Photodynamic therapy (PDT) is a promising cancer treatment which involves a photosensitizer (PS), light at a specific wavelength for PS activation and oxygen, which combine to elicit cell death. While the illumination required to activate a PS imparts a certain amount of selectivity to PDT treatments, poor tumor accumulation and cell internalization are still inherent properties of most intravenously administered PSs. As a result, common consequences of PDT include skin photosensitivity. To overcome the mentioned issues, PSs may be tailored to specifically target overexpressed biomarkers of tumors. This active targeting can be achieved by direct conjugation of the PS to a ligand with enhanced affinity for a target overexpressed on cancer cells and/or other cells of the tumor microenvironment. Alternatively, PSs may be incorporated into ligand-targeted nanocarriers, which may also encompass multi-functionalities, including diagnosis and therapy. In this review, we highlight the major advances in active targeting of PSs, either by means of ligand-derived bioconjugates or by exploiting ligand-targeting nanocarriers. A critical limiting factor of cancer treatment’s success is the lack of specificity associated with many traditional cancer therapeutics. Moreover, most anti-cancer drugs accumulate in normal and cancer tissues indiscriminately. Damage is instigated in proportion to the sensitivity of the tissue exposed . This noTargeted drug delivery in the context of cancer is mainly achieved by two approaches: passive and active targeting. The first is highly dependent on the physicochemical properties of drugs/nanocarriers and the pathophysiological features of the tumors . It is p1O2 -phenanthroline)]Cl2, known as TLD1433) with Tf. The Tf-targeted conjugate was associated with enhanced internalization and phototoxicity in rat bladder cancer cells when compared with the non-targeted counterpart. In vivo studies with mice bearing the highly immunogenic CT26.CL25 tumors revealed approximately 70% of overall survival with the Tf-targeted conjugate , whereas only ≈30% was attained with the ruthenium complex alone [In 1994, Hamblin and Newman  were ther et al.  reportedex alone ,140,141.Antibodies and their fragments constitute another class of moieties commonly used for PS delivery which has increased in popularity with the progression of personalized medicine. Conjugation through lysine (amide and isothiocyante conjugation) or cysteine , SNAP-Tag conjugation and “click” chemistry  are the most common synthetic strategies for the development of tetrapyrrole-based antibody-PS conjugates. This has been recently discussed in great detail by Sandland and Boyle .2) [One of the most promising examples of antibody-targeted PS relies on the water-soluble silica phthalocyanine-based PS IRDye700DX (IR700), which has been conjugated to different mAbs. Initially, studies performed with trastuzumab or panitumumab (anti-EGFR mAb)-targeted IR700 showed a preferential accumulation of the PS at the A31 cell membrane, inducing necrotic cell death upon illumination at 690 nm. In vivo specific A431 (epidermoid) and 3T3/HER2 (breast) tumor accumulation and shrinkage were initially reported  . This st2)  or upon 2) . Additio2) ,146; ora2) ,148; gli2) ; and mel2) .Overall, mAb-IR700 has the ability to induce specific cell death of cancer cells while sparing adjacent healthy tissue, tumor vessels and infiltrating-immune cells ,149,150.Work continues to explore antibody-IR700 conjugates, such as the case-study reported by Isobe et al., wherein this PS was conjugated with an antibody targeting delta-like protein 3  . PDT resIR700 has also been successfully targeted to different types of cancer cells by means of nanobodies. Nanobodies are small but fully-functional fragments of the classical antibodies, each consisting of only a single variable heavy chain. The single domain structure leads to not only reduced immunogenicity in targeting but enhanced tumor diffusion and a more homogenous tissue distribution in comparison to intact mAbs. Driel et al. demonstrated that EGFR nanobody-IR700 conjugate selectively accumulated, at a time point as short as 1 h, in orthotopic OSC head and neck tumors, leading to ≈90% tumor necrosis while sparing adjacent healthy tissues . HeukersLastly, affibodies are another interesting class of targeting moieties. Affibodies are synthesized peptide mimetics of antibodies that have high specificity towards specific proteins. Owing to their small size (6–7 kDa), they exhibit better tissue penetration. Yamaguchi et al. reported the conjugation of IR700 to an affibody targeting HER2 . The resThe use of small peptides for the delivery of PS generally improves solubility in aqueous solutions, leading to higher phototoxicity and therapeutic efficacy . Solutio4) conjugate (RedoxT) for theranostics [The peptide GE11 , discoveanostics ,164. Theanostics . Triple-anostics . A correanostics .Recently, Zhang et al. developed an approach which envisages the targeting of the cell membrane of cancer cells without promoting cellular internalization . To achiWhile the abovementioned targeting strategies are the most used, additional approaches have been investigated for the development of targeted-PS conjugates . Along wThe metabolic changes of tumors may be explored as another approach to develop targeting strategies for cancer. Due to the high demand for glucose (Warburg effect) and cholesterol by the cancer cells, conjugation of PS with sugar molecules or lipoproteins  is being successfully used to improve the selectivity and phototoxicity of PDT ,175,176.The development of delivery formulations that enable the systemic administration of a hydrophobic PS is an important aspect for its clinical translation. One promising strategy relies on the use of nanotechnology to create new drug delivery strategies . The useThe attachment of targeting moieties to the NPs’ surfaces is a strategy widely used to enhance tumor accumulation and the treatment specificity. However, with regard to tumor accumulation, the success of a targeted system is not straightforward, as many factors come into play. Indeed, the nanocarrier’s physicochemical properties , the type of ligand , the target receptor  and the pathophysiology of tumor (namely the blood and lymphatic vessels network) strongly impact tumor accumulation and cellular internalization . For insTo date, many types of organic and inorganic nanoplatforms have been developed for delivery of PSs . Typical®) which is used for the treatment of age-related macular degeneration [Lipids offer significant potential as natural and biocompatible materials for drug delivery . Due to neration ,185.Liposomes are currently the most promising lipid-based NPs. Due to the development of liposomes by Bangham in 1965  and thanNanocarriers offer the possibility of combining multiple therapeutic agents  and other functions  within the same system, which helps to tackle different aspects related to cancer treatment. For instance, liposomes composed of thermosensitive lipids were used to simultaneously encapsulate the chemotherapeutic drug doxorubicin (DOX) and the near-infrared photothermal (PTT) and PDT agent indocyanine green (ICG). FA and gadolinium chelates were further attached to the liposomal surface. The developed multifunctional liposomes allowed in vivo imaging by fluorescence, photoacoustic spectroscopy and magnetic resonance while tumor eradication was mediated by the combination of chemotherapy, PTT and PDT. Indeed, the FA-targeted nanoplatform caused effective phototoxicity in vitro against HeLa cells and site-specific accumulation of the FA-targeted formulation in HeLa tumors after systemic administration, which was correlated with tumor eradication for at least 2 weeks following tumor illumination .6 as PS, ICG as a PTT agent, and the hypoxia activated prodrug tirapazamine (TPZ) as a cytotoxic agent. Surface modification was employed with cRGD and conjugation of gadolinium chelates. The targeting ability of the formulation to the αvβ3 integrin receptor was confirmed via intracellular fluorescence of the chlorin e6. Measurements confirmed enhanced cRGD-mediated endocytosis and distribution of the targeted-PS in the cytoplasm; no fluorescence signal was detected for the ligand-free formulation. Phototoxicity studies carried out in A549 lung cancer cells resulted in 97% cell death after illumination at 808/660 nm (PTT and PDT effects), and only 75% cell death was caused by illumination specifically at 808 nm (exclusively PTT effect). Further studies in A549 tumor-bearing mice revealed 5.63-fold enhanced tumor accumulation of the cRGD-targeted PS in comparison with the non-targeted control 8 h post-injection. No tumor was observed for at least 2 weeks post-treatment with the cRGD-targeted formulation and the dual-illumination at 808/660 nm, and tumor regrowth was observed for single illuminations at 808 nm. In addition, the combination of chlorin e6, gadolinium and ICG permitted a theranostic use of the formulation, by allowing in vivo fluorescence/photoacoustic/MRI imaging [An analogous approach was evaluated for a liposomal formulation combining chlorin e imaging . HA-targ imaging . DespiteAlthough liposomes are the best-known lipid-based NPs, new delivery strategies based on lipids other than phospholipids have emerged in recent years. Solid lipid NPs (SLNs) are usually composed of a crystal lipophilic core  which is solid at room and physiological temperatures, in which hydrophobic drugs can be encapsulated. The lipid matrix is composed of physiological lipids. Their preparation does not require the use of organic solvents and is easily scaled-up. As drug mobility decreases in the solid lipid state, drug release can be tuned by the adjustment of the composition of the solid matrix, allowing sustained release . ImprovePolymeric NPs can be prepared from naturally occurring (HA ) or synt6 and DOX [PLGA is a co-polymer thermo-responsive polyester used in approved therapeutic devices and widely explored in NPs for drug delivery. It is synthesized upon ring-opening copolymerization of lactic acid (LA) and glycolic acid (GA). This has been the most popular, widely studied and most improved method for NP production over the past few decades. It allows control over the polymerization process while special attention is paid to the LA/GA ratio. The latter has a tuning impact on the hydrophobic properties of the formulation, thereby controlling the drug release kinetics . Many at and DOX . The Ns 2O2-activatable catalase was incorporated in the NPs. Cellular selectivity of the formulation toward αvβ3 integrin was tested by comparing cellular uptake of the targeted and non-targeted formulation on αvβ3 integrin overexpressed U87-MG cells. After 3 h of incubation, strong fluorescence was detected, but only for the targeted formulation, while remaining low for the control group. Phototoxicity experiments resulted in 98% cancer cell death, while only 15% was reached with the catalase-free NPs. The benefit of the cRGDfK moieties was demonstrated in mice bearing U87-MG tumors. Higher tumor accumulation and complete inhibition of tumor growth was observed for the catalase and targeting moiety containing formulation, while other approaches led to tumor growth within 8 days post-treatment.Chen et al. proposed cRGDfK-targeted PLGA-based NPs, aiming specifically at targeting glioblastoma cells . In orde3)2-(CH2)3N(CH3)2, . The GE11-targeted NPs exhibited 15% more internalization in SCC-15 human squamous cell carcinoma cells compared to the non-targeted control. Phototoxicity in the range of 95% and reduced clonogenicity were attained with low doses of the PS (400 nM). It is important to point out that the in vivo study carried out with SCC-15 tumor bearing mice resulted in comparable tumor regression within the first 30 days of treatment for both approaches. However, unlike the GE11-targeted formulation, after that time tumor regrowth was observed in the non-targeted nanoplatform treated group [Another promising example relies on the use of GE11-targeted PEG-polycaprolactone (PCL) NPs containing HOSiPcOSi(CHed group .N-isopropylacrylamide)) polymers. Hydrogels, due to their ability to swell in aqueous media, have been used in the PDT field to overcome the low solubility of PSs in polar media, while preventing the premature release of the PS without affecting its photophysical properties [Recently, hydrogels, cross-linked three-dimensional scaffolds of hydrophilic polymers with the ability to swell in aqueous media, have been gaining attention in pharmaceutical engineering . Common operties . Moreoveoperties  or activoperties  and antioperties , to the 2-TPP) [N-methyl-4-pyridyl)porphyrin tetratosylate (TMP), a highly hydrophilic PS with limited ability to be internalized by cells. Antibodies targeting the death receptor 5 (DR5), which is upregulated in several types of cancer, were conjugated onto the NPs’ surfaces. In vitro studies conducted in HCT116 colorectal carcinoma cells showed two-times more cellular uptake and phototoxicity than the non-targeted control [Belali et al. developed a FA-targeted and pH-sensitive chitosan-based hydrogel conjugated with 5,10,15,20-tetrakis(4-aminophenyl)porphyrin (NH2-TPP) . With th2-TPP) . The sur2-TPP) . Chitosa control . Similar control . Mice beD-glucopyranose units  [CDs, natural cyclic oligosaccharides, are another example of materials used for the development of nanocarriers. Natural CDs are obtained mainly by enzymatic intramolecular transglycosylation of starch and are classified as alpha (α)-CD, beta (β)-CD or gamma (γ)-CD based on their number of linked ctively) . CD’s apctively) . The usectively) . Introduβ-CDs have been widely used for drug delivery owing to their ready availability and cavity size; however, low aqueous solubility might challenge their use in parenteral administration. Despite this limitation, several works using β-CD-based NPs for the delivery of PSs have been reported. As an example, HA-targeted β-CD-based NPs, containing adamantane-modified camptothecin prodrug  and adamantane-modified THPP, were recently described. This multi-functional formulation combines PDT with light-controlled chemotherapy. Significant internalization was observed in MDA-MB-231 breast cancer cells, which overexpress CD44 receptors, but not in cells with poor expression of CD44 receptors (MCF7), thereby indicating enhanced and specific uptake of the developed HA-targeted NPs. In vitro evaluation demonstrated low cytotoxicity in the dark while high phototoxicity was observed at low doses (50 μg/mL). Of note, in vivo experiments using mice bearing MDA-MB-231 tumors showed 3.7- and 2.2-fold higher tumor inhibition comparing to free THPP and camptothecin, respectively . Similar2sp  or 3sp (mostly for CD) hybridization that are typically arranged in hexagonal lattices. CNMs have versatile electrochemical properties which have resulted in a wide range of applications, such as sensors for diverse materials . Due to their small size , large surface area and light absorption in the NIR region, CNMs have been explored for drug delivery, including in PDT [CNMs are low dimensional carbon-based constructs which were introduced for the first time in the mid-1980s. The largest applications of CNMs in medicine have been found for fullerenes, graphene oxide (GO), carbon nanotubes (CNTs) and carbon dots (CDs). CNMs can be classified based on their dimensionality. 0D carbon nanomaterials include CDs and fullerenes, which can be defined as hollow cages and quasi spherical NPs, respectively. The 1D group involves cylinder-shaped CNTs, whereas graphene is a 2D structure. CNMs contain carbon atoms in g in PDT . Furtherg in PDT . In receg in PDT . Among tg in PDT .Significant advances in the field have been made in the last few years . MultifuAnother interesting study was provided by Zheng et al. . The autDOX loaded fullerene NPs, containing polymeric shell with tumor targeting NGR peptide were also tested against 4T1 breast cancer cells. The fullerene-based nanoplatform, with switch on/off properties, allowed for burst chemotherapeutic release after 532 nm laser irradiation. In vitro studies confirmed the impact of the peptide for enhanced targeting, resulting in 42% cell death after laser irradiation in comparison with only 20% obtained with the non-targeted counterpart. Moreover, after systemic administration, NP accumulation in the tumor area was 7.4-fold higher than that obtained with the non-targeted CDs. Reduced accumulation in heart and kidneys and decreased side effects were observed .Metals and metal oxides have been introduced to the field of medicine as potential composites for electron microscopy and drug delivery . The hisMOFs can be defined as hybrid and crystalline constructions of metal ions clusters coordinated by multifunctional organic ligands/linkers. Due to their versatile properties regarding size, morphology, biodegradation and chemical composition, MOFs have found a very broad spectrum of applications, such as for targeted drug delivery ,289. A fTumor selectivity is widely regarded as an essential consideration in the development of any new cancer treatment and PDT is no exception. Indeed, the clinical application of PDT is often limited by the PS’s inability to preferentially accumulate in the tumor. As a consequence, side effects, such as severe skin photosensitivity, may be developed, ultimately leading to reduced quality of life for the patient. As discussed in this review, targeting ligands that are recognized and internalized by receptors overexpressed on cancer cells and/or other cells of the tumor microenvironment are being used as an attempt to enhance tumor selectivity. Despite promising, this strategy often fails to meet full expectations. This is likely explained by the high dependence of active targeting (like passive targeting) on the EPR effect to effectively reach the tumor cells. Additionally, the use of standard 2D monolayer cell cultures for in vitro testing of active targeting strategies may provide a limited view of in vivo potential. Thus, 3D cell cultures that better mimic the tumor microenvironment complexity might be a valuable tool to be explored when bridging results from 2D cell culture and in vivo experiments . In addiDespite these limitations, active targeting continues to be a promising and advantageous approach to promote effective internalization of the PSs into the targeted tumors cells. Thus, to realize the full potential of active targeting, research efforts must continue towards the development of new and improved targeting ligands with multi-targeting abilities and trans-tissue transport abilities. Along with better formulations for systemic administration of PSs, such improvements are expected to promote specific and enhanced PS tumor accumulation accompanied with internalization by different cells of the tumor microenvironment.


On February 7, 2020, this report was posted online as an MMWR Early Release.In December 2019, a cluster of cases of pneumonia emerged in Wuhan City in central China’s Hubei Province. Genetic sequencing of isolates obtained from patients with pneumonia identified a novel coronavirus (2019-nCoV) as the etiology , clinical information, epidemiologic risk factors, and 2019-nCoV test results. To allow for delays in specimen shipping and testing, data for PUIs for whom an initial inquiry was received during January 2020 were collected through February 4, 2020.During January 2020, approximately 30 CDC physicians and nurses responded to inquiries regarding approximately 650 persons. Testing was recommended for 256 persons  across 3All 210 persons who were tested were symptomatic: 143 (68%) had subjective fever or a measured temperature ≥100.4°F (≥38°C), and 189 (90%) had cough or shortness of breath. Upper respiratory tract symptoms  were common and were present in nine persons who did not have cough or shortness of breath. Thirty persons were reported to test positive for another respiratory viral pathogen, including influenza or respiratory syncytial virus. Forty-two (20%) patients were hospitalized, and four (2%) were admitted to an intensive care unit. One patient was deceased at the time of notification; testing for this person was negative, and an alternative cause of death was established. Travel-related risk was identified for 148 (70%) persons, 42 (20%) had close contact with ill patients with laboratory-confirmed 2019-nCoV infection or PUIs, 18 (9%) had both travel- and contact-related risks, and two (<1%) had possible contact with a laboratory-confirmed 2019-nCoV patient and were therefore tested.Among the 210 persons tested, 11 (5%) were found to have 2019-nCoV infection. Nine of these persons had traveled to Wuhan City; two persons had not traveled but had been in close contact with patients with laboratory-confirmed 2019-nCoV in the United States. All were symptomatic with fever (subjective or measured) or cough.Quickly identifying persons at risk for 2019-nCoV is critical to slowing the potential spread of 2019-nCoV in the United States. This report describes CDC’s current approach to facilitating recommended diagnostic testing of persons who might have 2019-nCoV infection. In response to the emergence of 2019-nCoV in China during a time of rapidly evolving understanding of the epidemiology and clinical presentation of 2019-nCoV infection, CDC has provided consultation regarding persons suspected of being at risk for 2019-nCoV to public health officials and health care providers throughout the United States.Epidemiologic risk factors among the 210 persons tested for 2019-nCoV were not limited to travel: 20% of PUIs tested had not recently traveled to China but reported close contact with a person being evaluated for 2019-nCoV infection. Because person-to-person transmission is expected to continue, and as further travel restrictions are implemented, it is likely that the proportion of PUIs with such contact risk in the United States will increase among all persons evaluated for 2019-nCoV.CDC mobilized early in the response and state and local health departments similarly increased capacity to provide clinical consultation regarding 2019-nCoV. The collection of clinical and epidemiologic data that described characteristics of persons tested for 2019-nCoV helped to inform changes to criteria for PUI evaluation.On January 31, 2020, CDC published updated PUI guidance  infection, CDC provided consultation to public health officials and health care providers evaluating persons at risk for 2019-nCoV infection.During January 2020, CDC responded to clinical inquiries regarding approximately 650 persons in the United States and tested 210 for 2019-nCoV, one fifth of whom reported no recent travel-related risk but had close contact with a 2019-nCoV patient or a person under investigation for 2019-nCoV in the United States.Health care providers should remain vigilant regarding possible 2019-nCoV exposure not only among returning travelers, but also among persons in close contact with 2019-nCoV patients in the United States.


Biomarkers in cerebrospinal fluid (CSF) are useful in the differential diagnosis between frontotemporal dementia (FTD) and Alzheimer’s dementia (AD), but require lumbar puncture, which is a moderately invasive procedure that can cause anxiety to patients. Gradually, the measurement of blood biomarkers has been attracting great interest. Testing blood instead of CSF, in order to measure biomarkers, offers numerous advantages because it negates the need for lumbar puncture, it is widely available, and can be repeated, allowing the prediction of disease course. In this study, a systematic review of the existing literature was conducted, as well as meta-analysis with greater emphasis on the most studied biomarkers, p-tau and progranulin. The goal was to give prominence to evidence regarding the use of plasma biomarkers in clinical practice. Frontotemporal dementia (FTD) is a heterogeneous group of related conditions resulting from neurodegenerative disorders in the frontal and/or anterior temporal lobe of the brain . Clinica(MAPT)-gene on chromosome 17, granulin (GRN)-gene on chromosome 17, and chromosome 9 open reading frame 72 (C9orf72)  [FUS), TAR DNA-binding protein (TARDBP), integral membrane protein 2B (ITM2B) and tank-binding kinase 1 (TBK1) and TATA box binding protein (TBP), sequestosome 1 (SQSTM1), ubiquilin 2 (UBQLN2), coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10), optineurin (OPTN) and cyclin F (CCNF). These rare mutations account for less than 5% of all FTD mutations and can be found in a limited number of families worldwide [FTD is the third most common cause of neurodegenerative dementia, following Alzheimer’s disease (AD) and dementia with Lewy Bodies, and represents up to 20% of dementia cases of adults under 65 years old . About 3orldwide .MRI), resting state functional MRI, 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET) and 99mTechnetium-hexamethylpropanolamine oxime single photon emission computed tomography (HMPAO-SPECT), may be helpful in the diagnostic process [The differential diagnosis of frontotemporal dementia can be a real challenge. Neuroimaging, including magnetic resonance imaging , 2 studies referred to transactive response DNA binding protein 43 (TDP-43), and 3 studies referred to glial fibrillary acidic protein (GFAP).From the initial research of 604 results, 25 studies met the inclusion criteria. Additionally, 18 more articles, found as references from the included studies, were used in the qualitative synthesis of the review . From th2 and X2 were also reported, I2 was the most important measure of heterogeneity . For publication bias, a funnel plot was created (Trim and Fill method), and Egger’s regression was performed by Meta-Essentials 1.5 (2020) [Meta-analysis was performed following the random effects model with DerSimonian–Laird method, as performed by the RevMan software . Althoug5 (2020) . Sensiti5 (2020) . However5 (2020) .Fluid biomarkers in frontotemporal dementia are measured in CSF and blood (plasma or serum). They can be used in differentiating FTD from Alzheimer’s disease (AD) or even identifying presymptomatic patients of familial cases. In CSF, neuronally derived molecules can be found at higher concentrations compared to blood. Blood, on the other hand, has increasingly attracted interest as a more accessible fluid alternative. Apart from diagnosis, blood biomarkers may be used as a screening tool for families of patients with familial FTD or to assess the effectiveness of a potential treatment .Neurofilament light chain protein (NfL) has been measured in many studies as a CSF biomarker of FTD cases , and hasRegarding studies measuring NfL in the different genotypes of FTD , NfL levels in patient-carriers are elevated compared to both the presymptomatic carriers and control groups . Among tStudies display higher blood NfL levels in FTD patients and a correlation between serum levels of NfL and brain atrophy, suggesting longitudinal NfL measurements for mutation carrier identification and for disease progression , and sugAnother biomarker that has been studied both in CSF and in blood is TDP-43. Cytoplasmic neuronal and glial inclusions of TDP-43 are commonly found in certain histological forms of frontotemporal lobar degeneration (FTLD), known as FTLD-ubiquitinated (FTLD-U), which are clinically expressed as FTD variants . The exiGlial fibrillary acidic protein (GFAP) is a measure of astrogliosis and has been used in many studies as a potential biomarker. Although the initial studies did not reveal encouraging results, one study of plasma GFAP in FTD-gene variants revealed an increased level of GFAP in GRN-mutation carriers than C9orf72 or MAPT mutations, and a significantly higher concentration in the symptomatic GRN mutation carriers versus the presymptomatic . Among tPlasma tau has been measured in many studies. Increased plasma total tau levels may be linked with cognitive impairment, but it is not related to AD or FTD . A studyProgranulin is a glycoprotein coded by the GRN gene, on the chromosome 17q21. Among the most frequent genetic causes of FTD are the GRN mutations . They arAccording to the literature, low levels of plasma progranulin can be used as an accurate method to discriminate GRN carriers from control groups with a very high sensitivity and specificity. Studies suggest different levels of blood progranulin as a cut-off in discriminating GRN mutations, with a more recent study rising the threshold level to 71.0 ng/mL.Plasma progranulin levels have a wide range both in control groups and patient groups, leading to the question of whether other factors may contribute to regulating progranulin levels. Some studies suggest gender being a modifying factor, which has not been statistically proven. Age and body mass index do not influence plasma levels. On the other hand, autoimmune diseases, diabetes , cancer The differential diagnosis of FTD compared to AD has been based on the CSF biomarkers of Aβ42, total tau and p-Tau. In an effort to make biomarkers more accessible for clinical practice, apart from plasma total tau, blood p-Tau has also been studied in cognitive impaired patients . PhosphoOther molecules that have been investigated as possible biomarkers include cytokines and chemokines, synaptic markers, and micro-RNA. Proinflammatory interleukins (ILs), such as IL-6 in plasma , IL-8 5 or IL-15As already mentioned, the purpose of this study was to investigate biomarkers that may be useful in everyday clinical practice. For this reason, our meta-analysis focused on biomarkers that could be used as a differential tool of FTD vs. AD, or among genetic FTD subtypes. Therefore, only the studies of progranulin and p-Tau were processed with statistical analysis. Data from the existing studies of the other biomarkers did not fulfill our purpose.2 = 0.81), although all studies agreed that GRN mutations resulted in lower levels of plasma progranulin. Most of the studies measured progranulin by ELISA kits provided by Adipogen Inc  [p = 0.373).Furthermore, meta-analysis was conducted for studies regarding plasma progranulin levels in carriers of GRN mutations vs. FTD with no GRN mutation or controls. Only one study containing familial cases was included . Throughh Korea) ,45,46,47h Korea) ,44 and Bh Korea) , did not2 = 0.68), although all studies agreed that AD showed higher p-Tau181 levels as compared to FTD. Sensitivity analysis showed that removal of the fourth study . The random effects model was used, indicating that patients with AD have significantly higher levels of p-Tau181 as compared to FTD a. Moderapulation ), also rA number of studies show promising results in using blood biomarkers for the  diagnostic workup of patients with FTD in everyday practice. As a result, it is worth exploring whether these biomarkers could be utilized in the treatment decision process.As already mentioned, NfL levels have been correlated to disease severity and brain atrophy. Monitoring NfL levels in patients with FTD as the disease progresses as well as comparing NfL levels among FTD patients of different stages may lead to the future recognition of NfL as a useful biomarker not only for the differential process of FTD but also for the disease intensity.TDP-43 has also been suggested as a potential biomarker for the discrimination of patients with FTD or AD with TDP-43 pathology from those without TDP-43 pathology, but the existing evidence is insufficient. Measuring blood TDP-43 may not be useful in differentiating different types of dementia but may become valuable if TDP-43-based treatments become available.In addition, GFAP seems to be a potential biomarker of FTD patients, especially for GRN mutation carriers. Given the fact that the symptomatic GRN mutation carriers have higher concentration levels versus presymptomatic patients, GFAP could provide a prognostic tool to symptom onset.Progranulin levels in blood have been assessed in patients with FTD carrying the GRN mutations, patients with FTD without GRN mutations, and in control groups. Furthermore, progranulin levels in GRN mutation carriers are significantly lower compared to both non-carriers and the control group, making progranulin a useful biomarker in discriminating GRN mutation carriers. There is also much evidence that this protein could be used instead of molecular genetic analysis to discriminate GRN carriers from non-carriers in families with FTD patients.Different cut-off levels are proposed from the studies, with the most recent proposing a threshold of 71ng/mL. Although there are studies displaying indications about gender influence on the progranulin level, this has not been statistically supported.From the current studies, patients with AD have increased p-Tau levels compared to both the FTD patients and the control group. Comparing subjects with cognitive impairment—both FTD and AD groups—to control groups, a weak correlation of cognitive impairment to p-Tau levels was observed. Moreover, mean values of p-Tau were higher in the cognitive-impaired groups compared to control groups, but among the cognitive impaired subjects only AD patients had significantly higher p-Tau levels. This evidence suggests that p-Tau could be a useful tool in differentiating FTD from AD. p-Tau217 may have higher accuracy than p-Tau181, but more research needs to be conducted.There is a great variety of blood biomarkers studied in FTD, some more promising than others. The future in biomarkers is finding sensitive molecules that will differentiate the FTD variants, predict disease intensity, or even assist the treatment choice. More trials with larger sample collection are yet to be performed in order to fulfill this purpose.


Some studies have reported the association between maternal serum lipid profile abnormalities and pre-eclampsia. However, many studies have reported controversial results. Hence, this systematic review and meta-analysis was planned to generate summarized evidence on the association between maternal serum lipid profiles and pre-eclampsia in African women.Four electronic databases such as; PubMed, Hinari, Google Scholar, and African Journals Online were searched for studies published in English. Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument and Newcastle-Ottawa Scale were used for data extraction and quality assessment of the included studies. The meta- regression analysis was performed by Stata 14 software. The standardized mean difference (SMD) values of lipid profiles were computed to assess their association with pre-eclampsia at 95% CI.In this review a total of 15 observational studies were included. The mean values of triglyceride (TG), total cholesterol (TC), low density lipoprotein- cholesterol (LDL-c) and very low density lipoprotein- cholesterol (VLDL-c) were significantly higher in pre-eclamptic women as compared with normotensive pregnant women , respectively. The serum high density lipoprotein cholesterol (HDL-c) level was lower, but it is not statistically significant (HDL-c = 51.02 ± 16.01 and 61.80 ± 25.63) in pre-eclamptic women as compared with controls. The pooled standardized mean difference (SMD) of TG, TC, LDL-C and VLDL-C were significantly increased in pre-eclamptic women as compared with normotensive pregnant women with the SMD of , TC = 0.84 , LDL-C = 0.95  and VLDL-C = 1.27 ) at 95% CI, respectively, but the pooled SMD of HDL-cholesterol was decreased in pre-eclamptic women as compared with normotensive pregnant women .In this review, the maternal serum levels of TG, TC, LDL-c and VLDL-c were significantly associated with the risk of preeclampsia. However, HDL- cholesterol was not significantly associated but it was lower in pre-eclamptic women. Further, large scale prospective studies should verify these outcomes and it is recommended that lipid profiles should be included as a routine diagnostic test for pre-eclamptic women. Pre-eclampsia is a pregnancy related metabolic syndrome characterized by hypertension and proteinuria occurred after 20 weeks of gestation. It is the most common cause of maternal and prenatal morbidity and mortality . The cauEarly pregnancy dyslipidemia is associated with an increased risk of pre-eclampsia . In the Different studies have tried to elucidate the association between the maternal serum lipid profiles and pre-eclampsia, but many of them have reported conflicting results. Some studies have shown higher levels of lipid profiles in pre-eclamptic women as compared to normotensive pregnant women , 11–13. https://www.crd.york.ac.uk/prospero/#recordDetails).This review protocol is registered at the National Institute for Health Research; PROSPERO international prospective register of systematic reviews with registration number CRD42020192865 at  guideline was utilized to conduct this systematic review and meta-analysis.A systematic review and meta-analysis of published studies was conducted to assess the association between maternal serum lipid profiles and risk of pre-eclampsia in African pregnant women. We searched for the following databases: PubMed, Hinari, African Journals Online (AJOL) and Google Scholar. The search was done by using the following Medical Subject Heading (MeSH) terms; “Lipids, Triglycerides, Cholesterol, HDL, VLDL, LDL, Pre-eclampsia and AfricaInclusion and exclusion criteria;Studies conducted on human subjects were included.Studies with case-control, cross-sectional and cohort designs in Africa were included.Articles that report pre-eclampsia as an outcome variable were included.Published and unpublished articles written in English were included.Studies considering lipid profiles as the determinant variable and reporting the result in mean and standard deviation were included.Studies conducted in the community or in the health institution were included.Conference papers, editorials, reviews and randomized control trials were excluded.All citations identified by our search strategy were exported to EndNote -X9- and duplicate articles were removed. And then the titles and abstracts of the identified articles were screened by two independent reviewers, and eligible studies were included for further review. The full texts of selected articles were retrieved and read thoroughly to ascertain the suitability prior to data extraction. In case of disagreement between the two reviewers, discussion was held to reach consensus and the third reviewer was consulted. The search process was presented in PRISMA flow chart that clearly shows the studies that were included and excluded with reasons of exclusion  16]..16].The primary outcome of this study is to evaluate the association between maternal serum lipid profiles with the risk of pre-eclampsia in African pregnant women.Hypertension is defined as the systolic blood pressure ≥140mmHg and/or diastolic ≥90mmHg that are measured at least two times within four hours interval.+ on qualitative dipstick examination or a total protein: creatinine ratio ≥30 mg/ mmol (or ≥0.3 when both are measured in mg/dL).Proteinuria: urinary protein excretion of ≥300mg /24-h urine sample or ≥1Gestational hypertension: hypertension diagnosed after 20 weeks of gestation.Pre-eclampsia is defined as hypertension plus proteinuria after 20 weeks of gestation.Eclampsia: Seizures in women with hypertension that cannot be attributed to other causes .For case-control and cohort studies, we used Newcastle-Ottawa Scale (NOS) to assess the quality of the included studies while for cross sectional studies the modified version of NOS was used to assess the quality of the studies for inclusion . The NOSn. Lipid profiles measured in mmol/L was converted into mg/dL by multiplying their conversion factors. For few studies that didn’t report VLDL value we estimated from TG level by dividing into five.The data extraction was done using a tool developed by the 2014 Joanna Briggs Institute Reviewers’ Manual data extraction form . The absThe data were entered into Microsoft excel and the meta-analysis was performed using Stata 14 software and SPSS version 20. Forest plot of standardized mean difference (SMD) were used to assess the effect size between the serum levels of lipid profiles and pre-eclampsia at 95% CI. The SMD is the ratio of the mean difference to the pooled standard deviation. Standard error of mean (SEM) was also computed by dividing standard deviation to the square root of the sample size. Subgroup analysis was done by country . Variables including; maternal age, gestational age, BMI, mean lipid profiles were assessed through paired sample test to know their difference among pre-eclamptic and normotensive pregnant women.2 statistic and P-value. If I2 statistic values < 25%, 25–50%, and ≥50% were used to declare the heterogeneity test as low, medium and high, respectively. In this review, a random effect model (REM) was used for analysis. To cope with the reasons of high heterogeneity subgroup analysis and sensitivity test were performed. Publication bias was assessed through funnel plot and Egger’s test.Statistical heterogeneity was estimated through Cochrane Q, IA total of 537 articles were retrieved through electronic search by using different search terms of which 454 article were eligible for title and abstract assessment after removal of 83 duplicate records. Out of 454 articles screened for eligibility 414 records were excluded after assessing their title and abstract. A total of 40 articles underwent full- text assessment, 25 studies were excluded due to different reasons (21 articles were done outside the study area and four articles didn’t report outcome variable).In this review a total of 15 studies were included. Ten of them were case-control and three studies were Cross-sectional and the other two were cohort. Studies that have been conducted in Africa up- to July 30, 2020 were included. Ten studies were conducted in Nigeria and the other three and two studies were conducted in Ghana and Egypt respectively. In this review a total of 2,106 pregnant women were included  .In this analysis, we compared the mean values of variables among preeclamptic and normal pregnant women. Statistical significant difference was not observed between the two groups in regards to the mean values of maternal age, and gestational age. However, statistical significant difference were observed in the mean values of systolic blood pressure (SBP), diastolic blood pressure (DBP), TC, TG, LDL-C and VLDL-C levels between preeclamptic and normotensive pregnant women .In this sub-categorical analysis 15 studies were included to compare the serum levels of total cholesterol between pre-eclampsia and normotensive pregnant women –31. EighIn this sub-categorical analysis 15 studies were included to compare the serum triglyceride levels between pre-eclamptic and normotensive pregnant women –31. ThirIn this sub-categorical analysis 15 studies were included to compare the serum HDL-c levels between pre-eclamptic and normotensive pregnant women –31. NineIn this sub-categorical analysis 15 studies were included to compare the serum LDL-cholesterol levels between pre-eclamptic and normotensive pregnant women –31. NineIn this sub-categorical analysis 15 studies were included to compare the serum level of VLDL-c between pre-eclampsia and normotensive pregnant women –31. TwelA sensitivity test was done by omitting one study at a time to assess the stability of the results. There was no significant change in the pooled SMD after excluding one of the studies at 95% CI. This means there is no individual study that excessively influences the pooled effects of the serum lipid profiles in pre-eclamptic women . Due to This study is the first systematic review and meta-analysis in African pregnant women which provides information on the association of maternal serum lipid profiles with pre-eclampsia. In this study, maternal age and gestational age were comparable between the two groups and these variables didn’t show a statistical significant association with pre-eclampsia. The mean BMI, systolic and diastolic blood pressure measurements were significantly different among pre-eclamptic and normotensive pregnant women.The cause of pre-eclampsia is not well understood but it is believed that reduced uteroplacental perfusion as a result of abnormal spiral artery remodeling causes the disease. Placental ischemia causes an increased synthesis of endothelin, thromboxane and different chemical mediators which affects the endothelium and resulted maternal syndromes . It is aIn this review, we found that the mean serum total cholesterol level was significantly higher in preeclamptic women as compared to normotensive pregnant women (221.84 ± 47.61 and 190.43 ± 40.55), respectively and its pooled SMD was . Similar results were reported in the studies conducted in China and India , 37. TheThe mean serum triglyceride level of the current study was significantly higher in preeclamptic women than normotensive pregnant women (228.04 ± 91.38 and 145.67 ± 121.61), respectively and its pooled SMD was . Similar, findings were reported in the studies conducted in China and Pakistan , 38, 39.In this review, we found that the mean serum HDL-c level was lower in preeclamptic women as compared to normotensive pregnant women (51.62 ± 16.44 and 62.74 ± 26.33), respectively and its pooled SMD was . Similar findings were reported in the studies conducted in Nigeria and China , 36. RepIn the current study, we found that the mean serum LDL-cholesterol level was significantly higher in preeclamptic women than normotensive pregnant women (139.12 ± 34.38 and 116.43 ± 33.77), respectively and its pooled SMD was . Similar, evidences were reported in the studies conducted in China, Bangladesh and Nigeria , 36, 46.In this review, we found that the mean serum VLDL-cholesterol level was significantly higher in preeclamptic women than normotensive pregnant women (40.81 ± 20.26 and 26.18 ± 7.96), respectively and its pooled SMD was ). Similar finding were reported in the studies conducted in China and Nigeria , 36. VLDThis systematic review and meta-analysis generated pooled data showing lipid profiles and risk of pre-eclampsia in African women. In addition, this review serves as baseline information for further study.The search strategy was limited to articles published in English, and this could lead to reporting bias. We include small number of studies and most of them were from Nigeria, and this may influence its generalizability to African women. Moreover, presence of high statistical heterogeneity among the included studies would decrease the generalization of evidence from this review.In this systematic review and meta-analysis the mean serum lipid profiles were significantly higher in pre-eclamptic women than in normotensive pregnant women. The pooled standardized mean difference of serum lipid profiles such as: total cholesterol, triglyceride, LDL-cholesterol, and VLDL-Cholesterol were significantly higher in pre-eclamptic women than normotensive pregnant women but HDL-cholesterol was lower in preeclamptic women. Thus, we conclude that dyslipidemia could play certain roles in the pathogenesis of pre-eclampsia. However, concrete evidence on the roles of dyslipidemia in pre-eclampsia in African pregnant women should require large scale prospective studies.S1 Checklist(DOC)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(DOCX)Click here for additional data file.S4 File(DOCX)Click here for additional data file.


Frailty is increasingly recognized as a better predictor of adverse postoperative events than chronological age. The objective of this review was to systematically evaluate the effect of frailty on postoperative morbidity and mortality. Studies were included if patients underwent non-cardiac surgery and if frailty was measured by a validated instrument using physical, cognitive and functional domains. A systematic search was performed using EMBASE, MEDLINE, Web of Science, CENTRAL and PubMed from 1990 - 2017. Methodological quality was assessed using an assessment tool for prognosis studies. Outcomes were 30-day mortality and complications, one-year mortality, postoperative delirium and discharge location. Meta-analyses using random effect models were performed and presented as pooled risk ratios with confidence intervals and prediction intervals. We included 56 studies involving 1.106.653 patients. Eleven frailty assessment tools were used. Frailty increases risk of 30-day mortality  and 30-day complications . Risk of 1-year mortality was threefold higher . Four studies (N=438) reported on postoperative delirium. Meta-analysis showed a significant increased risk (RR 2.13 [95% CI 1.23-3.67). Finally, frail patients had a higher risk of institutionalization . Frailty is strongly associated with risk of postoperative complications, delirium, institutionalization and mortality. Preoperative assessment of frailty can be used as a tool for patients and doctors to decide who benefits from surgery and who doesn’t. Life expectancy has increased with the focus on the quality of added life-years . This prSeveral studies have described age as an independent risk factor for postoperative morbidity and mortality in both cardiac and non-cardiac surgery -7. AdvanRecently the concept of frailty has come into view . FrailtyIn order to adequately inform our patients of significant perioperative risks, additional information on frailty as a risk factor influencing postoperative outcome is essential. During the preoperative assessment, this information can guide the clinician in shared decision making on whether the older patient benefits from surgery or not. The aim of this study was to evaluate the predictive role of frailty on postoperative outcomes after non-cardiac surgery by conducting a systematic review and meta-analysis of literature.A search of literature was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement and MOOSE criteria . The objTwo reviewers independently (EKMT and JMKvF) screened potentially relevant articles from the initial search, first by title and abstract and later on by full text. Any disagreements between the two reviewers were resolved by discussion and consensus with a third reviewer (SH). Studies were found eligible for inclusion if their subjects underwent non-cardiac surgery and if frailty was measured by a frailty instrument using at least physical, cognitive and functional domains. Also, the relationship between frailty and primary outcomes of 30-day mortality, or 30-day complications should be evaluated, with stratification of the outcome (frail versus non-frail). Studies were excluded if they were review articles, case reports, editorials or comments, or if full text was not available. Duplicate articles were removed during the initial search.The following data were gathered from eligible publications: publication date, study design, sample size, type of surgery, proportion of females, mean age, the frailty score and outcome. Outcome was measured by the following adverse events: 30-day mortality, 30-day complications, one-year mortality, manifestation of postoperative delirium (POD) and discharge to a specialized facility. 30-day complications are generally defined as suggested by the Clavien-Dindo classification system; otherwistudy participation (i.e. the study sample represents the population of interest on key characteristics), second study attrition (i.e. whether the study was able to obtain a complete follow up), third prognostic factor measurement (i.e. a clear definition or description of the prognostic factor measured is provided), fourth outcome measurement(i.e. a clear definition of the outcome of interest), fifth confounding measurement and account  and sixth analysis. After the evaluation of these six areas of potential bias, all studies were subsequently divided According to the Quality in Prognosis Study Tool into good (11 or 12 points), fair (9 or 10 points) and poor (< 9 points) quality.Two reviewers performed assessment of quality. In case of disagreement a third reviewer was consulted. The quality assessment tool for prognosis studies as proposed by Hayden et al. was used for the appraisal of all included studies . This to2 statistic was calculated, which is the percentage of variation across studies due to heterogeneity rather than random error. Since all reported outcomes were adverse events, a positive relative risk indicates that frailty is associated with worse patient outcome. A meta-regression analysis was carried out to assess the influence of the patient’s mean age (using mean or median age of the study populations as a proxy) on 30-day mortality. Finally, an additional sensitivity analysis was performed (excluding studies using ACS-NSQIP database) to circumvent the issue of possible duplicate cases and demonstrate the effect of frailty on postoperative outcome.Numerical values reported by the studies were used for analysis. In some cases, further calculation was required for ascertaining outcomes. In the studies using the modified frailty index (mFI) patients were categorized into two groups: “not frail” (mFI < 0.27), or “frail” (mFI ≥ 0.27). The decision to divide patients into those categories was based on thresholds most commonly used to indicate the presence of frailty and was made before analysis. In the remaining studies, using ten different frailty instruments, outcome was also dichotomized according to predefined criteria as “not frail” or “frail”. Random effects models for meta-analysis were used because of the large expected heterogeneity in determinant and other study characteristics. The primary outcome measures 30-day mortality and 30-day complications were stratified by frailty score. Furthermore, a subanalysis per surgery type was performed to better understand the effect of frailty according to the surgical risk category. Effect estimates are presented as pooled risk ratios (RR) with 95% confidence intervals (CI’s). Robust meta-analytic conclusions of prognosis studies will be more appropriately signaled when prediction intervals are provided . Thus, tData gathering and data analysis was performed using Excel (version 14.7.2) and Rstudio (version 1.1.463) respectively.Initial literature search identified 2117 manuscripts as potentially relevant. Of these, 1904 were excluded due to unrelated research questions or study type. Full text was not available in one study; therefore 212 full text articles were thoroughly screened for eligibility. A total of 56 studies were found suitable for this systematic review. A total of eleven different frailty assessment tools were used. The majority of studies (twenty-four) used the Modified Frailty Index (mFI), created by Saxton and Velanovich . The mFIThe quality assessment of the included studies is provided in Stratified for frailty assessment tool, the association of frailty and 30-day mortality was observed according to the ACG frailty-defining diagnosis indicator, Fried frailty criteria, Frailty-based Risk Analysis Index and the Modified Frailty Index.Stratified per surgical risk category, pooled RR’s for 30-day mortality were 2.75 [95% CI 2.48-3.05] for high-risk surgery (4 studies), RR 4.79 [95% CI 3.42-6.70] for intermediate-risk surgery (18 studies) and RR 3.06 [95% CI 2.35-3.97] for mixed surgical population (8 studies). The association of frailty and the primary outcome 30-day complications was also stratified per surgical risk category and again a positive relationship was observed with pooled RR’s of 1.62 [95% CI 1.43 -1.82] for high-risk surgery (3 studies) and RR 2.94 [95% CI 2.44-3.54] for intermediate-risk surgery (24 studies).Six studies investigated the association between frailty and one-year mortality . In mostA meta-regression analysis investigating showed no influence of age on primary outcome. Finally, to circumvent the issue of possible duplicate cases, the additional sensitivity analysis excluding studies using ACS-NSQIP database, showed an overall pooled RR of 3.62 [CI 95% 2.21-5.92]  for 30-day mortalitySince life expectancy keeps rising, the number of frail patients being offered for surgical treatment will dramatically increase. Frail patients are vulnerable and may excessively decompensate after stressors such as surgery, because of their lack of physiological reserve .In this systematic review and meta-analysis, we found frailty to be a strong predictor of post surgical complications, delirium, institutionalization and all-cause mortality. After reviewing fifty-six articles, 30-day mortality shows the strongest association with preoperative frailty with almost 4 times increased risk.Our results are congruent with several other reviews investigating the effect of frailty on postoperative outcome. -30 HowevThe strength of the present study is the extensiveness of the search, the inclusion of different validated frailty scores and the inclusion of different types of non-cardiac surgery, both elective and acute. The quality of this meta-analysis is dependent on the quality of the studies reviewed. Of all studies included 95% were of at least fair quality, with more than half assessed as good quality. Ninety-one percent of all studies were prospectively designed.Recently, relevant developments have been made towards methodological frameworks, in order to improve the reliability and applicability of prediction studies . AlthougThe studies in this review and meta-analysis describe eleven different frailty assessment tools. Moreover, the surgical procedures included could basically be divided into six different groups, which will have contributed to the heterogeneity. Heterogeneity, as assessed with I2, t2, Cochran’s Q and prediction intervals, was estimated as a high degree of statistical heterogeneity. Importantly, the association between frailty and outcome seems robust throughout the reviewed articles regardless of the frailty assessment tool used. Furthermore, prediction intervals of 30-day mortality, one-year mortality and postoperative discharge location showed exclusion of the null value, which strengthens our findings.A plausible explanation may be the fact that frailty was consistently measured by instruments using physical, cognitive and functional domains. Studies using only measurements of body composition or patients’ phenotype, such as sarcopenia, hypoalbuminemia or cachexia were not included, as these studies did not use an established frailty assessment tool. The frailty instrument used in most studies was the modified frailty index (mFI), which has been validated as a reliable assessment tool in several studies -36. It sLimitations of this study are those commonly seen with systematic reviews and meta-analysis. Hence, the results of this review and meta-analysis should be interpreted with caution. Besides the heterogeneity, another possible limitation is a variation among studies in the definition of discharge location. Despite these small differences, ten studies confirm that frail patients, when compared to healthier counterparts, struggle to return to their own home. Unfortunately, in many countries, availability of beds and nursing staff in specialized facilities are a topic of current concern. To overcome this limitation the need for rehabilitation or nursing home placement was defined as “not able to return home”. Comparable heterogeneity was found within the definition of postoperative complications. Although most authors defined 30-day complications as suggested by the Clavien-Dindo classification system, others used the American College of Surgery National Surgical Quality Improvement Program definition, or other standardized complication definitions. It should be recommended that future studies in the area of frailty use a standardized postoperative complication definition as this might create a more accurate comparison. The International Consortium for Health Outcomes Measurement (ICHOM) recently developed the first global standard set of outcome measures in older persons. Their effort towards standardization of outcome measures can possibly improve care pathways and quality of care .Although we have performed an exhaustive literature search, the broad scope of our research question could have resulted in the omission of some studies.Many studies in this systematic review and meta-analysis are observational registry studies, but several studies have derived their outcomes from clinical trials. Since many studies have used the ACS NSQIP database, there may be studies, which are double counted from the same cohort of patients. However, In a previous study we have found that the occurrence of postoperative complications is an important prognostic factor of late mortality . EffortsPreoperative identification of frail patients provides an opportunity for prehabilitation, which subsequently may lead to reduced postoperative morbidity. Besides prehabilitation, regionalization in health care might improve surgical outcome in complex oncological surgery. Regionalization is about enabling appropriate allocation and integration of health resources, focusing on the local populations needs. Frail patients may benefit from high-volume hospitals with high-volume surgeons in so called centers of excellence .This study demonstrates that the presence of preoperative frailty increases the risk of adverse outcome after non-cardiac surgery. It should be noted that heterogeneity of the frailty scores is high, but associations with postoperative outcome are robust. Frailty status should be considered to be part of the preoperative screening, at least in patients who seem to have a lack of physiological reserve. Identification of potentially reversible health deficits is important, as may provide an opportunity to optimize patients’ clinical condition prior to surgery. Conversely, irreversible frailty should be taken most seriously, as it can guide both clinician and patient in their decision making on whether the patient benefits from surgery or not.www.aginganddisease.org/EN/10.14336/AD.2019.1024.The Supplemenantry data can be found online at:


A new slim modiolar electrode (CI532/632) has been reported to ensure better modiolar proximity than conventional electrodes. Better modiolar proximity has been proposed to yield better electrode discrimination capability and potentially better speech outcomes, necessitating its efficient measurement. Currently, intracochlear positional index (ICPI), the most reliable indicator for evaluating modiolar proximity, has been measured exclusively through ‘metal artifact-less’ cone beam CT. However, popular use of this index is precluded due to lack of cone beam CT in many institutions. Thus, eyes are now on elucidation of easy-to-measure indicators of modiolar proximity derived from conventional CT, which is accessible in all centers. We observed that enhanced tomographic resolution significantly reduces partial volume artifacts, providing better visualization of modiolus-electrode distance. Aided by ultra-high kernel specification with high-resolution index, we developed a novel and easy-to-measure, conventional CT-specific indicator, “modified ICPI”, for evaluation of modiolar proximity. Further, we showed that it closely correlates with the previously proposed parameter of modiolar proximity, the spiral diameter, measured from post-insertion radiograph, reiterating the value of X-ray-based spiral diameter. Through this study, we have taken a step toward the stage of immediate visual feedback regarding modiolar proximity and changes in insertion technique intraoperatively, ensuring optimal modiolar proximity. For modiolar hugging electrodes, better auditory performance depends on the final intracochlear positioning of the electrode array, such as scalar location and modiolar proximity13. The slim modiolar electrodes have been reported to provide a consistently higher scalar tympani position than conventional perimodiolar electrodes14. In addition, 4.1–4.6% rate of tip-fold over has been reported in the literature14, but tend to gradually decrease with experience15. Thus, specifically for slim modiolar electrodes, degree of modiolar proximity may be one of the critical determinants of better auditory performance. Recently, cochlear implant recipients with slim modiolar electrodes  led to either similar or statistically superior audiological results compared with those with straight electrodes  strictly matched for age and preoperative hearing thresholds2. Furthermore, a growing body of evidence suggests that the enhanced modiolar proximity of slim modiolar electrodes would lead to improved place-pitch spectral discrimination16, and speech perception outcomes17, as compared with conventional perimodiolar electrodes. However, not all reports in literature fully support this phenomenon19, probably due to confounding variables such as heterogeneous degrees of modiolar proximity even with slim modiolar electrodes20. Indeed, better modiolar proximity has been proposed to attenuate the substantial overlap  in the electrical field between electrode contacts, resulting in better electrode discrimination capability21, and potentially better speech outcomes than conventional electrodes21. In addition, positioning of the electrodes close to the spiral ganglion neurons can reduce the effects of neural-electrode interaction by improving channel discrimination16, lowering threshold levels22, and reduction of power consumption23. Therefore, robust and efficient measurement of modiolar proximity is mandatory for slim modiolar electrodes which were designed to achieve the best modiolar proximity amongst all electrodes.The new slim modiolar electrodes  combine the slim electrode diameter of slim-straight electrodes and the modiolus-hugging feature of conventional perimodiolar electrodes. This new commercially available slim modiolar electrode ensures better modiolar proximity24. The wrapping factor has been suggested to be inversely correlated with the degree of modiolar proximity. However, the wrapping factor has been reported to yield an inconsistency to determine the relative relationship of the electrode array against the lateral wall between the cone-beam CT and the histologic finding, requiring a more accurate and refined radiological value for modiolar proximity25. Recently, intracochlear positioning of the electrode array in close proximity to the modiolus—with good modiolar hugging, as evidenced by the wrapping factor normalized or intracochlear positioning index (ICPI)25—would lead to better hearing outcomes for cochlear implantees with the slim modiolar electrodes.To date, there are different approaches to measure the electrode position relative to the modiolar wall distance. One of the widely accepted measurements is the wrapping factor to determine how the electrode array is located relative to the lateral wall27. Although a previous ex vivo study showed that the average electrode-to-modiolus distance value measured by two imaging modalities  was not different28, measurement of electrode-to-modiolus distance using conventional CT is not feasible due to metal artifacts blurring the region of interest. A recent study proposed the most reliable and finely tuned indicator reflecting the degree of modiolar proximity, called ICPI25, which was obtained exclusively through ‘metal artifact-less’ cone-beam CT. However, lack of such cone-beam CT in many institutions preclude widespread use of this index. Thus, eyes are now on the elucidation of easy-to-measure indicators of modiolar proximity derived from conventional CT that is accessible to all cochlear implantation centers.With the advent of cone-beam CT based on flat-panel volumetric technology, significantly better image quality enables clear delineation of the intracochlear electrode array with more definition of the fine osseous structures surrounding the temporal boneHerein, we observed that higher tomographic resolution significantly attenuates imaging blurring and enhances imaging sharpness, thereby enabling elaborate measurement of electrode-to-modiolus distance even in conventional CT. Aided by ultra-high kernel specification with a high-resolution index, we came up with a novel and easy-to-measure, conventional CT-specific indicator, modified ICPI, for evaluation of modiolar proximity. Further, we evaluated whether or not modified ICPI obtained from conventional CT correlates with the previously proposed parameter of modiolar proximity, the spiral diameter, measured from a post-insertion radiograph during or after the operation. If that is the case, simple X-ray would eventually be a nice substitute for conventional CT in terms of obtaining modiolar proximity and comparison of it just for practice within a single center. This should be the case especially for pediatric patients, where radiation matters. However, the role of ICPI obtained from conventional CT does not seem to swiftly wane, especially for comparison of the parameter across centers, especially for adults. Simple X-ray technique is not standardized across centers, precluding comparison of modiolar proximity values across centers. Therefore, CT measurement should not be underestimated as just an interim approach, but it would better regard the use of CT as a valuable independent approach per se. Collectively, these results offer otologists a novel and easy-to-calculate indicator for modiolar proximity through conventional CT and reiterates the value of X-ray-based measurement of the spiral diameter, enabling immediate visual feedback and changes in insertion technique intraoperatively, thereby ensuring optimal modiolar proximity.29. Only patients with 0.4 mm slice thickness on temporal bone CT and a high-resolution filter specification were included. Subjects with the following conditions were also excluded from this study: (1) history of explantation or reimplantation, (2) severe cochlear ossification, and (3) obvious cochlear anomalies on radiological images based on the classification of inner ear anomalies. Ultimately, a total of 30 recipients (33 ears) of CI532  or CI632  cochlear implants were enrolled. In our current study, two of 33 ears were implanted using the extended pull-back maneuver20, due to short cochlear duct length measured preoperatively. The study protocol and a waiver of consent for this retrospective chart review were approved by the review board of the Clinical Research Institute at Seoul National Bundang Hospital . All methods employed in this study were in accordance with the approved guidelines and the Declaration of Helsinki.We retrospectively reviewed cochlear implant recipients in whom slim modiolar electrodes, such as the CI532 or CI632, were implanted by a single surgeon (B.Y.C) using the round window approach, exclusively with the pull-back technique. Recently, the insertion technique that ensures better modiolar proximity, called the pull-back maneuver, has been introduced for slim modiolar electrodes, based on a human cadaveric temporal bone study30. All data were reconstructed using two sets of ultra-high resolution kernels with different resolution indices /cm; Ur81, 19.7 lp/cm). Importantly, no difference in effective dose was found between the two different filters (Uh59 vs. Ur81), as they are based on the difference in the reconstruction algorithm of the raw data obtained from the imaging scans, regardless of the scan parameters such as kVp and mAs in the conventional temporal bone CT.High-resolution temporal bone CT scans were performed on the day after the surgery, particularly in adult cochlear implant recipients, whenever available. Axial images were obtained with 0.4 mm slice thickness using 120 kV, 64 × 0.6 mm collimation, 1-s rotation, pitch factor of 0.85, and 205 mAs, in accordance with the age of the subjects by 256-channel multi-detector computed tomography 32. A board-certified neuroradiologist  and an otologic surgeon (B.Y.C) independently performed visual inspection of the “Cochlear View” on the conventional CT with ultra-high kernel specification of Uh59 (low resolution index) and Ur81 (high resolution index). As modified from the version of Kidoh et al.33, the degree of image sharpness under the bone window setting  was assessed using a 4-point visual score, and the overall subjective image quality was separately examined according to a 5-point visual score  refers to the ratio of the Euclidean distance between the modiolus (M) and the electrode (Ei) relative to the distance between the modiolus and the lateral wall (LWi). Specifically, the modiolus (M) value was determined as a crossing point in relation to the two lines associated with the modiolus and the round window. In this study, we defined the “modified ICPI,” a novel parameter that reflects the degree of modiolar proximity. The modified ICPI is the average value of ICPI(i) measured at four fixed positions under a two-axis crossing modiolus  indicate scalar translocation of the inserted electrodes35.After the final intracochlear positioning of the electrode arrays, telemetry recordings were made under sterile conditions in the operating field. “Electrically evoked compound action potential (ECAP) thresholds” were measured in every channel for all subjects using software-based neural response telemetry (NRT) recordings (Cochlear Custom Sound 4.0) with automatic NRT mode. As outlined by guideline, stimulation rate (Hz), maximum current level (CL), and the number of sweeps were set as 250 Hz, 255 CL, and 35, respectively. Furthermore, to evaluate and describe the scalar position of the electrode arrays, ‘NRT ratio’ was proposed previouslyhttps://www.rstudio.com/). Then, all the analyses illustrated used the GraphPad Prism version 8.0.0 for Windows, GraphPad Software, San Diego, California USA (www.graphpad.com), An independent t-test (two-tailed) was used to compare the quantitative and qualitative assessments between the two different filter specifications (UR59 versus UR81). One-way ANOVA (within-subject design) and Tukey’s post-hoc test was used to determine if the ICPI(i) value at the four points differ from each other. Pearson correlation analyses were performed to identify the relationships between the modified ICPI, related parameters, and spiral diameters, because these parameters were normally distributed. P values < 0.05 were considered statistically significant.All statistical analyses were performed using R Statistical Software  and RStudio    Fig. . The sizst) Fig. .As depicted in Fig. P < 0.001 by one-way ANOVA and post-hoc Tukey test) , point 2 , and point 3 , while point 4  showed a sudden significant decrease  value, displayed the lowest ECAP threshold  relative to other ICPI values, likely indicating that modiolus-electrode distance at position 1 would most significantly contribute to spiral diameter.  Interestingly, the most significant correlation was obtained between average value of four ICPIs (modified ICPI) and spiral diameter   Fig. b. This s28. Further, upon ultra-high kernel specification with high-resolution index, the enhancement of intracochlear visualization of the electrode array in conventional CT could justify the newly introduced indicator  specialized for modiolar proximity evaluation. The modified ICPI measured from our cohort in conventional CT ranged from 0.34 to 0.54, which showed a normal distribution. Introduction of modified ICPI would make it possible to accurately and routinely evaluate modiolar proximity for slim modiolar electrodes in cochlear implantation centers where it was previously impossible due to lack of cone-beam CT. This would popularize analysing postoperative speech outcome with relation to modiolar proximity.To the best of our knowledge, the present study is the first to come up with a reliable and simple parameter reflecting the modiolar proximity of slim modiolar electrodes based on conventional CT. Specifically, we adopted ultra-high kernel specification with high resolution index for conventional CT, finally achieving better image sharpness and reduced metal artifacts . This improved image quality allowed accurate assessment of the intracochlear electrode position and elaborate measurement of modiolar proximity. The vendor-specific application of noise amplitude and texture modification technique in ultra-high kernel specification may decrease noise level and improve resolution. Indeed, conventional CT-based scalar position and distance from electrodes to the modiolus were comparable to the results of cone beam CT in certain circumstances36, raising the importance of a de facto real-time imaging modality visualizing degree of modiolar proximity on the spot. A recent study highlighted that the cochlear duct length-based customized insertion technique might potentially ensure better modiolar proximity20, which would potentially lead to better speech outcomes. Specifically, short cochlear duct length subsequently leads to less modiolar proximity, which in turn renders some subjects with short cochlear duct length less amenable to this pull-back maneuver. If that is the case, readjustment of the electrode position by pulling the electrode array further back 1–2 mm more than in the conventional pull-back maneuver, called ‘extended pull-back maneuver’, likely leads to enhanced modiolar proximity, as evidenced by our recent study20. Coupled with reloadable design of the slim modiolar electrodes, simple X-ray imaging would serve as a great alternative. Previous studies have demonstrated the excellent performance of the post-insertion simple radiographs in the evaluation of the depth and angle of insertion of electrodes in intraoperative and postoperative settings37. What about evaluation of modiolar proximity?Recent studies have shown a diverse range of spiral configuration of slim modiolar electrodes due to intrinsic and extrinsic factors38 seems judicious, particularly in children. Taken together, our results reiterate the value of X-ray-based measurement of spiral diameter, which enables immediate visual feedback and changes in insertion technique during operation, thereby ensuring optimal modiolar proximity.Despite previous reports addressing the parameter of modiolar proximity  based on the post-insertion simple radiograph, whether or not two-dimensional spiral diameter measured at a fixed position could comprehensively reflect three-dimensional spiral configuration of slim modiolar electrodes remained elusive. In this perspective, the present study merits strong attention since the modified ICPI comprehensively reflects electrode position at four points of the first cochlear turn, exhibited much tighter correlation with the spiral diameter on the post-insertion radiograph than did any of each ICPI at four points. This, in turn, suggests that the X-ray imaging-based spiral diameter would reflect the distance between the several contacts and the modiolus. Intraoperative use of simple radiographs to evaluate the degree of modiolar proximity, angular insertion depth and intracochlear positioning of electrodes under minimal exposure to radiation29. Indeed, our measurement herein showed no difference of the distance among the electrode contacts from modiolus at point 1 , 2 (middle turn), and 3 . This enhanced modiolar proximity, especially at point 1  and 2 (middle turn), could be the result of the pull-back technique. Meanwhile, the distance between the modiolus and the lateral wall, which gradually decreased along the trajectory approaching the apical region, was consistent with the histological findings of the human cochlea39. Remarkably, we noticed that ICPI (1) with the lowest value also had the most tight correlation with X-ray imaging-based spiral diameter amongst the four ICPI values. This may indicate that changes in modiolar proximity in the upper basal cochlear region corresponding to ICPI (1) may be the most sensitive in influencing the spiral configuration of the electrode array. With a reduction of the electrode volume up to 75% similar to that of the current lateral wall electrodes4, the thinner and flexible properties of the slim modiolar electrode may make it more prone to variable spiral configuration in the upper basal cochlear region, compared with the middle and apical region. Further, the highest standard deviation of ICPI (1) indicating a wide range of degree of modiolar proximity, particularly in the upper basal region, may have contributed to the most significant correlation of it with the X-ray imaging-based spiral diameter.However, CT measurement should not be underestimated as just an interim approach, but we would better regard it as a valuable independent approach per se. Indeed, simple X-ray is not possible to indicate the degree of modiolar proximity of the electrodes, without being equipped with cone beam CT and calculation of ICPI through it. Importantly, each ICPI (i) could provide otologists with clinically significant information on intracochlear positioning of slim modiolar electrode, which is primarily related to the distance of each contact relative to the modiolus at specific points. Importantly, these values can be measured at a fixed position based on the two lines associated with the modiolus and the round window, thus permitting excellent reproducibility. Among them, ICPI (1) measured at junction of proximal basal and distal middle region  showed the lowest value due to the longest distance from the modiolus to the lateral wall, while relatively maintaining the distance from the modiolus to the electrode. The enrolled subjects were exclusively implanted using the pull-back technique, enabling closer positioning of this slim modiolar electrode array to the modiolus. Recently, a human cadaveric temporal bone study revealed that the pull-back technique led to better modiolar proximity of the slim modiolar electrode array, especially in upper basal and middle turn of the cochlea28, in vivo evaluation of the modified ICPI itself, was not validated histologically in our study. We therefore suggest that future studies should include large scale histological evaluation. Third, the structure of the cochlea is relatively small and irregular; therefore, it is difficult to designate the ROI when performing quantitative and qualitative assessments between standard and high-resolution filter specifications. As a result, the average ROI was relatively small and heterogeneous. Lastly, we cannot fully explain the impact of electrode position on speech performance at present, just postulating that improved modiolar proximity might lead to better speech perception outcomes in cochlear implant recipients. Specifically, Holden et al. proposed that a tightly wrapped array  elicits significantly higher word recognition scores1. Furthermore, a prediction model has revealed that the average modiolus-to-electrode distance strongly correlated with speech perception scores for perimodiolar electrodes, including slim modiolar electrodes13.As with introduction of significant novel findings in literature, the present study also has limitations that should be addressed in future studies. First, the small sample size and retrospective study design could be associated with weak statistical power, despite the fact that our observed values exhibited well-preserved normality, which followed a Gaussian distribution. Second, although previous studies substantiated that the electrode to modiolus distance based on conventional CT was significantly correlated with that based on a histological evaluation, the gold standard techniqueIntroduction of conventional CT-based modified ICPI would make it possible to accurately and routinely evaluate modiolar proximity for slim modiolar electrodes in all cochlear implantation centers. Further, our results reiterate the value of X-ray-based measurement of spiral diameter which enables immediate visual feedback and changes in insertion technique intraoperatively, thereby ensuring optimal modiolar proximity. Additional pre-processing techniques, such as the metal artifact reduction and three-dimensional image fusion techniques, could further enhance the clinical significance of conventional CT-based measurement of several parameters in cochlear implantation.Supplementary Table S1.Supplementary Table S2.Supplementary Figure S1.Supplementary Figure S2.Supplementary Figure S3.Supplementary Figure S4.