Pigmented paravenous retinochoroidal atrophy (PPRCA) is an uncommon fundus disease characterized by perivenous aggregations of pigment clumps and retinochoroidal atrophy distributed along the retinal veins. We report a Chinese female case of unilateral PPRCA with acute angle-closure glaucoma (AACG).A 50-year-old Chinese female presented with vision loss and elevated intraocular pressure (IOP) in the right eye and then underwent trabeculectomy. She referred to our clinic for further evaluation and treatment. The funduscopic examination revealed grayish retinochoroidal atrophy and osteocyte-like pigment clumping lesions along the retinal veins and peripapillary preretinal hemorrhage in the right eye. The patient also presented with AACG in the same eye on the basis of past medical history of acute attack, shallow anterior chamber depth (ACD), narrow angle showed by ultrasound biomicroscopy (UBM) and glaucomatous neuropathy identified by optical coherence tomography (OCT). Other examinations like fluorescein fundus angiography (FFA), electroretinogram (ERG) and electrooculography (EOG) all confirmed the aforementioned diagnose.PPRCA is a rare disease, uncommon in females and symmetrical in both eyes. We present a rare case of unilateral PPRCA accompanied with AACG. Pigmented paravenous retinochoroidal atrophy (PPRCA) is a rare fundus disease in which there is aggregations of osteocyte-like pigmentation associated with perivenous retina and choroid atrophy . It usuaIn this case report, we presented a unique case of unilateral PPRCA in a middle-aged Chinese female who was diagnosed with PPRCA by accident when acute angle-closure glaucoma (AACG) attacked.A 50-year-old female complained of loss of vision in her right eye accompanied by ocular pain, headache, nausea and vomiting. The intraocular pressure (IOP) was 55 mmHg in the right eye and 11 mmHg in the left eye at the time of her visit to the local clinic. The fundus could not be seen clearly due to corneal edema. She denied any remarkable systemic, ocular disease history and was not taking any medication. She later underwent trabeculectomy in the right eye there and the IOP decreased to normal level and the cornea became clear. However, the visual acuity remained poor and she was referred to our glaucoma clinic for further evaluation and treatment.At the time of current visit, visual acuity was 20/500 in the right eye and 20/20 in the left eye, with IOPs of 16.0 mmHg and 11.3 mmHg respectively. Slit lamp revealed the cornea was clear and the anterior chamber was free of cells or flare in right eye and the pupil diameter was 4 mm with extensive posterior synechia and no response to the light. A diffuse superior subconjunctival filtering bleb and a peripheral iridotomy at 9 o’clock were observed.Ultrawide-field fundus photography showed grayish retinochoroidal atrophy and osteocyte-like pigment clumping lesions along the retinal veins and peripapillary preretinal hemorrhage in the right eye Fig. a, withouEarly fluorescein fundus angiography (FFA) of the right eye revealed transmitted hyperfluorescence consistent with retinal pigment epithelium (RPE) atrophy with more extensive areas of choriocapillaris atrophy Fig. c and latLaboratory studies including complete blood count, serum electrolytes, serum protein electrophoresis, erythrocyte sedimentation rate, and C-reactive protein were within normal limits. Antinuclear antibody test was negative. Toxoplasma, rubella virus, cytomegalo virus, Hepatitis B surface antigen, human immunodeficiency virus antigen/antibody, T. pallidum antibody and Hepatitis C virus tests were all negative. Chest X-ray ruled out tuberculosis and other active inflammatory process.The patient had received no specific treatment for RPE or choriocapillaris atrophy and was followed up with IOP at a local clinic. Her IOP were within normal limits during 1-year follow-up period.PPRCA is a rare disease with chorioretinal atrophy in which there is bilateral paravenous RPE atrophy and osteocyte-like pigment clumping . It was The etiology of PPRCA remains unclear, but genetic, developmental and inflammatory causes have been postulated. PPRCA has been previously reported in association with tuberculosis, congenital syphilis, Behçet disease, measles, rubella  and VogtPrevious researchers suggested that PPRCA was typically symmetrical in bilateral eyes and rarely affects the macula and central vision. A recent study in a large cohort, however, found that 40% of cases exhibited asymmetry in fundus findings . UnilateAACG was known to occur in eyes with specific anatomy, such as short axial length, anterior segment crowding and narrow anterior chamber angle. The reason for concurrent manifestation of the PPRCA and AACG remains unclear. Sun et al. described a 55-year-old female who had bilateral PPRCA with AACG and posterior subcapsular cataract, which was the only reported case presented with PPRCA and AACG. Comparison between the two patients are summarized in Table In summary, we present a rare case of unilateral PPRCA accompanied with AACG. To the best of our knowledge, this is the first such case to be reported.


Multicystic biliary hamartoma (MCBH) is an extremely rare benign liver lesion characterized by a gross well-circumscribed multicystic honeycomb appearance. This report presents a MCBH case with a marked peribiliary gland component which showed unusual histology.A 63-year-old Japanese male was admitted to our hospital for a detailed examination of a hepatic cystic lesion, which was originally detected 14 years ago and had slowly enlarged. A preoperative imaging study revealed a well-demarcated multicystic lesion without communication to the biliary tracts. The possible clinical diagnoses were mucinous cystic neoplasm (MCN) or MCBH. The lesion was successfully resected by purely laparoscopic right anterior sectionectomy. The cut surfaces of resected specimens grossly exhibited a well-circumscribed multicystic lesion with a thick septum. Histologically, the cyst wall was covered by cuboidal epithelial cells resembling epithelium of the bile duct while abundant small ducts, which morphologically resembled peribiliary glands, were observed among the fibrous stroma of the thick septum. Although possible pathological diagnosis varied, including intrahepatic cholangiocarcinoma, intraductal papillary neoplasm of the bile duct, biliary adenofibroma, MCN and MCBH, the lesion was finally diagnosed as MCBH with a marked peribiliary gland component.MCBH can contain abundant peribiliary glands in the fibrous stroma. A pathologist should be careful not to diagnose such peribiliary glands in MCBH as neoplastic glands. Multicystic biliary hamartoma (MCBH) is an extremely rare benign liver lesion which was initially defined by Zen et al. in 2006 . The typWe have recently experienced a MCBH case with a marked peribiliary gland component which showed unusual histology as MCBH and needed particular attention for discrimination from mucinous cystic neoplasm (MCN), biliary adenofibroma (BAF), or intrahepatic cholangiocarcinoma. This case was successfully treated by purely laparoscopic anatomical liver resection that involved complex laparoscopic surgical procedures that could only be performed in very few institutions .A 63-year-old Japanese male was admitted to our hospital for the detailed examination of a hepatic cystic lesion, which was originally detected 14 years ago and had slowly enlarged . Laboratory tests including tumor markers showed no remarkable abnormality. Abdominal computed tomography (CT) revealed a well-demarcated multicystic lesion with a thick septum that was 4.2 × 4.1 cm in diameter across segment 8 of the liver  . Histologically, the cyst wall was covered by cuboidal epithelial cells resembling epithelium of the bile duct and many small ducts resembling peribiliary glands were observed in the fibrous stroma (Fig. The cut surfaces grossly showed a well-circumscribed multicystic lesion with a thick septum Fig. d. Histoloma Fig. a. The smoma Fig. b. Thus, Ovarian-like stroma, which are necessary for the pathological diagnosis of MCN , were noBAF usually presents as a solid and/or sponge-like microcystic gross appearance and glandular structure of biliary-type epithelium , and theMBCH was initially reported as a hamartomatous lesion located around the hepatic capsule close to the fissure of the falciform ligament that protrudes from the liver . HoweverIt is most important that the peribiliary glands in fibrous stroma of MCBH are never diagnosed as an invasive component of MCN or intrahepatic cholangiocarcinoma. Careful observation for cytological atypia, assessment of mitotic activity using Ki-67 IHC, the presence of uniform glands resembling peribiliary glands, and strict differential diagnosis of MCN focusing ovarian-like stroma will prevent misdiagnosis.In conclusion, we have reported a case of MCBH with an abundant peribiliary gland component that was successfully treated by purely laparoscopic anatomical liver resection. We believe that this case report will be good reference for both pathologists and clinicians alike when they encounter a similar case in the future.


Frontiers in Human Neuroscience: Brain Imaging and Stimulation Research Topic includes six contributions  from a total of 28 co-authors. Efforts were centered around the effects of tCS when applied to M1 or cerebellum to improve upper- or lower-extremity locomotor or musculoskeletal functions in healthy individuals or clinical populations.Over the last decade, there has been growing interest in the use of non-invasive brain stimulation techniques such as transcranial current stimulation (tCS) to improve physical performance and locomotor functions. In essence, tCS delivers weak currents to the cortex transcutaneously, with active electrode(s) placed on the area(s) of the scalp overlying the cortical target(s) and reference electrode(s) placed elsewhere, traditionally over the contralateral supraorbital area or a non-cephalic location. Electrical currents that reach the cortex can transiently depolarize or hyperpolarize neuronal resting membrane potentials and thereby alter excitability and action potential generation probability. The majority of tCS studies target the primary motor cortex (M1), which plays important roles in the acquisition and execution of locomotor and musculoskeletal functions. It is thought that M1 tCS can facilitate various aspects of motor function such as movement precision, learning, strength, and endurance. Notably, some of these improvements include hand and leg functions used in activities of daily living  on bimanual handgrip strength, which is difficult to predict because of complex neural dynamics that involve interhemispheric interactions and ipsilateral projections. Their results revealed that bimanual handgrip strength improved with a left M1 anode - right M1 cathode electrode placement montage, and not with a right M1 anode – left M1 cathode montage or sham stimulation. These findings provide important preliminary evidence to suggest that with specific e-field patterns, M1 tDCS can improve bilateral upper limb functions in healthy individuals.Motor cortex tCS can facilitate contralateral unimanual movements  tDCS on sensorimotor functions in healthy individuals and clinical populations must be further explored.Most tDCS studies use currents of 1-2 mA, but higher intensities are safe and tolerable  closed-loop brain stimulation and robot-assisted knee joint training was used to improve post-stroke gait disturbance in a 57-year-old patient with chronic post-stroke hemiparesis. Transcranial alternating current stimulation (tACS) was applied to the lesioned M1 foot area with a 1.5 mA positive DC offset and 3 mA sine-wave current triggered by paretic heel contact to deliver maximum current immediately before the swing phase. The combination of closed-loop stimulation and robot training improved 10-meter gait speed, timed up and go time, and lower limb muscle strength. Improvements in gait and balance functions persisted 2 weeks after the intervention.In a case report by Schmitter and Straube used cerebellar tDCS as a causal probe to assess the role of the cerebellum in these processes. Compared with cathodal, dual-hemisphere, and sham cerebellar tDCS, changes in sensorimotor recalibration after anodal cerebellar tDCS indicate a generalized role of the cerebellum in temporal recalibration across sensorimotor and perceptual domains. In addition, differences in temporal recalibration effects across delay levels suggest that cerebellar-dependent sensorimotor temporal recalibration processes are probable and may depend on the availability of action-based predictions.In situations where complex environments introduce delays between actions and sensory outcomes, flexible recalibration of the corresponding temporal predictions is required. While the cerebellum has long been associated with sensorimotor functions, its relative contributions to sensorimotor and inter-sensory temporal recalibration are unknown. Nguemeni et al. examined the effect of ipsilateral (to fast leg) anodal 2 mA cerebellar tDCS on locomotor adaptation and consolidation in 40 individuals with mild-to-moderate MS and 30 healthy controls. Locomotor adaptation and consolidation did not differ between groups, and the immediate post-task application of anodal cerebellar tDCS did not improve adaptation or consolidation compared with sham. In addition to suggesting that locomotor adaptation capacity is maintained in mild-to-moderate MS, these findings highlight the importance of efforts to further optimize cerebellar tDCS parameters such as timing and intensity.Multiple sclerosis (MS) is a central nervous system inflammatory disease that involves demyelination and neurodegeneration. The complexity of the disease and heterogeneous nature of clinical symptoms and progression necessitates tailored approaches that combine pharmaceutical and physical rehabilitation therapies. The non-invasive modulation of cerebellar activity may be useful as an adjunct therapy to improve gait function in individuals with MS. Using a split-belt treadmill paradigm, Shima, Tanaka et al. presented the results of a backward gait training intervention combined with synchronized cerebellar tACS in an individual with progressive supranuclear palsy-Richardson's syndrome, which is characterized by postural instability. tACS was applied to the right cerebellum in accordance with the lateralized severity of motor symptoms. Stimulation was delivered at 3 mA and timed to coincide with right leg backward gait frequency. In contrast to asynchronized or sham stimulation, synchronized stimulation reduced postural instability, and long-term stimulation further improved postural stability and related outcomes such as gait speed, balance function, and fall-related self-efficacy. These preliminary results support continued efforts to develop non-invasive brain stimulation protocols that leverage endogenous physiological activity to enhance therapeutic efficacy.In another case report, real-time analysis of complex sensorimotor signals with unparalleled sensitivity. Machine learning techniques will also benefit efforts to improve tCS efficacy by “closing the loop” with better stimulus timing accuracy and the identification of more effective physiological “triggers”. In addition to acute effects, concerted efforts to understand the effects of repeated tCS are needed. To improve tCS efficacy, especially when combined with locomotor or musculoskeletal behaviors and therapies, the nature of tCS interactions with past and current physiological activity must be further elucidated. Similarly, while progress has been made, there is a need to further emphasize the investigation of tCS in the target clinical populations.What near-term advances can we expect in the use of tCS to improve locomotor and musculoskeletal system function in health and disease? As highlighted by the work included in this Research Topic, efforts to identify the most effective and safe stimulation parameters will continue. Such efforts will be aided by machine learning techniques that enable the SP and SF wrote and revised the final version of the manuscript. Both authors have read and approved the final submitted version.


Potentially self-reactive B cells constitute a large portion of the peripheral B cell repertoire in both mice and humans. Maintenance of autoreactive B cell populations could conceivably be detrimental to the host but their conservation throughout evolution suggests performance of a critical and beneficial immune function. We discuss herein how the process of clonal redemption may provide insight to preservation of an autoreactive B cell pool in the context of infection and autoimmunity. Clonal redemption refers to additional recombination or hypermutation events decreasing affinity for self-antigen, while increasing affinity for foreign antigens. We then review findings in murine models and human patients to consider whether clonal redemption may be able to provide tumor antigen-specific B cells and how this may or may not predispose patients to autoimmunity. A complex series of recombination events during development inexorably culminates in formation of self-reactive B cell receptors. Although these cells can be eliminated prior to egress from the bone marrow in central tolerance, a significant number of self-reactive B cells can be isolated from the peripheral blood of healthy individuals; indeed, 55-75% of new immature B cells and 20% of mature naïve B cells in humans are potentially autoreactive . These cIn the context of cancer—since many cancer antigens are self or near-self—a theory of clonal redemption may provide a useful conceptual framework to investigate the relationship between B cell-mediated anti-tumor immunity and B cell–mediated autoimmunity in cancer patients. In this review, we expand the definition of clonal redemption to include elaboration of tumor-reactive antibodies via entry into the GC or extrafollicular production without further SHM. The overall goal is to develop an understanding that would result in therapeutic approaches that minimize B cell-driven autoimmune events while concomitantly enhancing the therapeutic efficacy of humoral anti-tumor immunity.Humoral immunity mediated by B cells is critical in response to both acute and chronic infections. Recent evidence also points to a role for B cells in anti-tumor immunity, as presence of B cells and tertiary lymphatic structures (TLS) in the tumor microenvironment (TME) correspond with improved patient outcomes in a variety of cancers including: high grade serous ovarian (HGSOC) , colorecAn inherent autoreactive proclivity is present within the B cell compartment as evidenced by the ability to produce antibodies to tumor antigens, which often possess highly concordant structures with native protiens. Here, potential tumor antigens, or near-self antigens, include bonafide neoantigens (secondary to somatic mutations), overexpression of native proteins, ectopic protein expression, altered post-translational modifications, or potentially alterations of protein structure within the TME. As tumors arise from autologous cells expressing self-antigen, the production of antibodies to self- or near-self antigens has been thought to represent improved immune surveillance in the setting of increased presentation of tumor self-antigen, and autoantibodies have been suggested as a prognostic biomarker for early disease in a number of cancer types –19. For).in vitro stimulation with BCR ligation, CD40, TLR9, showing reduced calcium flux and proliferation  were initially defined as CD21- CD27- . This then provides context to the observed correlation between ABCs, defined as CD11chi, and reactivity to many self-antigens  as well as a disease severity score  is the most effective isotype for controlling viral infections in mice , 42 and nt cells . Togethein vitro with TLR4 signaling in combination with IFNγ or IL-27  significantly reduces kidney pathology and improves overall survival in several murine models of lupus. Development of autoantibodies (anti-chromatin) and CSR to IgG2a is significantly delayed with a concurrent reduction in frequency and number of CD11c+ B cells in these knockouts . Tbet exor IL-27 . CollectThese studies point to a role for ABCs in direct cellular cytotoxicity as well as humoral immunity and autoimmunity. This range of activities can be explained by the observation that Tbet+ IgM+ B cells–encompassing CD11c+, CD11c-, and interconversions thereof–can differentiate into all effector and memory lineages, while also ensuring long-term persistence through self-renewal . Since uFrom an evolutionary perspective, clonal redemption is postulated to have developed in order to avoid large gaps in the B cell repertoire and better combat infection. In contrast, because cancer typically afflicts organisms after reproductive age it would not be expected to exert a selective pressure for such a potentially dangerous mechanism. This then raises the question: can clonal redemption contribute to an anti-tumor immune response? There is emerging evidence that suggests accumulation of ABCs within the TME. Although it seems likely that ABCs would be able to undergo clonal redemption and generate tumor-reactive antibodies, this has yet to be explicitly demonstrated.Recently, Mazor et al. demonstrated IgG binding to the surface of tumor cells from a range of primary human tumor tissue specimens. Their findings suggested a functional relevance to the autoantibodies observed in cancer, as tumor coating was associated with improved patient outcomes. Analysis focused on high grade serous ovarian (HGSOC), and these patients harbored frequent autoantibodies to MMP14 (overexpressed in HGSOC). They next sequenced heavy and light immunoglobulin chains of several intratumoral ASCs and reconstructed clonal lineage trees to show clonal diversification through progressive SHM. Their findings suggest tumor-specific antibodies can be generated secondary to SHM (denoted class I) or from germ-line sequence (denoted class II). After SHM reversion, a similar number of analyzed MMP14-reactive antibodies exhibited decreased binding as no change in binding. Additionally, there were two cases of increased binding after SHM reversion. Interestingly, in a large retrospective analysis there was no increased incidence of autoimmunity of HGSOC patients with autoantibodies . This woA major obstacle limiting our understanding of a possible role for clonal redemption in cancer is identification and isolation of a tumor neoantigen-specific BCR. Here, repertoire cloning could facilitate lineage tracing and direct evidence for clonal redemption in cancer, as has been done following infection or vaccination with defined antigens. In murine studies, the presence of a defined antigen would enable transfer of ABCs into tumor-bearing mice with subsequent lineage tracing and mapping of clonally related BCRs. In this way providing direct evidence for clonal redemption as well as the spectrum of potential ABC fates in the context of cancer. Phenotypic and transcriptional analysis of that lineage could then inform possible therapeutic strategies. It is also unclear whether clonal redemption could be accomplished in a mature tumor-associated TLS. Because ABCs do not express typical homing receptors for secondary lymphatic tissues, it is unclear if they might be able to enter a GC, or if clonal redemption might take place through extrafollicular mechanisms. Although it is tempting to speculate, this area of investigation is yet in the early stages and our understanding of whether clonal redemption plays a biologically significant role in cancer will continue to evolve.d of approximately 10-4 to 10-6) polyreactive binding  in humans and their Ly-1 expressing counterparts in mice. Although expanded in disease states, these populations are also a normal component of the circulating B cell repertoire in healthy subjects , account binding , though  binding . Antibod binding . Their b binding . Such st binding , 70 and  binding . VH4-34  binding .Abundance in the neonatal period and waning frequencies with age (though consistent numbers) suggest a phylogenetically distinct role for this population. Use of germline sequences and T cell independent antibody secretion enables these innate-like cells to sequester commensal bacteria within the gut and provide a first line of defense against pathogens , 74. To in vitro culture  revealed anergy in both populations to be established by EGR2/3, whose expression was proportionate to downregulation of surface IgM by self-antigens. Importantly, though, these populations largely segregated on clustering analysis  may present an opportunity to better understand the mechanisms underlying this loss of tolerance. Anti PD-1 and CTLA-4 treatment has resulted in distant organ-specific autoimmune adverse events, even in cancer types that had not previously been associated with spontaneously occurring paraneoplastic syndromes . As thesAutoimmunity in cancer has been demonstrated to have positive prognostic value in a number of settings. Patients who develop immune adverse events following ICI have improved response to treatment –101 and ABCs may participate in promoting autoimmunity by presenting self-antigens to potentially autoreactive T cells. Indeed, in mouse spleens these cells colocalize with T cells at the T:B cell border, express MHCII and costimulatory molecules , and potently induce T cell proliferation . This suDespite their state of hyporesponsiveness, ABCs can also be activated to differentiate into ASCs, supplying antibodies targeting tumor associated antigens. Tbet-mediated CSR preferentially drives production of IgG1 and IgG3 isotypes  and thesIn this review we have discussed the phenomenon of clonal redemption of B cells and how it may participate in the anti-tumor immune response. Tumor antigens include neoantigens, over or ectopically expressed native proteins, altered post-translational modifications, or alterations of protein structure within the TME. ABCs might then recognize these antigens, become activated, and produce tumor reactive antibodies, representing clonal redemption in either a GC dependent or independent manner. A similar mechanism of extrafollicular clonal redemption may exist for B1 cells. Interestingly, cancer patients frequently harbor tumor-reactive antibodies but do not incur systemic autoimmunity. The reasons for this remain to be elucidated but may represent a local breach of tolerance within the tumor and/or draining lymph node but not systemically. Nonetheless, further investigation is merited as clonal redemption of anergic B cell populations could provide a potent substrate with which to amplify immunotherapeutic modalities.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.TM: Conceptualization, Writing – original draft. SL: Writing – original draft. JC: Conceptualization, Writing – review & editing.


The most common cause of revision arthroplasty is prosthetic joint infection (PJI). Chronic PJI is commonly treated with two-stage exchange arthroplasty involving the placement of antibiotic-laden cement spacers (ACS) in the first stage, often containing nephrotoxic antibiotics. These patients often have significant comorbidity burdens and have higher rates of acute kidney injury (AKI). This systematic review aims to assess the current literature to identify (1) AKI incidence, (2) associated risk factors, and (3) antibiotic concentration thresholds in ACS that increase AKI risk following first-stage revision arthroplasty.An electronic search was performed of the PubMed database of all studies involving patients undergoing ACS placement for chronic PJI. Studies assessing AKI rates and risk factors were screened by two authors independently. Data synthesis was performed when possible. Significant heterogeneity prevented meta-analysis.Eight observational studies consisting of 540 knee PJIs and 943 hip PJIs met inclusion criteria. There were 309 (21%) cases involving AKI. The most commonly reported risk factors included perfusion-related factors , older age, increased comorbidity burden, and nonsteroidal anti-inflammatory drug consumption. Only two studies found increased risk with greater ACS antibiotic concentration ; however, these were reported from univariate analyses not accounting for other potential risk factors.Patients undergoing ACS placement for chronic PJI are at an increased risk for AKI. Understanding the risk factors may lead to better multidisciplinary care and safer outcomes for chronic PJI patients.Level of evidence III. As total joint arthroplasty (TJA) becomes more prevalent in the USA, the burden of revision arthroplasty is expected to increase as well . One of One such complication is acute kidney injury (AKI), which has been extensively studied in primary TJA but less so in the two-stage revision arthroplasty setting , 11. ThiThe goals of this systematic review were to assess the existing literature to (1) establish an incidence of AKI following first-stage exchange arthroplasty, (2) identify perioperative risk factors for AKI risk, (3) determine the antibiotic concentration thresholds in ACS over which AKI risk is significantly increased.This systematic review was conducted in accordance with the PRISMA  guidelines . An elecN ≥ 10 (case series and case reports excluded).Studies were included for review if they (1) involved subjects undergoing ACS placement in the first stage of treatment for PJI, (2) included AKI as an outcome, as defined by either the Kidney Disease Improving Global Outcomes (KDIGO)  or the RAll screening and text review was conducted independently by two authors (YPC and ML). All disagreements were resolved through discussion among screening authors, with senior author involvement included as needed (RMA).All data extraction was performed by three authors . Extracted variables included country in which the study was conducted, study inclusion and exclusion criteria, patient characteristics , procedure type (knee vs. hip revision), cement spacer type, antibiotic impregnated in the spacer, quantity of antibiotic used, systemic antibiotics administered during the study period, AKI definition, and incidence of AKI. Risk factors for AKI based on univariate and multivariate analysis were also extracted, as well as the subsequent odds ratios (OR) with 95% confidence intervals (CI). Given the high heterogeneity in antibiotics and spacer types, a meta-analysis could not be performed.Quality appraisal was performed using the Methodological Index for Non-Randomized Studies (MINORS) criteria for non-randomized studies, which is scored out of a maximum 16 points for non-comparative studies and 24 points for comparative studies [A total of 882 citations were identified Fig.  and screPerfusion-related factors such as lower preoperative hemoglobin, higher median number of units of blood transfused or intraoperative transfusion, and postoperative hypovolemia were commonly found to have an association with increased risk for AKI. Other commonly reported risk factors included increasing age, perioperative use of nephrotoxic medications such as nonsteroidal anti-inflammatory drugs, and comorbidity burden . Six studies performed multivariate analysis along with univariate analysis, while two studies only performed univariate analysis , 23. OneTwo studies reported thresholds of antibiotic concentration in ACS associated with increased AKI risk. One found that > 3.6 g of vancomycin or aminoglycosides per batch of cement in first-stage knee revisions was associated with increased AKI risk ), while The results of quality appraisal for the included studies are presented in Table Acute kidney injury (AKI) has been shown to increase morbidity and mortality following revision TJA. The incidence of AKI after the first stage of a two-stage revision arthroplasty in the current literature ranges between 10 and 33%. Although current evidence is limited and precludes meta-analysis, the most commonly associated risk factors reported include perfusion-related factors , older age, increased comorbidity burden, and perioperative nephrotoxic drug use. Only two studies found that certain antibiotic concentration thresholds in ACS were linked to increased AKI risk, but neither of these were the result of multivariate analysis accounting for other risk factors.A similar systematic review performed by Luu et al. in 2013 on ten studies consisting of 544 patients reported an AKI incidence of approximately 5% , a substIn assessing the risk factors for AKI following ACS implantation, the most commonly reported were related to poor perfusion, such as low hemoglobin, and perioperative blood transfusions or hypovolemia. These are well-established risk factors in primary TJA literature, but it is important to recognize the increased rates of blood loss and transfusion with septic revision arthroplasty , 28. ThiRegarding the ideal concentration of antibiotics in an ACS, this review included two studies that demonstrated ACS antibiotic concentration thresholds associated with increased risk of AKI , 20. DagA significant limitation of the current review was the heterogeneity of the included studies with regards to ACS type, concentrations, concomitant systemic antibiotics, and study design. This variation unfortunately did not allow for meta-analysis. Additionally, AKI is a multifactorial diagnosis—it is difficult to state a cause–effect relationship regarding systemic antibiotic use in two-stage revision. Strengths of this review include the strict inclusion criteria when screening studies, particularly the requirement for a clear and widely recognized definition for AKI. Additionally, revision TJA for PJI is difficult to study in volume, as coding for these procedures is notoriously inaccurate making database studies unreliable . Large dThe high incidence rates of AKI following the first stage of two-stage revision arthroplasty must be considered by providers in the treatment of chronic PJI. Identification of associated risks should be used to better guide preoperative optimization and treatment of these patients, such as reducing the risk of perioperative hypovolemia. Further study is warranted to identify the AKI risk attributed to ACS versus other potential causes of nephrotoxicity as well as the ideal dosage of antibiotics added to ACS constructs.


Deep brain stimulation (DBS) is a well-established and effective treatment for patients with advanced Parkinson's disease (PD), yet its underlying mechanisms remain enigmatic. Optogenetics, primarily conducted in animal models, provides a unique approach that allows cell type- and projection-specific modulation that mirrors the frequency-dependent stimulus effects of DBS. Opto-DBS research in animal models plays a pivotal role in unraveling the neuronal and synaptic adaptations that contribute to the efficacy of DBS in PD treatment. DBS-induced neuronal responses rely on a complex interplay between the distributions of presynaptic inputs, frequency-dependent synaptic depression, and the intrinsic excitability of postsynaptic neurons. This orchestration leads to conversion of firing patterns, enabling both antidromic and orthodromic modulation of neural circuits. Understanding these mechanisms is vital for decoding position- and programming-dependent effects of DBS. Furthermore, patterned stimulation is emerging as a promising strategy yielding long-lasting therapeutic benefits. Research on the neuronal and synaptic adaptations to DBS may pave the way for the development of more enduring and precise modulation patterns. Advanced technologies, such as adaptive DBS or directional electrodes, can also be integrated for circuit-specific neuromodulation. These insights hold the potential to greatly improve the effectiveness of DBS and advance PD treatment to new levels. Deep brain stimulation (DBS) is a promising treatment option for individuals suffering from advanced Parkinson’s disease (PD), especially those who initially respond well to dopamine replacement therapy but develop complications such as dyskinesia and "on–off" fluctuations over time , 2. In tDBS stands as a neurosurgical intervention with the potential to leverage neural adaptations for therapeutic purposes . EssentiCurrently, optogenetics is increasingly being used in animal models to investigate the underlying mechanisms of DBS , 34. OptIn PD, depletion of dopamine is thought to disrupt the balance of activity between the direct and indirect pathways within the striatum , leadingThe question of whether DBS elicits neural excitation or inhibition during treatment remains a topic of discussion. Initial experimentation supported the "inhibition hypothesis", indicating that high-frequency electrical subthalamic and pallidal stimulation enhances PD motor symptoms by obstructing overactive ganglia output and aligns with the classical rate model , 41. Non+ neurons and significantly inhibits 58% of α7+ neurons, potentially due to α4β2+ neurons receiving more glutamatergic inputs and α7+ neurons receiving more GABAergic inputs within the STN [The variations of local neural response to HFS-DBS at the same target can be explained by a biophysically realistic computational framework . This fr the STN . Therefo2+ conductivity or inactivation of neurotransmitter release sites causes a reversible decline in synaptic efficacy due to the delayed recovery of vesicle fusion events [Furthermore, computational studies suggest that repetitive HFS results in decreased site-specificity and neuronal suppression mediated by short-term synaptic depression , 50. Thin events –59.In summary, at stimulation frequencies below the synaptic depression threshold, the local neuronal responses to DBS depend on the relative distributions of excitatory and inhibitory afferent inputs (site-specific effects), while at stimulation frequencies above the synaptic depression threshold, the local neuronal responses to DBS are progressively reduced, due to the synaptic depression effect (frequency-dependent effects).In addition to the intermingling of neurons exhibiting diverse responses to HFS, the modulation of neuronal firing patterns linked to intrinsic excitability further complicates the DBS effects –62. For 2+ currents and Ca2+-activated inward currents [N-methyl-D-aspartate ionotropic receptors (NMDARs), and the ether-à-go-go-related gene (ERG) K+ channels have been identified as factors that can regularize neuronal firing patterns [Similarly, experiments with HFS in PD animals have shown that most STN neurons are inhibited and burst firing is reduced  Fig. 2)2). Electcurrents , 73. Notcurrents , 62. In patterns –76.Firing pattern conversions have also been observed in the GPe and GPi. Studies in unanesthetized patients have shown that DBS in the GPi does not uniformly silence local neuronal activity, but rather disrupts pathological firing patterns by loosely entraining neuronal activity . SimilarIn summary, these findings suggest that the local response to DBS is influenced by both variations in synaptic inputs and alterations of intrinsic neuronal excitability through manipulation of membrane potential and ion channels to normalize firing patterns Fig. . The intAs discussed previously, DBS can affect various neural elements, including soma, axons, and dendrites of neurons. Studies have shown that DBS activates axons and dendrites in the stimulation region, increasing the frequency of action potential (AP) output from the soma of neurons . ComputaA computational model  proposesAs an intrinsic property, electrical stimulation propagates in multiple directions, thus DBS can modulate neural circuits in various disease states. The sustained changes in neural activity induced by DBS may trigger adaptive changes within the nervous system, including activity-dependent synaptic adaptations in clinical settings –33. ThisA substantial body of research supports this synaptic adaptation theory, with observations indicating that DBS normalizes the distribution of corticostriatal glutamatergic terminals, thereby altering striatal glutamatergic neurotransmission in animal models . In addiThe STN controls two basal ganglia output nuclei: the GPi and the substantia nigra pars reticulata (SNr) . This suAs downstream nuclei of the STN Fig. , the SNrIn addition to its orthodromic effects, several studies have suggested that DBS can also modulate neuronal activity in upstream nuclei through antidromic stimulation Fig.  82, 99––99–101. + and activating somatostatin (SST)-expressing (SST+) GABAergic interneurons [+ interneurons can mimic the effects of DBS and alleviate motor symptoms in a PD mouse model, suggesting that STN-DBS may recruit cortical GABAergic networks to inhibit the hyperactivity of cortical-subthalamic projections.Studies have shown that the layer-5 primary motor cortex (M1) neurons project extensively to the STN , 109. Oprneurons . This stParadoxically, another study in rats found that the average spontaneous firing rate of corticofugal projection neurons (CxFn) was reduced after 6-OHDA treatment, accompanied by increased episodes of burst firing. STN-DBS at 125 Hz significantly increased the spontaneous firing of CxFn, disrupting the dominance of the beta rhythm . AntidroWithin the STN, the hyperdirect and indirect pathways serve as the main motor inhibitory circuits in the basal ganglia . The hypThe thalamus is a critical node in the basal ganglia network, and several studies indicate that STN-DBS can affect the firing rate and the bursting activity of thalamic neurons , 113. Am+ STN neurons prevents this LTP-based recovery, highlighting the critical role of PV+ STN neurons in this rescue process [A study shows that optogenetic stimulation (ChR2-H134R) of Pf projections to the STN leads to improved motor function, whereas stimulation of the Pf-striatum cell body or terminal does not have the same effect . Unilate process . These fGPi, one of the commonly targeted brain regions for DBS, has shown therapeutic effects like STN. Studies have demonstrated that GPi-DBS can reduce the activity of neurons within the STN. The suppression could be attributed to the activation of fibers that originate in the GPe and pass through the GPi. Recently, researchers have discovered a phenomenon called evoked resonant neural activity (ERNA) occurring in GPi-DBS , 122. ERIn practice, while both GPi and STN are recommended as potential DBS targets, their clinical outcomes differ. STN-DBS typically results in a greater reduction of levodopa usage, whereas GPi-DBS is linked with a lower frequency of neuropsychiatric side effects . A viralTherefore, with regards to its orthodromic effects, GPi-DBS has the potential to regulate neuron activity in the VAL/VM thalamus, thus improving motor function. Additionally, it may also yield emotional and neuropsychological benefits by impacting the LHb activity.Due to the position-dependent nature of DBS therapy, the positioning of electrodes and their active contacts is a crucial parameter in DBS treatment, which requires precise programming by physicians. Clinically, the electrodes are often placed in regions that yield the maximal DBS benefits, such as the dorsolateral STN –139, theThe position-dependent effects are influenced by topological factors Fig. a. DespitSimilarly, the GPi also exhibits a topological distribution . The ant+ and PV− neurons in the STN. The glutamatergic PV+ neurons predominantly occupy the dorsolateral and middle portions of the STN and exhibit characteristics of phasic burst firing compared to the PV− subpopulation [+ neurons are the source of excessive burst firing in PD. Their distribution in the dorsolateral and middle parts of STN likely underlies the position-dependent effects observed in STN-DBS [The position-dependent effects of DBS are influenced not only by topological factor but also by the composition of neuronal populations within targeted regions Fig. b. A clospulation . Electropulation . This bupulation , suggest STN-DBS , 13.+) neurons promote locomotion within an exploratory speed range [Similarly, for PPN-DBS, the position-dependent effects are pivotal for addressing freezing gait and postural abnormalities in PD patients who are resistant to dopaminergic treatments –158. Howed range , 163, whed range  and decred range , 163. Thed range , 163.+ PPN neurons can rescue movement deficits in PD mice [Studies indicate that the motor-enhancing effect of PPN-DBS is specifically attributed to the caudal PPN –145. Che PD mice , and DBS PD mice . This is PD mice . Importa PD mice . As a reIn summary, both the topological structure and the composition of neuronal subpopulations contribute to the spatial distribution of inputs and outputs in targeted brain regions. These factors collectively determine the position-dependent therapeutic effects of DBS.DBS programming, the adjustment of electrical stimulation parameters to optimize clinical benefit for individual patients, is a critical aspect of DBS. Physicians must carefully fine-tune parameters such as frequency, pulse width, voltage, and electrode contact to achieve the best symptom relief with minimal side effects . The selFrequency is a crucial parameter in DBS programming. Studies have found that the magnitude of the beneficial effect in PD patients is most pronounced within the frequency range of 130–185 Hz, with a progressive improvement in motor symptoms as the frequency increases from 50 to 130 Hz . SimilarHowever, when attempting to directly activate local excitatory STN neurons using optogenetic methods like ChR2, results were less favorable, with only minimal changes in rotational behavior and even motor deficits in the contralateral limb , 170. ThRecent human studies have proposed that the shape and the amplitude of ERNA, generated by DBS, also depend on the frequency and duration of stimulation , 125. ThB receptors, which lead to longer-lasting inhibitory effects at higher frequencies compared to lower frequencies [2+ conductance. Reductions in Ca2+ conductance, both on autoreceptors located on GABA-releasing terminals and on heteroreceptors in neighboring terminals, are thought to be induced by HFS. This ultimately results in the inhibition of neurotransmitter release [Another hypothesis regarding synaptic depression suggests the involvement of presynaptic metabotropic GABAquencies . This me release , 177–179 release –33. ConsThe therapeutic efficacy of DBS is profoundly influenced by the spatial distribution of the stimulation field in relation to the brain's anatomy –182. CliPreclinical data reinforce these findings. The effectiveness of STN-DBS, as measured by improvements in movement speed in PD mice, has exhibited a linear correlation with pulse width and current intensity . Neverth2+-activated non-specific cation channels [In vitro electrophysiological studies have illuminated the role of pulse width in determining the type of neuronal response elicited by HFS in the GPi. Low charge density HFS (60 μs) primarily induces excitation, while high charge density HFS (400 μs) triggers a distinct subtype of excitation characterized by late inhibition, which involves glutamatergic and cholinergic modulation, as well as Cachannels . Furtherchannels . The ampchannels , 188. ThWhile DBS has demonstrated symptomatic efficacy in PD, its effects are transient and vanish once the stimulation is discontinued, leading to a swift return of motor symptoms , 189. Ho+ neurons using ChR2 and inhibition of Lim homeobox protein 6 (Lhx6)-expressing (Lhx6+) neurons via Arch (a light-activated inhibitory proton pump), two subpopulations in the GPe with distinctive intrinsic physiological and projection properties, ameliorate locomotor deficits in dopamine-depleted mice four hours following stimulation [+ and Lhx6+ GPe neurons. Burst stimulation not only improves bradykinesia in 6-OHDA-lesioned mice but also provides long-lasting therapeutic benefits that persist for hours post-stimulation [+ GPe neurons relative to Lhx6+ GPe neurons.Furthermore, Spix and colleagues have delineated a precise DBS stimulation protocol with long-term efficacy in mice, highlighting distinct responses of two types of neurons in the GPe to electrical stimulation . The GPemulation . Buildinmulation . These f+ and Lhx6+ GPe neurons are one mechanism underpinning their distinct firing responses and the sustained effects observed. Despite receiving similar levels of excitatory input from the STN, Lhx6+ GPe neurons receive proportionally more inhibition than PV+ GPe neurons from the D1-dopamine receptor-expressing spiny-projection neuron (D1-SPN) afferents. The specific electrical stimulation applied is likely skewed toward the antidromic activation of D1-SPNs, thereby producing more potent inhibition of Lhx6+ GPe neurons than PV+ GPe neurons. This disruption in the network's balance through the stimulation of distinct neuronal subpopulations results in sustained therapeutic benefits  is a promising avenue for DBS application, which seeks to enhance the effectiveness and safety of DBS by dynamically adjusting stimulation parameters based on real-time feedback signals. Unlike conventional open-loop DBS, aDBS operates as a closed-loop system, which is capable of bidirectional communication and automatic parameter adjustment , 207. ThTo effectively implement aDBS, it is essential to identify an electrophysiological biomarker that can accurately reflect the clinical characteristics of the disease and serve as a feedback for the system. The LFP, particularly beta oscillation across the motor network, has been widely employed as a biomarker for aDBS , 212. HoOne promising candidate is the narrowband gamma activity (60–90 Hz) observed in the motor cortex and STN during dyskinesia . This gaIn summary, further refinement of biomarkers is needed to advance aDBS application. Future research endeavors may explore new biomarkers to unlock even better therapeutic outcomes through aDBS treatments.Directional stimulation technology represents a promising frontier in the evolution of DBS therapy. It introduces a level of precision previously unseen in DBS treatments, achieved by manipulating or configuring electrodes with radially segmented contacts, anodes, and cathodes to guide the flow of current in specific directions. This innovative approach offers a potential for a more nuanced and adaptable stimulation field , 220, caClinical investigations have demonstrated that directional electrodes can deliver more efficient stimulation at a given amplitude compared to omnidirectional electrodes –223. TheRecent advances in neuroscience and brain function research have provided deeper insights into the topological connections between different brain regions and the distribution patterns of distinct neuronal subgroups within various nuclei. These advances have partially illuminated the electrophysiological and circuit mechanisms underpinning the clinical effects of DBS, while also directing the development of DBS technology. The intricate anatomical complexity and circuitry interconnections among numerous brain nuclei suggest that non-selective DBS stimulation may lead to unintended clinical side effects.The emerging cutting-edge technologies such as aDBS and directional stimulation improve DBS therapies toward delivering more efficient and targeted interventions. It is increasingly evident that leveraging more specific DBS stimulations to achieve precise modulation of neural function is a future direction of development in this field.DBS stands as a valuable treatment modality for advanced PD. In this review, we have delved into recent opto-DBS studies, shedding light on the potential mechanisms of neuronal and synaptic adaptations that underlie the efficacy of DBS in PD. Response of local neural circuits to DBS can be affected by a complicated interplay of many factors, including the distribution of presynaptic inputs, frequency-dependent synaptic depression, and the intrinsic excitability of postsynaptic neurons, which involves membrane potential dynamics and ion channel functionality. These factors collectively enable both antidromic and orthodromic modulation of neural circuits, laying the foundation for understanding the position- and programming-dependent therapeutic effects and side effects associated with DBS.


The bottom-up productionof chiral gold nanomaterials holds greatpotential for the advancement of biosensing and nano-optics, amongother applications. Reproducible preparations of colloidal nanomaterialswith chiral morphology have been reported, using cosurfactants orchiral inducers such as thiolated amino acids. However, the underlyinggrowth mechanisms for these nanomaterials remain insufficiently understood.We introduce herein a purposely devised chiral inducer, a cysteinemodified with a hydrophobic chain, as a versatile chiral inducer.The amphiphilic and chiral features of this molecule provide controlover the chiral morphology and the chiroptical signature of the obtainednanoparticles by simply varying the concentration of chiral inducer.These results are supported by circular dichroism and electromagneticmodeling as well as electron tomography to analyze structural evolutionat the facet scale. Our observations suggest complex roles for thefactors involved in chiral synthesis: the chemical nature of the chiralinducers and the influence of cosurfactants. Near-field electromagneticenhancements deriving from the resonance of oscillating conductionelectrons (surface plasmons) in metal nanomaterials make the sensingof chiral small molecules and biomolecules using circularly polarizedlight demonstrably viable.5 Furthermore, the observations that the surface plasmonsof chiral structures are also chiral, and that enhancement effectsare collectively applied to the structure as a whole,6 have encouraged advances in the development of chiral plasmonicnanomaterials.One does notneed to look beyondtheir own hands to realize that chirality, a property that describesobjects lacking internal or mirror symmetry, is ubiquitous. Even apolarized plane of light can itself be considered chiral, possessingright- and left-handed components.8 and the wide range of chiral templates,10 several types of plasmonic NPs have been reported and a wider varietyis expected.11 Chiral nanomaterials havealready found relevant applications, mainly due to their strong circulardichroism (CD), and their specific interactions with chiral biomolecules,including molecular sensors13 and immunotherapy.15 Further expansion of such applications largely depends on our abilityto tailor the chiral intricacy of the nanomaterial and to understandits influence on the resulting optical activity and spectral range.Consequently, the development of synthetic methodologies capable ofyielding chiral nanomaterials with novel morphologies holds paramountimportance for emerging areas such as nanomedicine, enantioselectivecatalysis, and even nanorobotics. In these applications, control overparticle size is highly relevant, regarding the prominence of absorptionor scattering in the optical response.Lending to the adaptable nature of plasmonicnanoparticle (NP)synthesis methods18 More challenging has been the colloidal synthesis of plasmonic nanomaterialswith a chiral morphology at the single-particle level. Seeded-growthsynthesis has emerged as an efficient methodology for the preparationof chiral nanostructures with a high optical activity. Among variousother parameters, the geometry of the NP seed largely determines thefinal morphology of the resulting chiral NPs; here we focus on theuse of gold nanorods (Au NRs) as seeds.19 Recent reports have shown that chiral seeded growth on Au NPs canbe achieved through several alternative pathways, according to thechemical nature of the molecular inducer of dissymmetry.Arrangement of a nonchiralmaterial into a configuration that impartschiral properties in a bottom-up approach is foundational for theflexible and reproducible design of chiral nanomaterials.20 This method was initiallyapplied to other NP seed morphologies,22 using aminoacids (such as cysteine) or short peptides containing the same aminoacid, as the dissymmetry inducers. Asymmetric growth on the plasmonicseeds has been claimed to be induced by the enantioselective adsorptionof chiral inducers on high-index facets with atomic-scale chirality.This preferential interaction with a particular chiral facet promotesthe kinetic growth of crystallographic facets with the opposite handedness,ultimately resulting in the formation of twisted shapes.23 The same strategy has been applied to prepare several types of twistedAu NRs by the overgrowth of preformed achiral Au NRs. However, theoutcome of the overgrowth process is significantly influenced by theexperimental conditions employed. Our research team reported a cysteine-mediatedmultistep growth method, enabling the synthesis of 4-fold-twistedgold nanorods with a g-factor reaching values ashigh as 0.10.20 In contrast, Wu et al.achieved the fabrication of helical plasmonic nanorods through thesynergistic combination of cysteine and the achiral molecule 4-aminothiophenol,in the presence of a significant amount of Ag+ ions, yieldinga g-factor of 0.04.24 However,the specific role of the various additives has yet to be determined.Onesynthetic pathway results in the formation of plasmonic nanorodswith twisted geometry 1a.20 Thi26 in which the presence of a chiralcosurfactant leads to helical micelles wrapped around the Au NR seeds.Such helical micelles act as templates during seeded growth, resultingin a dense array of quasihelical wrinkles around a central NR -2-amino-N-decyl-3-mercaptopropanamide, which we term (R)-LipoCYS(Supporting Information), as the chiral inducer for the seededgrowth of gold nanorods. The presence of a cysteine-like headgroupand a longer hydrophobic tail was foreseen to provide a dual function,allowing high affinity for both the gold surface and the micellarsystem. The choice of gold nanorods as achiral seeds provides a largersurface area per particle for adsorption of the cysteine moiety, whilecapitalizing on the potential for micelle formation, maximizing theirelongation and promoting the growth of distinct chiral features. Weshow that LipoCYS is a versatile inducer that can produce both twistedand wrinkled chiral plasmonic nanoparticles as described above, dependingon its concentration. At relatively low concentrations, LipoCYS behavessimilarly to cysteine and generates twisted gold nanorods. In contrast,high concentrations of LipoCYS lead to the formation of NPs with well-definedhelical wrinkles, typically obtained through micelle-directed growth.The observed morphological changes are also reflected in distinctoptical features with varying intensities and spectral positions.Emboldened by the success of chiral synthesis usingamino acidsand inspired by the putative micellar template growth mechanism, weexplored the role of a purposely devised chiral molecule consistingof a modified cysteine,  using CTAC as a surfactant and ascorbic acid (AA) asa reducing agent. This protocol has been previously applied to producecolloidal dispersions of chiral nanoparticles with an intense chiropticalresponse using BINAMINE as the chiral inducer.25 As a means to monitor the quality of the produced chiralNRs, circular dichroism (CD) spectroscopy was used to quantify thechiroptical response, i.e. the unequal extinction of left- and right-handedcircularly polarized light.27 Additionally,to characterize surface wrinkles and other geometrical features, high-angleannular dark-field scanning transmission electron microscopy (HAADF-STEM)was combined with tomography to investigate the morphology and structuralfeatures in 3D, which can hardly be discerned in conventional 2D HAADF-STEMimages. Through the modification of experimental parameters, we aimedat maximizing the g-factor, while monitoring theresulting structural evolution.To evaluate the performance of LipoCYS as a chiral inducer, weimplemented experimentally the growth of preformed gold nanorods -LipoCYS and0.009 for (S)-LipoCYS. g-factors are consistently achieved with the R enantiomer,which may be related to inherent challenges associated with thiolatedmolecules and their potential oxidation by atmospheric oxygen.A gradual increase of the LipoCYSconcentration  resulted in a spectral red shift of the chiropticalsignature and a corresponding change in particle morphology 2. The NPg-factor wasobserved for wrinkled particles synthesized with 90 μM LipoCYS. Theseparticles have average dimensions of 190 ± 9.9 nm × 75.9± 3.7 nm and maximum g-factors (at 720 nm) of0.066 for (R)-LipoCYS and 0.043 for (S)-LipoCYS. Additional wrinkling on particles at higher LipoCYS concentrationresulted in weaker chiroptical activity, which might be related toa lower degree of order in surface topography at higher concentrationsor a complex directional geometry developing at the particle tips.28 This hypothesis is supported by the resultsof a quantitative helicity analysis  based on HAADF-STEM tomography, which confirms the direct correlationbetween the handedness of the studied NPs and the type of enantiomerused during the synthesis.29 For the NRsprepared with the highest LipoCYS concentration (200 μM), aless defined helicity plot was obtained, indicating undefined chirality.A plateau in the maximum obtained Figure S4 and the Supporting Information for details).30 We used 3D models, based on the electron tomographyreconstructions in g-factor bands observed for increasing LipoCYS concentrationsare related to the formation of well-defined wrinkles, in agreementwith a detailed computational analysis reported elsewhere.31 The effect of disorder in the wrinkled structure(for the highest LipoCYS concentrations) was also accounted for inthe simulations, indeed revealing a loss of CD signal when the surfacefeatures are disordered  discretizedby the method of moments (MoM) . Three-dimensional reconstructionsof the NPs indicate an evolution from relatively smooth surfaces ata low LipoCYS concentration to densely wrinkled shapes at a high LipoCYScontent. Similar morphological studies were also applied to the 90μM sample . HAADF-STEMshowed an average length of the wrinkles of around 22 nm, a distancebetween them of ∼2 nm, and a thickness of ∼4 nm.A detailed analysis of the morphologyof the produced particleswas thus performed using HAADF-STEM tomography for both enantiomers. For nanoparticles as complex as those investigatedhere, 2D HAADF-STEM images do not enable a straightforward identificationof the crystallographic nature of the overall surface structure, inparticular, the concave surfaces. We therefore performed simultaneousHAADF-STEM and electron diffraction (ED) tomography on a selectedNP, obtained using 20 μM (R)-LipoCYS (Movie S1). Orthoslices orthogonal to the [001]direction -LipoCYS, thisselective overgrowth occurs on the top left and bottom right cornersof each concave face, as also illustrated in the idealized model  indicates that they are twisted in a similar manneras the helicoids reported by Lee et al.,21 likely intertwined with the presence of chiral facets.Through the former analysis, weconclude that the observed concavefaces mainly consist of two facets belonging to the {520} family.Correspondingly, we present an idealized morphology in ed model . Finally21 Theresulting morphology is thus similar to the 4-fold twisted gold nanorodsdescribed in ref . This result can also beelucidated through the earlier hypothesis, given that hydrophobicforces drive LipoCYS toward clustering, thereby initiating the formationof elongated micelles. A lower amount of LipoCYS would thus yielda reduced number of wormlike micelles, leading to a correspondinglylower count of grooves and resulting in the formation of larger wrinkles.To elucidatethe underlying mechanism governing chiral growth athigh LipoCYS concentrations, it is crucial to emphasize that LipoCYSwas synthesized with a specific design, aimed at facilitating bothinteraction with CTAC micelles, through the incorporation of the aliphaticchain, and the gold surface, via the thiol group. Effective interactionwith the plasmonic surface becomes apparent at concentrations exceeding20 μM, as indicated by previous findings. Concerning its impacton the micellar system, the low concentration of LipoCYS utilizedin chiral growth experiments, i.e., 0.2% LipoCYS relative to CTACmolarity for the 90 μM sample, is insufficient to induce anydiscernible alterations in the morphology of CTAC micelles withinthe bulk phase. This was verified through diffusion-ordered spectroscopy(DOSY) and dynamic light scattering (DLS) experiments, as depictedin 26 It should be noted that above a certain concentration of LipoCYS,the observed chiroptical response decreases significantly as a resultof the observed lower degree of order in the wrinkled structure. Therelative contribution to the overall chiroptical signature of micelle-directedformation of wrinkles and stabilized facet-directed twisting of theparticle geometry warrants further investigation.We have contended in this work that chiral growth on gold nanorodscan be modulated through rational control over the underlying growthmechanisms, which may provide valuable information for the predictablesynthesis of chiral plasmonic nanomaterials. We have demonstratedreproducible control over the obtained nanoparticle structure at differentscales: both fine-detailed wrinkles and the larger overall particlegeometry can be tailored through the synthesis conditions. Such avariation can be achieved by modifying a single parameter  for a given chiral synthesis. Theseresults are supported by observations that the deposition of goldon the nanorod (seed) surface, and even the preference of facet growth,is heavily influenced by the presence of cosurfactants.An additionalrelevant finding of this study is related to micellartemplate growth: to date, this synthetic protocol has been based onapplying a very particular type of molecules with axial chiralityas inducers of dissymmetry. Herein, we found that molecules with centralchirality are also capable of giving rise to the same chiral morphology.Comparison of the chemical structure of LipoCYS and the previouslyused inducers suggests that micellar template growth requires chiralinducers with two different regions, a polar head with high affinityfor the gold surface and a hydrophobic part that endows affinity forthe micelles. Taken together, these results suggest an expanded rolefor cosurfactants that can be applied for the preparation of nanomaterialswith chiral morphology. The availability of a diverse range of goldseeds of various shapes and sizes further emphasizes the significanceof these findings.


Diagnosis is the most important step in treating and managing kidney cancer, requiring accurate identification, localization, and classification of tumor regions. The selection of appropriate surgical procedures for malignant cases is further based on tumor volume and relative severity. In recent years, machine-learning-based approaches have been proposed to localize, quantify, and stratify kidney tumors using contrast-enhanced computed tomography (CT) images. However, previous studies have largely neglected the integration of patient metadata with clinical images to better diagnose and guide surgical interventions. In the current study, we developed a combined clinical and image-based approach to classify kidney cancers using a publicly available dataset. We show that the inclusion of clinical features alongside medical images improves the performance of kidney tumor classification. We further used clinical data together with a machine-learning approach to predict the expected surgical procedure employed in individual kidney cancer patients. In addition to cancer stage and tumor volume, some surprisingly common demographic features were revealed to be key determinants of the surgical procedure later selected for nephrectomy.Kidney cancers are one of the most common malignancies worldwide. Accurate diagnosis is a critical step in the management of kidney cancer patients and is influenced by multiple factors including tumor size or volume, cancer types and stages, etc. For malignant tumors, partial or radical surgery of the kidney might be required, but for clinicians, the basis for making this decision is often unclear. Partial nephrectomy could result in patient death due to cancer if kidney removal was necessary, whereas radical nephrectomy in less severe cases could resign patients to lifelong dialysis or need for future transplantation without sufficient cause. Using machine learning to consider clinical data alongside computed tomography images could potentially help resolve some of these surgical ambiguities, by enabling a more robust classification of kidney cancers and selection of optimal surgical approaches. In this study, we used the publicly available KiTS dataset of contrast-enhanced CT images and corresponding patient metadata to differentiate four major classes of kidney cancer: clear cell (ccRCC), chromophobe (chRCC), papillary (pRCC) renal cell carcinoma, and oncocytoma (ONC). We rationalized these data to overcome the high field of view (FoV), extract tumor regions of interest (ROIs), classify patients using deep machine-learning models, and extract/post-process CT image features for combination with clinical data. Regardless of marked data imbalance, our combined approach achieved a high level of performance . When selecting surgical procedures for malignant tumors (RCC), our method proved even more reliable . Using feature ranking, we confirmed that tumor volume and cancer stage are the most relevant clinical features for predicting surgical procedures. Once fully mature, the approach we propose could be used to assist surgeons in performing nephrectomies by guiding the choices of optimal procedures in individual patients with kidney cancer. Chronic kidney diseases (CKDs) are progressive conditions that confer gradual loss of renal function, ultimately leading to kidney failure . CKDs arKidney scans typically comprise X-rays , ultrasoKidney cancer diagnosis using abdominal CT images is one of the most crucial tasks in clinical management ,28,29,30Computed tomography (CT) images and clinical metadata from the KiTS21 dataset were used to differentiate four major classes of renal cancer: clear cell (ccRCC), chromophobe (chRCC), papillary (pRCC) renal cell carcinoma, and oncocytoma (ONC);Tumor subclass predictions were integrated with clinical metadata to determine the optimal surgical approach in malignant cases ;To the best of our knowledge, this is the first study to determine kidney tumor subclass using a combination of CT images and corresponding clinical features;This pioneering study paves the way for future refinement of tools that can guide surgical interventions in kidney cancer by applying machine-learning algorithms trained on relevant clinical data.In this study, we propose a machine-learning-based approach that combines contrast-enhanced CT images with corresponding clinical metadata from individual patients to classify kidney tumors into major subclasses and guide the selection of an optimal surgical procedure. The main contributions of this study are as follows:In According to the American Cancer Society (ACS), kidney tumors rank among the ten most common types of malignancy . In receThe Kidney and Kidney Tumor Segmentation Challenge (KiTS) was first launched in 2019 , continuAccurate identification of tumor subtype and progression/severity are crucial aspects of kidney cancer diagnosis and key determinants of whether surgery will be required . In addiKidney cancers—especially malignant cases—often require surgery to remove the tumorous regions. Depending on case complexity, surgeons might elect to perform open, robotic, or laparoscopic surgery , using eThe overall workflow of this study is presented in In this study, we used the publicly available “Kidney and Kidney Tumor Segmentation Challenge 2021” (KiTS21) dataset . The conThe KiTS21 dataset is provided in Neuroimaging Informatics Technology Initiative (NIFTI) file format  and compAs proposed by the challenge organizers , the abiLogSoftmax’ [The original DenseNet architecture was proposed in 2018 by Huang et al.  as a setSoftmax’  as the aExtracted 2D-CT slices containing kidney footprints can be used directly for tumor subclass classification based on labels, but it is important to note that other organs present in the image heavily impact the decision-making process. To mitigate this, a region of interest (ROI) around the kidney can be extracted from whole CT slices so that multiclass classifiers can focus only on tumorous regions in the next stage. Extracting an ROI for kidney detection or segmentation from CT images has been a common practice across a range of published 2D/3D approaches. For example, three of the four top performers ranked by the KiTS19 challenge extracted ROIs from 3D-CT images, using methods extending from coarse segmentation to extracting volume of interest (VOI)  . In recex/y coordinates of the bounding box center point), whereas contours provide height, width, and x/y coordinates, and define the origin  as the left-uppermost corner of the bounding box. We, therefore, generated labels for YOLO using Equations (2)–(5);The original KiTS21 annotations feature ground-truth masks for segmentation but do not contain bounding-box labels as required for training YOLO frameworks. We, therefore, used the segmentation masks to generate three classes of rectangular bounding boxes for the YOLO framework, corresponding to the three-pixel levels used to denote kidney, tumor, and cyst regions. First, contours were generated and unified around the masks, then bounding boxes were positioned to encompass the four extreme corners of these contours. During the generation of ground-truth bounding boxes, we observed that tumor regions appeared very distorted or blurry if these were either very irregular in shape or small in size (resulting in upsampling/interpolation to fixed dimensions). To avoid this impacting model performance, the bounding boxes were adjusted to form squares based on the highest dimension of length or width. Next, we removed any slices in which the bounding box area for a kidney region was less than 48 pixels height/width or <1% of the total slice area . The overall bounding box generation process is summarized in For the YOLO framework, labels are saved in text files linked to each image (with matching file names). Since we used YOLO models pretrained on the COCO dataset , images The KiTS metadata file available via GitHub  containsThe prepared dataset was trained and evaluated using a 2D-CNN-based multiclass classifier. The models used for this task were the same as those employed for scope reduction  format which was converted into a tabular format for preprocessing. The clinical features can be divided broadly into preoperative, intraoperative, and postoperative categories . For this task, the primary aim is to boost the tumor subtype classification performance of machine-learning algorithms by combining clinical data with features extracted from the CT images. Subsequently, these clinical features were also used to classify whether radical or partial nephrectomy was selected when operating on malignant tumors (RCCs).After extracting clinical metadata, we used only preoperative elements to inform our diagnostic framework, since only presurgical features would be available to guide decision-making in real-life scenarios. In addition, intraoperative characteristics and postoperative outcomes arise from surgical decisions taken by a diverse range of clinicians, rather than being objective features of individual patients and kidney tumors. Key preoperative clinical parameters included tumor size (radiographic and pathologic), demographic information , as well as alcohol/smoking/tobacco history, and the presence of 19 common comorbidities . For predicting surgical procedure, we also included tumor subtype and Fuhrman grade  since opIn the TNM grading system, T refers to the size and extent of the primary tumor, N indicates the number of malignant lymph nodes nearby, and M denotes whether cancer has metastasized  . Based oImage features were extracted from the penultimate layer of the best-performing 2D-CNN-based classifier (DenseAUXNet201). The final classifier was removed for feature extraction, and a total of 4480 features were obtained from each image (using the latent layer of DenseAUXNet201). Features from all images for a test subject were concatenated and reduced through principal component analysis (PCA) . For theFor this study, we used different types of ML-based classifiers for both tumor sub-typing (combined approach) and surgical procedure assignment: logistic regression, k-nearest neighbors (kNN), support vector machine (SVM), random forest, extra trees, linear discriminant analysis (LDA), gradient boost (GradBoost) , adaptivWe used two broad types of machine-learning applications for classification (deep or standard ML) and object detection (deep ML). Distinct evaluation criteria were applied for each approach.TP), true negative (TN), false positive (FP), and false negative (FN) labels from the confusion matrix, then these metrics were formulated for subject-wise evaluation based on Equations (6)–(10);The performance of the classifiers (both standard and deep ML) was evaluated based on accuracy, precision, recall/sensitivity, specificity, and F1-score. We initially extracted the number of true positive . For accuracy, we reported the overall macro value calculated from the confusion matrix for the entire dataset. We also show the confusion matrix for the best-performing model at individual stages of each task.mAP), at various intersections over union (IoU) levels. Precision and recall metrics have been defined in Equations (7) and (8), respectively (computed based on ground truth and predicted bounding box coordinates). Average precision (AP) can be defined as a technique to summarize the whole precision-recall curve into a single value, as formulated in Equation (11).The metrics most commonly used to assess the accuracy of bounding-box generation by YOLO frameworks are precision, recall, and mean average precision  = 0 and Precision(n) = 1. The mAP value can be derived from AP by calculating the average AP from all the classes. If there are ‘c’ number of classes, mAP can be defined as:AP in all classes will be divided by three to obtain mAP, which is a key metric of object detection performance . Both large/obvious objects and small/challenging cases are captured by mAP calculation. For YOLO, the common practice is to measure mAP at IoU threshold 0.5 and IoU range 0.5–0.95 [The current study includes three distinct classes, namely kidney, tumor, and cyst regions. In this case, the sum of To further assess YOLO performance, we plotted ground truth and estimated bounding boxes side-by-side for various types of sample cases. We also plotted the performance curves   of the bHere we present the quantitative and qualitative outcomes of tumor subclass classification by deep learning from kidney CT images . Assignment of surgical procedures for malignant tumors based on clinical parameters is also assessed.As depicted in Scope reduction was performed to remove non-kidney CT slices from the dataset, thus allowing the object detection networks to focus on kidney, tumor, and cyst ROI extraction without any impact of irrelevant slices. We extracted 64,603 2D-CT slices from a total set of 300 CT images. Among these, approximately 41,675 (64.5%) were non-kidney slices, which would represent a major confounder for object detection if not removed. The proposed DenseAUXNet201 framework displayed the best performance across all evaluation metrics and achieved the lowest number of missed cases. While only a modest increase in performance was noted, this nonetheless represented a significant improvement in the detection and removal of non-kidney slices (and vice-versa).As plotted in In mAP at the IoU threshold of 0.5 and range of 0.5–0.95 [mAP values indicate more efficient detection of very small and/or challenging regions . We, therefore, selected basic YOLOv7 as the best-performing model for our experiments.We experimented with six models from two different generations of YOLO to extract kidney, tumor, and cyst ROIs using the scope-reduced 2D-CT dataset . This was not the case for the processing of tumor ROIs i.e., the primary goal of this study. Example outputs from the YOLOv7 network alongside their corresponding ground-truth values are shown in We next compared the performance of kidney cancer classification using extracted tumor ROIs (image-based) and the combined approach . After curation, the dataset contained n = 272 cases for classification. Data were split subject-wise in the same way for all experiments  so that These analyses revealed that random forest, XGBoost, and CatBoost algorithms performed far better than the other methods. We selected XGBoost due to its higher F1-score . From tAs discussed earlier, the raw clinical features included 29 parameters with the potential to influence the classification of kidney tumor surgical procedures. First, we removed highly correlated features to avoid redundancy and reduce overfitting. As before, the ‘pathologic size’ feature was detected as being highly correlated with ‘radiographic size’ and was therefore removed. The remaining 28 features were then ranked based on their relevance to surgical procedure selection. Among the three feature ranking techniques experimented with in this study , we opted to use random forest  due to iFeature ranking by random forest  and extrWe finally chose the top 20 features as ranked by random forest for the surgery classification task. We removed any feature with <0.1% relevance to the target and then trained the classifiers over 1000 epochs or until convergence . Outcomes were evaluated in terms of overall accuracy and weighted precision, recall/sensitivity, specificity, and F1-score. The combined (averaged) fivefold classification results are provided in According to Cancer Research UK , surgeonAI-based tumor detection and subtype classification can help guide medical and surgical decision-making for kidney cancer patients. Locating kidneys, tumors, and cysts from CT slices using deep-learning approaches is itself a useful application for aiding or training clinicians and radiologists during a cancer diagnosis. Provided acceptable levels of performance, AI-based smart systems can inform the choice of therapy or surgical procedure in kidney cancer, thereby preserving renal function in patients who require only partial nephrectomy or saving the lives of patients with end-stage cancers requiring radical intervention. The primary limitation of this study was the generality of the KiTS dataset. The proposed AI tool could be significantly improved by collecting a large, objective-driven dataset designed to refine this approach. The collected custom dataset should be more balanced in terms of tumor subtypes and cancer stages, ideally containing thousands of diverse cases to make the AI tool more robust for a large population group. More clinical biomarkers, patient medical history, immediate relevant parameters to the surgical table, and other important habits and comorbidities should also be recorded to render this tool more reliable and further improve performance.


Imaging has a pivotal role in neuro-oncology for the management of primary and secondary brain tumors. To this regard, positron emission tomography (PET) is increasingly used to supplement magnetic resonance imaging (MRI) in the management of patients with brain tumors, including gliomas, meningiomas, central nervous system lymphomas and brain metastases for specific clinical settings ,2,3.PET imaging is performed using different radiopharmaceuticals which evaluate several biological processes including different metabolic pathways or receptor expression ,2,3. FurAn umbrella review published in 2019 which summarizes evidence-based data on PET using different radiopharmaceuticals in brain tumors showed a good diagnostic performance of PET using different radiopharmaceuticals for specific indications in brain tumors and a significant prognostic value . Recent Gliomas are the most common neuro-epithelial tumors of the central nervous system in adults; most of gliomas are highly malignant tumors with high rate of recurrence and a dismal prognosis. Advanced imaging methods including PET with different radiopharmaceuticals are useful to differentiate among tumor progression and treatment-related changes in gliomas; this differential diagnosis has prognostic and therapeutical implications . InteresMeningioma is the most common intracranial tumor, typically a slow-growing neoplasm that forms from the meninges and it can be incidentally detected by PET imaging using different radiopharmaceuticals . FurtherPrimary central nervous system lymphoma (PCNSL) is an uncommon neoplasm with a poor prognosis. PET with fluorine-18 fluorodeoxyglucose has a defined role for the management of PCNSL in immunocompetent and immunocompromised patients. This imaging method is useful for assessing the disease spread at the time of diagnosis. In addition, it can provide valuable information for differential diagnosis and outcome prediction, and for treatment response assessment .Brain metastases can be also evaluated by PET with different radiopharmaceuticals, and in particular amino acid tracers. Along with MRI, the gold standard for diagnosis of brain metastases, PET is a useful complementary imaging method technique for evaluation of selected indications in patients with brain metastases. Current evidence highlights the relevant role of amino acid PET radiotracers in brain metastases, in particular for the differentiation among tumor progression/disease relapse after treatment and treatment-related changes .PET/CT is currently the most used hybrid imaging modality used for the evaluation of brain tumors. However, there is growing evidence that a multimodal approach using hybrid PET/MRI can achieve several improvements in the diagnostics of brain tumors .Beyond the technology advancements of PET tomographs, future perspectives about PET imaging in neuro-oncology are represented by novel PET radiopharmaceuticals evaluating different biological processes of brain tumors ,17,18,19Even if increasing evidence-based data about PET imaging in brain tumors are available, high-quality studies are still warranted (“we just can’t get enough”) to strengthen the role of this imaging method in neuro-oncology.