In autoimmune rheumatic diseases, immune hyperactivity and chronic inflammation associate with immune dysregulation and the breakdown of immune self-tolerance. A continued, unresolved imbalance between effector and regulatory immune responses further exacerbates inflammation that ultimately causes tissue and organ damage. Many treatment modalities have been developed to restore the immune tolerance and immmunoregulatory balance in autoimmune rheumatic diseases, including the use of peptide-based therapeutics or the use of nanoparticles-based nanotechnology. This review summarizes the state-of-the-art therapeutic use of peptide-based therapies in autoimmune rheumatic diseases, with a specific focus on lupus. Other immunosuppressive agents, including disease-modifying anti-rheumatic drugs (DMARDs) and biological therapies have shown some efficacy in inducing long-term remission but carry the risk of adverse events including the development of malignancy.,7 In addition, treatments with biologics can be costly and increase the risk of systemic immune suppression.In systemic lupus erythematosus (SLE), corticosteroids are widely used to manage inflammation including in lupus nephritis, yet they carry significant side effects., 10, 11 We discuss below the promise of peptide-based immunotherapies and related clinical trials.A safe alternative to the use of drugs carrying important side effects has been the use of peptide-based tolerogenic therapeutics for the induction of immune tolerance to self-antigens though the inhibition of autoreactive T, B, and dendritic cells together with the promotion of the activity of immunoregulatory cell populations.Peptide-based therapeutics can be broadly categorized into two categories that are based on their chief mechanism of action: immunogenic or tolerogenic. Immunogenic peptide therapy induces an immune response against a specific antigen, whereas the tolerogenic peptide therapy induces immune tolerance to self-antigens., 13, 14 Although this approach has mainly been used in cancer immunotherapy to activate cytotoxic T lymphocytes (CTLs) against tumor antigens, several immunogenic peptide therapeutics have been developed as well for autoimmune diseases including SLE,,16 rheumatoid arthritis,,18 type 1 diabetes,,20 and multiple sclerosis, with varying success.Immunogenic peptide therapy aims to activate the immune system to a specific antigen by presenting it to the immune cells in a way that mimics a natural infection.regs) and tolerogenic dendritic cells (DCs)., 27, 28 This approach has been tested in several autoimmune diseases, including SLE, rheumatoid arthritis and multiple sclerosis. Tolerogenic peptide therapy can be further subcategorized according to the type of peptide(s) used, specifically:Tolerogenic peptide therapy aims instead to induce immune tolerance to self-antigens by selectively targeting and suppressing self-reactive T cells, while promoting the expansion of regulatory T cells  Epitope-specific peptides: These peptides are derived from specific epitopes of self-antigens and are used to selectively target autoreactive T cells.,32,33(2) Whole protein peptides: These peptides are derived from full-length self-proteins and can induce a broader immune response against multiple epitopes of the protein. They can be used to induce immune tolerance or to modulate the immune response in autoimmune diseases., 35, 36(3) Mimotopes: They are typically a series of linear overlapping peptides designed to pinpoint either T cell or antibody epitopes and can be used to induce immune tolerance and/or to activate regulatory immune cells.A central characteristic of autoimmune diseases is the breakdown of self-tolerance with the activation of autoreactive immune cells that secrete pro-inflammatory cytokines and chemokines that amplify inflammation.  against these proinflammatory biomolecules to inhibit their activities. In this strategy, the target immune cells are mostly B cells.The first strategy aims to antagonize proinflammatory cytokines and chemokines that induce and sustain inflammation and favor the development of tissue damage., 45, 46 The target immune cells in this strategy are autoreactive T cells, regulatory T cells (Tregs), and tolerogenic dendritic cells (tol DCs), as schematized in The second strategy involves the development of peptide-based tolerogenic molecules that aim to restore immune homeostasis and rebalance immune dysregulation.Although peptide-based therapeutic approaches have shown promising results in inducing immune tolerance in autoimmune diseases, an optimization of the design and delivery of the peptides is still crucial to improve clinical efficacy.Since pro-inflammatory cytokines and chemokines play a critical role in the pathogenesis of many autoimmune diseases, peptide-based vaccines have been designed to antagonize the pro-pathogenic cytokines and chemokines to reduce inflammation and tissue damage. while targeting the CXC chemokine ligand 10 (CXCL10) attenuated experimental autoimmune encephalomyelitis. Of interest, a peptide therapy targeting pro-inflammatory tumor necrosis factor alpha (TNF-α) induced the generation of Tregs and reduced inflammation in a mouse model of collagen induced arthritis.,51Modified peptides can target pro-inflammatory cytokines or chemokine receptors selectively. For example, a modified DNA peptide therapy targeting pro-inflammatory interleukin (IL)-17 significantly reduced organ damage and increased the survival of treated lupus-prone mice, Despite the promising results in preclinical studies, there are still challenges that need to be addressed before translation into the clinic, including the identification of the optimal peptide targets and delivery methods, as well as the potential off-target effects and long-term safety.Potential biologics have been generated to target pro-inflammatory cytokines, such as IL-1, interferon (IFN)-α, IFN-γ, IL-6, TNF-α, IL-17, and IL-21, and several clinical trials that aim at inhibiting the activities of these mediators have been initiated.in vitro and in vivo have identified several peptides that are useful in lupus treatment. Recent studies both H regions of anti-DNA antibodies from (NZB x NZW) F1 (BWF1) mice.,28,43,53 pCons peptide induce immune tolerance therapy in BWF1 lupus-mice by promoting the generation of autoantigen-specific regulatory T cells that suppressed effector T cells,54 and autoantibody-producing B cells.pCons (pConsensus-FIEWNKLRFRQGLEW) is a 15-mer peptide, derived from the V+ and CD4+ Tregs.,28,53,56 pCons-induced Tregs suppress the production of anti-dsDNA autoantibodies, reduce proteinuria, and delay nephritis in murine lupus.,53 Notably, oral administration of different forms of pCons peptide, including D and L forms, delayed anti-ds-DNA Ab production and lupus nephritis, and increased the survival of lupus mice.pCons peptide therapy induces immune tolerance by promoting expansion of CD8regs in lupus patients. When the lupus patients’ peripheral blood mononuclear cells (PBMCs) were cultured with pCons peptide, the expansion of fully functional Tregs occurred in those patients that were seropositive for anti-DNA autoantibodies. This is in line with the antigen-specificity of the response promoted by peptide immunotherapy, and resulted in the suppression by the pCons-induced Tregs of the proliferation of CD4+CD25- T effectors cells and reduced production of proinflammatory cytokines. Clinical trials are awaited to address whether the promising effects of pCons can be translated into clinical settings.Importantly, pCons peptide induced Tregs and by downregulating the production of IFN-α in both murine and human SLE., 60, 61 Tolerization with hCDR1 induced both CD4+CD25+ and CD8+CD28− Tregs in mice, which suppressed lymphocyte proliferation and autoantibody production., 63, 64 Earlier studies had shown that hCDR1 induced anergy in antigen presenting cells (APCs) and the generation of Tr1 Tregs, which expressed tolerance-associated genes.,59,60 hCDR1 also downregulated IL-1β, IFN-γ, and TNF-α in addition to IFN-α, and upregulated the immunosuppressive cytokine transforming growth factor-β (TGF-β). It also reduced expression of Lymphocyte function-associated antigen 1 (LFA-1) and CD44 and regulated Jun-N terminal kinase (JNK) in the reduction of the apoptosis of T cells.,66 hCDR1 treatment delayed the production of both anti-DNA antibodies and proteinuria, and increased the survival of lupus-prone mice by regulating B cell activating factor (BAFF). Additionally, hCDR1 improved cognitive behavior and brain pathology in lupus mice and downregulated the expression of the indoleamine 2, 3-dioxygenase (IDO) gene, which is increased in SLE patients.hCDR1 (edratide) is a 19-mer peptide based on the heavy chain complementarity-determining region one (CDR1) sequences of a human anti-DNA monoclonal antibody. Edratide reduced autoreactive T cells responses by inducing T  Secondary outcomes were improvement in the British Isles Lupus Assessment Group (BILAG) Responder Index and medicinal flare analysis. There was a positive trend in the Composite SLE Responder Index in the Intention-to-treat (ITT) cohort, and post-hoc analysis showed that the BILAG secondary endpoint was met for a number of subgroups dosing levels, including low or no steroids, seropositivity, and patients with 2 grade BILAG improvement.A phase II clinical trial with hCDR1 (Edratide) was conducted in 340 SLE patients and demonstrated that it was safe and well-tolerated. However, the co-primary endpoints of a reduction of SLE disease activity index (SLEDAI-2K) and adjusted mean SLEDAI (AMS) in patients compared with controls using a landmark analysis were not met.+ and CD8+ Treg responses, and reduce lupus nephritis and B cell activation in (SWR x NZB) F1 (SNF1) mice,, 71, 72 also blocking pathogenic autoimmunity in human SLE.,74Endogenous peptide epitopes of histones from nucleosomes induce immune tolerance and promote CD4, 76, 77 including the phosphorylated spliceosomal epitope peptide P140, which represses B cell differentiation and protects against murine lupus., 79, 80 Encouraging clinical trials indicate that it may improve clinical parameters in SLE patients.,81,82Other peptides derived from histone proteins have shown similar effects and have been investigated as therapeutic candidates in SLE,, 85, 86 It inhibits the R4A mAb from binding to dsDNA in animal models of lupus and SLE patients. It has been shown that the nephritogenic mouse monoclonal antibody R4A binds to a consensus pentapeptide sequence D/EWD/EYS/G (DWEYS), present in both NR2A and NR2B subunits of the mouse and human N-methyl-d-aspartate receptor (NMDAR).,85,87 Anti-DWEYS and anti-dsDNA antibodies have cross-reactivity with NMDAR. Intravenous administration of the DWEYS peptide to gestating mice had protective effects on the fetal brains when exposed to toxic doses of anti-NMDAR antibodies. In ex vivo studies in lupus patients with anti-DNA antibodies and active lupus nephritis, the DWEYS peptide inhibited DNA binding., 89, 90 Furthermore, the peptide suppressed human autoreactive B cells and the production of anti-dsDNA antibodies in vitro.DWEYS ((D/EWD/EYS/G)) peptide was identified using the mouse monoclonal anti-dsDNA R4A antibody.in vitro and in vivo., 92, 93 It inhibits lupus autoantibody-mediated antigen recognition by human SLE patient serum and further prevents pathogenic interactions with tissue antigens. In addition, it suppresses pathogenic deposition of SLE autoantibodies into the kidney glomeruli, and blocks neurotoxicity in vivo. Based on its structure-activity relationships, several analogues of FISLE-412 have been developed and found to neutralize anti-lupus antibodies in vitro and ex vivo. FISLE-412 is well-tolerated and not immunogenic; as well as being stable, easily synthesized in high-throughput, and inexpensive to produce.,94FISLE-412 is a small molecule peptidomimetic that can neutralize anti-dsDNA autoantibodies associated with SLE. FISLE-412 has shown effectiveness  ALW peptide exhibits isotype-dependent binding to anti-DNA antibodies in a sequence-specific manner. In addition, it markedly inhibits the binding of anti-DNA antibodies in human and mouse lupus sera to dsDNA and to laminin self-antigen. A protective effect of ALW peptide was demonstrated in MRL lymphoproliferation strain lupus mice, where it inhibited glomerular deposition of antibodies, reduced serum-anti-dsDNA antibodies, and improved overall renal pathology. Due to the absence of amino acids such as methionine, cysteine, and glutamine, ALW is physiologically stable and is resistant to peptide oxidation, cyclization, and degradation. It is nontoxic, non-immunogenic, and has a net neutral charge that reduces non-specific protein-protein interactions. As such, ALW or its analogues are seen as good potential novel candidate therapeutics in SLE.ALW (ALWPPNLHAWVP) is a 12-mer peptide mimic identified from the four different types of murine monoclonal anti-DNA immunoglobulin G  by screening phage display libraries. It is a tetrameric oligonucleotide conjugate that can reduce anti-dsDNA antibody levels, minimize nephritic flares, and act as a B cell tolerogen. It has been suggested that the relative affinity of dsDNA antibodies from SLE patients for LJP-394 may impact their responses to the drug, and patients with high-affinity antibodies to LJP-394 experience a reduction in affinity after four months of weekly treatment.LJP-394 (Abetimus sodium) is a synthetic peptide developed to induce immune tolerance to double-stranded DNA (dsDNA), a key autoantigen in SLE. and has shown to be safe and reduce circulating anti-dsDNA antibodies and disease activity in patients with active SLE. However, two pivotal trials failed to meet the primary endpoint of a statistically significant prolongation in the time to renal flare.,102 In another clinical trial, a dosage of 100 mg/week of LJP-394 significantly reduced anti-dsDNA antibody levels but did not significantly prolong the time to renal flare compared to placebo. Nonetheless, several positive trends in endpoints were observed in the treated group, leading to wonder how to improve targeting of this agent to the most suitable SLE patients.LJP-394 has been evaluated in 14 clinical trials, 106 In SLE, nanotechnology-based strategies have been developed to induce immune tolerance to self-antigens and to deliver peptides that modulate the immune response.Nanotechnology is a promising field for the development of new therapeutics including in autoimmune rheumatic diseases. In SLE, nanoparticles have been used to deliver lupus-specific peptides, selectively targeting autoimmune B cells, and inducing immune tolerance. For instance, poly-(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with a lupus-specific peptide (P140) have demonstrated efficacy in reducing autoantibody production and renal damage in lupus-prone mice. Another study utilized T cell targeted PLGA-nanoparticles encapsulating IL-2 and TGF-β resulting in the expansion of both CD4+ and CD8+ Tregsin vivo and suppression of murine lupus. Additionally, the delivery of a calcium/calmodulin-dependent protein kinase-IV (CAMK4) inhibitor via nanoparticles ameliorated murine SLE.,112 Furthermore, microRNA125a-loaded nanoparticles have also been found to restore homeostasis and ameliorate murine lupus by regulating the balance between T effector cells and Tregs.Nanoparticles offers several advantages over traditional drug delivery systems, including improved pharmacokinetics, enhanced stability, and reduced toxicity., 117 Similarly, magnetic nanoparticles (MNPs) coated with a lupus-specific peptide have been shown to selectively target lupus B cells and induce immune tolerance.,118,119 Furthermore, nanotechnology-based strategies enable the delivery of immunomodulatory agents such as immunosuppressants to target specific immune cells and tissues. For instance, PLGA nanoparticles loaded with rapamycin, an immunosuppressant, have shown effectiveness in reducing autoantibody production and renal damage in lupus-prone mice.,121 Also, dendrimers loaded with anti-inflammatory IL-10 reduce disease activity in mice., 124Apart from delivering lupus-specific peptides, nanoparticles can be engineered to target specific immune cells and tissues. For example, mesoporous silica nanoparticles (MSNs) functionalized with lupus-specific peptides and antibodies have been developed to selectively target immune cells and tissues.Peptide-based therapies for lupus have shown great promise in preclinical but clinical studies have been so far rather limited. This mandates additional clinical studies to better elucidate the potential of peptide-based therapies in SLE. In clinical studies, peptides have demonstrated safety and tolerability; however, only variable efficacy has been demonstrated in reducing disease activity in SLE patients, possibly due to trial design that cannot preselect those patients that might benefit the most from peptide immunotherapy. Of note, peptides have nonetheless consistently shown the potential to induce immune tolerance, which is dysregulated in SLE patients. Peptide-based therapies have also shown the potential to selectively target specific immune cell populations, either B cell or T cell populations.Peptides such as ALW and FISLE-412 have demonstrated the ability to neutralize lupus autoantibodies and prevent their pathogenic interactions with tissue antigens. More recently, the encapsulation of peptides in nanocarriers is leading to agents that can have improved pharmacokinetics, biodistri-bution, and bioavailability, as well as enhanced targe specificity. Nanoparticles can also help to reduce toxicity.Despite this all, there are still challenges that need to be addressed. One is identifying the optimal peptide sequences and dosage to achieve the most effective outcomes. Another challenge is to develop the proper biomarkers to monitor response and predict treatment outcomes. One important consideration is that combination therapies that involve peptides and other immunomodulatory agents can developed but have so far not been tested.To conclude, peptide-based therapies can promote immune tolerance and have shown great potential in reducing disease activity in lupus patients. With further research, new technologies such as nanotechnology and more information on how to better refine what we know for better clinical trials, peptide-based therapies could become a new avenue of treatment for SLE.


Chemotherapy was started immediately. Three days later, the patient was clinically stable, and as part of a prospective study comparing the two scans, [123I]mIBG-scintigraphy-SPECT/LDCT could be performed, showing only a large thoracal tumour (blue arrow) and a single certain liver metastasis (blue arrow). The spinal involvement was unclear, and the BM involvement, the cervical lymph node and several liver lesions could not be identified. The BM biopsy taken from the iliac crests was negative using standard staining, but a novel more sensitive GD2-antigen test  verified bilateral BM involvement mFBG-LAFOV-PET/CT without GA in a critically ill 9-month-old boy revealed a concise extension of neuroblastoma relevant for staging and treatment.In conclusion, a fast [


Centromeres are unique chromosomal loci that form the anchorage point for the mitotic spindle during mitosis and meiosis. Their position and function are specified by a unique chromatin domain featuring the histone H3 variant CENP-A. While typically formed on centromeric satellite arrays, CENP-A nucleosomes are maintained and assembled by a strong self-templated feedback mechanism that can propagate centromeres even at non-canonical sites. Central to the epigenetic chromatin-based transmission of centromeres is the stable inheritance of CENP-A nucleosomes. While long-lived at centromeres, CENP-A can turn over rapidly at non-centromeric sites and even erode from centromeres in non-dividing cells. Recently, SUMO modification of the centromere complex has come to the forefront as a mediator of centromere complex stability, including CENP-A chromatin. We review evidence from different models and discuss the emerging view that limited SUMOylation appears to play a constructive role in centromere complex formation, while polySUMOylation drives complex turnover. The deSUMOylase SENP6/Ulp2 and the proteins segregase p97/Cdc48 constitute the dominant opposing forces that balance CENP-A chromatin stability. This balance may be key to ensuring proper kinetochore strength at the centromere while preventing ectopic centromere formation. The ability to successfully partition replicated genomes to daughter cells during mitosis and meiosis is of vital importance to cells and organisms. Eukaryotic chromosomes feature centromeres, specialized genomic regions that assemble the kinetochore, a large multiprotein complex, during mitosis. These form the attachment site for spindle microtubules driving accurate genome segregation during cell division . TypicalMoreover, once formed, CENP-A chromatin is heritable through a self-templating mode of CENP-A chromatin assembly . While cin vitro and in vivo  was discovered as a ubiquitin-like protein , that isSaccharomyces cerevisiae, several centromere proteins are SUMOylated, including Ame1CENP-U, Okp1CENP-Q, Mcm16CENP-H and Mcm22CENP-K and Mcm21CENP-O, which is functionally required for high fidelity chromosome segregation  or Cdc48 in worms and yeast . p97 conArabidopsis thaliana, p97 removes CENP-A in a SUMO-dependent manner selectively in non-dividing pollen vegetative cells during pollen tube formation . To what extend this occurs at centromeres is still unclear. Early work on CENP-I showed that its SUMOylation results in its subsequent degradation and depletion of the STUbL RNF4 stabilized polySUMOylated CENP-I. This suggests RNF4 ubiquitinates polySUMOylated CENP-I , althougFurther, direct analysis of CENP-K and CENP-T showed these CCAN proteins to be ubiquitylated only at low levels. Proteasome inhibition did not stabilize these proteins, indicating these SUMOylated CCAN proteins are not targeted for a STUbL-dependent degradation . AdditioInterestingly, the key CENP-A assembly factor Mis18BP1 has also been reported to be SUMOylated in a manner that is under SENP6 control . In the S. cerevisiae, the deposition of non-centromeric CENP-A (Cse4) is facilitated by SUMOylation near its C-terminus, suggesting a positive role for SUMO in centromere assembly (In the yeast assembly . Howeverassembly ; 2018. Tassembly . Mislocaassembly . Psh1-meassembly  (Figure assembly . In humaassembly . Moreoveassembly , non-cenassembly . It willThe current literature on SUMO control of centromere maintenance identifies a destructive role where polySUMOylation is primarily driving disassembly and turnover via p97, countered by SENP6. A key point that is merging is that CENP-A maintenance by these opposing forces occurs not only to remove CENP-A from ectopic sites as shown in yeast  but evenImportantly, underlying the seemingly destructive force of polySUMOylation, there may be a functional requirement for SUMO moieties, where limited SUMOylation may have a role in stabilizing interactions within the centromere complex as has been shown in yeast . This maThe putative functional requirement for limited SUMOylation while excessive SUMOylation is detrimental requires an optimal level and thus tight regulation of the SUMOylation events at the centromere. This allows for a rapidly adaptable CCAN that can either shrink or grow during stochastic fluctuations and disruptive events such as transcription, DNA damage or even pulling forces by the mitotic spindle during mitosis. The central outstanding questions are; what is the functional role of SUMO, what are its relevant CCAN targets and does SUMO-driven turnover serve as a mechanism to selectively stabilize CENP-A at the centromere, while preventing ectopic accumulation elsewhere?


This study aims to investigate the presence of SARS-CoV-2 in public spaces and assess the utility of inexpensive air purifiers equipped with high-efficiency particulate air (HEPA) filters for viral detection. Samples were collected from six community-based organizations in underserved minority neighborhoods in Northwest Miami, Florida, from February to May 2022. Reverse transcription–quantitative polymerase chain reaction (RT-qPCR) was used to detect SARS-CoV-2 in air purifier filters and surface swabs. Among 32 filters tested, three yielded positive results, while no positive surface swabs were found. Notably, positive samples were obtained exclusively from child daycare centers. These findings highlight the potential for airborne transmission of SARS-CoV-2 in indoor air, particularly in child daycare centers. Moreover, the study demonstrates the effectiveness of readily available HEPA filters in detecting the virus. Improving indoor ventilation and implementing air filtration systems are crucial in reducing COVID-19 transmission where people gather. Air filtration systems incorporating HEPA filters offer a valuable approach to virus detection and reducing transmission risks. Future research should explore the applicability of this technology for early identification and mitigation of viral outbreaks. The COVID-19 pandemic caused by SARS-CoV-2 presented significant challenges for public health, particularly indoors where transmission occurs through respiratory fluids and airborne routes , an academic–community partnership addressing the social determinants of health (SDOH) at the Florida International University Herbert Wertheim College of Medicine , placed in a TapeSeal 95kPA specimen transport bag, sealed, and transported to the laboratory. In some locations, multiple rounds of sampling were performed, with purifiers wiped with disinfectant and replacement filters placed for subsequent collections.TM Viral/Pathogen Nucleic Acid Isolation Kit, and eluted total RNA was used for RT-qPCR for SARS-CoV-2 detection. The RT-qPCR assay used in this study is a laboratory-developed test (LDT) based on the CDC’s 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel (CDC 2019-Novel Coronavirus (2019-NCoV) Real-Time RT-PCR Diagnostic Panel for Emergency Use Only Instructions for Use, A 15-cm × 2-cm-long strip from the middle of the HEPA filter and a 3-cm × 3-cm square of the pre-filter were cut into small pieces and placed into a 50-mL conical tube with 3 mL of Integrated DNA Technologies Tris EDTA buffer (IDTE)  for risk mitigation. The absence of positive surface swabs suggests that surface transmission may not have been a primary mode in these settings, with close contact, droplets, and aerosols likely playing a more significant role. On the other hand, it may be related to the frequent wipe down with sanitizers common during the pandemic.Air filtration with HEPA filters provides a potential strategy for reducing the risk of airborne transmission of SARS-CoV-2 in community-based organizations since they are low-cost, easily accessible to the community, and easy to use. HEPA filters have high efficiency in capturing particles as small as 0.3 μm  can play a valuable surveillance role, making widespread monitoring strategies more accessible and feasible. Past research on aerosol sampling for SARS-CoV-2 focused on hospital settings and used laboratory sampling methods not well suited to community settings (Chia et al., In conclusion, our study provided evidence for the effectiveness of widely accessible and affordable HEPA filters in monitoring the presence of SARS-CoV-2 in community-based settings, particularly in child daycare facilities. These results have significant implications, emphasizing the role of environmental monitoring and the potential for widespread strategies using air purification systems for monitoring respiratory viruses in the urban microbiome.


ELOVL4 transgene studies have had positive outcomes. However, much remains to be understood about their role in retinal health and the potential for targeted therapies against retinal disease.Lipids serve many roles in the neural system, from synaptic stabilization and signaling to DNA regulation and neuroprotection. They also regulate inflammatory responses, maintain cellular membrane structure, and regulate the homeostatic balance of ions and signaling molecules. An imbalance of lipid subgroups is implicated in the progression of many retinal diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy, and diet can play a key role in influencing these diseases’ onset, progression, and severity. A special class of lipids termed very-long-chain polyunsaturated fatty acids (VLC-PUFAs) is found exclusively in mammalian vertebrate retinas and a few other tissues. They comprise <2% of fatty acids in the retina and are depleted in the retinas of patients with diseases like diabetic retinopathy and AMD. However, the implications of the reduction in VLC-PUFA levels are poorly understood. Dietary supplementation studies and  Very-long-chain polyunsaturated fatty acids (VLC-PUFAs) were first isolated and analyzed in bovine retinas by Aveldaño in 1987  Figure . Most reVLC-PUFAs are important in maintaining photoreceptor structure, function, and health. Research into the mechanisms of age-related macular degeneration (AMD) pathology shows lipid dysregulation is an underlying factor in AMD and other retinal dystrophies. Patients with AMD were found to have lower levels of VLC-PUFAs and omega-3 to omega-6 (n-3/n-6) fatty acids ratios compared to healthy controls. The low abundance and difficulty synthesizing VLC-PUFAs have made them difficult to study until recently. Moreover, their confinement to specialized tissue makes them not easily obtainable through a Western diet. Thus, assessing how these lipids affect eye health has been difficult, especially in patients with blinding diseases like diabetic retinopathy and AMD. In this review, we will discuss the current knowledge of VLC-PUFAs concerning eye health and disease and the strategies used to study their function in vivo and in vitro.While much research exists on the relevance of LC-PUFAs, such as docosahexaenoic acid (DHA), to infant development and eye health, epidemiological studies on VLC-PUFAs’ relevance to eye health and development are scarce. Dietary supplementation with omega-3 fatty acids such as DHA has beneficial effects on membrane stability, calcium signaling, and as precursors for anti-inflammatory molecules. High intake of omega-3-rich diets seems to have neuroprotective effects against retinal degeneration in patients with AMD , StargarThe retina has one of the highest contents of PUFAs in all human tissues. As the retina is regularly exposed to oxidizing light damage, retinal lipids—including beneficial LC-PUFAs, such as DHA, are susceptible to lipid peroxidation. Aging retinas are even more vulnerable to lipid peroxidation due to the accumulation of A2E and iso-A2E, which are pyridinium bisretinoids that contribute to drusen formation in dry AMD . ConcentVLC-PUFAs are biosynthesized in cells expressing the enzyme, elongation of very-long-chain fatty acids-4 (ELOVL4). ELOVL4 is a 3-keto acyl-CoA synthase that catalyzes the rate-limiting condensation step of very long-chain fatty acid (VLC-FA) synthesis from shorter-chain fatty acid precursors. After condensation by an ELOVL enzyme to attach two-carbon units to the fatty acyl chain, the fatty acid goes through three other enzymatic steps within the elongase complex with associated enzymes, including reduction with a β-ketoacyl-CoA reductase; dehydration with a β-hydroxy acyl-CoA dehydratase; and another reduction with an enoyl-CoA reductase. Through a series of elongation and desaturation reactions, VLC-PUFAs of different chain lengths and degrees of unsaturation are synthesized from dietary precursors. The elongated fatty acyl-CoA is metabolized by the cell or used as a substrate for further elongation . Like otThree mutations in the ELOVL4 gene are known to cause STGD3, a rare form of autosomal dominant early-onset macular degeneration and an orphan disease in the United States. These mutations are found in Exon 6 and include a 5-bp deletion rs1131690770), two 1-bp deletions (rs587776613), and a C > G transversion mutation (rs104893946), all of which lead to a truncated protein product which mislocalizes from the ER. Two other recessive variants in trans in the promoter region of ELOVL4 were found in one Stargardt patient; the authors provide evidence that these variants could lead to the downregulation of ELOVL4 expression . More re90770, twOther mutations in ELOVL4 have been associated with spinocerebellar ataxia, dry eye, ichthyosis, mental retardation, nystagmus, poor eye contact, latent visual responses, reduced electroretinogram (ERG) responses, retinitis pigmentosa, and myopathy ,28,29,30VLC-PUFAs make up <2% of total fatty acids in the retina. There are enriched in the photoreceptor outer segment disks of the retina. VLC-PUFAs in the eye are commonly found in the sn-1 position of di-polyunsaturated phosphatidylcholines, with DHA attached to the sn-2 position . The metIn contrast to diseases of ELOVL4 dysfunction and VLC-PUFA deficiency, VLC-PUFA overabundance due to peroxisomal dysfunction is known to cause several diseases under the Zellweger Spectrum of Disorders (ZSD). Peroxisomes are responsible for very-long fatty acid β-oxidation and degradation. ZSD causes craniofacial abnormalities, reduced DHA levels, and increased levels of VLC-PUFAs in plasma and various tissues . ZSD perThe retinal pigment epithelium (RPE) is a monolayer of pigmented polarized cells whose apical side faces the photoreceptor outer segments and whose basal side faces the choroid. Aside from nutrient and metabolic support, the RPE offers structural support to photoreceptors and phagocytoses rod and cone outer segments, which is crucial for recycling photopigments. VLC-PUFAs have been implicated in RPE health in various studies, and the RPE phagocytoses VLC-PUFA-enriched photoreceptor outer segments . STGD3 pOmega-3-rich diets are also known to improve RPE health. For instance, mice with photoreceptor-specific activated MTORC1 (to recapitulate AMD pathology) were fed DHA and were reported to have enhanced phagocytosis of photoreceptor outer segments by the RPE and a reduction of the other retinal symptoms associated with AMD . More reVLC-PUFAs have been linked to neurotransduction in photoreceptors. In addition to being situated in photoreceptor outer segments, they are also located in photoreceptor ribbon synapses . Very loVLC-PUFAs and ELOVL4 have been associated with rhodopsin, the main G-protein coupled receptor (GPCR) involved in phototransduction ,21,51. Dn-retinylidene phosphatidylethanolamine (n-retinyl-PE), which is why STGD3 pathology somewhat phenocopies ABCA4-related pathology in STGD1 disease [Although their role in cellular processes remains unclear, their unique hybrid structure has led researchers to believe VLC-PUFAs maintain the curvature of photoreceptor disks by their unique ability to occupy both leaflets of a phospholipid bilayer. Their concentration and orientation in the plasma membrane may also allow them to uniquely interact with and differentially stabilize certain proteins and molecules in photoreceptor disks’ inner and outer laminae . VLC-PUF disease .ELOVL2 is one of the elongases upstream of ELOVL4 on the VLC-PUFA biosynthetic pathway. It is another member of the seven-member family of ELOVL elongases responsible for LC-PUFA elongation in humans. ELOVL2 has also been implicated in AMD and retinal health, and mutations in this gene have been used to model visual abnormalities in mice, zebrafish, and cell culture models ,56, lendOmega-3 and omega-6 PUFAs are critical for membrane stability and cell signaling within the retina. They are also precursor molecules for important inflammatory regulators such as prostaglandins and leukotrienes. Although it is unclear if VLC-PUFAs serve as signaling molecules or immune modulators, there is research on elovanoids, which are C32 (ELV-N32) or C34 (ELV-N34) n-3 VLC-PUFA-derivatives involved in many signaling and metabolic processes. Elovanoids are lipid mediators that regulate neuroprotection, immune response, and apoptosis in the retina and central nervous system. Elovanoids are not the only PUFA-derived neuroprotectants, as DHA-derived docosanoids and EPA-derived eicosanoids are also involved in similar activities against neurodegeneration . These nThe effect of DHA supplementation on visual function has been well-studied; however, only a few studies exist on the effect of VLC-PUFA supplementation on vision. Oral gavage studies show that C32:6 n-3 VLC-PUFA is bioavailable in mice’s eyes and retinas and improves visual function ,60. SimiRecently, mice fed deuterated docosahexaenoic acid (D-DHA) also exhibited increased D-DHA levels in the retina, reduced oxidative damage, and improved visual function compared to mice fed chow supplemented with non-deuterated DHA ,64. DeutFurthermore, as an indirect route, research has shown that fatty acids modify gut microbiota and influence γ-aminobutyric acid (GABA) signaling in the gut-brain axis . The addAlthough ELOVL4 is known to synthesize VLC-PUFAs >24 carbon in chain length, little is known about its tissue-specific substrate specificities for fatty acids of different chain lengths and degrees of unsaturation. Cell culture studies have revealed ELOVL4’s substrate specificity through fatty acid elongation studies in primary and transgenic cell lines ,70,71. HElovl4a, and Elovl4b, with different spatiotemporal expression patterns, substrate specificities, and sub-functionalizations [Elovl4 genes, Elovl4a, and Elovl4b, have distinct substrate specificities for saturated compared to unsaturated VLC-FAs when analyzed in yeast tested through heterologous gene expression. While Elovl4a primarily elongated VLC-SFAs, Elovl4b was the primary enzyme responsible for VLC-PUFA synthesis [Like mammals, Elovl4 is highly expressed in the eyes, brain, and gonads of zebrafish and also synthesizes many of the same fatty acids as human ELOVL4 . Fish VLizations . While zynthesis . Nonetheynthesis , ELOVL4 Elovl4 knock-in and knockout mutations have been generated to understand the mechanism of STGD3 pathology in the retina. These studies have presented conflicting results in mutant mice of varying phenotypes because STGD3 is a complex disease involving many cell types, and it is unclear what role ELOVL4 haploinsufficiency and VLC-PUFA-depletion play in STGD3 pathology.Animal and cell culture models with dysfunctional ELOVL4 proteins can serve as tools to study VLC-FA depletion. Since no specific pharmacological inhibitors of ELOVL4 or VLC-PUFA biosynthesis exist, scientists have mostly relied on genetic models to study the role of ELOVL4 and VLC-PUFAs in health and disease. Mice with Elovl4 is lethal in postnatal mice, as they dehydrate shortly after birth due to the loss of ceramides in their skin [Global knockout of eir skin . This iseir skin . Some steir skin . In thiseir skin . This fieir skin , whereinElovl4 mRNA still influenced the phenotype at the neonatal stage.A developmental origin of STGD3 pathology was challenged in studies by Li et al., where homozygous STGD3 mouse neonates appeared to have normal retinal morphology . AlthougElovl4-knockout mice had normal retinal development before death, and heterozygous knockout mice even had superior a- and b-wave photoreceptor responses on an electroretinogram [Other sources have claimed that haploinsufficiency is not the cause of STGD3 pathology, as tinogram . Two tratinogram .Elovl4 conditional knockout mice to Karan et al.’s STGD3 transgenic mice. They found that the tissue-specific conditional knockout of the Elovl4 did not recapitulate STGD3 pathology. However, the caveat is that the tissue-specific knockout mutations did not completely deplete VLC-PUFA levels in adult mouse retinas [Elovl4 expression is not limited to cells with the rod-specific opsin and cone-specific human red-green pigment (HRGP) promoters used to generate the conditional knockouts. More research is needed on if mutant and wild-type ELOVL4 or its enzymatic products can diffuse or be transported into other cells surrounding the photoreceptors.Moreover, Barabas et al. compared rod-cone conditional  retinas , which mELOVL4 showed significant abnormalities and signs of cellular stress. In contrast, animal studies by McMahon et al. found no signs of cellular stress in their heterozygous STGD3 mutant mice, lending credence to the school of thought that VLC-PUFA depletion rather than cellular stress underlies STGD3 pathology [Copy number variations (CNV) are another source of variability in the STGD3 mouse models. CNVs have been implicated in the etiology of many inherited retinal dystrophies (IRDs) . Cell liathology . A detaiathology .The last review of the methods and tools used in VLC-PUFA analysis was done by Berdeaux and Acar in 2011 . Since tThe first steps of VLC-PUFA analyses usually involve total lipid extraction from homogenized tissue or cell cultures through supercritical fluid extraction or solvent-based methods such as Folch, Bligh and Dyer, or Matyash. These methods prevent oxidative damage or thermal degradation of fatty acid analytes. Since VLC-PUFAs are quite low in abundance, samples from small animals, cell cultures, or organoids are typically pooled and concentrated to obtain a detectable signal. Subsequently, VLC-PUFA-containing lipid groups can be separated through thin layer chromatography (TLC), derivatized into fatty acid methyl esters (FAMEs), concentrated, then resuspended in a suitable analysis buffer. The concentrated analyte is then subjected to gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS). And finally, post-analysis peak integration and lipid quantification. LC-MS/MS is a good way to understand the complex lipid groups containing VLC-PUFAs with FAME derivatization. At the same time, GC-MS is a great way to analyze VLC-PUFA concentrates in low quantities. Some groups have skipped the chromatographic step entirely and directly analyzed VLC-PUFAs in complex lipids using ionization and MS strategies ,79,81.m/z) as much as possible to identify larger, more complex compounds.Different forms of ionization exist to generate precursor and fragment ions for mass-spectrometry analysis. Hard ionization leads to extensive fragmentation and better compound identification because mass spectrometry detects each molecule’s unique fragmentation pattern. On the other hand, soft ionization ionizes the lipids but retains the precursor mass-to-charge ratio (3-TLC), and high-performance liquid chromatography (HPLC) before oxidative ozonolysis and gas chromatography-mass spectrometry with electron impact ionization (GC-EI-MS) analyses. Through these methods, they could identify VLC-PUFAs by their degree of unsaturation, chain length, and lipid species. They identified both omega-3 and omega-6 penta-unsaturated VLC-PUFAs, omega-3 hexa-unsaturated, and omega-3 tetra-unsaturated VLC-PUFAs in bovine retinas by oxidative ozonolysis [One of the main ways to analyze VLC-PUFAs is gas chromatography-mass spectrometry (GC-MS). For GC-MS analysis, total fatty acids are extracted and converted to FAMEs before solid phase extraction or reverse phase TLC, concentration, and then GC-MS analysis . Aveldañonolysis ,3.3-TLC to separate FAMEs based on the degree of saturation. After the removal of cholesterol and saturated fatty acid impurities, they then injected FAMEs of each band for GC-EI-MS analysis and identified positive precursor and fragment ions [M+} on their MS analyses. Suh et al. determined that m/z 79 was the diagnostic fragmentation ion for PUFAs. They also determined that m/z 108 fragment ions identified n-3 PUFAs, while m/z 150 fragmentation ions are from the n-6 series [n-3 and n-6 VLC-PUFAs. In 2008, Agbaga et al. modified Suh et al.’s method to identify low-concentration VLC-PUFAs in cell culture through selective ion monitoring (SIM) mode mass spectrometry [Subsequently, in 1994, Suh et al.  extracte6 series . The rattrometry .n-3 and n-6 VLC-PUFAs, then SIM to quantify VLC-PUFAs based on fragmentation ions with m/z 79, 108, and 150 as used by Suh and Agbaga [In 2010, Liu et al. developed a method to quantify VLC-PUFAs without using TLC to purify FAMEs. They performed solid-phase extraction using silica gel cartridges to remove cholesterol contaminants and reduce processing time to avoid lipid peroxidation. They used a combination of liquid chemical ionization (LCI) and electron ionization to identify d Agbaga , and matd Agbaga . This med Agbaga ,83,84.Sparus aurata using positive atmospheric pressure chemical ionization (APCI). This soft ionization mode was coupled with gas chromatography and a quadrupole orthogonal acceleration time-of-flight mass spectrometer source. Lipids were extracted using the Folch method and separated using TLC, and FAMEs were then derived from sphingomyelin, phosphatidylcholine, and cholesteryl ester fractions. Unlike Suh and Agbaga, Serrano et al. used soft ionization and performed peak acquisition using a form of tandem mass spectrometry, MSE, which obtains accurate mass for precursor and product ions using low (4 eV) and high-energy (25–20 eV) collision acquisition functions. They validated their experiments by recovering VLC-PUFA peaks after internal standard (C27:0) and VLC-SFA (C28:0–C30:0) fortification of Sparus aurata eye samples and re-studying mass spectra [−3 pmol/mg lipid [Serrano et al.  recently spectra . Throughmg lipid .m/z pairs for specific glycerophospholipids [m/z [A second way to analyze VLC-PUFAS is through liquid chromatography-tandem mass spectrometry (LC-MS/MS). VLC-PUFAs in glycerophospholipids can also be analyzed through normal-phase HLPC-MS with mass spectrometry conducted in negative electrospray ionization mode and multiple reaction monitoring (MRM) mode using precursor and fragment ion holipids . Berdeauholipids . VLC-PUFholipids . VLC-PUFholipids . They usids [m/z . Moreoveids [m/z . Similarids [m/z .VLC-FAs have also been analyzed using Orbitrap mass spectrometry and LC-MS/MS  because Since commercial VLC-PUFA standards are limited in availability, VLC-PUFAs can be quantified using a combination of bovine retina  and odd-n-3 or n-6 tetraenes, pentaenes, and hexaenes.In 2007, McMahon et al. analyzed underivatized phosphatidylcholine-containing VLC-PUFAs in the retinas of their STGD3 knock-in mice by electrospray ionization and tandem mass spectrometry using a Q-TOF Global Ultima mass spectrometer (ESI-MS/MS). They also employed LiCl salt to get better fragmentation patterns and structural understanding of their VLC-PUFA-containing PCs . Their aAnother soft ionization technique recently used to characterize VLC-PUFAs qualitatively is matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). MALDI-IMS uses special laser-absorbing matrices to minimize ion fragmentation in frozen sections. Berry et al.  used MALUltimately, the decision on what method to use depends on access to available technologies, sample state , and the desired readouts from the assay. While LC-MS/MS in combination with soft-ionization techniques allows for more robust detection of the different chemical forms of VLC-PUFAs, GC-MS combined with hard ionization allows for the quantification of VLC-PUFAs in minute quantities with predetermined structures and fragmentation patterns. A combination of analysis, derivatization, and detection methods, with validated chemical standards, may be used to capture the diversity of VLC-PUFAs in their various chemical forms and degrees of unsaturation.Metabolic changes that occur with aging and disease can also disrupt the homeostatic balance of lipids in sensitive tissue such as the retina. AMD is associated with abnormal retinal morphology and sub-RPE lipid deposits . These aCholesteryl esters regulate lipid metabolism by being involved in cholesterol storage and transportation. Cholesteryl esters are also elevated in specific brain tissue of patients with neurodegenerative diseases such as Huntington’s . In humaElevated acylcarnitine levels are associated with dysfunctional fatty acid oxidation and metabolic disorders such as Type II diabetes ,97,98. AFurthermore, VLC-FA-containing -acylcarnitines are acylcarnitines with very-long-chain saturated, monounsaturated, and polyunsaturated fatty acyl moieties. Due to their chain length, these lipids are primarily metabolized by peroxisomes instead of mitochondrial β-oxidation like their shorter chain counterparts ,103. In Since LC-PUFAs have some benefits in slowing down the progression of retinal disorders, it would be interesting to determine whether dietary supplementation of VLC-PUFAs would also improve vision in disease models. More research needs to be conducted on VLC-PUFA transport pathways, metabolism, and tissue incorporation to determine which delivery method  and chemical form  would be most efficiently incorporated in targeted organs.The translational value of VLC-PUFAs is their inherent potential for treatment against retinopathies and other conditions where the loss of VLC-PUFAs is implicated in disease etiology. There is a gap in non-invasive therapies against AMD. The addition of omega-3 fatty acids in the AREDS2 Study did little to improve the visual outcomes of patients with AMD, compared to formulations without the fatty acid supplement . This coAlthough much remains unknown about the physiological role of VLC-PUFAs in human retinas, the development of new technologies and progress in integrative, science-driven approaches to studying lipid dysregulation yield promise for elucidating the role of VLC-PUFAs in eye health and their potential therapeutic uses. Moreover, much remains unknown about the role of desaturases, peroxisomes, transporters, and other players involved in VLC-PUFA metabolism. It would be interesting to investigate if VLC-PUFAs play a role in other inherited retinal dystrophies like macular telangiectasia and other forms of Stargardt Disease.An integrative approach is needed to improve our current understanding of the role of VLC-PUFAs in eye health, one which combines structural and functional studies and reflects clinical data. ELOVL4 pathologies such as STGD3, ichthyosis, and spinocerebellar ataxia-34 highlight the importance of VLC-PUFAs in normal human development and function. Retinal degenerations such as AMD are multi-faceted, complex and involve many cell types and extrinsic factors. Thus, it is important to study the contributions of each cell type and factor to VLC-PUFA pathologies. In addition, it is important to know how VLC-PUFAs, in various chemical forms, derivatives, concentrations, and tissue distributions, can be used as biomarkers for overall health.


Ig subclasses were reduced by −70–89% (p < 0.0001) post-TPE with subsequent complete (IgM/IgA) and incomplete (IgG) recovery throughout the follow-ups. Mean IL-6 and CRP concentrations increased by a factor of 3–4 at post-TPE (p > 0.05) while PCT remained unaffected. We found no alterations in B- and T-cell populations. No adverse events related to TPE occurred. TPE induced a profound but transient reduction in circulating antibodies, while the investigated soluble immune components were not washed out. Future studies should explore the effects of TPE on particular cytokines and assess inflammatory lymphocyte lineages to illuminate the mode of action of TPE beyond autoantibody removal.Therapeutic plasma exchange (TPE) is used for drug-resistant neuroimmunological disorders, but its mechanism of action remains poorly understood. We therefore prospectively explored changes in soluble, humoral, and cellular immune components associated with TPE. We included ten patients with neurological autoimmune disorders that underwent TPE and assessed a panel of clinically relevant pathogen-specific antibodies, total serum immunoglobulin (Ig) levels, interleukin-6 , C-reactive protein , procalcitonin  and major lymphocyte subpopulations (cells/µL). Blood was collected prior to TPE , immediately after TPE (post-TPE), as well as five weeks (follow-up1) and 130 days (follow-up2) following TPE. Pathogen-specific antibody levels were reduced by −86% ( Autoimmune disorders can affect any part of the central and the peripheral nervous system (CNS and PNS). Moreover, they differentially involve the humoral and cellular components of the immune system ,2. IrresThe aim of this pilot study was to evaluate the extent and duration of the immunomodulatory effects induced by TPE. For this reason, we longitudinally explored the TPE-associated serologic dynamics of pathogen-specific antibody-levels and immunoglobulin classes, of lymphocyte counts and that of soluble components of the immune system including interleukin-6 (IL-6) among a cohort of 10 patients diagnosed with neurological autoimmune disorders.Of the 10 patients enrolled, three were woman. The median age of the cohort was 53 years (interquartile range (IQR) 36–72 years). Patient characteristics and indications for TPE are listed in p < 0.0001). This effect was transient and antibody levels recovered to an average of 55%  at follow-up1 and reached pre-TPE baseline values at follow-up2. Pathogen-specific antibody dynamics associated with TPE are graphically illustrated in p = 0.0084). The highest recovery rate was found in tick-borne encephalitis (TBE)-IgM, as antibody levels were reduced by −88%  at post-TPE and approached baseline values at follow-up1 . Slowest recovery rates were observed in hep-B antibody levels, as the follow-up1 concentrations only increased to an average of 27% (95% CI: −21–75%) compared to pre-TPE baseline levels.The average washout of pathogen-specific antibodies from pre-TPE baseline values to post-TPE was −86% . At follow-up1, the measured antibody levels recovered to an average of 80%  compared to pre-TPE levels. Data at follow-up2 suggest that antibody levels fully recover to pre-TPE baseline state after few months . IgG was the most profoundly affected IgG, while the impact of TPE on IgA and IgM was less pronounced. These latter subclasses almost completely recovered at follow up-1 (Dynamics of immunoglobulin washout behaved similar to those of pathogen-specific antibodies as shown in low up-1 a–c.p = 0.0006), but we observed differences in the respective recovery dynamics. At follow-up1, IgG3 exhibited the highest recovery rates  and IgG2 the lowest  at post-TPE  at pre-TPE to 16.2 pg/mL  and TPE was performed at the department’s intensive care unit.Demographic and clinical data were obtained during hospital courses and at routine follow-up visits. Blood was collected prior to TPE  and immediately after TPE (post-TPE). Moreover, blood was drawn approximately one month (follow-up1) and approximately four months (follow-up2) after TPE. Once patients received subsequent IVIG or immunosuppressant treatment, further laboratory data were excluded from this study to prevent a possible impact of these therapies on the here investigated parameters.This study was approved by the local ethics committee  and all patients gave written informed consent.The procedural indication for TPE was addressed by the referring neurologists. TPE was performed at the intensive care unit according to current guidelines ,33 and iPeripheral venous blood was collected in anticoagulated EDTA whole-blood tubes  for lymphocyte subtyping and native blood tubes  for the analysis of humoral factors and proinflammatory soluble molecules. All parameters were considered routine laboratory analyses and performed by the local Department of Laboratory Medicine certified according to the ISO-9001 standard and working according to ISO-15189 standards.Pathogen-specific IgG antibody concentrations to measles, mumps, rubella, VZV, hepatitis B (hep-B), diphtheria, tetanus toxins, TBE, and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) were quantitatively analyzed by chemiluminescent microparticle immunoassay (CMIA) or enzyme-linked immunosorbent assay (ELISA) test. Details on measurement instruments and assay cut-off values are depicted in Lastly, IL-6 and procalcitonin (PCT) were determined using electrochemiluminescence (ECL) technology-based immunoassays and c-reactive protein (CRP) via clinical chemistry assays. Assessment of IL-6, PCT and CRP was available in nine patients. The analyses were performed on COBAS 600 .p < 0.05.Demographics and patient baseline characteristics were descriptively explored. The range of estimates were determined via the delta method for computation of the 95% confidence interval (CI) of geometric means. We measured percentual changes in pathogen-specific antibody levels and immunoglobulin concentration for each patient after TPE referenced by their respective pre-TPE baseline values. We calculated the average percentual removal of alloantibodies and immunoglobulins. Proportional changes in pathogen-specific antibody levels, immunoglobulin concentration as well as absolute counts of immunocompetent cells and IL-6 concentration were plotted as XY data interconnected with lines. Significance testing was performed using paired t-test and overall significance set at All statistical analysis and graphical illustrations were performed using GraphPad Prism .TPE leads to a profound but transient removal of circulating antibodies, and precautions for successive maintenance therapy should be taken without delay to prevent permanent disability. On the other hand, the recovery rates of pathogen-specific antibodies together with preserved lymphocyte counts may explain the good safety profile associated with TPE observed among our cohort. Moreover, we found no washout of soluble components of the immune system associated with TPE, especially of IL-6. Future studies should investigate the effects of TPE on specific pro-inflammatory immune cell subsets and on cytokines beyond IL-6 to understand the mode of action in neuroinflammatory disorders that are presumably not antibody mediated.


Plasmodium falciparum is the most lethal parasite of its genus but has evaded many treatment and vaccine efforts due to its complex life cycle and redundant invasion mechanisms. Epitope-based vaccines hold significant promise for malaria vaccine development due to their ease of development and ability to target dominant regions in antigenically variable pathogens. The recently characterized protein P. falciparum merozoite Rh5 interacting protein (PfRipr) is nonredundant, highly conserved, and essential for erythrocyte invasion, making it an ideal target for a bloodstage malaria vaccine.Malaria infections remain an enormous contributor to global fatalities with an estimated death toll of 619,000 in 2021 and 77% of deaths being children aged under 5 years. Transmitted via mosquito, Merozoite InvasionModel of binding and insertion of PRCR complex to erythrocyte basigin in merozoite invasion. Adapted from Scally et al. 2022.P. falciparum sequences collected from Burkina Faso and Uganda, we assessed the immunogenic potential of PfRipr epitopes with regard to T-cell receptor binding and B-cell recognition. T-cell receptor binding was predicted using NetMHCpan searching against MHC I and II alleles with high regional frequencies. Using an in-silico 3D model of PfRipr predicted via AlphaFold, tertiary structures of all PfRipr sample sequences were predicted via SWISS-MODEL then analyzed by ElliPro to identify linear and discontinuous B-cell epitopes. Putative epitopes were filtered using allele coverage, conservation, antigenicity, and allergenicity.Using B-Cell Epitope PredictionProtocol for B-cell epitope prediction using AlphaFold for template modeling, Swiss-Model for homology-based modeling of sample sequences, and ElliPro for continuous and discontinuous epitope prediction.Epitope Sorting and FilteringProtocol for sorting T-cell epitopes using Average Allele Coverage  and B-cell epitopes using ElliPro Score (Protrusion Index representing surface accessibility of the epitope).P. falciparum.Between the two datasets, there were 19 matching epitopes with 7 MHC I, 9 MHC II, 1 linear, and 2 discontinuous. These epitopes were used to design a multi-epitope-based bloodstage vaccine construct against MHC EpitopesPartial list of MHC epitopes found in Burkina Faso and Uganda datasets.B-Cell EpitopesB-cell epitopes found in Burkina Faso and Uganda datasets.PfRipr 3D Structure with B-cell Epitopes3D model of PfRipr predicted via AlphaFold with labeled B-cell epitopesin silico protein stabilization and docking simulations, in vitro methods such as HLA stabilization or T-cell activation assays, and in vivo methods using transgenic mouse models. The pipeline of immunoinformatic analyses formulated in this project can be further applied to P. falciparum sequence datasets collected from other malaria endemic regions to develop vaccines effective against circulating strains.To validate their predicted immunogenicity, epitopes can be further investigated using Multi-Epitope Vaccine ConstructSchematic representation of hypothetical multi-epitope vaccine construct. FliC is added to the N-terminus to stimulate and amplify immune response. The EAAAK linker is used to separate the bifunctional fusion protein domains. AAY linkers are used to amplify MHC I and II epitopes and prevent junctional epitope binding. GPGPG linkers between B-cell epitopes function to minimize junctional epitopes and retain conformational-dependent immunogenicity. A six amino acid Histidine (6H) chain was added to the C-terminus to aid during lab purification processes.All Authors: No reported disclosures


The efficacy of ginger supplementation remains controversial for non-alcoholic fatty liver disease. We conduct this meta-analysis to explore the influence of ginger supplementation versus placebo on the treatment of non-alcoholic fatty liver disease.We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through November 2021 and included randomized controlled trials (RCTs) assessing the efficacy of ginger supplementation versus placebo for non-alcoholic fatty liver disease. This meta-analysis was performed using the random-effect model.Four RCTs involving 177 patients were included in the meta-analysis. Overall, compared with non-alcoholic fatty liver disease, ginger supplementation was associated with significantly reduced alanine aminotransferase =-0.43; 95% confidence interval [CI]=-0.85 to -0.02; P=0.04), homeostatic Model Assessment of Insulin Resistance , but revealed no obvious impact on aspartate-aminotransferase , total cholesterol , low density lipoprotein  or body mass index .Ginger supplementation benefits to treat non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease was identified by Ludwig in 1980 and accumulation of more than 5% triglyceride in hepatic parenchyma without notable alcohol consumption is defined as non-alcoholic fatty liver disease, which has become one global public health problemThere is still lack of effective treatment for non-alcoholic fatty liver disease, and new therapeutic approaches should be developed to improve the treatment efficacyIn patients with non-alcoholic fatty liver disease, ginger supplement resulted in significant improvement in alanine aminotransferase (ALT), total cholesterol, low-density lipoprotein (LDL) and insulin resistance index (HOMA) compared to placebo Ethical approval and patient consent were not required because this was a meta-analysis of previously published studies. This meta-analysis was conducted and reported in adherence to PRISMA  Two investigators have independently searched the following databases (inception to November 2021): PubMed, EMbase, Web of science, EBSCO and Cochrane library databases. The electronic search strategy was conducted using the following keywords: “non-alcoholic fatty liver disease” OR “steatohepatitis” AND “ginger”. The inclusive selection criteria were as follows: (i) patients were diagnosed with non-alcoholic fatty liver disease; (ii) intervention treatments were ginger supplementation versus placebo; (iii) study design was RCT.We extracted the following information: author, number of patients, age, female, weight, body mass index and detail methods in each group etc. Data were extracted independently by two investigators, and discrepancies were resolved by consensus. The primary outcomes were alanine aminotransferase (ALT) and aspartate-aminotransferase (AST). Secondary outcomes included homeostatic Model Assessment of Insulin Resistance (HOMA-IR), total cholesterol, low density lipoprotein (LDL) and body mass index (BMI).Methodological quality of the included studies was independently evaluated using the modified Jadad scale We estimated the standard mean difference (SMD) with 95% confidence interval (CI) for continuous outcomes. The random-effects model was used regardless of heterogeneity. Heterogeneity was reported using the I2 statistic, and I2 > 50% indicated significant heterogeneityA detailed flowchart of the search and selection results was presented in These outcome data were analysed with the random-effects model, and compared to control group for non-alcoholic fatty liver disease, ginger supplementation was associated with significantly reduced ALT  with low heterogeneity among the studies  Several reasons may account for the beneficial effect of ginger supplementation on non-alcoholic fatty liver disease. Firstly, ginger has substantial ability to improve insulin sensitivity to adipocytes Regarding the sensitivity analysis, significant heterogeneity remained for AST. After excluding the study conducted by Rahimlou et al. Ginger supplementation provides additional benefits to treat non-alcoholic fatty liver disease.


PET imaging using radiolabeled amino acids in addition to MRI has become a valuable diagnostic tool in the clinical management of patients with brain tumors. This review provides a comprehensive overview of PET studies in glioma patients with a mutation in the isocitrate dehydrogenase gene (IDH). A considerable fraction of these tumors typically show no contrast enhancement on MRI, especially when classified as grade 2 according to the World Health Organization classification of Central Nervous System tumors. Major diagnostic challenges in this situation are differential diagnosis, target definition for diagnostic biopsies, delineation of glioma extent for treatment planning, differentiation of treatment-related changes from tumor progression, and the evaluation of response to alkylating agents. The main focus of this review is the role of amino acid PET in this setting. Furthermore, in light of clinical trials using IDH inhibitors targeting the mutated IDH enzyme for treating patients with IDH-mutant gliomas, we also aim to give an outlook on PET probes specifically targeting the IDH mutation, which appear potentially helpful for response assessment. With the fifth edition of the World Health Organization (WHO) classification of tumors of the Central Nervous System (CNS) from 2021, gliomas with isocitrate dehydrogenase (IDH) mutations are classified either as diffuse astrocytoma of the WHO CNS grade 2–4, or as oligodendroglioma of the WHO CNS grade 2–3, if a 1p/19q co-deletion is additionally present -fluoroethyl)-L-tyrosine (FET), [11C]-methyl-L-methionine (MET), and 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA). Their uptake is facilitated by large neutral amino acid transporters of the L‑type (LAT) in gliomas and brain metastases , which are regularly overexpressed in both brain tumor types [18F-labeled tracers with a considerably longer half-life (110 min) such as FET and FDOPA allows transport to other facilities and has led to the replacement of MET predominantly by FET, especially in Europe [The most used amino acid tracers for PET imaging to date are O- has gained clinical interest particularly for imaging of primary and secondary brain tumors. Intratumoral transport of Fluciclovine seems to be mediated by LAT1, but predominantly by the neutral alanine, serine, cysteine transporter 2 (ASCT2), another neutral amino acid transporter [In recent years, the synthetic amino acid analog anti-1-amino-3-[nsporter .Brain lesions presenting hyperintense FLAIR signal alterations on anatomical MRI without concomitant contrast enhancement may frequently suggest an IDH-mutant non-enhancing glioma. On the other hand, these lesions constitute a heterogeneous group of diseases including non-neoplastic lesions such as cerebral hematoma, ischemic lesions, inflammatory or infectious processes, and even malignant gliomas without disrupted blood–brain barrier. False interpretation of these findings may result in necessary treatment being deferred or unnecessarily indicated.Amino acid PET has a sensitivity of more than 90% to detect gliomas –30, but Regarding the diagnostic performance of FET PET for differential diagnosis, a meta-analysis evaluating 13 studies with a total of 462 patients reported a specificity of 76% and a sensitivity of 82% for differentiating primary brain tumors from non-tumoral lesions . A subseFor differential diagnosis within the subgroup of gliomas, patients with oligodendroglioma characterized by an IDH mutation and a 1p/19q co-deletion . For exaIn summary, amino acid PET may add differential diagnostic information in patients with brain lesions suggestive of non-enhancing glioma. Of note, available studies do not primarily focus on patients with IDH-mutant gliomas. Thus, the impact of this genetic alteration on the diagnostic performance of amino acid PET warrants further investigation.Particularly in patients with non-enhancing gliomas, it is difficult to identify the biopsy target including the most malignant tumor parts using anatomical MRI –41, espeUsing dynamic FET PET acquisition, additional imaging parameters derived from time-activity curves such as time-to-peak values  or quantitative approaches to characterize time-activity curve patterns  can be obtained . For insFurthermore, accurate delineation of tumor extent to ensure a maximal resection is also of particular interest in patients with IDH-mutant gliomas, as even minimal tumor remnants after surgery may negatively impact overall survival . A recenThe differentiation of treatment-related changes such as pseudoprogression or radiation necrosis from tumor progression is of utmost importance in clinical routine. Especially amino acid PET using FET –65 or FDTwo studies evaluated the response to temozolomide chemotherapy in patients with previously untreated WHO grade 2 gliomas classified according to older WHO classifications , 32 usinIn a more recent study by Suchorska et al.  FET PET In patients with IDH-mutant gliomas, the efficacy of novel therapies targeting the mutant IDH enzyme using oral IDH1-inhibitors , IDH2-inhibitors such as endasidenib, inhibitors of both IDH1 and IDH2 mutations , and vaccines targeting the IDH1 (R132H) neoepitope are currently under investigation. Initial phase I clinical trials suggested promising antitumoral activity –78. At i14C-labeled acetate is significantly higher in IDH-mutant cells than in IDH-wildtype cells [18F-fluoroethylcholine [Regarding PET imaging of IDH mutations, novel PET tracers such as radiolabeled triazinediamine or butyl-phenyl sulfonamide analogs, and the radiolabeled IDH1 inhibitor AGI-5198 may be valuable candidates –83. Furtpe cells . An initlcholine . OverallAmino acid PET has become increasingly relevant in the clinical care of patients with gliomas. While most amino acid PET studies focused mainly on IDH-wildtype glioma patients, the available literature regarding its use in patients with IDH-mutant gliomas suggests that this technique also adds valuable clinical information for decision-making. In particular, this has been demonstrated for detecting the most malignant tumor parts, delineating glioma extent, diagnosing treatment-related changes, and assessing treatment response in IDH-mutant glioma patients.Nevertheless, it has to be pointed out that in a considerable fraction of available studies, the neuropathological characterization of the patients’ gliomas is either based on older WHO classifications for CNS tumors  or is only partially histomolecularly characterized according to current classifications . Thus, further studies in more homogenous patient groups with well-defined glioma characteristics in line with the latest 2021 WHO classification for CNS tumors, preferably in a prospective setting, are warranted.One prospect is the specific PET imaging of IDH mutations for response assessment in patients undergoing IDH-targeted therapies. The added clinical value is related to the considerably increased specificity of these PET probes for IDH mutations. Therefore, it offers a more reliable response evaluation since FLAIR signal alterations may be unspecific for neoplastic tissue, and 2-hydroxyglutarate MR spectroscopy is highly susceptible to artifacts.


Coronavirus disease 19 (COVID-19) has shown to be an infectious disease affecting not only of the respiratory system, but also cardiovascular system leading to different COVID-19-associated vasculopathies. Venous and arterial thromboembolic events have been frequently described among hospitalized patients with COVID-19 and inflammatory vasculopathic changes have also been observed. Several of the reported COVID-19 associated vasculopathies exhibit differences on epidemiology, clinical characteristics and outcome compared to non-COVID-19 types. This review focuses on the epidemiology, clinical, diagnostic and therapeutic characteristics as well as outcome data of COVID-19 associated thromboembolic events and inflammatory vasculopathies, elaborating similarities and differences with non-COVID-19 cohorts. In the end of 2019, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) spreads rapidly worldwide leading to the coronavirus disease 2019 (COVID-19) with various clinical manifestations ranging from asymptomatic cases to fatal acute respiratory distress syndrome. COVID-19 has been initially defined as a contagious disease affecting primarily the upper and lower respiratory tract. However, at a later stage in the pandemic, non-respiratory symptoms and the involvement of other organ systems than respiratory system were also observed in COVID-19. COVID-19-associated vasculopathies, including venous (VTE) and arterial thromboembolism (ATE) and to a minor extent also vasculitic changes, have been frequently described among patients with COVID-19, which potentially complicate the clinical course and increase mortality  of approximately 8% and of deep vein thrombosis (DVT) of approximately 11%, respectively. In addition, both studies revealed significantly higher VTE rates in patients admitted to intensive care unit (ICU) compared to a mixed cohort or to non-ICU patients   demonstrDespite a common occurrence in COVID-19, only a few data are available that investigate signs and symptoms of COVID-19 associated PE and DVT. Data of a prospective registry including patients with symptomatic and confirmed acute VTE in COVID-19 reported similar symptoms of PE as in conventional PE. 20% of patients with COVID-19 associated PE suffered from hypotension with systolic blood pressure < 100 mmHg or requirement of vasopressors and 18% had a tachycardia (heart rate > 110/min) . HoweverCOVID-19 symptoms typically preceded CVT-related signs in 90% of cases, and neurological signs and symptoms seemed to be analogous to conventional CVT. Headache was the most commonly described symptom (85%), followed by epileptic seizures (42%), and altered mental status (28%), while encephalopathy, focal signs, and hemiparesis also occurred as main presenting complaints , 38. COVCompared to VTE, ATE seems to occur less frequently in COVID-19 with a reported pooled frequency of 2.0%  in hospitalized COVID-19 patients , 43. RatClinical features of COVID-19 associated acute coronary syndrome (ACS) seem to differ partially compared to non-COVID-19 ACS. Higher prevalence of atypical symptoms, such as dyspnea and syncope, than typical chest pain was observed in COVID-19 in comparison to a pre-COVID-19 cohort with ST-elevation myocardial infarction (STEMI), although chest pain was still a common symptom with up to 60% –51. AddiCOVID-19 associated ischemic stroke seems to have a predominance of large vessel involvement compared to small vessel disease, which was present in only 2-4.4% of COVID-19 cases while pre-COVID-19 stroke data attribute 20% of stroke cases to small vessel disease –73. In cAs mentioned above, COVID-19 associated ALI is a rare finding among patients with COVID-19 . In the Other COVID-19 associated ATE include mesenteric ischemia, splenic, and renal arterial infarctions. All three conditions are, however, rarely reported in the literature and mostly only in case reports –107. WhiEpidemiological data of COVID-19 associated vasculitides are scarce as specific vasculitides other than COVID-19 associated endotheliitis are a rare manifestation in COVID-19 . The mosIn patients with COVID-19 associated CLL, abnormal D-dimer levels and antinuclear antibodies were found in 14.8% and in 11.5% while abnormalities of inflammatory parameters like ferritin, CRP or lymphocytes were found only sporadically . COVID-1During the pandemic, various antithrombotic treatment and management approaches have been evaluated and discussed. As the occurrence of VTE dominated, different trials primarily investigated the outcomes of hospitalized COVID-19 patients without suspected or with confirmed VTE depending on prophylactic or therapeutic anticoagulation regimens , 135. OnAll included panels recommend against the prescription of anticoagulants in non-hospitalized COVID-19 patients with normal risk for VTE and no indication for post-discharge prophylaxis when no VTE was detected –138. HowEpidemiological data attribute hospitalized COVID-19 patients an increased risk for COVID-19 associated VTE, also if compared to other viral infectious diseases. Studies emphasized notably higher rates of VTE in COVID-19 ICU cohorts, especially if a systematical screening approach was used. As screening approaches led to even higher detection rates of VTE, and data revealing a predominance of smaller vessel affection, the question arises whether these examinations actually caused the increased rates of otherwise occult thrombi. Consequently, screenings in other infections, such as influenza, might also detect higher rates of occult and asymptomatic thrombi. However, in the case of COVID-19 patients being transferred to ICU because of clinical deterioration, the screening approach could unveil its cause and is therefore reasonable.COVID-19 associated ATE and vasculitic disorders seem to occur with a comparable extent like in other viral infectious diseases, although frequencies rise with severity of COVID-19. Of interest is the finding that PE was comparable or even more prevalent to DVT in some studies, suggesting a role of in-situ pulmonary thrombi formation, which may be a disease-specific feature in COVID-19. In-situ pulmonary thrombi formation may be driven by endothelial dysfunction, immunothrombotic processes and formation of NETs –7. HowevDespite tremendous knowledge growth in the field of COVID-19 associated vasculopathies, the gained knowledge is still subject to limitations. Firstly, reported prevalence and incidence varied partially widely across the studies and different screening approaches for the respective VTE or ATE were used. Additionally, the increasing administration of anticoagulation in newer studies and the fact that cohorts included patients from different time points during the pandemic may substantially influence epidemiological and outcome data. Furthermore, on the one hand, several meta-analyses included mainly retrospective studies, and on the other hand, several studies on specific clinical data, including symptomatology and subtypes of COVID-19 associated vasculopathies, included only a small sample size. All of this limits the significance. Moreover, diagnostic and treatment recommendations, which originated from the initial stage of the pandemic, might be outdated, and, as most studies solely declared all-cause mortality within their cohorts, the actual proportion of thromboembolic deaths remains still elusive.Overall, specific vascular diseases seem to occur frequently in COVID-19 which may complicate the clinical course. Although numerous studies on clinical aspects of COVID-19 associated vasculopathies are available, the gained knowledge has still limitations. Therefore, further clinical research is required for specific diagnostic and therapeutic options and to reveal robust outcome and long-term sequelae data in COVID-19 associated vasculopathies.


Athletes with an anterior cruciate ligament (ACL) injury followed by ACL reconstruction(ACLR) often perform various testing to guide return to sport, but preinjury data arerarely available for comparison. This longitudinal case-control study reports absolutevalue and between-leg symmetry data on maximal performances for single-leg hop height anddistance, muscle strength, and side hop landing mechanics of an 18-year-old female soccerathlete collected 5 months before sustaining an ACL injury and again at 10, 13, and 29months post-ACLR. Her data were compared across test sessions and to cross-sectional dataof 15 asymptomatic female athletes. However,further pre- and post-ACL injury comparisons are needed to better grasp the consequences ofinjury.Few studies report anterior cruciate ligament (ACL) preinjury and repeated post-ACLreconstruction (ACLR) testing for functional performances and biomechanics. Case reports havepresented pre- and post-ACL injury data for knee strength and gait mechanics,We had the opportunity to compare longitudinally data on hop performances, muscle strength,and knee mechanics of an 18-year-old female elite athlete collected 5 months before shesuffered an ACL injury with data collected again at 10, 13, and 29 months post-ACLR.2)played soccer in the second-highest national division and sustained a contact ACL injury onher nondominant  leg. The injury was verified usingmagnetic resonance imaging and treated with ACLR using a hamstring tendon autograft 1 monthafter injury. The IA completed 13 months of physiotherapist-led rehabilitation . Before fullyreturning to soccer, standardized evaluation was performed at the outpatient physiotherapyclinic attended by the IA at 10 and 13 months postsurgery . She had no history of injury or surgery to theback or lower extremities. The data from the IA were compared across test sessions and tocross-sectional data of 15 asymptomatic female athletes  competing in the highest/second-highestnational divisions in floorball or soccer. These athletes were screened for musculoskeletalor neurological pathology before testing.The injured athlete  and 1-leg vertical hop height , the standardized rebound sidehop  for biomechanicalevaluation, and isometric peak knee extension and flexion strength (knee in ~65° flexion)using a KinCom isokinetic dynamometer. Limb symmetry indexes  were calculated for peak values for OLHD, OLVH, and strength tests. Jump distancewas also reported in percentage of body height. The biomechanical analysis of knee jointmechanics in frontal and sagittal planes was performed using a model of 56 passive sphericalmarkers and an 8-camera Qualisys motion capture system (240 Hz) synchronized with 2 Kistlerforce plates (1200 Hz).The IA regained preinjury OLHD and knee extension strength at 10 months post-ACLR, OLVH at13 months post-ACLR, and knee flexion strength at 29 months post-ACLR. Peak OLHD inpercentage of body height was, at preinjury testing, 89%/89% (soon-to-beinjured/noninjured), at 10 months post-ACLR 90%/90% (injured/noninjured), at 13 monthspost-ACLR 90%/97%, and at 29 months post-ACLR 95%/89%, whereas controls on averagedemonstrated 79% (SD 12%)/82% (SD 10%) (nondominant/dominant leg). The knee extension andflexion strength of the IA for the noninjured leg decreased after injury and was notregained until the 29-month test . During 58Our main finding was that the recovery profile of hop performances, knee strength, and kneelanding mechanics of the IA was neither congruent nor fully regained upon returning tocompetitive sports. The IA completed 13 months of physiotherapist-led rehabilitation whileprogressively participating in sport-specific training with her soccer team, decided inagreement with the team professionals. Knee flexion strength took the longest to regain,likely explained by the hamstring graft donor site. Preinjury knee extension strength ofboth limbs was lower than for the controls and never reached the commonly referred toclinical norm of 3.0 Nm/kg despite increasing over the course of, and beyond,rehabilitation. These results corroborate previous findings showing that recovery differsacross outcome measures from preinjury to post-ACLR. We observed this effect primarily for knee extension strength, where the asymmetricpreinjury LSI of the IA was symmetric at 10 and 13 months post-ACLR due to reduced strengthfor the noninjured limb. Similar to the preinjury data of the IA, we recently reported thatmost athletes, irrespective of having had ACLR or being noninjured, fail 90% LSI criteria ina test battery of hop and strength tests. These matters are important when considering outcomes and return-to-sport decisionspost-ACLR.The often-used LSI criteria have been criticized because they do not relate to normativedata or account for the decreased function of the noninjured leg and, therefore,overestimate the ACLR leg. An asymmetric movement pattern may reflect permanent deficits in sensorimotor kneefunction not restored by ACLR.The asymmetrical knee landing mechanics of the IA post-ACLR corroborate previouslydemonstrated asymmetric gait mechanics long after achieving symmetrical strength and highfunctional performance.In conclusion, after ACLR, the time needed for the IA to recover her preinjury performancesand between-leg symmetry in single-leg hops and muscle strength differed. Despitedemonstrating symmetric hop and strength performances, she persistently showed asymmetricside hop landing mechanics. These findings highlight the need for multiple outcomes toinform return-to-sports decisions post-ACLR.Click here for additional data file.Supplemental material, sj-docx-1-sph-10.1177_19417381221147305 for A LongitudinalCase-Control Study of a Female Athlete Preinjury and After ACL Reconstruction: HopPerformance, Knee Muscle Strength, and Knee Landing Mechanics by Josefine E. Naili, JonasL. Markström and Charlotte K. Häger in Sports Health: A Multidisciplinary Approach


Optimal duration of antimicrobial therapy (AT) for catheter-related septic deep venous thrombosis (DVT) is unknown. We aimed to compare the outcomes of patients receiving short-course AT (≤21 days) versus prolonged-course AT (>21 days).This was a monocentric retrospective study comparing adults with catheter-related septic DVT from 2015 to 2020 treated with short- or prolonged-course AT. A propensity score–weighted analysis was used to mitigate potential bias. The primary outcome was a composite of all-cause mortality or recurrent bloodstream infection 30 days after AT discontinuation.P = .192). No differences in 90-day all-cause mortality and 90-day relapse were observed between the treatment groups .Of 172 patients with catheter-related septic DVT, 104 were treated with prolonged-course AT and 68 with short-course AT. In the propensity score analysis, we found no significant difference in 30-day all-cause mortality or relapse between the 2 groups  is unknown. According to this propensity score–weighted study on 172 patients, short-course antimicrobial therapy (≤21 days) could be an effective and safe option to treat catheter-related septic DVT. Healthcare-associated primary bloodstream infections (BSIs) result in increased morbidity, mortality, and costs . Indeed,Clostridioides difficile infections (CDIs) FDG (2-[18F]fluoro-2-deoxy-D-glucose)–PET/CT uptake receiving 14-day AT or oral switch therapy, compared to patients treated with prolonged-course intravenous AT for S aureus catheter-related DVT [18F]FDG-PET/CT-guided AT duration should be prospectively evaluated.Possible CRBSIs were included despite the risk of lower specificity of this definition, as for half of these infections, we found additional arguments to enhance diagnostic performance . Fewer patients with certain CRBSI-DVT diagnoses were noticed in the short-course AT group and therefore possibly more nonseptic thromboses were treated in this group, leading to the lack of difference observed in the study. However, we have taken these limitations into account by performing a sensitivity analysis based only on certain CRBSIs. Nevertheless, confirming the septic nature of a thrombus is challenging as its microbiological culture is almost never realized. Some authors suggest using positron emission tomography–computed tomography [PET/CT]) in order to confirm septic thrombosis in cases of bacteremia associated with catheter-related DVT. In a retrospective study, Gompelman et al found that 90-day all-cause mortality or relapse was not significantly different in patients with nonremarkable [ated DVT . NeverthReduction of AT duration is a keystone of antimicrobial stewardship, considering the potential risks of excessive AT duration: CDI, new resistance, and longer hospital stays , 22, 23.The major limitation of our study is its retrospective design. Potential selection biases may have occurred in that some prognostic factors may have influenced treatment decision, such as clinical severity, which we could not accurately characterize with scoring. We tried to overcome these biases with the use of a PS-weighted analysis, and groups were well-balanced in IPTW analysis. However, we cannot exclude the possibility of additional, unmeasured confounding factors that could impact the association between AT duration and mortality or relapse. Thanks to available death records from the national registry, we had no missing data concerning all-cause mortality and we made sure that there was a regular hospital follow-up to monitor the absence of relapse.Future fields of study could focus on the development of better diagnostic methods of septic thrombosis using nuclear imaging methods. Moreover, wide variability in AT duration suggests a need to produce high-quality evidence to identify optimal AT duration according to etiology microorganism. Further prospective and randomized trials are needed to validate our findings.Candida spp septic DVT and in oncohematologic patients.In conclusion, our study provides interesting data regarding optimal treatment duration of catheter-related septic DVT. A 21-day AT for such infections appears as safe as longer-course AT. Nevertheless, pending additional studies, consideration should be given to prolonged treatment durations in patients with ofad530_Supplementary_DataClick here for additional data file.