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Abstract How the human eye focuses for near; i.e. accommodates, is still being evaluated after more than 165 years. The mechanism of accommodation is essential for understanding the etiology and potential treatments for myopia, glaucoma and presbyopia. Presbyopia affects 100% of the population in the fifth decade of life. The lens is encased in a semi-elastic capsule with attached ligaments called zonules that mediate ciliary muscle forces to alter lens shape. The zonules are attached at the lens capsule equator. The fundamental issue is whether during accommodation all the zonules relax causing the central and peripheral lens surfaces to steepen, or the equatorial zonules are under increased tension while the anterior and posterior zonules relax causing the lens surface to peripherally flatten and centrally steepen while maintaining lens stability. Here we show with a balloon capsule zonular force model that increased equatorial zonular tension with relaxation of the anterior and posterior zonules replicates the topographical changes observed during in vivo rhesus and human accommodation of the lens capsule without lens stroma. The zonular forces required to simulate lens capsule configuration during in vivo accommodation are inconsistent with the general belief that all the zonules relax during accommodation.

More than 10 million Europeans show signs of mild cognitive impairment (MCI), a transitional stage between normal brain aging and dementia stage memory disorder. The path MCI takes can be divergent; while some maintain stability or even revert to cognitive norms, alarmingly, up to half of the cases progress to dementia within 5 years. Current diagnostic practice lacks the necessary screening tools to identify those at risk of progression. The European patient experience often involves a long journey from the initial signs of MCI to the eventual diagnosis of dementia. The trajectory is far from ideal. Here, we introduce the AI-Mind project, a pioneering initiative with an innovative approach to early risk assessment through the implementation of advanced artificial intelligence (AI) on multimodal data. The cutting-edge AI-based tools developed in the project aim not only to accelerate the diagnostic process but also to deliver highly accurate predictions regarding an individual's risk of developing dementia when prevention and intervention may still be possible. AI-Mind is a European Research and Innovation Action (RIA H2020-SC1-BHC-06-2020, No. 964220) financed between 2021 and 2026. First, the AI-Mind Connector identifies dysfunctional brain networks based on high-density magneto- and electroencephalography (M/EEG) recordings. Second, the AI-Mind Predictor predicts dementia risk using data from the Connector, enriched with computerized cognitive tests, genetic and protein biomarkers, as well as sociodemographic and clinical variables. AI-Mind is integrated within a network of major European initiatives, including The Virtual Brain, The Virtual Epileptic Patient, and EBRAINS AISBL service for sensitive data, HealthDataCloud, where big patient data are generated for advancing digital and virtual twin technology development. AI-Mind's innovation lies not only in its early prediction of dementia risk, but it also enables a virtual laboratory scenario for hypothesis-driven personalized intervention research. This article introduces the background of the AI-Mind project and its clinical study protocol, setting the stage for future scientific contributions.

Objectives Basic tools that measure a hospital’s performance are required in order to benchmark or compare hospitals, but multispecialty institutional registries are rarely reported, and there is no consensus on their standard definitions and methodology. This study aimed to describe the setting up and first results of a hospital-wide surgical complication register that uses a minimal set of patient-related risk factors based on bedside data and produces outcomes data based on severity of complications.Design Cohort study.Setting Perioperative data related to all adult surgical procedures in a tertiary referral centre in Finland for 3 years (2016–2018) were included in the study. Complications were recorded according to a modified Clavien-Dindo classification, and the preoperative risk factors were compiled based on the literature and coded as numerical measures. The associations of preoperative risk factors with postoperative complications were analysed using the χ2 test or Fisher’s exact test.Results In total, 19 158 operations were performed between 2016 and 2018. Data on complications (Clavien 0–9) were recorded for 4529 surgical patients (23.6%), and 779 complications were reported (Clavien 1–9), leading to an overall complication rate of 17.2%. Of these, 4.6% were graded as major (Clavien 4–7). Patient-related risk factors with the strongest association with complications were growing American Society of Anesthesiologists Physical Status Classification System score (p

Background: Suck-swallow rhythmicity and the integration of breathing into infant feeding are developmentally regulated. Neurological injury and breathing abnormalities can both impact feeding in preterm infants.Objective: To determine the effects of neurologic injury independent of effects of disordered breathing on feeding biorhythms in premature infants.Methods: Low-risk preterm infants (LRP), infants with Grade 3–4 Intraventricular Hemorrhage (IVH), those with bronchopulmonary dysplasia (BPD), and those with both BPD and IVH (BPD+IVH) were identified. Forty-seven infants, 32–42 weeks Postmenstrual Age (PMA) were evaluated on one or more occasions (131 studies). Of these, 39 infants (81 studies) were performed at >35 weeks PMA. Coefficient of variation (COV) (=standard deviation of the inter-event (e.g., suck-suck, swallow-breath, etc.) interval divided by the mean of the interval) was used to quantify rhythmic stability.Results: To adjust for PMA, only those infants >35–42 weeks were compared. Suck-suck COV was significantly lower (more rhythmically stable) in the LRP group [COV = 0.274 ± 0.051 (S.D.)] compared to all other groups (BPD = 0.325 ± 0.066; IVH = 0.342 ± 0.072; BPD + IVH = 0.314 ± 0.069; all p < 0.05). Similarly, suck-swallow COV was significantly lower in LRP babies (0.360 ± 0.066) compared to the BPD group (0.475 ± 0.113) and the IVH cohort (0.428 ± 0.075) (p < 0.05). The BPD+IVH group (0.424 ± 0.109), while higher, was not quite statistically significant.Conclusions: Severe IVH negatively impacts suck-suck and suck-swallow rhythms. The independent effect of neurological injury in the form of IVH on feeding rhythms suggests that quantitative analysis of feeding may reflect and predict neurological sequelae.

AIM: To compare the results of in vivo human high resolution image registration studies of the eye during accommodation to the predictions of mathematical and finite element models of accommodation. METHODS: Data from published high quality image registration studies of pilocarpine induced accommodative changes of equatorial lens radius (ELR) and central lens thickness (CLT) were statistically analyzed. RESULTS: The mean changes in ELR and CLT were 6.76 μm/diopter and 6.51 μm/diopter, respectively. The linear regressions, reflecting the association between ELR and accommodative amplitude (AAELR) was: slope=6.58 μm/diopter, r2=0.98, P

Abstract Background D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma. Methods To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test. Results D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC50 = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC50 = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge. Conclusions These data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma.

Standard treatment, unfortunately, yields a poor prognosis for patients with primary or metastatic cancers in the central nervous system, indicating a necessity for novel therapeutic agents. Immunotoxins (ITs) are a class of promising therapeutic candidates produced by fusing antibody fragments with toxin moieties. In this study, we investigated if inherent resistance to IT cytotoxicity can be overcome by rational combination with pro-apoptotic enhancers. Therefore, we combined ITs (9.2.27-PE38KDEL or Mel-14-PE38KDEL) targeting chondroitin sulfate proteoglycan 4 (CSPG4) with a panel of Bcl-2 family inhibitors (ABT-737, ABT-263, ABT-199 [Venetoclax], A-1155463, and S63845) against patient-derived glioblastoma, melanoma, and breast cancer cells/cell lines. In vitro cytotoxicity assays demonstrated that the addition of the ABT compounds, specifically ABT-737, sensitized the different tumors to IT treatment, and improved the IC50 values of 9.2.27-PE38KDEL up to >1,000-fold. Mechanistic studies using 9.2.27-PE38KDEL and ABT-737 revealed that increased levels of intracellular IT, processed (active) exotoxin, and PARP cleavage correlated with the enhanced sensitivity to the combination treatment. Furthermore, we confirmed the synergistic effect of 9.2.27-PE38KDEL and ABT-737 combination therapy in orthotopic GBM xenograft and cerebral melanoma metastasis models in nude mice. Our study defines strategies for overcoming IT resistance and enhancing specific antitumor cytotoxicity in primary and metastatic brain tumors.

Background Pancreatic digestive enzymes present in meconium might be responsible for meconium-induced lung injury. The local Renin Angiotensin System plays an important role in lung injury and inflammation. Particularly, angiotensin converting enzyme-2 (ACE-2) has been identified as a protective lung enzyme against the insult. ACE-2 converts pro-apoptotic Angiotensin II to anti-apoptotic Angiotensin 1-7. However, the effect of meconium on ACE-2 has never been studied before. Objective To study the effect of meconium on ACE-2, and whether inhibition of proteolytic enzymes present in the meconium reverses its effects on ACE-2. Methods Alveolar epithelial A549 cells were exposed to F-12 medium, 2.5% meconium, meconium + a protease inhibitor cocktail (PIc) and PIc alone for 16 h. At the end of incubation, apoptosis was measured with a nuclear fragmentation assay and cell lysates were collected for ACE-2 immunoblotting and enzyme activity. Results Meconium caused a fourfold increase in apoptotic nuclei (p < 0.001). The pro-apoptotic effect of meconium can be reversed by PIc. Meconium reduced ACE-2 enzyme activity by cleaving ACE-2 into a fragment detected at ~ 37 kDa by immunoblot. PIc prevented the degradation of ACE-2 and restored 50% of ACE-2 activity (p < 0.05). Conclusion These data suggest that meconium causes degradation of lung protective ACE-2 by proteolytic enzymes present in meconium, since the effects of meconium can be reversed by PIc., Author(s): Chintan K. Gandhi [sup.1] [sup.2] , Romel Holmes [sup.3] , Ira H. Gewolb [sup.1] , Bruce D. Uhal [sup.4] Author Affiliations: (1) 0000 0001 2150 1785, grid.17088.36, Division of [...]