Quantification of finger grasps during activities of daily life using convolutional neural networks: A pilot study.

Quantifying finger kinematics can improve the authors' understanding of finger function and facilitate the design of efficient prosthetic devices while also identifying movement disorders and assessing the impact of rehabilitation interventions. Here, the authors present a study that quantifies grasps depicted in taxonomies during selected Activities of Daily Living (ADL). A single participant held a series of standard objects using specific grasps which were used to train Convolutional Neural Networks (CNN) for each of the four fingers individually. The experiment also recorded hand manipulation of objects during ADL. Each set of ADL finger kinematic data was tested using the trained CNN, which identified and quantified the grasps required to accomplish each task. Certain grasps appeared more often depending on the finger studied, meaning that even though there are physiological interdependencies, fingers have a certain degree of autonomy in performing dexterity tasks. The identified and most frequent grasps agreed with the previously reported findings, but also highlighted that an individual might have specific dexterity needs which may vary with profession and age. The proposed method can be used to identify and quantify key grasps for finger/hand prostheses, to provide a more efficient solution that is practical in their day-to-day tasks.

Electrical impedance tomography image reconstruction for lung monitoring based on ensemble learning algorithms.

Electrical impedance tomography (EIT) is a promising non-invasive imaging technique that visualizes the electrical conductivity of an anatomic structure to form based on measured boundary voltages. However, the EIT inverse problem for the image reconstruction is nonlinear and highly ill-posed. Therefore, in this work, a simulated dataset that mimics the human thorax was generated with boundary voltages based on given conductivity distributions. To overcome the challenges of image reconstruction, an ensemble learning method was proposed. The ensemble method combines several convolutional neural network models, which are the simple Convolutional Neural Network (CNN) model, AlexNet, AlexNet with residual block, and the modified AlexNet model. The ensemble models' weights selection was based on average technique giving the best coefficient of determination (R2 score). The reconstruction quality is quantitatively evaluated by calculating the root mean square error (RMSE), the coefficient of determination (R2 score), and the image correlation coefficient (ICC). The proposed method's best performance is an RMSE of 0.09404, an R2 score of 0.926186, and an ICC of 0.95783 using an ensemble model. The proposed method is promising as it can construct valuable images for clinical EIT applications and measurements compared to previous studies.

Do Perineuronal Nets Stabilize the Engram of a Synaptic Circuit?

Perineuronal nets (PNNs), a specialized form of extra cellular matrix (ECM), surround numerous neurons in the CNS and allow synaptic connectivity through holes in its structure. We hypothesize that PNNs serve as gatekeepers that guard and protect synaptic territory and thus may stabilize an engram circuit. We present high-resolution and 3D EM images of PNN-engulfed neurons in mice brains, showing that synapses occupy the PNN holes and that invasion of other cellular components is rare. PNN constituents in mice brains are long-lived and can be eroded faster in an enriched environment, while synaptic proteins have a high turnover rate. Preventing PNN erosion by using pharmacological inhibition of PNN-modifying proteases or matrix metalloproteases 9 (MMP9) knockout mice allowed normal fear memory acquisition but diminished long-term memory stabilization, supporting the above hypothesis.

New Strides in Prevention of Malaria during Pregnancy Present Multitudinous Opportunities.

Pregnant women are at a higher risk of developing complications from malaria, a mosquito-borne disease caused by Plasmodium parasites, resulting in considerable maternal and infant morbidity and mortality. Malaria in pregnancy causes unfavorable and life-threatening outcomes for both the mother and fetus not limited to maternal anemia, hypoglycaemia, cerebral malaria, pulmonary edema, and puerperal sepsis. WHO recommends wide-ranging strategies for this detrimental but preventable disease; however, numerous challenges persist in ensuring high uptake of preventive therapies, effective usage of insecticide-treated bed nets, and early initiation and optimal antenatal care coverage for pregnant women. This work distils recent global advances in preventive strategies for malaria in pregnancy. We discuss three mainstay interventions by WHO, viz. intermittent preventive treatment of malaria in pregnancy (IPTp), utilization and outcomes of insecticide-treated bed nets (ITNs), and headways in malaria case management using therapeutic drugs. We cover multitudinous facets of antenatal care, WHO-advised community-based delivery of IPTp (c-IPTp), intermittent screening and treatment for malaria in pregnancy (ISTp), a malaria vaccine for pregnant women, and auxiliary factors that are crucial for improving prevention outcomes. Despite the reduction in malaria globally, malaria in pregnancy remains a prevalent issue in endemic areas, which warrants strengthening of preventative strategies. This work attempts to consolidate pivotal observations of the prevention of malaria during pregnancy by highlighting key advances, priority areas, new opportunities, research gaps, and challenges that need to be addressed to ensure improved outcomes in pregnant women infected with malaria.

Evaluation of bio-efficacy of field-aged novel long-lasting insecticidal nets (PBO, chlorfenapyr or pyriproxyfen combined with pyrethroid) against Anopheles gambiae (s.s.) in Tanzania.

Next-generation insecticide-treated bed nets (ITNs) combining two insecticides or an insecticide with a synergist are vital in combating malaria, especially in areas with pyrethroid-resistant mosquitoes where standard pyrethroid long-lasting insecticidal net (LLIN) may be less effective. A community durability study was conducted in Misungwi, Tanzania, during a cluster randomised controlled trial. This study assessed the bio-efficacy of three net brands combining a pyrethroid insecticide and either a synergist PBO for Olyset Plus, or a second insecticide pyriproxyfen for Royal Guard, and chlorfenapyr for Interceptor G2 over three years. These nets were compared to Interceptor, a standard pyrethroid-only net. A total of 1950 nets were enrolled across 10 clusters in each treatment arm. Thirty nets per type were collected every 6 months up to 30 months, with 50 nets sampled at 36 months. WHO cone bioassays and tunnel tests were performed at 0, 12, 24, 30 and 36 months. Both susceptible An. gambiae (s.s.) Kisumu strain and resistant An. gambiae (s.s.) Muleba-Kis strain were exposed. Over 80% of nets tested against the susceptible Kisumu strain met the WHO criteria after three years of community use. In tunnel tests, mortality (72 h) of the resistant Anopheles varied between 52% and 20%, in Interceptor G2 and was higher than standard Interceptor net up to 24 months. Olyset Plus mortality (24 h) ranged between 84% and 33% in tunnel tests with superior efficacy compared to Interceptor at 0, 24 and 36 months. Sterility effects in Royal Guard were higher when these nets were new and at six months but decreased to less than 10% after 12 months. Royal Guard consistently induced higher mortality compared to Interceptor up to 30 months while next-generation ITNs demonstrated higher efficacy in terms of mortality compared to standard LLINs against resistant strains; this superior bio-efficacy did not persist for the full three years. The impact of active ingredient (dual-AI) and PBO diminished relatively quickly. Aside from the initial period when the nets were new, the differences in mortality for Interceptor G2 and Olyset Plus and in sterility for Royal Guard, compared to the standard LLINs, were relatively small thereafter.

A dose-adjusted, open-label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis.

Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre-clinical studies showed benefit with a histone-neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose-adjusted, open-label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady-state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug-related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half-life values ranged from 5 to 7 h. The mean (±SD) terminal half-life for non-RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified.

Preoperative Glycosylated Hemoglobin A1C Impacts Long-Term Outcomes Following Curative-Intent Resection of Nonfunctional Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: To investigate the impact of preoperative glycosylated hemoglobin A1C (HbA1c) among patients following curative-intent resection of nonfunctional gastroentropancreatic neuroendocrine tumors (GEP-NETs). METHODS: Patients who underwent curative-intent resection for GEP-NETs from 2000 to 2020 were identified from the US Neuroendocrine Tumor Study Group (US-NETSG). Preoperative blood HbA1c levels were defined as high HbA1c (≥ 6.5%) versus low HbA1c group (< 6.5%). Impact of HbA1c level on postoperative short-term and long-term overall (OS) were investigated. RESULTS: A total of 130 patients with HbA1c < 6.5% and 60 patients with HbA1c ≥ 6.5% were included. Patients with HbA1c ≥ 6.5% had higher proportion of comorbidities, such as hypertension, obesity, anemia, and lower preoperative albumin levels versus patients with HbA1c < 6.5% (all p < 0.05). In addition, high level of preoperative HbA1c was associated with increased incidence of wound and infectious complications, as well as decreased long-term OS (median OS: high Hb1Ac 89.8 months vs. low Hb1Ac not reached, HR 3.487, p = 0.004) among patients with nonfunctional GEP-NETs, as well as among the subset of pancreatic NET patients (median OS: high Hb1Ac 74.3 months vs. low Hb1Ac not reached, p = 0.004), and patients with normal fasting blood glucose (< 140 mg/dL) (median OS: high Hb1Ac 75.4 months vs. low Hb1Ac not reached, p = 0.001). CONCLUSIONS: Hb1Ac might have value as a screening tool to identify high-risk patients following surgical resection of nonfunctional GEP-NETs for consideration of more strict postoperative surveillance and treatment of elevated Hb1Ac level.

Healthcare innovation adoption in Africa: the case of long-lasting insecticide nets in Ghana using protection motivation theory.

OBJECTIVE: Studies have shown that healthcare innovation adoption is complex. Using Long-lasting insecticidal nets (LLINs), an innovation for malaria prevention, the study aimed to understand factors considered in the adoption of healthcare innovations in Africa. METHODS AND MEASURES: Using qualitative methods, we interviewed 10 household heads in Ghana who had freely received LLINs during a malaria campaign. We analyzed our data using a deductive thematic analysis approach utilizing the protection motivation theory (PMT) as our framework. RESULTS: We found that the constructs of PMT: perceived severity, perceived vulnerability, perceived response efficacy, and perceived self-efficacy influenced the adoption of healthcare innovation (i.e. LLINs). We also found that misconceptions about malaria infection and prevention influenced the perceived response efficacy of LLINs which could undermine LLINs usage. CONCLUSION: The constructs of PMT are important in the decision to use LLINs. Misconceptions about malaria infection and prevention could undermine the decision to use LLINs. Future studies should investigate ways to address these misconceptions.

Genetic determinants of antidepressant and antipsychotic drug response.

Today, more than 90% of inpatients hospitalized with Major Depression or Schizophrenia are treated with psychotropic drugs. Since none of the treatment options is causal, response rates are modest and the course of recovery is very heterogeneous. Genetic studies on the etiology and pathogenesis of major psychiatric disorders over the past decades have been largely unsuccessful. Likewise, genetic studies to predict response to psychopharmacological treatment have also not been particularly successful. In this project we have recruited 902 inpatients with ICD-10 diagnoses of schizophrenic ("F2 patients") or depressive disorders ("F3 patients"). The study assessed today's acute inpatient treatment regimens with up to 8 repeated measurements regarding the time course of recovery and adverse side effects. The genotyping included 100 candidate genes with genotypic patterns computed from 549 Single Nucleotide Polymorphisms (SNPs). To predict response to psychopharmacological treatment, we relied on a multidimensional approach to analyzing genetic diversity in combination with multilayer Neural Nets (NNs). Central to this new method were the "gene vectors" that (1) assessed the multidimensional genotypic patterns observed with genes; and (2) evaluated the correlations between genes. By means of these methods, we searched for combinations of multidimensional genotypic patterns that were characteristic of treatment responders while being rare among non-responders. The chosen method of approach provided a powerful technique to detail the complex structures of SNP data that are not detectable by conventional association methods. Molecular-genetic NNs enabled correct classification of 100% "non-responders", along with 94.7% correctly classified "responders" among the F2 patients, and 82.6% correctly classified "responders" among the F3 patients. The F2 and F3 classifiers were not disjoint but showed an overlap of 29.6% and 35.7% between the diagnostic groups, thus indicating that clinical diagnoses may not constitute etiologic entities. Our results suggested that patients may have an unspecific physical-genetic disposition that enables, facilitates, impedes or prevents recovery from major psychiatric disorders by setting various thresholds for exogenous triggers that initiate improvement ("recovery disposition"). Even though this disposition is not causally linked to recovery, it can nonetheless be clinically used in the sense of a "surrogate". Indeed, clinicians are also interested in reliable tools that can "do the job", despite the fact that etiology and pathogenesis of the treated disorders remain unknown.

Fuzzy Petri Nets for Traffic Node Reliability.

Self-driving cars are one of the main areas of research today, but it has to be acknowledged that the information from the sensors (the perceptron) is a huge amount of data, which is now unmanageable even when projected onto a single traffic junction. In the case of self-driving, the nodes have to be sequenced and organized according to the planned route. A self-driving car in Hungary would have to be able to interpret more than 70,000 traffic junctions to be able to drive all over the country. Besides the huge amount of data, another problem is the issue of validation and verification. For self-driving cars, this implies a level of complexity using traditional methods that calls into question the economics of the already existing system. Fuzzy Petri nets provide an alternative solution to both problems. They allow us to obtain a model that accurately describes the reliability of a node through its dynamics, which is essential in perception since the more reliable a node is, the smaller the deep learning mesh required. In this paper, we outline the analysis of a traffic node's safety using Petri nets and fuzzy analysis to gain information on the reliability of the node, which is essential for the modeling of self-driving cars, due to the deep learning model of perception. The reliability of the dynamics of the node is determined by using the modified fuzzy Petri net procedure. The need for a fuzzy extension of the Petri net was developed by knowledge of real traffic databases.

Pramipexole, a D3 receptor agonist, increases cortical gamma power and biochemical correlates of cortical excitation; implications for mood disorders.

Major depressive disorder (MDD) has been associated with deficits in working memory as well as underlying gamma oscillation power. Consistent with this, overall reductions in cortical excitation have also been described with MDD. In previous work, we have demonstrated that the monoamine reuptake inhibitor venlafaxine increases gamma oscillation power in ex vivo hippocampal slices and that this is associated with concomitant increases in pyramidal arbour and reduced levels of plasticity-restricting perineuronal nets (PNNs). In the present study, we have examined the effects of chronic treatment with pramipexole (PPX), a D3 dopamine receptor agonist, for its effects on gamma oscillation power as measured by in vivo electroencephalography (EEG) recordings in female BALB/c and C57Bl6 mice. We observe a modest but significant increase in 20-50 Hz gamma power with PPX in both strains. Additionally, biochemical analysis of prefrontal cortex lysates from PPX-treated BALB/c mice shows a number of changes that could contribute to, or follow from, increased pyramidal excitability and/or gamma power. PPX-associated changes include reduced levels of specific PNN components as well as tissue inhibitor of matrix metalloproteases-1 (TIMP-1), which inhibits long-term potentiation of synaptic transmission. Consistent with its effects on gamma power, PNN proteins and TIMP-1, chronic PPX treatment also improves working memory and reduces anhedonia. Together these results add to an emerging literature linking extracellular matrix and/or gamma oscillation power to both mood and cognition.

AAV-mouse DNase I sustains long-term DNase I expression in vivo and suppresses breast cancer metastasis.

Neutrophil extracellular traps (NETs) have been implicated in the pathology of various inflammatory conditions. In cancer, NETs have been demonstrated to induce systemic inflammation, impair peripheral vessel and organ function and promote metastasis. Here we show that the plasma level of NETs is significantly higher in patients with metastatic breast cancer compared to those with local disease, or those that were considered cured at a 5-year follow-up, confirming NETs as interesting therapeutic targets in metastatic breast cancer. Administration of DNase I is one strategy to eliminate NETs but long-term treatment requires repeated injections and species-specific versions of the enzyme. To enhance administration and therapeutic efficacy, we have developed an adeno-associated virus (AAV) vector system for delivery of murine DNase I and addressed its potential to counteract cancer-associated pathology in the murine MMTV-PyMT model for metastatic mammary carcinoma. The AAV vector is comprised of capsid KP1 and an expression cassette encoding hyperactive murine DNase I (AAV-mDNase I) under the control of a liver-specific promotor. This AAV-mDNase I vector could support elevated expression and serum activity of murine DNase I over at least 8 months. Neutrophil Gelatinase-Associated Lipocalin (NGAL), a biomarker for kidney hypoperfusion that is upregulated in urine from MMTV-PyMT mice, was suppressed in mice receiving AAV-mDNase I compared to an AAV-null control group. Furthermore, the proportion of mice that developed lung metastasis was reduced in the AAV-mDNase I group. Altogether, our data indicate that AAV-mDNase I has the potential to reduce cancer-associated impairment of renal function and development of metastasis. We conclude that AAV-mDNase I could represent a promising therapeutic strategy in metastatic breast cancer.

S100A7 orchestrates neutrophil chemotaxis and drives neutrophil extracellular traps (NETs) formation to facilitate lymph node metastasis in cervical cancer patients.

Neutrophil extracellular traps (NETs) have been shown to promote the metastatic potential of many kinds of tumors. Our study aimed to investigate the role and mechanisms of NETs in lymph node metastasis (LNM) of cervical cancer (CCa), and evaluated the therapeutic value of targeting NETs in CCa. Immunohistochemistry demonstrated that neutrophil infiltration and NETs formation were increased in CCa patients with LNM, as well as confirming a positive correlation between S100A7 expression and neutrophil infiltration in CCa. NETs enhanced the migratory capability of CCa by activating the P38-MAPK/ERK/NFκB pathway through interaction with TLR2. Digesting NETs with deoxyribonuclease 1 (DNase 1) or inhibiting TLR2 with chloroquine eliminated the NETs-induced metastatic potential of CCa. Additionally, NETs promoted lymphangiogenesis and increased the permeability of lymphatic vessels, thus facilitating translymphatic movement of CCa. CCa-derived S100A7 exhibited a chemotactic effect on neutrophils and promoted NETs generation by elevating ROS levels rather than activating autophagy in neutrophils. The mouse model with footpad implantation illustrated that DNase 1 effectively reduced LNM in LPS-induced mice and in mice seeded with S100A7-overexpressing CCa cells. In conclusion, our study reveals a new tumor-promoting mechanism of S100A7, clarifies the crucial role and mechanism of NETs in LNM of CCa, and indicates that the NETs-targeted therapy emerges as a promising anti-metastasis therapy in CCa.

Neutrophil extracellular traps activate Notch-γ-secretase signaling in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is an inflammatory chronic skin disorder of unknown etiology characterized by inflamed abscess-like nodules and boils resulting in sinus tract formation, tissue scarring, and massive infiltration of neutrophils. Multiple lines of evidence have highlighted the potential association between alterations in the Notch pathway and HS pathogenesis, but the mechanisms remain incompletely characterized. OBJECTIVE: We aimed to elucidate the role of neutrophil extracellular traps in Notch-γ-secretase signaling. METHODS: Twenty-six HS lesional tissues, primary HS macrophages, and skin fibroblasts were interrogated by quantitative PCR, Western blot, and ELISA analyses. γ-Secretase and TNF-α converting enzyme activities were measured in HS skin lesions, macrophages, and skin fibroblasts. Immunofluorescence and RNAscope analyses were performed in HS and control skin. RESULTS: A prominent presence of Notch ligands, Delta-like ligand 4 (DLL4), and Jagged (JAG) 2 were detected at the protein and mRNA levels in HS skin lesion compared to control. Levels of DLL4, JAG1, citrullinated histone H3 DNA, and γ-secretase activity correlated with HS disease severity. Additionally, significantly elevated levels of Notch ligands and γ-secretase activity were found in dissected sinus tracts compared to the rest of HS tissue. Immunofluorescence microscopy of HS skin lesions revealed activation of Notch-1 signaling in macrophages and skin fibroblasts. Neutrophil extracellular traps (NETs) purified from HS patients displayed elevated levels of DLL4. HS NETs activated the Notch pathway in macrophages and dermal fibroblasts isolated from HS patients. HS skin fibroblasts displayed elevated levels of CD90 and DPP4 in association with increased migratory capacity and Notch activation. Inhibition of Notch decreased migratory capacity and profibrotic markers in HS fibroblasts. CONCLUSION: These data support a pathogenic connection between NETs, Notch-γ-secretase activation, and the release of profibrotic molecules that promote dysregulation of macrophages and skin fibroblasts in HS. Unveiling the relevance of these molecular events not only expands our understanding of HS but also opens new venues for the development of targeted therapies to address the fibrotic complications of advanced stages of HS.

Neutrophils: a key component in ECMO-related acute organ injury.

Extracorporeal membrane oxygenation (ECMO), as an extracorporeal life support technique, can save the lives of reversible critically ill patients when conventional treatments fail. However, ECMO-related acute organ injury is a common complication that increases the risk of death in critically ill patients, including acute kidney injury, acute brain injury, acute lung injury, and so on. In ECMO supported patients, an increasing number of studies have shown that activation of the inflammatory response plays an important role in the development of acute organ injury. Cross-cascade activation of the complement system, the contact system, and the coagulation system, as well as the mechanical forces of the circuitry are very important pathophysiological mechanisms, likely leading to neutrophil activation and the production of neutrophil extracellular traps (NETs). NETs may have the potential to cause organ damage, generating interest in their study as potential therapeutic targets for ECMO-related acute organ injury. Therefore, this article comprehensively summarized the mechanism of neutrophils activation and NETs formation following ECMO treatment and their actions on acute organ injury.

Neutrophil-fibroblast crosstalk drives immunofibrosis in Crohn's disease through IFNα pathway.

Introduction: Crohn's disease (CD) is characterized by chronic inflammation and intestinal fibrosis leading to lifelong complications. However, the disease pathogenesis remains elusive, and the therapeutic options are limited. Here, we investigated the interaction between neutrophils and intestinal fibroblasts in the development of CD immunofibrosis, a disease mechanism predisposing to inflammatory and fibrotic complications. Methods: Peripheral neutrophils, enriched neutrophil extracellular traps (eNETs), serum, primary intestinal fibroblasts (PIFs) and intestinal biopsies from CD, ulcerative colitis (UC) patients, and healthy individuals (HI), were studied. Transcriptome analysis of neutrophils, multi-cytokine profiling and cell-based functional assays at mRNA/protein level were performed. Results: Compared to UC, PIFs from CD patients, independently to the presence of strictures, displayed a distinct pro-fibrotic phenotype characterized by negative Krüppellike Factor-2 (KLF2) and increased cellular communication network factor-2 (CCN2) expression leading to collagen production. In both UC and CD, PIFs-derived IL-8 acted as a culprit chemoattractant for neutrophils in the intestine, where CD neutrophils were accumulated close to fibrotic lesions. Functionally, only CD neutrophils via eNETs induced a CD-like phenotype in HI PIFs, suggesting their fibrotic plasticity. High IFNa in serum and IFΝ-responsive signature in peripheral neutrophils were observed in CD, distinguishing it from UC. Moreover, CD serum stimulated the release of fibrogenic eNETs from neutrophils in an IFNa-dependent manner, suggesting the priming role of IFNa in circulating neutrophils. Inhibition of eNETs or JAK signaling in neutrophils or PIFs prevented the neutrophil-mediated fibrotic effect on PIFs. Furthermore, both serum IFNa levels and mRNA levels of key IFN signaling components in neutrophils were wellcorrelated with CD severity. Conclusions: This study reveals the important role of the IFNa/neutrophil/fibroblast axis in CD immunofibrosis, suggesting candidate biomarkers and putative therapeutic targets.

The Safety and Efficacy of Peptide Receptor Radionuclide Therapy for Gastro-Entero-Pancreatic Neuroendocrine Tumors: A Single Center Experience.

The aim of the present study was to evaluate the safety and efficacy of radionuclide therapy with [177Lu]Lu-DOTA-TATE according to our single center experience at the University of Naples Federico II. For the present analysis, we considered 21 patients with progressive, advanced, well-differentiated G1 and G2 in patients with gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs) treated with [177Lu]Lu-DOTA-TATE according to the decisions of a multidisciplinary team. All patients underwent four cycles of 7-8 GBq of [177Lu]Lu-DOTA-TATE every 8 weeks. A whole-body scan (WBS) was performed 4, 48, and 168 h after each treatment. The dosimetry towards the organ at risk and target lesions was calculated. For each patient, renal and bone marrow parameters were evaluated before, during, and 3 months after the end of the treatment. Follow-up data were obtained and RECIST criteria were considered as the endpoint. Among 21 patients enrolled (mean age 65 ± 9 years); 17 (81%) were men and the small intestine was the most frequent location of disease (n = 12). A mild albeit significant variation (p < 0.05) in both platelets and white blood cell counts among all time points was observed, despite it disappearing 3 months after the end of the therapy. According to the RECIST criteria, 11 (55%) patients had a partial response to therapy and 8 (40%) had stable disease. Only one (5%) patient had disease progression 4 months after treatment. Our data confirm that [177Lu]Lu-DOTA is safe and effective in controlling the burden disease of G1/G2 GEP-NETs patients.

Quantitative SPECT/CT Metrics in Early Prediction of [177Lu]Lu-DOTATATE Treatment Response in Gastroenteropancreatic Neuroendocrine Tumor Patients.

Our objective is to explore quantitative imaging markers for early prediction of treatment response in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) undergoing [177Lu]Lu-DOTATATE therapy. By doing so, we aim to enable timely switching to more effective therapies in order to prevent time-resource waste and minimize toxicities. Methods: Patients diagnosed with unresectable or metastatic, progressive, well-differentiated, receptor-positive GEP-NETs who received 4 sessions of [177Lu]Lu-DOTATATE were retrospectively selected. Using SPECT/CT images taken at the end of treatment sessions, we counted all visible tumors and measured their largest diameters to calculate the tumor burden score (TBS). Up to 4 target lesions were selected and semiautomatically segmented. Target lesion peak counts and spleen peak counts were measured, and normalized peak counts were calculated. Changes in TBS (ΔTBS) and changes in normalized peak count (ΔnPC) throughout treatment sessions in relation to the first treatment session were calculated. Treatment responses were evaluated using third-month CT and were binarized as progressive disease (PD) or non-PD. Results: Twenty-seven patients were included (7 PD, 20 non-PD). Significant differences were observed in ΔTBSsecond-first, ΔTBSthird-first, and ΔTBSfourth-first (where second-first, third-first, and fourth-first denote scan number between the second and first, third and first, and fourth and first [177Lu]Lu-DOTATATE treatment cycles), respectively) between the PD and non-PD groups (median, 0.043 vs. -0.049, 0.08 vs. -0.116, and 0.109 vs. -0.123 [P = 0.023, P = 0.002, and P < 0.001], respectively). ΔnPCsecond-first showed significant group differences (mean, -0.107 vs. -0.282; P = 0.033); ΔnPCthird-first and ΔnPCfourth-first did not reach statistical significance (mean, -0.122 vs. -0.312 and -0.183 vs. -0.405 [P = 0.117 and 0.067], respectively). At the optimal threshold, ΔTBSfourth-first exhibited an area under the curve (AUC) of 0.957, achieving 100% sensitivity and 80% specificity. ΔTBSsecond-first and ΔTBSthird-first reached AUCs of 0.793 and 0.893, sensitivities of 71.4%, and specificities of 85% and 95%, respectively. ΔnPCsecond-first, ΔnPCthird-first, and ΔnPCfourth-first showed AUCs of 0.764, 0.693, and 0.679; sensitivities of 71.4%, 71.4%, and 100%; and specificities of 75%, 70%, and 35%, respectively. Conclusion: ΔTBS and ΔnPC can predict [177Lu]Lu-DOTATATE response by the second treatment session.

Perineuronal Net Alterations Following Early-Life Stress: Are Microglia Pulling Some Strings?

The extracellular matrix plays a key role in synapse formation and in the modulation of synaptic function in the central nervous system. Recent investigations have revealed that microglia, the resident immune cells of the brain, are involved in extracellular matrix remodeling under both physiological and pathological conditions. Moreover, the dysregulation of both innate immune responses and the extracellular matrix has been documented in stress-related psychopathologies as well as in relation to early-life stress. However, the dynamics of microglial regulation of the ECM and how it can be impacted by early-life adversity have been understudied. This brief review provides an overview of the recent literature on this topic, drawing from both animal model and human post mortem studies. Direct and indirect mechanisms through which microglia may regulate the extracellular matrix-including perineuronal nets-are presented and discussed in light of the interactions with other cell types.

Parvovirus B19 Infection Is Associated with the Formation of Neutrophil Extracellular Traps and Thrombosis: A Possible Linkage of the VP1 Unique Region.

Neutrophil extracellular traps (NETs) formation, namely NETosis, is implicated in antiphospholipid syndrome (APS)-related thrombosis in various autoimmune disorders such as systemic lupus erythematosus (SLE) and APS. Human parvovirus B19 (B19V) infection is closely associated with SLE and APS and causes various clinical manifestations such as blood disorders, joint pain, fever, pregnancy complications, and thrombosis. Additionally, B19V may trigger the production of autoantibodies, including those against nuclear and phospholipid components. Thus, exploring the connection between B19V, NETosis, and thrombosis is highly relevant. An in vitro NETosis model using differentiated HL-60 neutrophil-like cells (dHL-60) was employed to investigate the effect of B19V-VP1u IgG on NETs formation. A venous stenosis mouse model was used to test how B19V-VP1u IgG-mediated NETs affect thrombosis in vivo. The NETosis was observed in the dHL-60 cells treated with rabbit anti-B19V-VP1u IgG and was inhibited in the presence of either 8-Br-cAMP or CGS216800 but not GSK484. Significantly elevated reactive oxygen species (ROS), myeloperoxidase (MPO), and citrullinated histone (Cit-H3) levels were detected in the dHL60 treated with phorbol myristate acetate (PMA), human aPLs IgG and rabbit anti-B19V-VP1u IgG, respectively. Accordingly, a significantly larger thrombus was observed in a venous stenosis-induced thrombosis mouse model treated with PMA, human aPLs IgG, rabbit anti-B19V-VP1u IgG, and human anti-B19V-VP1u IgG, respectively, along with significantly increased amounts of Cit-H3-, MPO- and CRAMP-positive infiltrated neutrophils in the thrombin sections. This research highlights that anti-B19V-VP1u antibodies may enhance the formation of NETosis and thrombosis and implies that managing and treating B19V infection could lower the risk of thrombosis.