk of clinically significant nerve injury. Secondly, by decreasing the injection speed, CAIT decreases the risk of intrafascicular injection or siphoning the LA to unwanted tissue planes. Thirdly, the pressures generated by CAIT also remain consistently stable throughout the injection period, unlike the syringe feel technique, which produces high peak pressures. It is likely due to the “cushioning” effect from the volume of air, which dampens the initial high pressure .In terms of disadvantages, firstly, CAIT may also present a potential risk of air injection due to accidental air injection into the vessel, potentially creating a venous air embolism . SecondlBSmartBSmart is a commercially available easy-to-use in-line injection pressure manometer Figure  for singApart from providing enhanced safety of PNBs, the BSmart offers some advantages such as objective monitoring of injection pressure, warning of high injection pressure, prevention of too forceful and rapid injections, consistent monitoring of resistance to injection regardless of who performs the actual injection, and standardized and objective documentation of injection pressure information. However, such assembly may produce false-positive readings during higher injection flow rates  due to cNerveGuardNerveGuard is another in-line automatic injection pressure limiter Figure , which oSAFIRANew technology SAFIRA Figure  has a buThe traditional practice of RA mainly involves two operators, an anesthetist (to position the needle using an ultrasound probe) and an assistant who injects the LA. In contrast, the SAFIRA system helps single-handedly manage infusion and aspiration while administering RA. It has provided a foot pedal or handheld switch system to control the entire injection. Both the foot pedal and hand switch systems are color-coded (yellow for aspiration and green for injection). The automatic built-in safety feature in SAFIRA stops injection at pressures >20 psi, giving anesthetists more confidence to provide safe RA .Thus, nerve injuries of multifactorial origins can be prevented by taking necessary undue precautions and using multimodal guidance at each step perioperatively. However, which of many is the best preventive measure has yet to be determined. Further studies and innovations are always welcomed to ensure safe RA.


While impairments in peripheral tissue insulin signalling have a well-characterized role in the development of insulin resistance and type 2 diabetes (T2D), the specific mechanisms that contribute to these impairments remain debatable. Nonetheless, a prominent hypothesis implicates the presence of a high-lipid environment, resulting in both reactive lipid accumulation and increased mitochondrial reactive oxygen species (ROS) production in the induction of peripheral tissue insulin resistance. While the etiology of insulin resistance in a high lipid environment is rapid and well documented, physical inactivity promotes insulin resistance in the absence of redox stress/lipid-mediated mechanisms, suggesting alternative mechanisms-of-action. One possible mechanism is a reduction in protein synthesis and the resultant decrease in key metabolic proteins, including canonical insulin signaling and mitochondrial proteins. While reductions in mitochondrial content associated with physical inactivity are not required for the induction of insulin resistance, this could predispose individuals to the detrimental effects of a high-lipid environment. Conversely, exercise-training induced mitochondrial biogenesis has been implicated in the protective effects of exercise. Given mitochondrial biology may represent a point of convergence linking impaired insulin sensitivity in both scenarios of chronic overfeeding and physical inactivity, this review aims to describe the interaction between mitochondrial biology, physical (in)activity and lipid metabolism within the context of insulin signalling. Type 2 diabetes (T2D) remains one of the most significant medical challenges of the 21st century. While the earliest reports of the disease extend back centuries, modern day technical revolutions have resulted in low physical activity combined with the overconsumption of inexpensive, calorically dense, and inadequately satiating food, leading to extraordinary increases in obesity and the incidence of metabolic disorders . Indeed,The regulation of lipid metabolism has been a focus of preventative approaches for decades, and given their primary role in fatty acid oxidation, mitochondria have a considerable impact on the accumulation/metabolism of both neutral (triacylglycerol (TAG)) and reactive (DAG/ceramides) lipids . In addiWhile several mechanisms have been proposed to regulate mitochondrial quality, including gene transcription, mitophagy and reticulum formation, the importance of these mechanisms are premised fundamentally on affecting mitochondrial bioenergetics. As a result, this review will emphasize the relationship between mitochondrial ‘function’ and insulin signalling before discussing possible mechanisms that negatively influence mitochondrial bioenergetics. Within this framework, we highlight that physical activity has a robust influence on a range of mitochondrial characteristics and can be used as a viable treatment strategy for insulin resistance and T2D.The accumulation of lipids in non-adipose tissues  is a distinguished event in various models of insulin resistance . ImportaReactive lipids have been proposed to attenuate insulin signalling through several mechanisms. Within skeletal muscle, DAGs have been demonstrated to activate PKC-θ and PKC-ε in both human and rodent models . PKC-medThe presence of excess lipids and the subsequent production of reactive lipid intermediates is a direct reflection of an imbalance between peripheral tissue lipid supply and intracellular utilization. Given that intracellular lipid utilization occurs via mitochondrial oxidative phosphorylation, an increase in substrate (lipid) delivery/transport to the mitochondrial matrix, beyond what can be readily oxidized, results in the rapid accumulation of reactive lipid intermediates  and stim2O2 demonstrate impaired PKB activation (N-acetylcysteine) prevent the induction of insulin resistance  resulting in serine phosphorylation of IRS-1, and attenuation of insulin signalling in a similar manner to DAGs . Additiotivation  and marktivation , while csistance . Though eostasis , overexp in mice . Additio in mice . Togethe in mice . In linetivation , highligThere is an abundance of evidence to suggest that the accumulation of reactive lipids within peripheral tissues can impair various aspects of mitochondrial bioenergetics and is associated with the induction of insulin resistance. Since the first description of mitochondrial dysfunction in the context of glucose intolerance more than 40 years ago , mitochoJO2), which ultimately lowers cytosolic free ADP  to re-establish metabolic homeostasis. While the importance of mitophagy in regulating cellular homeostasis has been previously reviewed , the funImpairments in insulin sensitivity have long been known as a physiological consequence of sedentary behaviour and even short-term inactivity . This idThe exact mechanism(s) causing insulin resistance during acute periods of inactivity remain debatable, as there are inconsistent reports of reactive lipid accumulation  . While sAn alternative hypothesis implicates attenuated transcriptional/translational processes and reductions in protein synthesis during the development of skeletal muscle disuse-induced insulin resistance. While an abundance of evidence clearly suggests that a reduction in ambulatory activity results in skeletal muscle atrophy and is often associated with impairments in insulin action and glucose tolerance  three times per week , fasting plasma insulin and fasting glucose following 25–60 min of walking or running at 50%–60% VOper week . Insulinper week . While lper week , which iper week . Notablyper week , indicat2 max  and transient glycaemic control when compared with moderate-intensity, longer duration exercise  and/or sprint interval training (SIT) in the treatment of metabolic disorders, has gained significant popularity in recent years. HIIT leverages repeated, brief bouts of vigorous exercise separated by short recovery periods, to elicit the metabolic effect of moderate intensity aerobic exercise in a condensed duration. An abundance of literature suggests that HIIT elicits a greater improvement in VOexercise . Howeverexercise , and whed to SIT . This isd to SIT . Preventd to SIT , as welld to SIT . Importad to SIT . Conversd to SIT . Howeverd to SIT . While sd to SIT , which md to SIT , resultiWhile much of the early research on exercise-mediated regulation of insulin sensitivity focused on aerobic exercise training, the use of resistance exercise as a training modality to improve insulin sensitivity should not be overlooked. Primary outcomes in studies evaluating the effects of resistance training in insulin resistant individuals have demonstrated a 10%–15% improvement in insulin sensitivity . SimilarWhile a single bout of exercise causes a transient improvement in insulin sensitivity as outlined above, the molecular mechanisms accounting for improvements in insulin sensitivity induced by chronic exercise training are complex and incomplete. Nonetheless, it is generally accepted that repeated bouts of regular exercise upregulate PGC-1α . While iWhile general apoptosis is not linked to exercise , our undIn this review, we aimed to highlight the central role of mitochondrial biology in various mechanisms thought to underly the etiology of peripheral insulin resistance. The accumulation of lipids in non-adipose tissues is a distinguished event in various models of insulin resistance, resulting in both direct (via reactive lipids) and indirect  impairments in peripheral insulin signalling. While several mechanisms have been proposed to regulate mitochondrial quality, including gene transcription, mitophagy and reticulum formation, the importance of these mechanisms are fundamentally premised on affecting mitochondrial biogenesis. However, clear evidence for the presence of impaired mitochondrial oxidative capacity in the induction of insulin resistance does not exist, and redox stress and reactive lipid accretion appears to be specific to scenarios of chronic overfeeding. Alternatively, it appears that lipids can competitively and/or allosterically inhibit mitochondrial ADP transport as a key event negatively affecting mitochondrial bioenergetics. In contrast to a high lipid environment, extreme physical inactivity attenuates protein synthesis and reduces mitochondrial and canonical insulin signaling proteins as alternative mechanisms-of-action to limit insulin action. While the effects of lipid-induced metabolic perturbations and physical inactivity are therefore likely additive with respect to the pathophysiology of insulin resistance, since exercise stimulates robust phenotypic changes in lipid homeostasis, mitochondrial bioenergetics and protein synthesis/gene transcription, the inclusion of physical activity represents an important treatment/prevention strategy for individuals at risk of the development of insulin resistance and T2D.


Sleep problems (SP) are highly prevalent among all age groups . ChronicZhang L. et al. showed that SP are also prevalent among university students. Their work aimed to create a prediction model (nomogram) that could be used to detect SP. Some intervention or preventive techniques, including quitting smoking and drinking, eating a healthy diet, avoiding midday naps, attending to chronic diseases, and managing worry and stress, may be very useful in improving sleep in university students. In the original article by Guo et al., the researchers used 24-h heart rate variability (HRV) as a biomarker to investigate the sleep quality and depression symptoms of medical students. The authors reported that SP were common among medical students and were associated with depressive symptoms. Students with SP had lower SDNN during the awake period and bedtime period and lower LF in the awake period. The use of HRV analysis may provide valuable information about SP and the different stages of sleep. During the different sleep stages, HRV patterns change, reflecting the varying activities of the autonomic nervous system.Two papers reported SP among university students. Recent umbrella reviews and meta-analyses of self-reported psychological and behavioral symptoms (PBS) in medical students showed that a global analysis of all self-reported PBS combined yielded a pooled prevalence rate of 30%. The highest reported prevalence was for SP, affecting about 42%. Appropriately targeted assessment (perhaps using HRV) and intervention efforts are clearly warranted to decrease the SP of university students during their education  for psychosis, as demonstrated by subjective and objective sleep measurements such as polysomnography, sleep electroencephalograms, and actigraphy. The review discussed the potential mechanisms and processes underlying the association between sleep and psychosis and highlighted its complicated and multifaceted nature, which remains to be determined and understood. The review by Albanese et al. showed that among the various treatments proposed for treating nightmares in PTSD patients, those involving imagery rescripting appear to be the most effective. These techniques provide direct access to the traumatic contents and emotions of nightmares without overwhelming patients, and they enable healthcare workers to quickly detect and modify trauma-related negative beliefs.Three papers focused on psychiatric populations. The meta-analysis by Xu et al. showed that in patients requiring MHT, older age, lower albumin, and calcium levels are all risk factors for SP. Lower albumin and calcium levels in these patients also correlating with SP is logically plausible, as nutritional deficiencies can affect sleep regulation. Albumin and calcium have important biological functions. In the same line of research, Tong et al. showed that SP were associated with declining renal function  in postmenopausal women. The findings suggested that postmenopausal women should prioritize maintaining excellent sleep quality, which provides clinical evidence for the feasible early diagnosis and effective prevention of kidney disease progression, such as MHT, in postmenopausal women. Mohamed et al. highlight that collaboration between the family and healthcare workers are essential to improving the quality of sleep in patients undergoing MHT.Three papers focused on the diagnosis and management of SP in patients undergoing maintenance hemodialysis therapy (MHT). Sun et al. found that using the slow-4 frequency range in OSA may be more specific. These findings imply that severe OSA patients exhibit frequency-related aberrant spontaneous brain activity, which could help us understand the pathology of OSA-related disorders and give us possible therapeutic targets for OSA patients. The study by Su et al. documented that despite considerable available OSA knowledge, medical residents have low confidence in OSA management. The authors suggested practical and small group teaching approaches that have the advantages of flexible time, short duration, and high participation, especially during clinical rotations. In a pediatric population, Lee et al. reported that a reduction in the overall obstructive sleep apnea (OSA) questionnaire score and the very low frequency (VLF) power of HRV mediated the improvement in the obstructive apnea-hypopnea index after adenotonsillectomy. These preliminary findings are innovative, and they point the way forward for further study into the impact of HRV-guided therapies on childhood OSA.As a common and formal sleep disorder, OSA yielded three papers. Duong-Quy et al. highlighted that during COVID-19 SP, depression symptoms and fatigue in healthcare workers worsened among frontline healthcare workers. Earlier studies established that the COVID-19 pandemic has put great strain on the global healthcare system, necessitating the development of numerous field hospitals and isolation camps around the world. This temporary solution has resulted in the suspension of proper environmental conditions for patients and healthcare workers  with the Health in All Policies (HiAP) for health promotion, which resulted in a comprehensive, evidence-based design for the implementation of a multi-sector integrated program to increase children's sleep health. Their blueprint document suggested that it be used to help build local (sleep) health promotion programs in other regions with distinct local governmental systems and cultures while keeping the policy environment in mind.Niu et al. demonstrated high sensitivity and specificity and excellent diagnostic ability of the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and Athens Insomnia Scale (AIS) questionnaires in screening for insomnia in stroke patients. The authors concluded that each of the three questionnaires has advantages and disadvantages when assessing insomnia.Xiang et al. aimed to investigate the changes in features and related aspects of several GABAergic system indexes in the peripheral blood of individuals with insomnia. They found that serum GABA inhibitory activity may be altered in insomnia patients, and decreased expression levels of GABAA receptor α1 and α2 subunit mRNA may become a reliable indication of insomnia disorders.While great strides have been made in understanding and treating SP, it remains an undertreated public health issue. A holistic, patient-centered approach combining multiple modalities tailored to the individual holds the most promise for optimal management of these conditions. Continued research to elucidate sleep-wake neurobiology and innovative technological solutions can help improve diagnosis, treatments, and quality of life for the millions affected by SP worldwide.HJ: Conceptualization, Data curation, Investigation, Project administration, Resources, Writing—original draft, Writing—review and editing.


Background: Tyrosine kinase inhibitors (TKIs) have significantly improved survival for patients with chronic myeloid leukemia (CML) but require long-term administration and non-adherence due to regimen requirements has been reported.Objectives: This study sought to identify how much patients value more convenient regimens and the potential impact that regimen may have on medication adherence.Methods: This cross-sectional, six-country study utilized a web-based discrete conjoint experiment (DCE) survey in which participants selected between hypothetical treatments that differed on three attributes: meal requirements/restrictions, frequency of administration, and monthly co-pay, to quantify willingness to pay. Attribute percent importance ratings were derived from a multinomial logit model, and utilities were summed for each product profile to determine the most preferred regimen profile. Additional survey questions asked about attributes perceived to affect adherence and the ease and convenience of participants’ current regimen.Results: A total of 318 patients completed the survey; median age 53 years (range 18-87); 43.7% male. Four participants were excluded from the conjoint analysis due to illogical responses. The most important regimen attribute driving preferences was the meal requirement/restriction, which was almost twice as important as dose frequency. The majority of participants preferred the profile of a once a day dosing taken with or without a meal, and estimates of willingness-to-pay helped to quantify this preference. In terms of adherence, the majority of participants perceived that having to fast before and after taking medication would be the most likely reason for missing a dose.Conclusions: The results suggest that patients value the convenience of CML treatments and perceive certain regimen characteristics, particularly meal requirements or restrictions, as likely to affect adherence. It is important for healthcare providers to be aware of the potential impact of treatment convenience on non-adherence and communicate closely with patients to decrease this potential.


Cardiovascular disease is characterized by significant prevalence and cost in the managed care setting. Despite overwhelming evidence in favor of statin use for lowering low-density lipoprotein cholesterol (LDL-C), medication compliance to these agents remains suboptimal, as it does in other disease states.To establish the benefits of statin therapy in cardiovascular disease, demonstrate the current lack of compliance to lipid-lowering agents, and present potential interventions to improve medication compliance.As evidenced by a consistent body of clinical trial data, intensive LDL-C reduction plays a critical role in the mitigation of cardiovascular risk. Yet, the effectiveness of lipid-lowering strategies is offset to a significant degree by both physician and patient factors that limit goal attainment. Despite extensive evidence demonstrating the benefits of lipid-lowering therapy, many patients are still not getting to goal because the transition from physician awareness to clinical practice is lagging. Patient noncompliance to therapy also limits goal attainment, thus resulting in poor health outcomes and increasing managed care costs.To overcome the issues surrounding LDL-C goal attainment, interventions designed to increase goal attainment should be based not only on the conclusions of clinical trials but also on successful patient and provider-focused behavioral strategies. Interventions for improving adherence to lipid-lowering medication will provide an opportunity to decrease morbidity, mortality, and hospitalization associated with cardiovascular disease.


To the editor:We have read with great interest the study conducted by Benites et al., which explores the impact of trunk inclination on ventilator efficiency in patients with ARDS . Similar2O, depending on trunk inclination (semi-recumbent at 40° vs. supine-flat), with lower values identified in semi-recumbent position [The first key issue is the potential influence of trunk inclination on PEEP titration. Our recent work revealed that the “best PEEP”, balancing overdistension and collapse , varies by an average of 5 cmH2 clearance in the supine-flat position suggest that PEEP may have been optimized in this position. In our opinion, it is highly plausible that such improvements would not have occurred if PEEP had been optimized in the semi-recumbent position. Indeed, in our recent study we observed similar lung compliance in supine-flat and semi-recumbent position, once PEEP was titrated considering trunk inclination [Although the authors do not specify the trunk inclination of patients during PEEP titration, their observations of significant improvements in respiratory mechanics and COlination .Another methodological issue that needs to be discussed is the use and comparison of absolute end-expiratory lung impedance (EELI) values. While changes in EELI within the same position are a useful proxy of lung aeration, caution is advised when interpreting absolute values and their differences according to trunk inclination. Indeed, these changes might be influenced by altered pressure on the electrodes and/or minor belt movements induced by the postural change itself.Beyond these methodological aspects, the major discrepancy with our findings is ventilation distribution. In a similar study conducted in volume-controlled ventilation, thus ensuring a constant tidal volume, we observed improved ventilation of the ventral area in supine-flat position . Given tIn conclusion, we think that some technical and methodological aspects require careful consideration when interpreting the findings. In addition, and in consideration of our current understanding of respiratory mechanics and physiological gravitational effects on aeration and ventilation distribution , it woul