Case Report: A 31-year-old female was evaluated for a temporal scotoma and photopsias that started two weeks after the second dose of the Moderna COVID-19 vaccine. Dilated fundus findings were remarkable for unilateral, small whitish-yellow dots scattered around posterior pole of the left eye, consistent with a diagnosis of MEWDS. The symptoms resolved three months later without treatment. Approximately one year after the first vaccine, the patient received the second Moderna COVID-19 vaccine booster and experienced a recurrence of symptoms with an enlarged scotoma and similar examination findings. The patient was treated with a course of systemic corticosteroids with subsequent clinical improvement. Conclusion: Although uveitis following COVID-19 vaccines is rare, our case highlights a need for increased awareness amongst practitioners regarding COVID-19-vaccine-associated onset or recurrence of ocular inflammatory diseases.To report a rare case of a patient with two recurrent episodes of Multiple Evanescent White Dot Syndrome (MEWDS) associated with the second dose and second booster of the mRNA-1273 COVID-19 vaccine (Moderna), and to perform a literature review on COVID-19-vaccine-associated MEWDS.  The white dot syndromes (WDS) refer to a group of ocular diseases that characteristically involve the outer retina and/or choroid and present with white-yellow lesions of varying morphologies on fundus examination. Amongst them, multiple evanescent white dot syndrome (MEWDS) has distinctive features, characterized by small spots at the level of the outer retina or RPE and is more commonly unilateral. This disease is usually self-limiting and occurs largely in healthy young adult females ,2.Although the pathogenesis of MEWDS remains poorly understood, different theories implicate a genetic and autoimmune predisposition contributing to the development of this disease. Interestingly, its onset has been associated with different viral vaccines including hepatitis A and B, human papillomavirus, influenza, measles-mumps-rubella, varicella virus, yellow fever, and most recently COVID-19 vaccines .The Food and Drug Administration (FDA) authorized the messenger RNA (mRNA) vaccines from Moderna and Pfizer-BioNTech for SARS-CoV-2 virus (COVID-19) disease for emergency use in December 2020 . Since tHerein, we report a case of recurrent MEWDS associated with the mRNA-1273 COVID-19 vaccine. Furthermore, we performed a literature review on COVID-19-vaccine-associated cases of MEWDS reported until 20 July 2022, using PubMed and Google scholar search engines for terms “multiple evanescent white dot syndrome, MEWDS, uveitis, and COVID-19 vaccine”.A 31-year-old white female was evaluated for a new onset temporal scotoma and photopsias, 14 days after the second dose of the mRNA-1273 COVID-19 vaccine (Moderna). She was seen by an outside ophthalmologist, and her fundus examination was remarkable for multifocal, outer retinal dots scattered around the posterior pole in the left eye consistent with a diagnosis of MEWDS. The patient was observed without any intervention, and her symptoms resolved within 3 months. Approximately 12 months after the second dose, the patient received the second booster dose and experienced a recurrence of symptoms, which prompted referral to our clinic.On our evaluation, the patient reported an enlarged scotoma in her left eye with increased photopsias. Past medical history was unremarkable, except for a remote episode of Lyme disease, which was successfully treated with doxycycline. Past ocular history was significant for myopia, and she was status-post myopic LASIK surgery in both eyes in 2019. On examination, best-corrected visual acuity (BCVA) was 20/16 on the right eye (OD) and 20/50 on the left eye (OS), and intraocular pressure (IOP) was 13 mm Hg in both eyes (OU). Slit-lamp examination revealed a quiet anterior chamber in both eyes and trace pigmented anterior vitreous cells in the left eye. On dilated fundus examination, a few scattered faint hypopigmented round dots of differing sizes, especially nasal to the optic nerve B were noWe report a de novo case of MEWDS following the second dose of COVID-19 mRNA-vaccination and a subsequent recurrence after the second booster. To the best of our knowledge, this is the second case of COVID-19-vaccine-associated MEWDS which developed a recurrent course, with both episodes temporally associated with vaccine doses. Recurrences are uncommonly reported in MEWDS. A large retrospective cohort of 111 patients with MEWDS, observed recurrent disease in only 14% of cases  AlthoughThe association between COVID-19 vaccines and MEWDS is yet to be elucidated. The causality assessment of an adverse event following immunization (AEFI) provides criteria to assess causality between a vaccine and an adverse event . In our To date, 13 cases of COVID-19-vaccine-associated MEWDS have been reported to date in the literature . The aveThese findings are highly comparable with those of other reported vaccine-associated MEWDS presentations. Ng et al. reviewed eight cases of vaccine-associated MEWDS, which included immunizations against rabies, HPV, hepatitis A and B, meningococcal, yellow fever, and influenza . PatientThe Pfizer BNT and Moderna COVID-19 vaccines are both mRNA vaccines and received their authorizations almost simultaneously in December 2020 (FDA and UK). This vaccine encapsulates the mRNA in lipid nanoparticles (LNP) that encode for the S protein of SARS-CoV-2 . Unlike COVID-19 vaccines have been associated with multiple ocular inflammatory diseases including anterior uveitis , acute mIn conclusion, we have reported a case of recurrent episodes of MEWDS following COVID-19 mRNA-1273 vaccines. The majority of vaccine-associated MEWDS episodes were previously in healthy, young females and resembled those of non-COVID-19-vaccine-associated MEWDS. Although the prognosis for this disease is favorable, physicians should be aware of this association so that these patients can be rapidly identified and offered prompt management and counseling.


Objectives Nursing homes (NH) confronted tremendous difficulties considering confirmed residents Covid-19 cases and deaths in the U.S. The Centers for Medicare & Medicaid Services (CMS) applies the Five-Star Quality Rating (FSQR) to indicate the quality of care in nursing homes based on health inspection surveys, staffing as well as care process and resident outcomes during the COVID-19 pandemic. This study aims to examine whether FSQR was related to the total number of NH resident Covid-19 cases and deaths.Design This study analyzed 6,978 nursing homes across the country with data from CMS Nursing Home Compare, CMS COVID-19 Nursing Home Public File, Long-term Care Focus, Payroll Based Journal, Rural-Urban Commuting Area. Negative binomial regressions were used to investigate associations between FSQR and NH COIVD-19 outcomes controlling for state fixed effects and clustering of nursing homes within counties. The characteristics of facility, residents, payer-mix, nursing staff, and geographic location were also controlled. ResultsComparing to NH with 1-star in Health Inspection, Staffing, or Overall ratings, NH with better performance have lower risk of having increased number of COVID cases and deaths among residents. Further, nursing home Quality Measures rating is not significantly associated with residents’ COVID-19 deaths. ConclusionOverall, the FSQR is a useful measure of quality in part when investigating NH’s performance during the COVID-19 pandemic. Future policymakers should pay special attention to providers performing poorly in FSQR when improving the quality of nursing homes, particularly regarding infection control.


Antibiotic overuse is high in patients hospitalized with coronavirus disease 2019 (COVID-19) despite a low documented prevalence of bacterial infections in many studies. In this study evaluating 65 COVID-19 patients in the intensive care unit, empiric broad-spectrum antibiotics were often overutilized with an inertia to de-escalate despite negative culture results. Broad-spectrum antibiotics (BSAs), such as piperacillin–tazobactam, are commonly prescribed for a mean duration of 5 to 7 days. However, antibiotics appear unlikely to improve outcomes in hospitalized COVID-19 patients. Antibiotic overuse in COVID-19 patients may be associated with unintended consequences including adverse events and the development of antimicrobial resistance. The purpose of this study was to examine outcomes and antibiotic use in ICU COVID-19 patients treated with an empiric antibiotic course compared to patients with documented bacterial infection and those whom antibiotics were stopped ≤72 hours given negative cultures.Nearly three-quarters of patients with coronavirus disease 2019 (COVID-19) receive antibiotics even though the prevalence of bacterial coinfections is low  result (the index regimen) and if blood and/or respiratory cultures were obtained ≤24 hours of antibiotic initiation. We applied the following exclusion criteria: death ≤72 hours of antibiotic initiation, antibiotics initiated prior to a positive SARS-CoV-2 result, transfer from an outside hospital, antibiotics initiated while in a non-ICU unit, or patient already on antibiotics for an alternate indication . Patients were still considered for inclusion if empiric antibiotics were ordered and then discontinued upon confirmation of SARS-CoV-2 infection, as long as they met the criteria above for the index regimen and culture obtainment. Prior antibiotic exposure was defined as receipt of intravenous antibiotics for ≥48 hours within the last 90 days. Multiple antibiotic courses following the index regimen were assessed but were not considered unique events. Eligible patients were categorized into 1 of 3 groups: (1) culture-negative, antibiotics discontinued ≤72 hours, (2) culture-negative, antibiotics continued >72 hours, or (3) culture-positive.Following institutional review board approval, patients were identified using electronic surveillance software and were followed until hospital discharge or in-hospital death. Electronic medical record review and Research Electronic Data Capture (REDCap) were used to collect and organize the following data: comorbidities with a high risk of progressing to severe COVID-19 illness (identified by study investigator during record review rather than ICD-10 code), supplemental oxygen requirement at antibiotic initiation, COVID-19-specific therapy, microbiological culture information, and antibiotic use. Secondary outcomes included time from antibiotic discontinuation until restart, in-hospital mortality, and time from antibiotic initiation to ICU discharge and hospital discharge or death. Adverse events were also assessed, including acute kidney injury, development of multidrug resistance, antibiotic-related rash, and Clostridioides difficile infection. Acute kidney injury as defined by the Acute Kidney Injury Network criteria was assessed following 24 hours of the initial regimen and up to 48 hours after discontinuation. Multidrug-resistant organisms included methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus, or Gram-negative bacteria resistant to 1 or more classes of antimicrobial agents per the Centers for Disease Control and Prevention definition.The primary outcome was clinical success, defined as being discharged alive or >2-point decrease in the World Health Organization Clinical Progression Scale score from day of antibiotic initiation to day 30.2 test or the Fisher exact test for nominal variables, the Kruskal-Wallis test for ordinal variables and time variables, and one-way analysis of variance for other interval variables. A 2-tailed P value of <.05 was considered statistically significant. No adjustments were made for multiple testing. All analyses were conducted using SAS Enterprise Guide version 7.1 software .The 3 groups were compared on baseline characteristics, antibiotic use, outcomes, and adverse events using the χDuring the 4-month study period, of 296 ICU COVID-19 patients screened, only 65 (22%) met inclusion criteria. The most common exclusions were antibiotic initiation prior to confirmed positive SARS-CoV-2 result (n = 84), no culture obtainment (n = 44), and non-ICU admission upon antibiotic initiation (n = 37). Of the 65 included patients, 23 (35%) had culture-positive infection; 32 (49%) were culture-negative and had antibiotics continued >72 hours; and 10 (15%) were culture-negative and had antibiotics discontinued ≤72 hours of initiation.Staphylococcus aureus (MSSA) isolated primarily from respiratory cultures in this group (Fig. Table oup Fig. . Median Outcomes of clinical success, in-hospital mortality, time to restart of antibiotics, and time to ICU and hospital discharge or death did not differ between the groups. Discontinuing antibiotics ≤72 hours if culture-negative did not impact clinical outcomes compared with groups treated with longer antibiotic courses with or without positive cultures. The highest rates of adverse events occurred among the 40.6% of patients who were culture-negative and had antibiotics continued >72 hours. However, these events did not reach statistical significance.Consistent with prior published literature, ICU COVID-19 patients were often treated with empiric BSAs despite low rates of corroborating culture-positive infections. The observed rate of 35% of COVID-19 patients with positive cultures in our study was higher than the rates described in other cohorts. However, in examining a variety of clinical outcomes, we identified no benefit for continuing antibiotics >72 hours in ICU COVID-19 patients with negative cultures. Instead, there was suggestion of harm with more adverse events in our cohort of patients treated >72 hours with negative cultures.Also consistent with prior data, BSAs with anti-MRSA and anti-pseudomonal activity were the most frequently prescribed despite low rates of cultures with these organisms. Given that MSSA accounted for nearly half the positive cultures in our study, opportunities for narrowing antibiotic regimens are evident. Antimicrobial stewardship efforts may also focus on ensuring appropriate treatment durations in this group based on the 10.5-day median duration observed for respiratory cultures.This study had several limitations. The study design was retrospective, we had a small sample size, and the study was conducted over a relatively short period prior to the emergence of new SARS-CoV-2 variants and the adjunctive use of tocilizumab or baricitinib. However, it was a multicenter study including multiple ICUs of both tertiary-level and rural community hospitals. It also represents real-world experience in treating ICU COVID-19 patients.In conclusion, significant opportunities exist to limit antibiotic exposure in ICU COVID-19 patients because empiric BSAs do not appear to be associated with benefit and may result in harm. When antibiotics are prescribed, spectrum of activity should be targeted at commonly identified pathogens. We observed high rates of anti-MRSA and anti-pseudomonal antibiotic use despite low rates of cultures with these pathogens.


Klebsiella pneumoniae (NDM-Kp) occurred in a large tertiary care hospital from August 2021–June 2022 in Florence, Italy, an area where NDM-Kp strains have become endemic. Retrospective analysis of NDM-Kp from cases observed in January 2021–June 2022 revealed that 21/52 were FDC-resistant. The outbreak was mostly sustained by clonal expansion of a mutant with inactivated cirA siderophore receptor gene, which exhibited high-level resistance to FDC (MIC ≥ 32 mg/L) and spread independently of FDC exposure.A nosocomial outbreak by cefiderocol (FDC)-resistant NDM-1-producing  Klebsiella pneumoniae (NDM-Kp) resistant to FDC, which occurred in a large tertiary care Italian hospital from August 2021 to June 2022. We describe the features of the strains involved in this outbreak.Cefiderocol (FDC) is one of the few novel antimicrobial agents active against multidrug-resistant Gram-negative bacteria strains producing metallo-beta-lactamases (MBLs) -3. Thus In late 2018, an outbreak of NDM-producing Enterobacterales emerged in Tuscany in central Italy, involving several hospitals especially from the north-western area ,8. The oSince its introduction in the hospital formulary  in June 2021, FDC has been occasionally used for treating infections caused by multidrug-resistant Gram-negative pathogens, mostly based on presumed susceptibility. In vitro susceptibility to FDC was not routinely tested because of the accuracy issues reported with available commercial systems ,11 and bSupplementary Table S1 for an overview of the clinical data of the cases). Among the resistant isolates, FDC minimum inhibitory concentrations (MICs) ranged from 4 to > 64 mg/L, with a bimodal distribution .In June 2022, following the detection of an FDC-resistant NDM-Kp isolate (tested upon specific request of an infectious disease consultant), FDC susceptibility was retrospectively evaluated by reference broth microdilution (BMD) with iron-depleted medium  on NDM-KOf the 21 patients ) from which FDC-resistant NDM-Kp were isolated, all experienced colonisation and nine experienced infections including bloodstream infections  and/or urinary tract infections  and/or lower respiratory tract infections  . NotablyWhole genome sequencing (WGS) was carried out either on the first isolate from patients who experienced only carriage of FDC-resistant NDM-Kp, or on the first isolate from the most clinically relevant infection (BSI > LRTI > UTI), when more isolates were available from the same patient n = 9 patients) . WGS was patientscirA siderophore receptor gene . Interestingly, all the NDM-Kp with cirA alterations exhibited high-level FDC resistance (MICs: ≥ 32 mg/L)  .cirA , but carried missense mutations in the baeS  or in the envZ  genes encoding the sensor kinases of two component systems which regulate the expression of cirA and fiu iron-uptake genes [The remaining four isolates showing low-level FDC resistance (MICs: 4–8 mg/L) did not carry alterations in either cirA  or otherke genes ,14. InteY253CfsTer5 and with the BaeST180I alterations, respectively, while the singletons with other cirA alterations or with an altered envZ were more divergent  clone was isolated in November 2021 from the surveillance swab of a patient transferred from another hospital in north-western Tuscany. Of the remaining 14 patients with CirAY253CfsTer5 NDM-Kp isolates, 13 were observed in inpatients who were not colonised or infected by NDM-Kp at admission, while only one (#22045_Pt10) was found to be already positive at admission, in March 2022. Epidemiological links could be traced among the cases associated with CirAY253CfsTer5 NDM-Kp, suggesting that this clone had entered the hospital with the index patient and had thereafter spread within wards attended by patients undergoing cardiac surgery. A colonised patient (#22045_Pt10), previously admitted for cardiac surgery, was the likely source for the subsequent dissemination of the CirAY253CfsTer5 NDM-Kp clone in a medical ward, following readmission (The index CirAdmission .T180I NDM-Kp strain (#22116_Pt12), isolated in March 2022 from the surveillance swab of a patient that was negative at admission, was associated with another cluster of transmission in another medical ward, while the three singletons were epidemiologically unrelated (The index BaeSnrelated .Supplementary Table S1 for FDC disk diffusion test data).Antimicrobial susceptibility testing of isolates subjected to WGS, carried out by reference methods  and inteSupplementary Table S1 for the list of the acquired resistance genes revealed by the in silico analysis), which overall reflected that of the Tuscan ST147-vir clone [The resistance profile was consistent with the resistome of the isolates  was also consistent with that of the ST147-vir clone [iucABCD-iutA) in the single isolate carrying the CirAG75W alteration  information about the outbreak was circulated among healthcare structures through the regional network for antimicrobial and diagnostic stewardship, (ii) FDC testing by disk diffusion  was recoY253CfsTer5 mutant of NDM-Kp by real-time PCR was developed to rapidly analyse the resistant isolates . In addition, in our hospital (i) all MBL-CRE isolates categorised as FDC-resistant by disk diffusion or with a result falling within ATU were tested with reference BMD , (ii) enDuring the subsequent period (1 July–15 October 2022), only two cases associated with an FDC-resistant NDM-Kp CirA mutants (one with Y253CfsTer5 and the other with D426Ter) were reported at our hospital, suggesting effectiveness of the intervention.We report a hospital outbreak caused by FDC-resistant NDM-Kp observed in an area of Tuscany, Italy, where NDM-Kp is endemic. Since FDC is among the very few treatment options available for MBL-CRE infections, this is a worrying phenomenon in terms of resistance evolution.cirA siderophore receptor genes with predominance of a CirAY253CfsTer5 mutant, which was found in 15 of 21 cases, and with a minor contribution by mutants with other resistance mechanisms. All 21 FDC-resistant mutants were derivatives of the ST147 NDM-Kp sublineage involved in the large ongoing Tuscan outbreak, which emerged in late 2018 [By genomic surveillance, the outbreak was traced mostly to NDM-Kp strains highly resistant to FDC, carrying mutated ate 2018 .The FDC-resistant mutants had likely been selected outside our hospital. None of the 21 observed cases have been treated with FDC before isolation of the resistant NDM-Kp. Moreover, during this outbreak and in the preceding period , the use of FDC in our hospital remained very limited. Admission of patients already colonised by FDC-resistant NDM-Kp followed by intra-hospital transmission was the apparent source of this outbreak, underscoring the role that transfer of colonised or infected patients from other hospitals or long-term-care facilities could play in spreading of resistant pathogens, and the importance of active surveillance.cirA mutant of NDM-Kp, selected in vitro, exhibited reduced fitness vs the parental strain in competition experiments, suggesting a low propensity to disseminate in the absence of sustained selective pressure [cirA mutants of NDM-Kp are able to spread in the hospital environment independently of a strong FDC selective pressure. Moreover, these strains can also retain a notable virulence potential, evident by the ability to cause nosocomial infections including BSI, LRTI and UTI. Further investigation regarding the fitness and virulence of the clone described in this study, as well as whether it carries compensatory mechanisms, may be necessary to explain this unexpected behaviour. One hypothesis could be that the lack of iron-catecholate outer membrane transporter CirA might be compensated by the presence of the structurally distinct siderophores yersiniabactin and aerobactin carried by the ST147-vir clone.A recent study reported that a pressure . HoweverThe importance of surveillance, including genomic surveillance and active surveillance, and of strict compliance with infection prevention and control measures – based on a tight collaboration between clinical and laboratory personnel – are fundamental to avoid further spread of these difficult-to-treat Gram-negative bacteria and to preserve the activity of novel antimicrobials.


The ongoing COVID-19 pandemic is known to affect several body organs, including the liver. This results from several factors such as direct effect of SARS-CoV-2 on the liver, side effects of drug therapy and pre-existing liver diseases. Drug-induced liver injury can result from a range of drugs used in the treatment of COVID-19 such as antiviral drugs, anti-inflammatory drugs, antibiotics, herbal medications and vaccines. Metabolism of most drugs occurs in the liver, and this leaves the liver at risk of medication-induced liver damage. Being among pathologies from the disease, COVID-19 liver injury presents with abnormally high liver-related enzymes, such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphate (ALP), and gamma-glutamyl transferase. It is reversible, generally not severe and occurs more mildly in children. However, COVID-19-associated liver injury is worsened by chronic liver diseases and vice versa. There is a high risk of abnormal ALT and AST, in-hospital liver injury and prolonged SARS-CoV-2 shedding in COVID-19 patients with previously existing metabolic-associated fatty liver disease. COVID-19-associated liver injury also appears to be severe and significantly associated with life-threatening COVID-19 and mortality in persons with a history of liver transplant. Where necessary, only supportive management is usually indicated. This paper evaluates the aetiology, clinical and laboratory features, occurrence and management of COVID-19-associated liver injury. It also elaborated on the role of drug therapy in the development of COVID-19 liver injury. The onset of coronavirus disease 2019 (COVID-19) pandemic has precipitated several human and economic losses. This is largely due to its associated high infectivity, morbidity and mortality. Among risk factors that have influenced disease progression are older age, immunodeficiency and underlying comorbidities, such as pre-existing liver disease. Although some drugs have shown positive outcomes in the management of COVID-19 . Among tCOVID-19 is associated with several pathologies, among which is liver injury which results from several factors. The severity of the resulting injury is suggestive of COVID-19 prognosis , includiTherefore, COVID-19-associated liver injury may be disease related and drug related or may result from aggravation of already existing chronic liver disease. It occurs in infants , childreSeveral mechanisms have been associated with the development of COVID-19-associated liver injury. More specifically, it results from hypoxic hepatitis which is caused by changes in the haemodynamics and oxygen delivery . This crAdditionally, direct infection of the liver cells by SARS-CoV-2 also raises risks of liver injury . The livExacerbation of previously existing chronic liver disease by medications used in COVID-19 therapy is also implicated in the aetiology of COVID-19 liver injury. As shown in previous studies, antivirals, antibiotics and anti-inflammatory drugs (such as steroids) have been used in the management of COVID-19 . Some ofCytokine storm or excessive systemic inflammatory response, usually occurring as elevated inflammatory markers, particularly interleukin-6 and ferritin, is significantly associated with development of mild, moderate and severe liver injury in COVID-19 patients . Severe Chronic liver disease in children appear not to be associated with elevated risks of SARS-CoV-2 infection or severity of COVID in the population . HoweverDevelopment of liver injury significantly correlates with increased incidence of mortality and critical disease state in liver transplant recipients with COVID-19 . High moGlobally, deaths due to liver diseases are estimated at 2 million per year with complications due to cirrhosis accounting for 1 million deaths . Also, dThough the prevalence of pre-exiting liver disease in COVID-19 has been reportedly low, ranging from 3 to 8% , a systeAs noted in previous studies, risk of severe COVID-19 is higher in persons with pre-existing MAFLD , 30–32. A range of comorbidities  which are independent risk factors for COVID-19 complications exist in chronic alcohol consumers who have developed alcohol-associated diseases . These aIt is hypothesized that reactivation and massive replication of hepatitis B virus (HBV) will occur in persons with a history of HBV liver disease coinfected with SARS-COV-2, which could then lead to prolonged viral shedding . HoweverSARS-COV-2 is a causal factor for significant liver injury leading to worse clinical outcomes in patients with decompensated cirrhosis . It alsoDrug-induced liver injury (DILI) can result from a range of drugs used in COVID-19 management, e.g. antiviral agents, nonsteroidal anti-inflammatory drugs, antibiotics  and herbA couple of factors that increase the probability of DILI include age (aged patients are more at risk), gender (men are more at risk), alcohol consumption  and pre-existing liver disease . From a Elevated liver enzymes have been observed following the use of immunosuppresants  in COVID-19 management . In patiThe use of the antiviral drugs: lopinavir and ritonavir, in the treatment of severe COVID-19, was reportedly associated with adverse liver effects in a randomized controlled trial . In a reHepatotoxicity following the use of vaccines for the prevention of COVID-19, though rare, occurs . A case Liver function laboratory tests are made up of all indices of liver injury biochemical indicators. These include higher values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and bile duct injury or cholestasis such as alkaline phosphate (ALP) and gamma-glutamyl transferase (GGT) , 50. BilCOVID-19 liver injury mostly presents as mildly abnormal plasma liver function tests. Among the most commonly observed are elevated AST and ALT . In a prAlso consistent with laboratory findings in COVID-19-related liver injury is hypoalbuminaemia. Other observed pro-inflammatory cytokines are inducible protein (IP)-1 and granulocyte colony-stimulating factor (GM-CSF). Others include monocyte chemoattractant protein (MCP), IFN-γ and macrophage inflammatory protein (MIP)-1α . AbnormaA previous study on post-mortem liver tissue biopsy showed several pathophysiological characteristics such as microvascular steatosis and liver lobular and portal activities . Among oHepatic damage in COVID-19 patients during disease progression or treatment, regardless of the pre-existing liver injury status of a patient, is referred to as COVID-19-related liver injury . PrevaleMost prevalent extrapulmonary clinical feature of COVID-19 is derangement of liver enzymes . Also, fElevated liver enzymes seen in COVID-19 patients from a meta-analysis were characterized by a prevalence of AST (23.2%), ALT (21.2%), GGT (15.0%), bilirubin (9.7%), and ALP (4.0%), respectively . BesidesCOVID-19-associated liver injury may be transient and often self-limiting; however, adequate attention to persons with history of existing liver disease and transplant recipients is essential. This is critical to preventing further deterioration of the liver function. ALP peak value is predictive of worse prognosis; however, liver function tests return to around baseline in COVID-19 patients who do not have pre-existing liver disease . EffectiProper evaluation of individual response to COVID-19 drug therapy is also critical to reducing the possibility of drug-induced liver injury and preventing further drug-induced hepatotoxicity. Identification and prompt withdrawal of any hepatotoxic drug, and initiation of more suitable alternative, prevent further damage while promoting the healing process.Supportive therapy is a major step in the effective management of COVID-19 liver injury. It includes use of necessary and appropriate therapeutic agents and substitution of offending drugs. COVID-19 liver injury is not associated with significant liver function impairment or failure, hence does not require specific drug therapy. Supportive therapy depends on the severity and may include treatment with immunosuppressants and anti-inflammatory drugs such as methylprednisolone. Other potentially relevant drugs include rifaximin and lactulose .COVID-19 liver injury results from several factors which may be drug therapy related or disease related. It usually presents with abnormal elevation of liver enzymes, skin pigmentations and darkened face. Its presentation is generally not severe; however, close monitoring is required for patients with existing chronic liver diseases and liver transplant recipients.


N-methyl-d-aspartate receptor (NMDAR) antibodies that satisfied the criteria of “probable anti-NMDAR encephalitis (ProNMDARE)” based on the Graus criteria 2016.We herein detail our experience with a unique patient with a primary central nervous system (PCNS) B-cell lymphoma concomitant with anti-A 73-year-old Japanese woman presented with acute pyrexia, agitation, and disturbance of consciousness. She gradually developed a reduction in speech frequency and truncal dystonia causing abnormal posture. Brain magnetic resonance imaging (MRI) demonstrated high-intensity lesions in the bilateral frontal lobes, and her cerebrospinal fluid revealed mild pleocytosis. She was diagnosed with acute encephalitis and treated with acyclovir and intravenous dexamethasone; however, no improvement was observed. She was transferred to our hospital 6 weeks after the onset of her symptoms, and anti-NMDAR antibodies were identified in her cerebrospinal fluid through indirect immunolabeling with rat brain frozen sections and cell-based assays with NR1/NR2 transfected HEK cells. Follow-up MRI showed enlargement of the lesions in the right frontal lobe with gadolinium enhancement, suggesting a brain tumor. Stereotactic surgery was implemented, with subsequent pathological examination revealing that the tumor was consistent with diffuse large B-cell lymphoma (DLBCL) without evidence of systemic satellite lesions. Stereotactic irradiative therapies were then added to her treatment regimen, which partly improved her neurological symptoms with only mild cognitive dysfunction still remaining. A decrease in anti-NMDAR antibody titer was also confirmed after immunotherapy and tumor removal.We herein report our experience with a novel case of PCNS-DLBCL masquerading as anti-NMDAR encephalitis that satisfied the diagnostic criteria of “proNMDARE.” Treatment, including tumor removal, ameliorated disease severity and antibody titers of the patient. Our findings suggest that anti-NMDAR antibody-associated autoimmunity can be triggered by PCNS B-cell tumors, although primary brain tumors need to be excluded before establishing a diagnosis of autoimmune encephalitis. N-methyl-d-aspartate receptor (NMDAR) encephalitis is a well-characterized autoimmune encephalitis (AE) associated with immunoglobulin (Ig) G against the GluN1 subunit of the NMDAR  concomitant with NMDAR antibodies in the CSF who developed acute encephalitis satisfying the diagnostic criteria of “proNMDARE.”3, monocyte predominant). She was diagnosed with acute encephalitis and was started intravenous acyclovir and intravenous dexamethasone.A 73-year-old Japanese woman was admitted to another hospital for pyrexia, agitation, and mild disturbance of consciousness. She was initially diagnosed with a urinary tract infection, for which antibiotics were administered. However, her neurological condition gradually deteriorated. Brain MRI showed high-intensity lesions in the right temporal and bilateral frontal lobes on fluid-attenuated inversion recovery (FLAIR) images. CSF examination showed mild pleocytosis . Her IgG index (0.50) was within normal range (cut-off < 0.67). Her CSF sample came back positive for oligoclonal bands. Brain MRI revealed high-intensity lesions in the right temporal and bilateral frontal lobes on FLAIR images, with the right frontal lesion demonstrating gadolinium (Gd) enhancement, which can be considered to indicate CNS inflammation or a high-grade brain tumor. Magnetic resonance spectroscopy of the right frontal lesion revealed an increase in the choline/creatine ratio and a normal N-acetyl aspartate level  13 (E4 V4 M5) with disorientation and agitation. She was able to answer some simple questions but showed a remarkable reduction in speech frequency. She presented with cervical and truncal dystonia causing abnormal posture. She did not experience seizures. Autonomic dysfunction and central hypoventilation were unremarkable. Electroencephalography (EEG) revealed a generalized slowness in activity (5–7 Hz) without epileptiform discharges. A cerebrospinal fluid (CSF) sample included 5 white blood cells/mmte level . Whole-bph nodes .via indirect immunohistochemistry with frozen sections of rat brain. Patient's CSF immunolabeled neuropil of the rat hippocampus  were detected  staining. Tumor cells were positive for CD20  and CD79a  suggesting B-cell lymphoma with high Ki-67  expression (90%). Immunological profiles of the tumor were consistent with primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) . In addiAfter tumor removal, the patient underwent whole-brain stereotactic irradiation therapies . The antibody titers of anti-NMDAR antibodies in the CSF decreased as the volume of brain tumor reduced after surgical and irradiative therapies  proposed by Graus et al. . In-housRecent studies have suggested the association between some types of neuronal surface antibodies (NSA) and hematologic neoplasms –10. For Conversely, it is wellknown that anti-NMDAR antibody titers in the CSF corresponded to the severity of the disorder and that most patients experienced a decrease in the titers following treatment that included tumor removal (for paraneoplastic cases) and intensive immunotherapies . The serThereafter, we reviewed previous cases with primary brain tumors concomitant with anti-NMDAR antibodies , 4, 16 . Fujii eRegarding the mechanism for the association between brain tumors and production of autoantibodies, Mariotto et al.  suggesteIn conclusion, we herein report a unique case involving PCNS-DLBCL who developed acute encephalitis satisfying the diagnostic criteria for “probable NMDARE.” The present case indicated that anti-NMDAR antibody-associated autoimmunity can be triggered by PCNS B-cell tumors, which are involved in anti-NMDAR syndrome presenting as a paraneoplastic NMDARE. Furthermore, brain tumor assessment even for patients suspected of AE can help prevent delays in the induction of appropriate treatment.The original contributions presented in the study are included in the article/Written informed consent was obtained from the individual(s) and/or minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.YY and MH drafted the manuscript. YY, MH, NO, TM, and HNa prepared patient's clinical data. HNi and HH performed the histological examination. MH, HH, and HNa supervised this study. All authors analyzed and interpreted the patient data and revised the manuscript for intellectual content. All authors approved the final manuscript.


Dear Sirs,Hereditary amyloidosis with autosomal-dominant mutations in the transthyretin-gene (TTR) represents a severe multi-system disorder. Treatment options are now available for TTR familial amyloid polyneuropathy (TTR-FAP): patisiran , inotersWe herewith present a case of a young man who had severe TTR-FAP progression after OLT. Tafamidis therapy did not stop disease progression, but the patient showed clinical improvement of the TTR-FAP after switch to patisiran.2). By cardiac MRI, a septal hypertrophy of 20 mm was detected, as well as an increased amount of late gadolinium enhancement. Native T1 and T2 relaxation time were elevated. Thus, despite preserved left ventricular function, a progressive cardiac involvement, as suggested by increasing septal thickness, cannot be ruled out. However, as a major limitation, echocardiography and MRI were used across different centres, and detailed off-line core-lab analysis was not available. NCS remained stable compared to the investigation in 2019 (Table A now 44-year-old man was diagnosed with TTR-FAP in 2012 caused by a rare TTR mutation (p.Glu54Gly) at the age of 36 years. The diagnosis occurred early because of his positive family history. Pre-existing conditions included chronic hepatitis B and D. At diagnosis, he reported autonomic disturbance causing gastrointestinal symptoms (constipation and diarrhoea) and noticed signs of small-fibre involvement (inability to detect temperatures) for approximately 1 year. Physical examination revealed slightly reduced muscle strength in the extensor muscles of the toes, distal hypesthesia in both feet, pallhypesthesia with 4/8 at the first metatarsophalangeal joints and absent achilles tendon reflexes. Nerve conduction studies (NCS) detected absent sensory responses in the lower limbs and decreased compound muscle action potential (CMAP) of the peroneal nerves. The mNIS + 7score was 31 points [This case provides evidence that change of treatment regimen in patients with disease progression after OLT is a valuable option. One possible explanation for the different therapeutic effect is the different mode of action of tafamidis and patisiran. Whereas tafamidis  acts as The cardiac amyloidosis showed no change in our study. However, cardiac examinations were performed at multiple centres with different examination protocols, which limits comparability and interpretability of the results. Most importantly, no MRI-derived quantitative baseline septal thickness (2013) was available. However, a dramatic deterioration of cardiac function can be excluded. Although patisiran is not approved in the cardiac indication, previous studies demonstrated positive effects of patisiran on cardiac parameters, although results were very heterogeneous with respect to reductions in MRI-derived extracellular volumes as an indicator of cardiac TRR-amyloid regression of . HoweverThe number of TTR-amyloidosis patients post-OLT will further decrease over the next years. However, in these patients, gene-silencing therapy might be an option. Although the use of patisiran improved the clinical status of the patient with the rare mutation (p.Glu54Gly), it cannot be concluded that this positive effect will also occur in patients with other TTR mutations. In summary, larger studies are needed to establish evidence-based treatment recommendations for medical therapy of TTR-amyloidosis patients after OLT.


Kinases are the component of superfamily enzymes known as phosphotransferases which involve transferring a phosphate group from phosphate-releasing high energy molecules to the specific substrates . KinasesThe novel Coronavirus Disease 2019 or COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (abbreviated as SARS-CoV-2) has become a universal outbreak and primary life-threatening disease at this point in time . For theFurther, monoclonal antibodies were developed to trigger the immune system to attack a specific invader, SARS-CoV-2. Monoclonal antibodies like Sotrovimab and Bebtelovimab were significant agents for treating COVID-19. This research topic aims to compile original research articles and reviews related to in silico design and synthesis of novel kinase inhibitors applicable in COVID-19 therapeutics by effective modulation of immune responses. About seven potential articles were published on the topic, ‘pharmacological and biochemical perspectives of kinase inhibitors in cancer and COVID-19 therapeutics.Mahanta et al., employed a computational approach to identify a novel molecule against SARS-CoV-2. This study focuses on the immunological perspective of the infection, involving the SARS-CoV-2 Membrane Glycoprotein (M protein), which focuses on the popularly studied receptor targets. In this study, 7,832 chemical structures from 32 medicinal plants were considered for screening against the homology model of the structure of SARS-CoV-2-M protein. This in silico study identified the compound ZIN1722 as a potential inhibitor to the SARS-CoV-2 M protein, which may subsequently prevent the immunosuppression in the human body during the COVID-19. Naik et al., highlighted the potential roles of kinase inhibitors in reducing COVID-19 symptoms and enhancing patient healthcare systems.Ghosh et al., identified potential tyrosine kinase inhibitors by virtual screening of natural compounds from the olive through the OliveNetTM database containing inhibitors of ALK and BTK kinases. Virtual screening was carried out using the ligand-based QSAR and the structure-based docking approaches. The virtually screened library of 161 natural compounds from olive was found to be overexpressed in ALK and BTK in metastatic and virus-host cells. Vimalraj et al., aimed to analyze the expression of long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in human osteosarcoma (OS) cells and investigated its role in OS-induced angiogenesis. The functional analysis indicated that MALAT1 enhanced OS-induced angiogenesis, in vitro and in vivo analyses, endothelial cell proliferation and migration, chick embryo angiogenesis assay, and zebrafish xenograft model. The authors suggested that MALAT1 promotes angiogenesis by regulating the miR-150-5p/VEGFA signalling in the OS microenvironment. Khayat et al., studied tirbanibulin, a first-in-class dual Src kinase (non-ATP competitive)/tubulin inhibitor as there are no literature reports available for its structure-activity relationships (SARs). The study is based on the replacement of the outer ring of the biphenyl system resulting in the identification of the pharmacophore of KX chemotype, with a heterocyclic ring. The newly synthesized compounds showed a range of activities in cell-based anticancer assays, which yielded a clear SAR profile. The most potent compound demonstrated cytotoxic IC50 values at 294 and 362 nM against HCT116 colon cancer and HL60 leukaemia cell lines, respectively. The ADME profiling of this compound confirmed its good drug-like properties. Gautam et al., evaluated diethylnitrosamine (DEN)-induced HCC in male albino Wistar rats was treated with Dimethyl itaconate (DI) as an anticancer drug. The function and molecular mechanism of DI against HCC in vivo were assessed using histopathology, enzyme-linked immunosorbent assay, and western blot studies. Serum metabolomics investigations using 1H-NMR revealed that aberrant metabolites in DEN-induced HCC rats were restored to regular following DI therapy.Furthermore, the authors incorporated sufficient information on FDA-approved kinase inhibitors studied through various clinical trials underway, completed, or terminated. Inhibitors including imatinib, ruxolitinib, silmitasertib, and tofacitinib , are now in clinical studies to determine their efficacy as possible anti-COVID drugs. Singla et al., studied the involvement of kinases and kinase inhibitors in the pathogenesis and treatment of endometrial cancer. The authors discussed the current literature describing natural products derived kinase inhibitors in managing endometrial cancer.Furthermore, the data revealed that the DI worked as an anti-HCC agent and was equivalent to that of the commercial chemotherapeutic drug 5-fluorouracil.


Following the significantdiscovery of van der Waals (vdW) layeredmaterials with diverse electronic properties over more than a decadeago, the scalable production of high-quality vdW layered materialshas become a critical goal to enable the transformation of fundamentalstudies into practical applications in electronics. To this end, solution-basedprocessing has been proposed as a promising technique to yield vdWlayered materials in large quantities. Moreover, the resulting dispersionsare compatible with cost-effective device fabrication processes suchas inkjet printing and roll-to-roll manufacturing. Despite these advantages,earlier works on solution-based processing methods  have several challengesin achieving high-performance electronic devices, such as structuralpolydispersity in thickness and lateral size or undesired phase transformation.These challenges hinder the utilization of the solution-processedmaterials in the limited fields of electronics such as electrodesand conductors. In the meantime, the groundbreaking discovery of anothersolution-based approach, molecular intercalation-based electrochemicalexfoliation, has shown significant potential for the use of vdW layeredmaterials in scalable electronics owing to the nearly ideal structureof the exfoliated samples. The resulting materials are highly monodispersed,atomically thin, and reasonably large, enabling the preparation ofelectronically active thin-film networks via successful vdW interfaceformation. The formation of vdW interfaces is highly important forefficient plane-to-plane charge transport and mechanical stabilityunder various deformations, which are essential to high-performance,flexible electronics. In this Perspective, we survey the latest developmentsin solution-based processing of vdW layered materials and their electronicapplications while also describing the field’s future outlookin the context of its current challenges. Furthermore, the synthesis of vdW heterostructureshas been successfully demonstrated through the assembly of two ormore vdW layered materials as building blocks with desired electronicproperties.23 Most importantly, the atomically clean, dangling-bond-free surfaceof 2D samples enables the demonstration of numerous fundamental prototypesthat rely on achieving efficient charge transport between the neighboringlayers at vdW interfaces.27 Despite having prototyped high-performance electronics based onvdW heterostructures which push the intrinsic limits of such 2D materials,the complicated processes for vdW device fabrication  hinder the scalingup of such devices while maintaining their performance for industrial-scaleapplications. To overcome these technological limitations, two mainissues should be addressed: scalable production of high-quality vdWlayered materials with high structural monodispersity and effectiveassembly of individual samples into vdW thin-film networks while minimizingdevice performance degradation.Sincethe discovery of monolayer graphene isolated from bulk graphiteby breaking weak van der Waals (vdW) interactions,36 Solution-based processing possesses almost unlimited scalabilityto produce an atomically thin 2D sample from nearly any existing layeredbulk crystal. The resulting dispersions readily assemble into thinfilms on any substrate and at low temperatures. This compatibilitywith cost-effective, scalable, and low-temperature processes (suchas inkjet printing and roll-to-roll manufacturing) is highly advantageous.Despite these promising aspects of demonstrated scalable processes,there remain several challenges including the generation of significantstructural polydispersity , small lateral size, and chemical degradation.35 In this Perspective, we review the extent to whichrecent advances in solution-based processing of vdW layered materialsfor electronics have addressed such challenges. Please note that wewill not cover other dimensional vdW materials including zero-dimensionalcolloidal quantum dots, fullerenes, and one-dimensional carbon nanotubes37 for in-depth discussion on vdW sheet-to-sheet contacts of 2D vdWmaterials and resulting properties.Solution-based processing hasbeen proposed as a promising routeto address these challenges.234 and intercalation-based van der Waals force weakening.41 Among solution-based approaches, we will not cover bottom-up methodssuch as liquid-phase precursor-assisted chemical vapor deposition,43 but we focus on the direct comparison of products generated fromeach top-down process, assuming that the starting material is identicalto a piece of layered crystal. 2 is required to overcome vdW interactions to exfoliate graphene fromlayered graphite crystals.44 At the sametime, the applied energy fragments bulk crystals, resulting in therelatively small lateral size of exfoliated nanosheets (∼100nm). Because the lateral dimension of 2D nanosheets is a criticalfactor in designing electronic device structures , the lateral size loss during theprocess has been considered as a significant drawback of direct liquid-phaseexfoliation methods. In addition, the resulting 2D samples possesspolydispersity in the lateral dimension and thickness,43 which hinders efficient vdW sheet-to-sheetcontact when forming thin-film network structures. The propertiesof 2D nanosheets are strongly dependent on their layer number dueto strong quantum confinement; therefore, 2D polydispersity in thicknessnecessitates postprocessing to enrich the desired thickness of thesamples; this is achieved through ultracentrifugation .46 Density gradient ultracentrifugationwas originally developed for the separation of biological macromolecules,and it is directly transferable to 2D nanosheet separation as theirmorphologies and buoyant densities are comparable to those of biologicalmolecules.33 Depending on the desired structureof nanosheets, density gradient ultracentrifugation can be split intotwo categories: sedimentation-based density gradient ultracentrifugationand isopycnic density gradient ultracentrifugation.34 Generally, the former is utilized for lateral size sorting basedon the size-dependent different sedimentation rates during ultracentrifugation,which is usually dominated by mass of the nanomaterial. Unlike thesedimentation-based process, the latter is dominated by buoyant densityof the nanomaterial and thus suitable for thickness sorting. Duringultracentrifugation, nanomaterials sediment to their correspondingisopycnic point in the density gradient medium. Following the isopycnicprocess, several bands are separated and visually observable in thetube, indicating nanomaterials are sorted based on their buoyant densities.The buoyant density of 2D nanosheets is strongly dependent on theirthickness, and this approach enables highly monodisperse samples withdifferent thickness. Although the postexfoliation process has enabledhigh 2D monodispersity in the required thickness, the resulting liquid-phaseexfoliated samples possessing small lateral sizes continue to motivatealternative routes for efficient exfoliation. For example, alkalimetal  intercalation-based exfoliation approacheshave been developed  becomes a metastable octahedral phase (1T-MoS2), resulting in an undesired semiconducting to metallic phase transitiondue to the insertion of Li+ ions and associated electrons.38 To overcome this limitation, approaches forpostprocessing have been proposed, which include mild annealing orlaser exposure, to partially recover the semiconducting 2H-MoS2. However, the resulting high defect densities and the residualmetallic phase hinder their full utilization for electronic applications.47 Alternatively, another intercalation-based exfoliation approachhas been reported by Duan et al. to produce atomically thin MoS2 nanosheets without any phase transformations using quaternaryalkyl ammonium molecules or other various ammonium molecules 4NBr, (C3H7)4NBr, (C4H9)4NBr, and (C10H21)4NBr) as an intercalant under electrochemical reaction possess a lateral size(>1 μm) relatively larger than that of liquid-phase exfoliatedsamples, whereas their thicknesses are atomically thin and highlymonodisperse. Larger sizes and narrower thickness distributions becomeessential when the nanosheets form electronically active thin-filmnetworks. As shown in the cross-sectional microscopic images, pointand/or line contacts with interfacial disorder and noticeable energybarriers are dominant between liquid-phase exfoliated samples, whilethe E-MoS2 nanosheets are clearly stacked by forming bonding-freevdW interfaces with a negligible energy barrier  analysis of theirthickness and lateral size 2a. Based (large)2b.48 The barrier 2c,d.35,4352 Similarly, gate-dependent electricaland optoelectronic properties have been reported based on individualInSe nanosheets processed in an additive-free, alcohol–watermixed cosolvent system  of liquid-phaseexfoliated InSe nanosheets indicates that additive-free liquid-phaseexfoliation enables the production of optoelectronically active, high-qualitymaterials on a large scale. Although the quality of various liquid-phaseexfoliated individual nanosheets has been verified for use in electronicapplications, the demonstration of scalable, gate-tunable high-performanceelectronics has been hindered by structural limitations includingsmall lateral size and polydisperse thickness. In order to achievegate-tunable devices, the channel should be electrically conductivebut thin enough to be fully depleted via gate-dependent electrostaticdoping over the entire channel. As shown in 55 For example, a controlledamount of 2D material dispersion can be collected on a porous membranesuch as anodic alumina (AAO) to form an electrically active percolatednetwork structure, followed by electrode array deposition (Ipc = Ilight – Idark) under light illumination. To minimizethe contact resistance of films originating from inefficient sheet-to-sheetcontact, a chemical welding approach has been developed to converta liquid-phase precursor, ammonium tetrathiomolybdate, to MoS2 at the interfaces under heat treatment.43 This approach significantly improves electrical conductionthrough the MoS2 film, while providing additional functionalityassociated with thermally controllable sulfur vacancies; however,the overall film thickness still needs to be optimized to achievegate-tunable devices  nanosheet structures enable the formationof compact thin films simply by spin coating, as shown in 2/Si wafer—a potential precursor for high-performance thin-filmelectronics on a rigid substrate  for electrostaticinteractions  at room temperature and a currenton/off ratio of 106  andcurrent on/off ratio (gray) o (gray) 5b. The fo (gray) 5c, whichl doping 5f. A repand NMAX 5h at the2 vdW thin films as semiconductingchannels has motivated the synthesis of other structurally analogousmaterials with various electrical properties. For example, the approachesdescribed in previous sections are also applicable to alternativelayered bulk crystals such as WSe2, Bi2Se3, NbSe2, In2Se3, Sb2Te3, and black phosphorus (BP).36 The representative structures of each sample are illustrated in 2, and insulatingHfO2 vdW thin films as electrodes, channels, and gate dielectrics,respectively  (PMMA) layer is coated onany 2D samples exfoliated/grown on an arbitrary substrate; the substrateis removed by etchant exposure; the PMMA/2D layer is carefully transferredonto a target substrate, and PMMA is removed. This wet-transfer methodis applicable not only for vdW material dispersions but also micromechanicallyexfoliated or chemically grown samples.To fully exploit solution-processedvdW layered materials for scalableapplications, many deposition or wet-transfer methods have been introducedto form electronically active vdW thin-film networks based on stabledispersion. The above-mentioned deposition methods  and other commonly usedthin-film deposition techniques  can successfully generate vdW thin filmsfor electronic device fabrication. In addition to the direct deposition,wet-transfer methods have been utilized for many purposes includingchanging substrates,64 Printing-based assembly is highly cost-effective due to its inherentwaste minimization; desired structures can be achieved in the mask-and vacuum-free process. Among the various printing approaches, inkjetprinting is the most accessible for the development of electronicdevice prototypes from 2D material inks. To successfully implementprinted electronic devices, 2D material inks should satisfy severalcriteria. First, 2D materials should be adequately stabilized withrespect to aggregation (for a reasonable period of time) to supportinkjet printing with high device-to-device reliability. In additionto ink stability, the rheological properties of the inks  also factor in considerablyto stable ink jetting. Finally, the structural properties of 2D nanosheets,such as thickness, lateral size, and the concentration of the ink,should be optimized to avoid clogging of the nozzle during printing.The development and optimization of 2D material inks have enabledthe prototyping of several printed electronic devices, such as field-effecttransistors, photodetectors, memory devices, and logic gates.64 For example, as shown in 2, and insulating HfO2 are used as electrodes,semiconductor channels, and dielectric layers, respectively. The AFMimages exhibits the stacking morphology of printed 2D nanosheets atthe center and edge of the pattern  MXene canalso be exploited as a stable ink for use in conductive thin-filmnetworks as electrodes.10 The optical absorbancespectra of the as-synthesized MXene and graphene inks are shown in 2 thin-film networks. Thorough investigation of the temperature-,gate-modulation-, and magnetic-field-dependent electrical propertiesrevealed that the charge transport mechanism of each material is dominatedby intrinsic intra-nanosheet or inter-nanosheet processes. For example,the charge transport of a printed graphene thin film is governed bynanosheet-to-nanosheet contacts, resulting in variable-range hopping(VRH) mechanisms, while printed MXene and MoS2 thin filmsshow a temperature-dependent transition of VRH to the nearest-neighborhopping mechanism because of the dominant intrananosheet charge transport  vacanciesin conjunction with the exfoliation of transition metal dichalcogenidesresults in heavily n-doped electronic behavior, which requires post-treatmentto reduce the chalcogen vacancy concentration. In this regard, a nonoxidizingorganic superacid  sulfonimide) treatmenthas been introduced to minimize sulfur vacancies on MoS2 nanosheets, resulting in significantly reduced off-current as wellas highly improved photoluminescence intensity.67 However, suchchemical treatment approaches for other chalcogen vacancies are stillmissing. Chemical oxidation is another potential issue to addressto extend the processing of ambient reactive materials .54 To minimizethis issue, the exfoliation process should be carefully performedunder controlled conditions in anhydrous solvents in an O2 and/or water-free environment. Third, both the synthesis of high-quality2D material dispersions and electronic device fabrication also requirethe full exploitation of solution-based processing. The previouslyreported MoS2-based state-of-the-art thin-film transistorsshowed an average field-effect mobility of 10 cm2/(V s),which lags far behind the promising device performance of other futureelectronics. For device fabrication, the properties of 2D ink formulationsare enable the use of printing-based, lithography-free techniques.However, current printing technologies should be further improvedto achieve minimum patternable resolution and spatial accuracy toprecisely form heterogeneous 2D materials into the desired devicestructures. Consequently, the development of the electrochemical exfoliationof 2D materials has introduced a new frontier into solution-basedprocessing for scalable electronic applications; however, there remainsignificant challenges and opportunities which must be navigated inrealizing their potential in next-generation electronics.Having achieved significantbreakthroughs in the development ofelectrochemically driven molecular intercalation-based exfoliationof layered crystals, the solution-based production of 2D vdW materialscan take us step closer to mass production for practical applications.Although many promising prototype studies have been demonstrated inthe domain of electronics based on these samples, several challengesremain to fully exploit their potential. First, layered crystals arenot always suitable for application in electrochemical exfoliation.To initiate the electrochemical reaction, bulk samples  should be electricallyconductive. Therefore, several conductive materials have been successfullyexfoliated, including metallic graphene and semiconducting MoS


Cyclodextrins (CDs) are cyclic oligosaccharide structures that could be used for theranostic applications in personalized medicine. These compounds have been widely utilized not only for enhancing drug solubility, stability, and bioavailability but also for controlled and targeted delivery of small molecules. These compounds can be complexed with various biomolecules, such as peptides or proteins, via host-guest interactions. CDs are amphiphilic compounds with water-hating holes and water-absorbing surfaces. Architectures of CDs allow the drawing and preparation of CD-based polymers (CDbPs) with optimal pharmacokinetic and pharmacodynamic properties. These polymers can be cloaked with protein corona consisting of adsorbed plasma or extracellular proteins to improve nanoparticle biodistribution and half-life. Besides, CDs have become famous in applications ranging from biomedicine to environmental sciences. In this review, we emphasize ongoing research in biomedical fields using CD-based centered, pendant, and terminated polymers and their interactions with protein corona for theranostic applications. Overall, a perusal of information concerning this novel approach in biomedicine will help to implement this methodology based on host-guest interaction to improve therapeutic and diagnostic strategies. Cyclodextrins are supramolecular structures derived from potato starch by enzymatic transformation. These compounds were discovered in 1891 by Villiers .CDs might be promising candidates for therapeutic and diagnostic purposes widely used in biomedicine. These structures can be chemically modified into branched star-copolymers forming various nanoparticles. Native CDs usually have primary and secondary faces where the hydroxyl groups are located. These faces are usually symmetrical and have different chemical properties creating torus-like molecules  3]. Sil. Sil3]. The CD interaction with various drug-like molecules is mainly mediated by van der Waals forces facilitating host-guest inclusion of multi-layered particles. On the other hand, CDs could be organized in the form of star-shaped polymers creating condensed frameworks with critical arm densities, efficient synthetic pathways, and specific dynamic and rheological properties ,8.Some CD advantages over other polymers include biocompatibility, biodegradability, bioadhesive properties, and organ targeting, making them ideal for medical approaches and smart drug delivery. Therefore, in this review, we focus on recent cyclodextrin-based polymers, particularly polymers consisting of centered polymers, pendant polymers, and terminated polymers, in biomedical approaches. The main advances achieved with CD-based polymers (CDbPs) have been concentrated on reactive functional groups. CDbPs are categorized depending on their structural resemblances and specified CDbPs as CD-containing polymers or polymeric networks. This review discusses the following topics: (1) Practical implementations of CDbP, including rational drug design theory and structure-activity/property relationship (SAR and SPR). (2) Strengths and weaknesses of SAR/SPR related to the blood-brain barrier (BBB), theranostics, and regenerative medicine.As a new-emerged branch of biomedicine, theranostics is aimed at a combination of diagnostic and therapeutic strategies. Mainly focused on patient-centered care, theranostics offers a platform to move from conventional medicine toward more personalized and precise medicine . The theTherefore, nanoparticles as potential therapeutic agents can overcome distinct restrictions of conventional drug delivery systems (DDSs) like nano-specific targeting, poorly water-soluble drugs and oral bioavailability of peptides and proteins, and low therapeutic indices (TI < 0.50) ,13. The 3O4@Au nanostructures and achieved physical loading of doxorubicin (DOX) as a common anticancer drug. They formed Fe3O4@AuNPs via a short Au nanolayer grown on larger magnetic NPs .,58.57,58At the beginning of the 1950s, Flory developed a hypothesis to describe the polymer network and the associations between the topology and mechanical properties such as elasticity . In the Due to their large amounts of hydroxyl groups on their external surfaces and hydrophobic cavities, CDs can link to different positions of the polymers. Recently, several interesting CD-based polymeric systems have been developed . The latStar polymers are composed of several centrally attached linear polymers with many chains and functional groups. The polymer core or center can be atoms, molecules, or macromolecules and chains or arms composed of organic chains of different lengths. Synthesis of star polymers using inexpensive and functional CDs has advantages such as cost efficiency, ease of manipulation, and easy access to multiple functions. Due to the relative order in which the polymer composite arms are made, the synthesis of star polymers using CD cores can be divided into two categories: core-first and arm-first approaches. The core-first approach uses CD-based initiators to grow polymer chains directly synthesizing CD-centric core star polymers. For the arm-first approach, a conjugation reaction is used to synthesize a CD-centred core star polymer, and the synthesized linear polymer is attached to a CD derivative. The advantage of the second method over the previous one is that each arm has the same chain length . As uniqIn this way, linear polymers can be easily defined by obtaining a specific analysis of the arms. Identifying specific compounds in CD-centred core star polymers is a major challenge, as abundant linear polymers need to be increased by enlarging all active sites of cyclodextrins. To achieve high purity for star polymers with CD-centric cores, free linear polymers should be eliminated, often requiring tedious purification processes.CD-capped polymers can be obtained by placing a CD at one or more termini of the polymer. CD-terminated polymers can be synthesized directly using CD-based macro-initiators. These polymers can also be obtained using linear polymer linkages with reactive sites on functionalized CDs.The CD side-chain polymers are synthesized in two ways: by direct polymerization of a large number of CD monomers or by functionalization of CDs onto the side chains of the polymer. Although it is difficult to synthesize supramolecular polymers with complex structures by conventional covalent routes, these compounds exhibit host-guest interactions in which a polymer with CD side chains and a polymer with a CD terminus act as a host can be obtained . FinallyFor example, important polymers synthesized as building blocks for CDs include star polymers, polyrotaxanes (PR), supramolecular block copolymers (BCPs), and comb polymers . These CKey polymers, such as CD-centric core polymers, CD-side polymers, and CD-terminated polymers, have a variety of applications, including materials fabrication for theranostic nanomedicine. Due to this, cyclodextrin-based polymers have been validated as effective scaffolds in nanomedicine ,83.CD-based polymers are an attractive platform for theranostic nanomedicine . It is wThe first method for preparing high molecular weight (Mw = 104) water-soluble polymers was described by Solms and Egli in 1965 .Industrial α-, β-, and γ-CD polymers have been investigated for use as eluents in adsorption chromatography (on cellulose thin films) using aqueous solvents. Lederer et al. developed an approach to improve a polymer elution compared to α-CD . VariousHyperbranched polymers (HBPs) and hyperbranched polyglycerols (RPGs) are among many dendritic structures that combine excellent functionalization capabilities and stability with low viscosity. Therefore, RPGs are considered promising for theranostic nanomedicine applications for cancer treatment .The rheological properties of star polymers are also important compared to linear polymers. These polymers have a low intrinsic viscosity, a small hydrodynamic radius, a large critical micelle concentration (CMC), and, therefore, low aggregation. Intrinsic viscosity increases with increasing branching functionality and molecular weight. Once the functional efficiency saturates, the viscosity limitation is related only to the molecular weight of the arms. This may be attributed to increased repulsive interactions due to more heterocontacts between different arms .Tang et al. prepared star-shaped polymers via ring-opening polymerization (ROP) followed by reversible addition-fragmentation chain transfer polymerization (RAFT). In this experiment, DOX was used as a standard drug to conjugate the copolymers via an acid-labile hydrazone bond. Analysis of the solution properties of as-prepared DOX conjugates is greatly influenced by the composition and different structures of the polymers. Among the conjugates studied, an eight-arm triblock star polymer related to poly (ethylene glycol) (PEG) and N-2-hydroxyl methacrylamide (PHPMA) showed a poor cell penetration and fragmentary colocalization within lysosomes .A particular star-shaped amphiphilic polymer consisting of a β-CD core with hydrophobic (lactic acid) (PLA) and hydrophilic (ethylene glycol) (PEG) poly arms was prepared for the delivery of anticancer drugs .The study revealed that this star-shaped single-molecule micelle generated from β-CD-PLA-PEG was more efficient than Genexol-PM for cancer treatment ,93.Namgung et al. reported a novel nano-assembled drug delivery device fabricated by multifunctional host-visitor interactions between polymer-cyclodextrin and polymer-paclitaxel (PTX) complexes .®-based, cholesterol end-capped cationic polyrotaxanes (PR+) mixed with 2-hydroxypropyl-β-cyclodextrin (HPβCD) for small interfering RNA (siRNA) delivery. The data confirmed 90% of cell viability and a significant silencing effect (>80%) in cell lines such as HeLa-GFP and NIH 3T3-GFP  can be a promising tool for gene and siRNA delivery .Dandekar et al. scrutinized the capability of a prepared cationic polyrotaxane for siRNA binding into nanosized compounds via transfection of siRNAs samples targeting nucleotides of firefly pGL3 luciferase (Luc siRNA) to develop small interfering RNA molecule for curative approaches . In cellMoreover, the hydrophobic tetraphenylethylene (TPE)-AIE (aggregation-induced emission)-active dye (TPE-Ad) was encapsulated inside a hydrophobic core, and the hydrophilic polymer covered the surface of the hydrophobic core and acted as a shell-forming material . TPE-β-C2  anthracene) and hyper branched polyglycerol functionalized beta-cyclodextrin (HPG-β-CD). In evaluating commonplace strategies for preparing AIE-active polymers, this strategy only specifies facile reaction circumstances at room temperature (RT), freed from catalysts and air surroundings. The An-HPG-β-CD configurations might self-gather into middle-shell micelles in an aqueous solution because of the amphiphilicity. The hydrophobic An-B(OH)2 become accumulated within the center and emitted brilliant Yellow fluorescent protein (YFP) because of its attribute of aggregation-induced emission (AIE). Hydrophilic HPG-β-CD will coat the floor of the supramolecular and form the shell to render them water dispersion. Most crucially, the holes of β-CD in An-HPG-β-CD compounds allow the encapsulation of several organic molecules. Therefore, it is emphasized to consider their biological imaging and drug shipping utilization. Given their enormous potential, it is thought the An-HPG-β-CD configurations have bright prospects in biomedical applications ..Fourier-The particular idea of protein corona adsorption adds to new techniques for dwindling potential nano hazards and for using a more logical design of nanoplatforms. It also is a principal program and mechanism for nanostructures to provoke protection from infection. The brand-new fundamental natures are prognosticated to increase the efficacy and bioavailability of nanostructures as possible drug delivery and theranostic factors.While polymeric materials (PMs) and nanocarriers (NCs) are introduced into a biological milieu, the protein-adsorbed PMs and NCs, as opposed to the bare PMs and NCs, indicate the real identities and therapeutic responses of the PMs and NCs. An improved understanding of PM-PC and NC-PC compounds is an extraordinarily significant opportunity to improve novel nanomaterials for developing their approachability to medical science and theranostic nanomedicine.The main advances of CDbPs, such as CD-centred core, CD-pendant, and CD-terminated polymers, are reactive functional groups. Typically, the great attributes of both cyclodextrin and nanotechnology systems will simultaneously suggest extra avenues for cancer treatment strongly. In addition, we have a prerequisite to creating usage of the efficiency of these CD-based nanocarriers utilizing in vitro models for targeted tumor therapy and the degree of toxicological tests of cancers, namely life-threatening diseases. CDbPs bring new opportunities for the arrangement and preparation of new functional nanostructured materials. CDs provide a wide range of derivatives that can be employed in developing moiety diagnostic and therapeutic agents through chemical combination and cross-linking interactions. Ultimately, CDs could be used to customize powerful anticancer drugs to bring about impressive treatment. In addition, the protein corona specifies the destiny of polysaccharide nanoparticles (PNPs), and they play a key role in nanotechnology, in particular, in theranostic nanomedicine. Thus, derivatives of CD such as the randomly methylated-β-CD, sulfobutylether-β-CD, glucosyl-β-CD, and poly (ethylene glycol)-CD copolymers were synthesized to realize the necessity for in vivo studies.Even though various endeavors appeared constructed to distinguish CD-PMs-PC compounds and the uses of CD-PMs-PC in biomedical sciences and demonstrated an outstanding enhancement, it is too soon to know if we understand proper usage with CD-PM-PC compounds.Multidisciplinary strategies are expected to acquire additional details referring to PCs and their influence on nanomedicines to realize the favorite neurological and therapeutic consequences with nano-scaled materials. Solubility and production problems need to be considered before the application of CD-based theranostics in human treatment.For the clinical translation of these prospectively favorable polymers, notable efforts must be taken in nano-processing, scale-up, and regulatory scientific work considering collaborative therapy and diagnostics. This is in addition to the latest clinical theranostic techniques. Using drug delivery techniques based on polymers and high molecular carriers CDs can enhance efficacy while minimizing the side effects. The excellent characteristics of CDs will offer opportunities for further development of theranostic nanomedicine methods. The appropriate assembly of CD-containing polymers can result in universally applicable polymers capable of serving in several fields, such as diagnosis, therapy, nanoscience, self-assembly, and cross-linked nanostructures. CDs make it possible to modify potent theranostic nano-medicines procedures to enhance treatment efficacy. Translation theranostics promotes multidisciplinary interaction between science and medicine to enhance disease research and drug development. The nano-bio interactions represent a major challenge in translating theranostic nono-medicine to clinics. The incompatibility or potential toxicity of bionanotechnology based on communication with natural material can cause disorders such as hyporesponsiveness, inflammation, or related diseases. The toxic influence is appreciably controlled by numerous parametric quantities like zeta potential, shape, and solubility of nano-formulations in solution .Considering recent investigative capabilities, developed strategies will bring more advantages to increasing quality observation; this could be described as the interface between nanotechnology and biology. Overall, protein corona aspires to be a fascinating viewpoint tool in theranostics. In the last decade, medicine has moved to more informed healthcare management and treatment guided by theranostics. The search for markers for disease subtypes and more personalized treatment responses has been accelerated by academic scientists and pharmaceutical companies. About the power and wonderfulness of novel molecular technologies, the future of diagnostics  must reside in imaging for CD-based polymers. Imaging should diagnose the existence of a tumor, describe it, and monitor it relative to medical care. From the perspective of anatomical reference computed tomography (CT), magnetic resonance imaging (MRI) is the most accurate method, although these approaches cannot frequently differentiate between tumor and normal tissues. The regulative standards for these complicated polymers and their clinical trial results will reveal a model for future CD-based theranostic polymers.Overall, these reports display novel approaches in the study of the theranostic nanomedicine field for superior management opportunities of diseases and their side effects. To our knowledge, no serious computational or experimental study has been reported on theranostic, nanomedicine, and CD-based polymers. Such a study can help improve the relevant strategies and provide the information for more in-depth studies. Considering recent analytical functionality, amended manners supply more occasions to boost quality declaration in theranostic nanomedicine.


Alzheimer’s disease (AD) is the most common form of dementia with millions of people affected worldwide. Pathophysiological manifestations of AD include the extracellular accumulation of amyloid beta (Abeta) pep-tides, products of the proteolytic cleavage of the amy-loid precursor protein APP. Increasing evidence sug-gests that Abeta peptides also accumulate intracellular-ly, triggering neurotoxic events such as mitochondrial dysfunction. However, the molecular factors driving formation and toxicity of intracellular Abeta are poorly understood. In our recent study [EMBO Mol Med 2022 – e13952], we used different eukaryotic model systems to identify such factors. Based on a genetic screen in yeast and subsequent molecular analyses, we found that both the yeast chaperone Ydj1 and its human ortholog DnaJA1 physically interact with Abeta, facili-tate the aggregation of Abeta peptides into small oli-gomers and promote their translocation to mitochon-dria. Deletion or downregulation of this chaperone pro-tected from Abeta-mediated toxicity in yeast and Dro-sophila AD models, respectively. Most importantly, the identified chaperone is found to be dysregulated in post-mortem human samples of AD patients. Here, we aim to outline our key findings, highlighting pathological functions of a heat shock protein (Hsp) family member, which are generally considered protective rather than toxic during neurodegeneration. Our results thus chal-lenge the concept of developing generalized chaperone activation-based therapies and call for carefully consid-ering also maladaptive functions of specific heat shock proteins. AD is considered as a "protein misfolding disor-der". Aggregation-prone Abeta accumulates in the brain of AD patients. Thus, the implication of Hsps in AD comes as no surprise. The cellular heat shock response is a highly conserved mechanism that acts as a critical defense in AD and other proteinopathies. Heat shock family proteins comprise chaperone function and assist the folding or unfolding of other proteins and peptides. Some of them bind misfolded or aggregation prone pro-teins, inhibiting early stages of aggregation or contrib-uting to the resolving of aggregates, respectively. There-fore, Hsps provide an attractive therapeutic target in AD. In addition to their function in proteostasis, Hsps are involved in translocation of their clients across different intracellular membranes, including mitochondria. Mito-chondria have a crucial role in generating ATP, amino-acid metabolism, calcium homeostasis, redox balance, lipid metabolism and programmed cell death. Disturb-ance of mitochondrial homeostasis can lead to several diseases, including neurodegenerative maladies. Cere-bral tissue has a high demand for energy supply and therefore critically depends on mitochondrial function, yet it is highly sensitive to oxidative stress, due to a low antioxidant capacity. The implication of dysfunctional mitochondria and oxidative stress in AD is well estab-lished. Accumulation of Abeta in mitochondria of AD patients, as well as Abeta driven mitochondrial damage have been reported several times. Yet, the pathological pathway of intracellular Abeta and regulation of its trans-location to mitochondria remain poorly understood.YDJ1 prevented cell death as assessed by measuring propidium iodide (PI) stained population. Us-ing a pull-down assay we showed that Ydj1 physically interacts with Abeta42, and subsequent analysis utilizing microscopy and immunoblotting demonstrated Ydj1’s impact on Abeta42 oligomerization and its translocation to mitochondria. These effects appear to be very specif-ic to this peptide, as deletion of YDJ1 did not rescue for alpha-synuclein-induced cell death in yeast model for Parkinson´s disease nor did it show physical interaction to the mutated form of Abeta42 (A42m2). We observed similar findings utilizing an alter-native AD yeast model, targeting expressed Abeta42 to the ER/secretory pathway via Kar2 localization sequence. To further test if the human ortholog of Ydj1, namely DnaJA1, manifests the same Abeta42 related actions as Ydj1, we introduced DnaJA1-FLAG into the YDJ1 deletion yeast strain co-expressing EGFP-A42. As a result, DnaJA1 restored Abeta42 in-duced toxicity in ydj1 mutant yeast, re-storing Abeta42-induced cell death, translocation of EGFP-A42 to mitochondria and preventing EGFP-A42 degradation. In subsequent experiments, we aimed to corroborate our findings from yeast using alternative approaches. We performed in vitro assays, following the oligomerization properties of synthetic Abeta42 with and without presence of DnaJA1 protein. These assays revealed a strong implication of DnaJA1 in Abeta42 ag-gregation by accelerating low- and high-n oligomer for-mation detectable by immunoblotting, while its bacterial counterpart DnaJ delayed the formation of thioflavin-detectable larger aggregates and fibrils. To tackle the question of the human relevance of our findings, we evaluated DnaJA1 protein levels in human hippocampi of AD patients. We found differential DnaJA1 expression between demented and non-demented elderly controls, observing reduced DnaJA1 levels in AD brain tissue. We further extended our investigation to the genetically tractable model organism, Drosophila melanogaster. Pan-neuronal expression of Abeta42 to the secretory pathway led to upregulation of the Drosophila Ydj1 homologue, Droj2, similar to our yeast model system. Downregulation of Droj2 decreased neuronal Abeta42 accumulation, rescued shorter life span on manganese stress, and improved cognitive abilities as determined by aversive associative short term memory assay in a sex-specific manner. By assessing mitochondrial morphology changes upon reduction of Droj2 levels, we observed decreased solidity and circularity, thus being more simi-lar to the mitochondria of the wild type (Droj2 contain-ing) controls in Abeta42 expressing flies.To dissect the molecular mechanism of intracellular Abeta toxicity, we employed a humanized yeast model, expressing the Abeta peptide containing 42 amino acids (A42) C-terminally fused to enhanced green fluores-cence protein (EGFP-A42) accompanied by a linker re-gion in between to allow proper folding of EGFP. The EGFP tag provides the Abeta42 peptide with sufficient stability and we found that this construct induces typical hallmarks of cellular toxicity during AD. This includes oxidative stress, decreased ATP production, induction of mitochondria-dependent cell death, and finally accumu-lation of small-n soluble oligomers as well as high molec-ular weight Abeta species (i.e. high-n oligomers) partially located at mitochondria. Yeast provides an excellent eukaryotic model to study conserved pathways of cellu-lar stress and death, paired with powerful genetics. We validated our model using different peptide controls, i) empty vector control containing only EGFP, ii) Abeta containing 40 amino acids (A40), iii) a non-aggregating mutated form of Abeta42 (A42m2) and iv) the C-terminal peptide of Amyloid Precursor Protein 57 amino acids long, which all showed reduced or no toxicity compared to the Abeta42 peptide. With the intention to identify the crucial players modifying Abeta 42 cytotoxicity, we carried out two independent approaches: (i) we per-formed a genetic screen, testing the impact of knockout mutants of genes involved in cellular stress and cell death pathways and (ii) conducted a mitochondrial pro-teomic analysis of Abeta42 expressing yeast. Both ap-proaches revealed prominent involvement of mitochon-dria and mitochondrial function-associated proteins re-quired for Abeta42 toxicity. Moreover, a specific Hsp40 family member was identified to drive Abeta42 toxicity. Upon expression of EGFP-A42, this protein, namely Ydj1, was found to be upregulated. Deletion of Figure 1). This would be consistent with previously re-ported cell-type specific vital functions of these Hsp40 proteins. However, if the balance of mitochondria-mediated proteostasis is disturbed or overwhelmed by high amounts of Amyloid proteins, this pathway could turn into a maladaptive response resulting in mitochon-drial dysfunction and cell death. Vice versa, mitochon-drial dysfunction itself, which occurs in aging and related co-morbidities, may drive such maladaptive response leading to a vicious cycle. In turn this would favor the progression to AD pathology, as observed in AD models examined in our study. Future experiments are needed to test this hypothesis and to demonstrate the potential dual role of Ydj1/DnaJA1 depending on the timing of disease progression. Thus, a critical question remains: When does the physiological function of this Hsp40 pro-tein turn pathological and what triggers this event in the human brain during AD development?AD is one of the leading causes of mortality in devel-oped countries, thus becoming a significant social and health burden. The failure rate of potential AD drugs in clinical trials is enormous, and it appears at present that finding a cure for AD is a "mission impossi-ble". What could be the reason for this struggle? The moment AD is diagnosed, the brain tissue is already damaged to a remarkable extent, and further progres-sion of AD can only be delayed to some extent with available drugs. Consistently, a number of studies sug-gest that AD starts two or three decades before the first symptoms appear, making this dementia a “timing dis-ease” divided in different stages. It is a challenge to dis-sect the events happening in the brain tissue prior to the first symptoms. Therefore, model organisms provide us with a powerful tool to study the pre-symptomatic pro-cesses. Increasing evidence suggest that damaged and stressed mitochondria are among the early pathologies of AD. Apparently, this organelle plays a crucial role in the development of this disease. The Auwerx group re-cently demonstrated that the induction of mitochondrial proteostasis reduces Abeta aggregation in three differ-ent AD models, using a human neuroblastoma cell line, worms and transgenic mice. In parallel, another study reported that aggregation prone proteins are imported from the cytosol into mitochondria for their degradation. We therefore venture to hypothesize that Ydj/DnaJA1 may assist the cell to get rid of aggregation-prone Abeta, by translocating this peptide and its oligomers to mito-chondria for subsequent degradation (in vitro approaches combined with different in vivo models we identified a new key player and potential drug target of Abeta42-mediated toxicity. Ydj1/DnaJA1 counterintui-tively promotes the stabilization of toxic Abeta42 oligo-mers, rather than preventing the formation of toxic ag-gregates, and also regulates their transport to mitochon-dria. The dysregulation of human DnaJA1 in the brains of AD patients suggests that this Hsp may be involved in the etiology of AD, but future studies are needed to unravel the timing of these events in the human brain. Identify-ing the exact moment at which DnaJA1 is involved in the progress of AD could open new opportunities for the development of novel therapeutic or preventive strate-gies.In sum, using


Orbital metastases are a rare but life-altering complication in cancer. Most commonly seen in breast cancer, metastases to the optic nerves or extraocular muscles can have a devastating impact on visual acuity and quality of life. Hormone receptor status plays a central role in metastatic breast cancer treatment, with endocrine therapy often representing first-line therapy in hormone-receptor-positive cancers. Staging and treatment response evaluation with positron emission tomography (PET) computed tomography (CT) imaging with 18F-fluorodeoxyglucose (18F-FDG) is limited by high physiologic uptake in the intracranial and intraorbital compartments. Thus, traditional staging scans with 18F-FDG PET/CT may under-detect intraorbital and intracranial metastatic disease and inaccurately evaluate active metastatic disease burden. In comparison, 18F-fluoroestradiol (18F-FES) is a novel estrogen-receptor-specific PET radiotracer, which more accurately assesses the intracranial and intraorbital compartments in patients with estrogen-receptor-positive (ER+) cancers than 18F-FDG, due to lack of physiologic background activity in these regions. We present two cases of breast cancer patients with orbital metastases confirmed on MR imaging who underwent PET/CT imaging with 18F-FES and 18F-FDG. Multimodality imaging with 18F-FES PET/CT offers higher detection sensitivity of orbital metastases, compared with traditional 18F-FDG PET/CT imaging, and can improve the assessment of treatment response in patients with estrogen-receptor-positive (ER+) cancers. Visual changes are a rare and devastating complication of metastatic breast cancer (MBC) ,2. The iMetastatic breast cancer has a predilection for involvement of the extraocular muscles and surrounding extraconal orbital fat, leading to ocular dysmotility and diplopia ,4. PatieOver 60% of breast cancers are estrogen-receptor-positive (ER+), with estrogen being a primary driver of proliferation and cell growth . FurtherIn comparison, 18F-fluoroestradiol (18F-FES) is a novel radiotracer that targets estrogen receptor expression, providing increased utility in imaging ER+ MBC in areas of high physiologic glucose uptake ,11,12,13A 53-year-old female with a history of metastatic ILC presented for staging PET/CT with 18F-FDG. The patient initially presented with stage I, ER+/Her2 negative invasive lobular carcinoma of the left breast in 2007 and underwent chemotherapy with six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF), lumpectomy, whole breast radiation, and was given adjuvant hormonal therapy with 5 years of tamoxifen. In 2018, a breast MRI demonstrated a large area of clumped, non-mass enhancement in her right lateral breast. Multiple abnormal-appearing right axillary lymph nodes were also identified. MRI-guided biopsy of the right breast revealed grade 2 ILC that was highly ER+/PR+ and Her2 negative.She underwent chemotherapy with four cycles of docetaxel and cyclophosphamide. After completion of chemotherapy, she presented with one month of progressive vertigo. Brain MRI demonstrated a solitary 3–4 mm enhancing foci located in the subcortical white matter of the right frontal lobe, consistent with metastatic disease. She received stereotactic radiosurgery treatment for the solitary metastasis and had resolution of symptoms and resolution of disease on subsequent brain MRI imaging. She was then started on systemic therapy with fulvestrant and palbociclib. In May 2020, she reported sudden onset of right-sided facial pain, diplopia, as well as increasing right breast pain. The breast MRI revealed the progression of the disease in the right breast. The brain MRI at that time was negative for obvious metastatic disease that might explain her neurologic symptoms, but given the progression of disease in her breast, her systemic treatment was changed to capecitabine. Due to the persistence of symptoms, brain MRI was repeated and this time revealed an enhancing tubular structure involving the optic nerve and the right medial rectus, as well as the superior aspect of the right inferior rectus muscles. She subsequently underwent 18F-FES PET/CT, which showed activity of the posterior orbit, right medial rectus, and right inferior rectus . This acA 63-year-old female with a history of invasive lobular carcinoma (ILC), recently diagnosed with osseous metastatic disease in the thoracic spine and peritoneal carcinomatosis presented for staging PET/CT with 18F-FES. She initially presented five years prior with a palpable right breast mass. Ultrasound-guided biopsy demonstrated grade 2 ILC, ER 95%, PR 90%, Her2/neu 0%. A biopsy of an axillary lymph node was positive for metastatic carcinoma. She underwent right lumpectomy and axillary lymph node dissection, which demonstrated 4.0 cm ILC with 15 of 17 ALN positive. Completion mastectomy subsequently revealed 1.5 cm additional ILC.Following adjuvant chemotherapy with dose-dense doxorubicin and cyclophosphamide (AC) and paclitaxel (T) for 12 weeks, she received post-mastectomy radiation to the right chest wall and regional lymph nodes. She was maintained on anastrozole for nearly 5 years until the diagnosis of metastatic disease. One month following discontinuation of anastrozole, 18F-FES PET/CT demonstrated increased activity involving soft tissue nodules in the left superior orbit, right inferior orbit and bilateral extraocular muscles, and numerous foci in the skeleton . AbnormaVision is crucial for the quality of life and mediates most of our day-to-day interactions. Loss of vision secondary to under-diagnosis of orbital metastatic disease represents an avoidable devastating outcome of non-specific tumor imaging agents. A more sensitive test is needed for detection of orbital metastases, more accurate staging and treatment planning, as well as early interventions that could spare vision. Chemotherapy and endocrine therapy based on hormone receptor status is the first-line systemic treatment for patients with advanced breast cancer . The maiHigh baseline physiologic uptake of glucose in the brain and extraocular muscles poses a challenge for intracranial and intraorbital imaging with 18F-FDG PET/CT ,12. BaseUsually, 18F-FES is injected intravenously over the course of one to two minutes at a dose of 222 MBq (6 mCi) . PET/CT Given current breast cancer treatment advances, improving median survival while maximizing long-term quality of life has never been more possible. Maintenance of vision is essential to these goals. Clinicians should be aware that 18F-FES could be a useful diagnostic adjunct when evaluating the presence of metastases in breast cancer patients, and should recognize its utility in patients presenting with orbital symptoms. Large-scale studies investigating detection rates of intraorbital metastases with 18F-FES may further extend the role of this radiotracer in breast cancer care, and for imaging ER+ lesions in other areas of high physiologic glucose uptake, such as in the muscles of mastication and salivary glands [