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Background/aim: Glioblastoma (GBM) is the most common and most lethal type of cancer of the central nervous system in adults. Despite aggressive treatment, which is based on surgical resection, if possible, followed by radiation and chemotherapy, a high recurrence rate and therapy resistance is observed. Thus, additional innovative therapies are urgently needed to improve the poor median survival of only 15 months. Treatment of solid tumours with non-invasive physical plasma (NIPP) represents such a novel and innovative anticancer procedure., Materials and Methods: In this study, we investigated the effect of NIPP, an ionized argon gas, on the in vitro growth of human GBM cell lines, LN-18 and U-87 MG. Proliferation was measured by live cell count. Subsequently, proliferative factors were analysed at the level of nucleic acids (polymerase chain reaction) and proteins (western blotting)., Results: For both GBM lines, a treatment time-dependent decrease in growth was observed compared to controls. Additionally, NIPP treatment resulted in reduced rates of AKT serine/threonine kinase 1 (AKT1) and extracellular-regulated kinase 1/2 ERK1/2 expression, whereas expression of p21, proliferating cell nuclear antigen, and heat-shock proteins 90α and 90β was not affected. In both cell lines, a strong increase in expression of tumour-suppressive microRNA-1 (miR-1) was detected after exposure to NIPP., Conclusion: Our results demonstrated that NIPP is able to efficiently attenuate growth of GBM cells and suggest AKT1, ERK1/2 and miR-1 to be pivotal factors of NIPP-modulated cellular signalling. Translated into the clinical setting, NIPP may represent a promising option for the treatment of GBM., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Low birth weight (BW) is associated with increased corneal aberrations in childhood and alterations of corneal geometry in adulthood. Increased corneal aberrations may be a factor contributing to decreased visual function in former low BW newborns in later life. Hence, the aim of this study was to analyze the long-term effect of low BW on corneal aberrations in adulthood., Methods: In the German population-based Gutenberg Health Study (GHS) participants (age: 40-80 years) were examined with Scheimpflug imaging (Pentacam HR, Oculus Optikgeräte GmbH, Wetzlar, Germany). The relationship between self-reported BW and the different types of corneal aberrations was analyzed using linear regression analysis as uni- and multivariable analysis with adjustment for potential confounders. The main outcome measures were corneal aberrations defined as astigmatism (Z 2 -2 ; Z 2 2 ), coma (Z 3 -1 ; Z 3 1 ), trefoil (Z 3 -3 ; Z 3 3 ), spherical aberration (Z 4 0 ) and root-mean square of higher order aberrations (HOA; 3rd up to 8th order; aperture size: 6 mm)., Results: Overall, 5,628 participants were included in this analysis (3,004 women, aged 56.0 +/- 10.3 years). In a multivariable analysis lower BW was associated with decreased horizontal trefoil (B = 0.004 [0.001; 0.006] µm/500 g; p=.008); higher spherical aberrations (B=-0.006 [-0.008;-0.003] µm/500 g; p<.001), higher RMS (B=-0.028 [-0.042;-0.014] µm/500 g; p<.001), increased HOA (B=-0.007 [-0.010;-0.003] µm/500 g; p<.001) and increased LOA (B=-0.027 [-0.041;-0.013] µm/500 g; p<.001). No association was observed between birth weight and the other types of corneal aberrations in multivariable model., Conclusion: Our results indicate an association between BW and spherical aberration in adults aged 40 to 80 years. This indicates that low BW may have an association with an altered corneal shape development which may affect optical image quality and, hence, visual function., Competing Interests: Conflict of interest The author reports no conflict of interest. Source of funding is listed in the acknowledgement section., (Copyright © 2021 Spanish General Council of Optometry. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Prior coronary artery bypass graft surgery (CABG) patients undergoing percutaneous coronary intervention (PCI) are often older and present with multiple comorbidities. Ticagrelor monotherapy after a short course of dual antiplatelet therapy (DAPT) has emerged as an effective bleeding-avoidance strategy among high-risk patients., Aims: We aimed to examine the effects of ticagrelor with or without aspirin in prior CABG patients undergoing PCI within the TWILIGHT trial., Methods: After 3 months of ticagrelor plus aspirin, patients were randomised to either aspirin or placebo, in addition to ticagrelor, for 12 months and compared by prior CABG status. The primary endpoint was Bleeding Academic Research Consortium (BARC) type 2, 3 or 5 bleeding. The key secondary endpoint was all-cause death, myocardial infarction (MI), or stroke., Results: Out of 7,119 patients, a total of 703 (10.8%) patients had prior CABG within the randomised cohort. Prior CABG patients had more comorbidities and a higher incidence of BARC type 2, 3, or 5 bleeding and death, MI or stroke at 1 year after randomisation, compared with patients without prior CABG. Ticagrelor monotherapy was associated with significantly less BARC 2, 3, or 5 bleeding among prior CABG patients compared with DAPT (4.9% vs 9.6%, hazard ratio [HR] 0.50, 95% confidence interval [CI]: 0.28 to 0.90; p interaction =0.676) and similar rates of death, MI or stroke (10.0% vs 8.7%, HR 1.14, 95% CI: 0.70 to 1.87; p interaction =0.484). When comparing target vessel type, treatment effects were consistent among graft- and native-vessel interventions., Conclusions: In high-risk patients with prior CABG, ticagrelor monotherapy reduced bleeding without compromising ischaemic outcomes compared with ticagrelor plus aspirin.

Background: The NVX-CoV2373-vaccine has recently been licensed, although knowledge on vaccine-induced humoral and cellular immunity towards the parental strain and variants of concern (VOCs) in comparison to mRNA-regimens is limited., Methods: In this observational study, 66 individuals were recruited to compare immunogenicity and reactogenicity of NVX-CoV2373 with BNT162b2 or mRNA-1273. Vaccine-induced antibodies were analyzed using ELISA and neutralization assays, specific CD4 and CD8 T-cells were characterized based on intracellular cytokine staining using flow-cytometry after antigen-specific stimulation with parental spike or VOCs., Results: Two doses of NVX-CoV2373 strongly induced anti-spike IgG, although IgG-levels were lower than after vaccination with BNT162b2 or mRNA-1273 (p = 0.006). Regardless of the vaccine and despite different IgG-levels, neutralizing activity towards VOCs was highest for Delta, followed by BA.2 and BA.1. The protein-based vaccine failed to induce any spike-specific CD8 T-cells which were detectable in 3/22 (14%) individuals only. In contrast, spike-specific CD4 T-cells were induced in 18/22 (82%) individuals, although their levels were lower (p<0.001), had lower CTLA-4 expression (p<0.0001) and comprised less multifunctional cells co-expressing IFNγ, TNFα and IL-2 (p = 0.0007). Unlike neutralizing antibodies, NVX-CoV2373-induced CD4 T-cells equally recognized all tested VOCs from Alpha to Omicron. In individuals with a history of infection, one dose of NVX-CoV2373 had similar immunogenicity as two doses in non-infected individuals. The vaccine was overall well tolerated., Conclusion: NVX-CoV2373 strongly induced spike-specific antibodies and CD4 T-cells, albeit at lower levels as mRNA-regimens. Cross-reactivity of CD4 T-cells towards the parental strain and all tested VOCs may hold promise to protect from severe disease., Competing Interests: Declaration of Competing Interest M.S. has received grant support from Astellas and Biotest to the organization Saarland University outside the submitted work, and honoraria for lectures from Biotest and Novartis. M.W. has received speaker fees from Astra Zeneca and grant support from Roche Molecular Diagnostics to the organization Goethe University Frankfurt outside the submitted work. All other authors of this manuscript have no conflicts of interest to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Glioblastoma is the most common and lethal primary brain malignancy that almost inevitably recurs as therapy-refractory cancer. While the success of immune checkpoint blockade (ICB) revealed the immense potential of immune-targeted therapies in several types of cancers outside the central nervous system, it failed to show objective responses in glioblastoma patients as of now. The ability of glioblastoma cells to drive multiple modes of T cell dysfunction while exhibiting low-quality neoepitopes, low-mutational load, and poor antigen priming limits anti-tumor immunity and efficacy of antigen-unspecific immunotherapies such as ICB. An in-depth understanding of the GBM immune landscape is essential to delineate and reprogram such immunosuppressive circuits during disease progression. In this view, the present study aimed to characterize the peripheral and intratumoral immune compartments of 35 glioblastoma patients compared to age- and sex-matched healthy control probands, particularly focusing on exhaustion signatures on myeloid and T cell subsets. Compared to healthy control participants, different immune signatures were already found in the peripheral circulation, partially related to the steroid medication the patients received. Intratumoral CD4+ and CD8+ TEM cells (CD62L low /CD45RO high ) revealed a high expression of PD1, which was also increased on intratumoral, pro-tumorigenic macrophages/microglia. Histopathological analysis further identified high PSGL-1 expression levels of the latter, which has recently been linked to increased metastasis in melanoma and colon cancer via P-selectin-mediated platelet activation. Overall, the present study comprises immunophenotyping of a patient cohort to give implications for eligible immunotherapeutic targets in neurooncology in the future.

Empathy enables human beings to understand and share the internal states of others. Studies show that empathy for pain is higher for in-group compared to out-group members. This might be driven by attitudes and biases towards out-groups. In a between subject design, N = 621 participants filled in questionnaires measuring xenophobia and trait empathy and were presented with photos of suffering individuals either from the in-group or an out-group, which had to be rated with respect to negative affect and the willingness to help the depicted persons. Results do not show more compassion with members of the in-group in general, but a negative effect of xenophobia on state empathy in the out-group condition. Additional moderation analyses show that this effect is less evident in presence of high trait empathy scores. Our results highlight the importance of empathy trainings to attenuate the effects of xenophobic attitudes on social cohabitation in our increasingly polarized and culturally diverse societies., (© 2022. The Author(s).)

Background:  In recent years, a correlation of thrombocytosis and a worse prognosis was shown for many solid cancers, including glioblastoma multiforme (GBM)., Methods:  A retrospective review was performed for all patients with a histologically proven and first-diagnosed GBM between 2005 and 2015 in our department. Clinical and paraclinical parameters were acquired from patient documentation and structured for subsequent data analysis. The association of potential risk factors with overall survival was assessed using the Kaplan-Meier survival analysis and Cox regression., Results:  The present study includes 309 patients first diagnosed with primary GBM. Our analyses validate well-known risk factors of a decreased overall survival such as higher patient age, a larger preoperative tumor volume, Karnofsky performance status, extent of resection, tumor localization, and adjuvant treatment. However, no correlation was observed between a preoperative thrombocytosis, the mean platelet volume, leucocyte count, activated partial thromboplastin time (apTT), fibrinogen level, and acetylsalicylic acid 100 co-medication. Patients with preoperative hemoglobin below 7.5 mmol/L had decreased overall survival., Conclusion:  The present study, enrolling the largest numbers of patients assessing this topic to date, did not find any association between a preoperative thrombocytosis and overall survival in 309 patients with GBM., Competing Interests: None declared., (Thieme. All rights reserved.)

Indications for surgery of pineal cysts without ventriculomegaly are still under debate. In view of the limited data for pineal cyst resection in the absence of hydrocephalus, and the potential risk of this approach, we have analyzed our patient cohort focusing on strategies to avoid complications according to our experience in a series of 73 pineal cyst patients. From 2003 to 2015, we reviewed our database retrospectively for all patients operated on a pineal cyst. Furthermore, we prospectively collected patients from 2016 to 2020. In summary, 73 patients with a pineal cyst were treated surgically between 2003 and 2020. All patients were operated on via a microscopic supracerebellar-infratentorial (SCIT) approach. The mean follow-up period was 26.6 months (range: 6-139 months). Seventy-three patients underwent surgery for a pineal cyst. An absence of enlarged ventricles was documented in 62 patients (51 female, 11 male, mean age 28.1 (range 4-59) years). Main presenting symptoms included headache, visual disturbances, dizziness/vertigo, nausea/emesis, and sleep disturbances. Complete cyst resection was achieved in 59/62 patients. Fifty-five of 62 (89%) patients improved after surgery with good or even excellent results according to the Chicago Chiari Outcome Scale, with complete or partial resolution of the leading symptoms. Pineal cysts resection might be an indication in certain patients for surgery even in the absence of ventriculomegaly. The high percentage of postoperative resolution of quality-of-life impairing symptoms in our series seems to justify surgery. Preoperatively, other causes of the leading symptoms have to be excluded., (© 2022. The Author(s).)

Purpose: Endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunting are well-established treatments of obstructive hydrocephalus (HCP) in adult and pediatric patients. However, there is a lack of data with regard to the quality of life (QoL) of these patients during long-term follow-up METHODS: Inclusion criteria were pediatric patients with endoscopic treatment of hydrocephalus at the University Medicine Greifswald between 1993 and 2016. Patients older than 14 years at present were assessed with the Short Form-12 (SF-12) questionnaire. Patients younger than 14 years of age were assessed with the KINDL-R questionnaire that was completed by their parents. Patients' values were compared with the scores of a corresponding age-matched group of the healthy population and with patients who received later shunt treatment. Information about comorbidities, current symptoms, and educational level were gained by an additional part. Comparative analysis between patients with ETV success and failure (defined as shunt implantation after ETV) was performed., Results: A total of 107 patients (53 m, 54f) were included. Fifty-seven/107 patients (53.3%) were considered as ETV success. Mean age at ETV was 6.9 ± 5.9 years. Fifty-four statements of 89 patients that are still alive were gained (response rate 63%). Of these, 49 questionnaires were complete and evaluable (23 m, 26f; mean age 19.8 ± 10.0 years with an average follow-up period of 13.7 ± 7.2 years). Twenty-six/49 patients (53.1%) are considered ETV success. No statistically significant differences could be obtained between patients with ETV success and ETV failure. Patients older 14 years show QoL within normal range, patients younger than 14 years show significantly lower result regarding their environment of peers and social contacts. Patients younger than 6 months at the time of ETV and patients with posthemorrhagic HCP show significantly lower physical QoL. Gait disturbance, fatigue, and seizures are associated with a lower QoL, and educational level is lower than in the normal population., Conclusions: Patients who underwent ETV in childhood do not have a lower health-related QoL in general. Subsequent insertions of ventriculoperitoneal (vp) shunts do not lower QoL. Certain subgroups of the patients show lower results compared to the healthy population., (© 2022. The Author(s).)

Significance: The dewetting process of contact lenses (CLs) is a result of material and solution properties as well as environmental factors. This article describes an investigational approach to observe and describe dewetting characteristics of different CL material and solution combinations., Purpose: This study aimed to determine the in vitro dewetting characteristics of various daily disposable CLs that were assessed using a noninvasive keratograph dewetting procedure (noninvasive keratograph dry-up time). In vitro dewetting data of the same CL materials soaked in saline solution and artificial tear solution (ATS) were measured to determine additional dewetting characteristics., Methods: Noninvasive keratograph dry-up time was measured for six different soft CL materials and three different test conditions, in their specific blister solution, after exposure to saline and an ATS. Twenty CLs of each solution/material combination were assessed after an 8-hour soaking, during a 180-second dewetting observation, and the results were expressed by area under the curve values., Results: Fastest dewetting occurred for all materials when measured out of saline, indicated by the highest averaged area under the curve value of 9243.3 ± 38.3 over all lens materials. Slower dewetting was detected for all materials when measured out of their specific blister solution (7755.9 ± 37.1) and out of ATS (7988.8 ± 40.0). Intragroup results were statistically significantly different for all solutions showing the smallest differences within the ATS group ( P < .001, Kruskal-Wallis test)., Conclusions: A pure saline thin film is not an ideal representation of a complex tear film layer of a healthy human because it lacks any evaporative protection by a lipid layer. The use of an ATS, which more likely mimics the natural tear film, allowed in this experimental in vitro project to decrease the gap to the in vivo field. In vitro dewetting information in connection with the blister solution allows only a theoretical conclusion about the initial lens wear after lens insertion., Competing Interests: Conflict of Interest Disclosure: None of the authors have reported a financial conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Optometry.)

Sphingosine-1-phosphate (S1P) is a versatile signaling lipid involved in the regulation of numerous cellular processes. S1P regulates cellular proliferation, migration, and apoptosis as well as the function of immune cells. S1P is generated from sphingosine (Sph), which derives from the ceramide metabolism. In particular, high concentrations of S1P are present in the blood. This originates mainly from erythrocytes, endothelial cells (ECs), and platelets. While erythrocytes function as a storage pool for circulating S1P, platelets can rapidly generate S1P de novo, store it in large quantities, and release it when the platelet is activated. Platelets can thus provide S1P in a short time when needed or in the case of an injury with subsequent platelet activation and thereby regulate local cellular responses. In addition, platelet-dependently generated and released S1P may also influence long-term immune cell functions in various disease processes, such as inflammation-driven vascular diseases. In this review, the metabolism and release of platelet S1P are presented, and the autocrine versus paracrine functions of platelet-derived S1P and its relevance in various disease processes are discussed. New pharmacological approaches that target the auto- or paracrine effects of S1P may be therapeutically helpful in the future for pathological processes involving S1P.

Purpose: Changes in peripheral corneal thickness are described in various corneal diseases such as corneal ectasia. However, few data exist describing the increase in corneal thickness from central to peripheral and reporting the normal distribution of corneal thickness in rings around the corneal centre. The aim of this study was to report these cornea characteristics and investigate associated factors in a population-based setting., Methods: The Gutenberg Health Study is a prospective, population-based study examining participants in a 5-year follow-up (age range 40-80 years) using Scheimpflug imaging. Corneal thickness was assessed in each participant at the apex, as well as in the corneal centre (thinnest corneal thickness) and in rings with 2, 4, 6, 8 and 10 mm diameter around the corneal centre, and the increase in corneal thickness towards the periphery. The relationship between corneal thickness at these locations and possible associated factors was determined using linear regression models. For this purpose, general and ocular parameters were included., Results: A total of 9729 participants were included in the present analysis (4874 women, age 59.2 ± 10.8 years). Multivariable analysis showed a correlation between the increase in corneal thickness in the circles from 0 to 10 mm (diameter) and the following parameters: age (B = -0.24 µm per year, p < 0.001); body height (B = -0.04 µm, p = 0.005); smoking (B = -0.72 µm, p < 0.001); spherical equivalent (B = -0.70 µm per dioptre, p < 0.001); white-to-white distance (B = -0.75 µm/mm, p < 0.001); mean corneal radius (B = -3.61 µm/mm, p < 0.001); intraocular pressure (B = -0.12 µm/mmHg, p < 0.001); glaucoma (B = -1.94 µm, p < 0.001); and pseudophakia (B = 0.89 µm, p < 0.001)., Conclusion: The results of the present study suggest that several general and ocular parameters are associated with peripheral corneal thickness. In the context of diagnosing glaucoma, a smaller increase in corneal thickness towards the periphery might be a new additional marker., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Glioblastoma is a highly aggressive brain tumor with limited treatment options. Several major challenges have limited the development of novel therapeutics, including the extensive heterogeneity of tumor cell states within each glioblastoma and the ability of glioma cells to diffusely infiltrate into neighboring healthy brain tissue, including the contralateral hemisphere. A T cell-mediated immune response could deal with these challenges based on the ability of polyclonal T cell populations to recognize diverse tumor antigens and perform surveillance throughout tissues. Here we will discuss the major pathways that inhibit T cell-mediated immunity against glioblastoma, with an emphasis on receptor-ligand systems by which glioma cells and recruited myeloid cells inhibit T cell function. A related challenge is that glioblastomas tend to be poorly infiltrated by T cells, which is not only caused by inhibitory molecular pathways but also currently utilized drugs, in particular high-dose corticosteroids that kill activated, proliferating T cells. We will discuss innovative approaches to induce glioblastoma-directed T cell responses, including neoantigen-based vaccines and sophisticated CAR T cell approaches that can target heterogeneous glioblastoma cell populations. Finally, we will propose a conceptual framework for the future development of T cell-based immunotherapies for glioblastoma., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Comparative analyses of the immunogenicity and reactogenicity of homologous and heterologous SARS-CoV-2 vaccine-regimens will inform optimized vaccine strategies. Here we analyze the humoral and cellular immune response following heterologous and homologous vaccination strategies in a convenience cohort of 331 healthy individuals. All regimens induce immunity to the vaccine antigen. Immunity after vaccination with ChAdOx1-nCoV-19 followed by either BNT162b2 (n = 66) or mRNA-1273 (n = 101) is equivalent to or more pronounced than homologous mRNA-regimens (n = 43 BNT162b2, n = 59 mRNA-1273) or homologous ChAdOx1-nCoV-19 vaccination (n = 62). We note highest levels of spike-specific CD8 T-cells following both heterologous regimens. Among mRNA-containing combinations, spike-specific CD4 T-cell levels in regimens including mRNA-1273 are higher than respective combinations with BNT162b2. Polyfunctional T-cell levels are highest in regimens based on ChAdOx1-nCoV-19-priming. All five regimens are well tolerated with most pronounced reactogenicity upon ChAdOx1-nCoV-19-priming, and ChAdOx1-nCoV-19/mRNA-1273-boosting. In conclusion, we present comparative analyses of immunogenicity and reactogenicity for heterologous vector/mRNA-boosting and homologous mRNA-regimens., (© 2022. The Author(s).)

Purpose: Controversies regarding venous compression and trigeminal neuralgia (TN) still exist. The study demonstrates our experience for microvascular decompression (MVD) in TN caused by purely venous compression. The goal was to identify prognostic anatomical or surgical factors that may influence the outcome., Methods: Between 2004 and 2020, 49 patients were operated with purely venous compression. Average age was 58.4 years. Mean history of TN was 7.8 years. Microsurgical procedures included transposition or separation of the vein, coagulation, and division. Several features have been analyzed with respect to BNI scores., Results: Evaluation on discharge revealed a complete pain relief in 39 (80%), partial improvement in 7 (14%), and no benefit in 3 (6%) patients. Facial hypesthesia was reported by 14 (28.6%) patients. Mean follow-up (FU) was 42.1 months. BNI pain intensity score on FU revealed 71.4% excellent to very good scores (score 1: 32 (65.3%); 2: 3 (6.1%)). BNI facial numbness score 2 could be detected in 13 patients (26.5%) during FU. There was no statistical relationship between immediate pain improvement or BNI pain intensity score on FU with respect to surgical procedure, size of trigeminal cistern, type of venous compression, venous caliber, trigeminal nerve indentation, or neurovascular adherence. BNI facial numbness score was dependent on type of venous compression (p < 0.05)., Conclusion: We did not find typical anatomical features that could either predict or influence the outcome regarding pain improvement or resolution in any form. Neither classic microvascular decompression (interposition/transposition) nor sacrificing the offending vein made any difference in outcome., (© 2022. The Author(s).)

The development of performance measures is not a new concept in the disaster preparedness space. For over a decade, goals have been developed and tied to federal preparedness grant programs. However, these measures have been heavily criticized for their inability to truly measure preparedness. There is also growing frustration at the local level that these performance measures do not account for local readiness priorities or the outcome-driven value of emergency response activities. To define an appropriate theoretical framework for the development of performance measures, a review of the literature on existing planning and preparedness frameworks was conducted, with an iterative feedback process with a local health agency. This paper presents elements of that literature review that were most directly along with the conceptual framework that was used as a starting point for future iterations of a comprehensive performance measure development project.

Congenital hydrocephalus affects approximately one in 1000 newborn children and is fatal in approximately 50% of untreated cases. The currently known management protocols usually necessitate multiple interventions and long-term use of healthcare resources due to a relatively high incidence of complications, and many of them mostly provide a treatment of the effect rather than the cause of cerebrospinal fluid flow reduction or outflow obstruction. Future studies discussing etiology specific hydrocephalus alternative treatments are needed. We systematically reviewed the available literature on the effect of ciliary abnormality on congenital hydrocephalus pathogenesis, to open a discussion on the feasibility of factoring ciliary abnormality in future research on hydrocephalus treatment modalities. Although there are different forms of ciliopathies, we focused in this review on primary ciliary dyskinesia. There is growing evidence of association of other ciliary syndromes and hydrocephalus, such as the reduced generation of multiple motile cilia, which is distinct from primary ciliary dyskinesia. Data for this review were identified by searching PubMed using the search terms 'hydrocephalus,' 'Kartagener syndrome,' 'primary ciliary dyskinesia,' and 'immotile cilia syndrome.' Only articles published in English and reporting human patients were included. Seven studies met our inclusion criteria, reporting 12 cases of hydrocephalus associated with primary ciliary dyskinesia. The patients had variable clinical presentations, genetic backgrounds, and ciliary defects. The ependymal water propelling cilia differ in structure and function from the mucus propelling cilia, and there is a possibility of isolated non-syndromic ependymal ciliopathy causing only hydrocephalus with growing evidence in the literature for the association ependymal ciliary abnormality and hydrocephalus. Abdominal and thoracic situs in children with hydrocephalus can be evaluated, and secondary damage of ependymal cilia causing hydrocephalus in cases with generalized ciliary abnormality can be considered.

Purpose: Meibomian glands (MG) are now easily imaged via clinical meibography machines. The purpose of this work was to explore the utility of the known MG morphology metrics for predicting dry eye disease (DED) in contact lens (CL) wearers., Methods: Successful and previous CL wearers were recruited. DED was diagnosed if the participant's worst eye had a reduced tear meniscus height (TMH) of <0.2 mm or non-invasive tear break-up time (NITBUT) of <10 s and a Standardized Patient Evaluation of Eye Dryness (SPEED) score >5.0. Meibography was performed and images were subjectively graded by two examiners for the following MG characteristics: distorted, tortuous, hooked, abnormal gap, overlapping, fluffy areas, tadpoling, thinned, thickened, ghost, no extension to lid margin, shortened and dropout (atrophy). DED diagnostic ability of each metric was determined with receiver operating characteristic (ROC) analysis., Results: A total of 112 participants were recruited, with 18.8% having DED and 60.7% being female. The only MG morphology metrics that were marginally predictive of DED were thickened upper eyelid MGs (p = 0.046), thickened mean upper plus lower eyelid MGs (p = 0.007), and atrophy of upper eyelid MGs (p = 0.043); however, none of these metrics reached a meaningful area under the curve in ROC analysis (all <0.70)., Conclusion: While abnormal MG morphology is likely suggestive of DED in CL wearers, none of the MG morphology metrics evaluated alone in this study had clinically meaningful predictive value for detecting DED in this group of current and previous CL wearers., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Spectroscopic studies of aluminum monofluoride (AlF) have revealed its highly favorable properties for direct laser cooling. All Q lines of the strong A 1 Π ← X 1 Σ + transition around 227 nm are rotationally closed and thereby suitable for the main cooling cycle. The same holds for the narrow, spin-forbidden a 3 Π ← X 1 Σ + transition around 367 nm, which has a recoil limit in the µK range. We here report on the spectroscopic characterization of the lowest rotational levels in the a 3 Π state of AlF for v = 0-8 using a jet-cooled, pulsed molecular beam. An accidental AC Stark shift is observed on the a 3 Π 0 , v = 4 ← X 1 Σ + , v = 4 band. By using time-delayed ionization for state-selective detection of the molecules in the metastable a 3 Π state at different points along the molecular beam, the radiative lifetime of the a 3 Π 1 , v = 0, J = 1 level is experimentally determined as τ = 1.89 ± 0.15 ms. A laser/radio frequency multiple resonance ionization scheme is employed to determine the hyperfine splittings in the a 3 Π 1 , v = 5 level. The experimentally derived hyperfine parameters are compared to the outcome of quantum chemistry calculations. A spectral line with a width of 1.27 kHz is recorded between hyperfine levels in the a 3 Π, v = 0 state. These measurements benchmark the electronic potential of the a 3 Π state and yield accurate values for the photon scattering rate and for the elements of the Franck-Condon matrix of the a 3 Π-X 1 Σ + system.

The SARS-CoV-2 pandemic has underscored the need for rapidly usable prophylactic and antiviral treatments against emerging viruses. The targeted stimulation of antiviral innate immune receptors can trigger a broad antiviral response that also acts against new, unknown viruses. Here, we used the K18-hACE2 mouse model of COVID-19 to examine whether activation of the antiviral RNA receptor RIG-I protects mice from lethal SARS-CoV-2 infection and reduces disease severity. We found that prophylactic, systemic treatment of mice with the specific RIG-I ligand 3pRNA, but not type I interferon, 1-7 days before viral challenge, improved survival of mice by up to 50%. Survival was also improved with therapeutic 3pRNA treatment starting 1 day after viral challenge. This improved outcome was associated with lower viral load in oropharyngeal swabs and in the lungs and brains of 3pRNA-treated mice. Moreover, 3pRNA-treated mice exhibited reduced lung inflammation and developed a SARS-CoV-2-specific neutralizing antibody response. These results demonstrate that systemic RIG-I activation by therapeutic RNA oligonucleotide agonists is a promising strategy to convey effective, short-term antiviral protection against SARS-CoV-2 infection, and it has great potential as a broad-spectrum approach to constrain the spread of newly emerging viruses until virus-specific therapies and vaccines become available., Competing Interests: M.S. and G.H. are inventors on a patent on RIG-I ligands., (© 2022 The Authors.)

Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Therapeutic options for glioblastoma are maximal surgical resection, chemotherapy, and radiotherapy. Therapy resistance and tumor recurrence demand, however, new strategies. Several experimental studies have suggested gas plasma technology, a partially ionized gas that generates a potent mixture of reactive oxygen species (ROS), as a future complement to the existing treatment arsenal. However, aspects such as immunomodulation, inflammatory consequences, and feasibility studies using GBM tissue have not been addressed so far. In vitro, gas plasma generated ROS that oxidized cells and led to a treatment time-dependent metabolic activity decline and G2 cell cycle arrest. In addition, peripheral blood-derived monocytes were co-cultured with glioblastoma cells, and immunomodulatory surface expression markers and cytokine release were screened. Gas plasma treatment of either cell type, for instance, decreased the expression of the M2-macrophage marker CD163 and the tolerogenic molecule SIGLEC1 (CD169). In patient-derived GBM tissue samples exposed to the plasma jet kINPen ex vivo, apoptosis was significantly increased. Quantitative chemokine/cytokine release screening revealed gas plasma exposure to significantly decrease 5 out of 11 tested chemokines and cytokines, namely IL-6, TGF-β, sTREM-2, b-NGF, and TNF-α involved in GBM apoptosis and immunomodulation. In summary, the immuno-modulatory and proapoptotic action shown in this study might be an important step forward to first clinical observational studies on the future discovery of gas plasma technology's potential in neurosurgery and neuro-oncology especially in putative adjuvant or combinatory GBM treatment settings.

Metal-organic frameworks (MOFs) as solid sorbents for carbon dioxide (CO 2 ) capture face the challenge of merging efficient capture with economical regeneration in a durable, scalable material. Zinc-based Calgary Framework 20 (CALF-20) physisorbs CO 2 with high capacity but is also selective over water. Competitive separations on structured CALF-20 show not just preferential CO 2 physisorption below 40% relative humidity but also suppression of water sorption by CO 2 , which was corroborated by computational modeling. CALF-20 has a low enthalpic regeneration penalty and shows durability to steam (>450,000 cycles) and wet acid gases. It can be prepared in one step, formed as composite materials, and its synthesis can be scaled to multikilogram batches.

Background: Hyperspectral imaging (HSI) could provide extended haemodynamic monitoring of perioperative tissue oxygenation and tissue water content to visualize effects of haemodynamic therapy and surgical trauma. The objective of this study was to assess the capacity of HSI to monitor skin microcirculation and possible relations to perioperative organ dysfunction in patients undergoing pancreatic surgery., Methods: The hyperspectral imaging TIVITA® Tissue System was used to evaluate superficial tissue oxygenation (StO2), deeper layer tissue oxygenation (near-infrared perfusion index (NPI)), haemoglobin distribution (tissue haemoglobin index (THI)) and tissue water content (tissue water index (TWI)) in 25 patients undergoing pancreatic surgery. HSI parameters were measured before induction of anaesthesia (t1), after induction of anaesthesia (t2), postoperatively before anaesthesia emergence (t3), 6 h after emergence of anaesthesia (t4) and three times daily (08:00, 14:00, 20:00 ± 1 h) at the palm and the fingertips until the second postoperative day (t5-t10). Primary outcome was the correlation of HSI with perioperative organ dysfunction assessed with the perioperative change of SOFA score., Results: Two hundred and fifty HSI measurements were performed in 25 patients. Anaesthetic induction led to a significant increase of tissue oxygenation parameters StO2 and NPI (t1-t2). StO2 and NPI decreased significantly from t2 until the end of surgery (t3). THI of the palm showed a strong correlation with haemoglobin levels preoperatively (t2: r = 0.83, p < 0.001) and 6 h postoperatively (t4: r = 0.71, p = 0.001) but not before anaesthesia emergence (t3: r = 0.35, p = 0.10). TWI of the palm and the fingertip rose significantly between pre- and postoperative measurements (t2-t3). Higher blood loss, syndecan level and duration of surgery were associated with a higher increase of TWI. The perioperative change of HSI parameters (∆t1-t3) did not correlate with the perioperative change of the SOFA score., Conclusion: This is the first study using HSI skin measurements to visualize tissue oxygenation and tissue water content in patients undergoing pancreatic surgery. HSI was able to measure short-term changes of tissue oxygenation during anaesthetic induction and pre- to postoperatively. TWI indicated a perioperative increase of tissue water content. Perioperative use of HSI could be a useful extension of haemodynamic monitoring to assess the microcirculatory response during haemodynamic therapy and major surgery., Trial Registration: German Clinical Trial Register, DRKS00017313 on 5 June 2019., (© 2021. The Author(s).)

Cervical cancer therapy is still a major clinical challenge, as patients substantially differ in their response to standard treatments, including chemoradiotherapy (CRT). During cervical carcinogenesis, T-helper (Th)-17 cells accumulate in the peripheral blood and tumor tissues of cancer patients and are associated with poor prognosis. In this prospective study, we find increased Th17 frequencies in the blood of patients after chemoradiotherapy and a post-therapeutic ratio of Th17/CD4 + T cells > 8% was associated with early recurrence. Furthermore, Th17 cells promote resistance of cervical cancer cells toward CRT, which was dependent on the AKT signaling pathway. Consistently, patients with high Th17 frequencies in pretherapeutic biopsies exhibit lower response to primary CRT. This work reveals a key role of Th17 cells in CRT resistance and elevated Th17 frequencies in the blood after CRT correspond with early recurrence. Our results may help to explain individual treatment responses of cervical cancer patients and suggest evaluation of Th17 cells as a novel predictive biomarker for chemoradiotherapy responses and as a potential target for immunotherapy in cervical cancer., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: Low birth weight (BW) is associated with altered ocular geometry such as a steeper corneal shape in adulthood. However, it is unclear whether low birth weight affects corneal thickness development in the center or periphery in adulthood which may contribute to ocular disease. The purpose of this study was to investigate corneal thickness in former low birth weight individuals in adulthood. Methods: The German Gutenberg Health Study is a prospective, population-based study in which every participant (age range 40-80 years) was measured with Scheimpflug imaging (Pentacam HR, Oculus Optikgeräte GmbH, Wetzlar, Germany). BW was collected by self-reports. The relationship between birth weight and corneal thickness at different locations were assessed. Linear regression models were carried out including uni- and multivariable analyses with adjustment for age, sex, mean corneal radius, and white-to-white distance. Main outcome measures were corneal thickness at the apex, at the pupil center, and at the corneal periphery. Results: Overall, 5657 participants were successfully measured (3019 females, aged 56.0 ± 10.3 years). In multivariable analyses a lower BW was associated with a thinner corneal thickness at the apex (B = 1.71 µm/500 g, p < 0.001) and at the pupil (B = 1.69 µm/500 g, p < 0.001). These effects diminished towards the corneal periphery resulting in no differences in the perilimbal regions. Conclusion: The present study provides evidence that lower birth weight goes along with corneal thickness alterations even into adult ages of 40 to 80 years. Thinner measurements of the cornea were particularly found in the corneal center and diminished in the periphery. This indicates that there may be fetal origins affecting corneal thickness development particularly in the corneal center.

Background:  The usefulness of the endoscopic sheath is underreported in the literature., Objective and Methods:  To explain the use of an endoscopic sheath and to highlight its benefits., Results:  In addition to protecting the surrounding brain parenchyma when inserting the endoscope, the endoscopic sheath is a very useful tool to retract neurovascular structures, achieve hemostasis, and create adequate working space within narrow ventricles. The sheath can be moved within the ventricular system, and the endoscope can be moved independently within the sheath. These movements represent all the advantages of the endoscopic sheath., Conclusions:  We used an endoscopic sheath in ∼ 300 intraventricular neuroendoscopic procedures and consider the sheath an essential part of a ventriculoscopic system. Proper use of the sheath can help avoid or manage endoscopic complications., Competing Interests: None declared., (Thieme. All rights reserved.)

Significance: Ultraviolet (UV) and visible light transmittance of soft contact lenses (SCLs) was measured. A significant difference in UV transmittance has been found between SCLs with a positive and negative back vertex power (BVP). It can be shown that thicker SCLs absorb more UV radiation., Purpose: This study aimed to determine UV and visible light transmittance of different SCLs with and without UV protection filters., Methods: Twenty-one lens brands were investigated in the BVP range of -12.00 to +6.00 D. Three SCLs were measured per BVP 25 times. Three hundred thirty-nine SCLs with UV filter (stenfilcon A, somofilcon A, narafilcon A, senofilcon A, senofilcon C, etafilcon A, nesofilcon A) and 489 SCLs without UV filter (delefilcon A, lotrafilcon A, lotrafilcon B, comfilcon A, balafilcon A, samfilcon A, asmofilcon A, nelfilcon A, omafilcon A, hilafilcon B, ocufilcon D, hioxifilcon A, omafilcon B) have been examined. The measurement setup was created according to ISO 18369-3., Results: All UV-absorbing labeled test SCLs meet UV protection class 2. senofilcon A, senofilcon C, and narafilcon A meet the higher UV protection class 1 level. A statistically significant difference in UV transmittance (280 to 380 nm) has been found between SCLs with a positive BVP (+1.00 to +6.00 D) and SCLs with a negative BVP (-1.00 to -12.00 D), both without (P = .04) and with UV filters (P = .02)., Conclusions: With the ISO-conforming, diopter-independent measurement setup, the UV-absorbing test contact lenses that meet the current international standards, regardless of their BVP, were identified. Lenses with increased center thickness absorb more UV radiation. Further studies may use a modified measurement setup with a larger aperture than 10 mm. It would also be worthwhile to examine the UV absorption of the contact lens over the complete corneal area and limbal area because UV radiation may damage inner ocular tissues like the crystalline lens as well as limbal stem cells., Competing Interests: Conflict of Interest Disclosure: None of the authors have reported a financial conflict of interest., (Copyright © 2021 American Academy of Optometry.)

Despite comprehensive therapy and extensive research, glioblastoma (GBM) still represents the most aggressive brain tumor in adults. Glioma stem cells (GSCs) are thought to play a major role in tumor progression and resistance of GBM cells to radiochemotherapy. The PIM1 kinase has become a focus in cancer research. We have previously demonstrated that PIM1 is involved in survival of GBM cells and in GBM growth in a mouse model. However, little is known about the importance of PIM1 in cancer stem cells. Here, we report on the role of PIM1 in GBM stem cell behavior and killing. PIM1 inhibition negatively regulates the protein expression of the stem cell markers CD133 and Nestin in GBM cells (LN-18, U-87 MG). In contrast, CD44 and the astrocytic differentiation marker GFAP were up-regulated. Furthermore, PIM1 expression was increased in neurospheres as a model of GBM stem-like cells. Treatment of neurospheres with PIM1 inhibitors (TCS PIM1-1, Quercetagetin, and LY294002) diminished the cell viability associated with reduced DNA synthesis rate, increased caspase 3 activity, decreased PCNA protein expression, and reduced neurosphere formation. Our results indicate that PIM1 affects the glioblastoma stem cell behavior, and its inhibition kills glioblastoma stem-like cells, pointing to PIM1 targeting as a potential anti-glioblastoma therapy.

Heterologous priming with the ChAdOx1 nCoV-19 vector vaccine followed by boosting with a messenger RNA vaccine (BNT162b2 or mRNA-1273) is currently recommended in Germany, although data on immunogenicity and reactogenicity are not available. In this observational study we show that, in healthy adult individuals (n = 96), the heterologous vaccine regimen induced spike-specific IgG, neutralizing antibodies and spike-specific CD4 T cells, the levels of which which were significantly higher than after homologous vector vaccine boost (n = 55) and higher or comparable in magnitude to homologous mRNA vaccine regimens (n = 62). Moreover, spike-specific CD8 T cell levels after heterologous vaccination were significantly higher than after both homologous regimens. Spike-specific T cells were predominantly polyfunctional with largely overlapping cytokine-producing phenotypes in all three regimens. Recipients of both the homologous vector regimen and the heterologous vector/mRNA combination reported greater reactogenicity following the priming vector vaccination, whereas heterologous boosting was well tolerated and comparable to homologous mRNA boosting. Taken together, heterologous vector/mRNA boosting induces strong humoral and cellular immune responses with acceptable reactogenicity profiles., (© 2021. The Author(s).)

Introduction: Microcirculatory alterations are key mechanisms in sepsis pathophysiology leading to tissue hypoxia, edema formation, and organ dysfunction. Hyperspectral imaging (HSI) is an emerging imaging technology that uses tissue-light interactions to evaluate biochemical tissue characteristics including tissue oxygenation, hemoglobin content and water content. Currently, clinical data for HSI technologies in critical ill patients are still limited., Methods and Analysis: TIVITA® Tissue System was used to measure Tissue oxygenation (StO2), Tissue Hemoglobin Index (THI), Near Infrared Perfusion Index (NPI) and Tissue Water Index (TWI) in 25 healthy volunteers and 25 septic patients. HSI measurement sites were the palm, the fingertip, and a suprapatellar knee area. Septic patients were evaluated on admission to the ICU (E), 6 h afterwards (E+6) and three times a day (t3-t9) within a total observation period of 72 h. Primary outcome was the correlation of HSI results with daily SOFA-scores., Results: Serial HSI at the three measurement sites in healthy volunteers showed a low mean variance expressing high retest reliability. HSI at E demonstrated significantly lower StO2 and NPI as well as higher TWI at the palm and fingertip in septic patients compared to healthy volunteers. StO2 and TWI showed corresponding results at the suprapatellar knee area. In septic patients, palm and fingertip THI identified survivors (E-t4) and revealed predictivity for 28-day mortality (E). Fingertip StO2 and THI correlated to SOFA-score on day 2. TWI was consistently increased in relation to the TWI range of healthy controls during the observation time. Palm TWI correlated positively with SOFA scores on day 3., Discussion: HSI results in septic patients point to a distinctive microcirculatory pattern indicative of reduced skin oxygenation and perfusion quality combined with increased blood pooling and tissue water content. THI might possess risk-stratification properties and TWI could allow tissue edema evaluation in critically ill patients., Conclusion: HSI technologies could open new perspectives in microcirculatory monitoring by visualizing oxygenation and perfusion quality combined with tissue water content in critically ill patients - a prerequisite for future tissue perfusion guided therapy concepts in intensive care medicine., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The endoscopic endonasal approach to suprasellar craniopharyngiomas has become popular as alternative to transcranial approaches. However, the literature lacks data regarding quality of life and olfactory function. The assessment of the long-term quality of life and olfactory function of all patients harboring a suprasellar craniopharyngioma who underwent surgery in our department has been done. Patient characteristics and perioperative data were gathered in a prospectively maintained database. At the last follow-up visit, the olfactory function and the quality of life (ASBQ, SNOT-22) as well as visual and pituitary function were assessed. Thirteen and 17 patients underwent surgery via a transcranial (T) and endonasal (E) route, respectively. No differences were seen in ASBQ, SNOT-22, and olfactory function between T and E, but in E were more full-time worker and less obesity. CSF leaks occurred in 15% of T and 29% of E (p = 0.43). Patients from group E had a superior visual outcome which was most pronounced in the visual field. The degree of new anterior and posterior pituitary gland deficiency after surgery and in the follow-up was lower in group E. The general and sinonasal quality of life and the olfactory function are equal in E and T. E is associated with a superior visual outcome, lower rates of diabetes insipidus, and lower rates of obesity, but has a higher risk for postoperative CSF leaks.

Background: Microvascular decompression (MVD) is the most effective treatment option for hemifacial spasm (HFS). However, deeply located forms of compression would require proper identification to allow for adequate decompression., Objective: To describe the usefulness of endoscopic visualization in one of the most challenging compression patterns in HFS, where the posterior inferior cerebellar artery (PICA) loop is severely indenting the brain stem at the proximal root exit zone of facial nerve along the pontomedullary sulcus., Methods: Radiological and operative data were checked for all patients in whom severe indentation of the brainstem by PICA at pontomedullary sulcus was recorded and endoscope-assisted MVD was performed. Clinical correlation and outcome were analyzed., Results: A total of 58 patients with HFS were identified with radiological and surgical evidence proving brainstem indentation at the VII transitional zone. In 31 patients, PICA was the offending vessel to the facial nerve. In 3 patients, the PICA loop was mobilized under visualization of a 45° endoscope. A total of 31 patients had a mean follow-up duration of 52.1 mo. The mean duration between start of complaints and surgery was 7.2 yr. In the last follow-up, all patients had remarkable spasm improvement. A total of 5 patients had more than 90% disappearance of spasms and 26 patients experienced spasm-free outcome., Conclusion: Although severe indentation of brain stem implies morphological damage, outcome after MVD is excellent. A 45° endoscope is extremely helpful to identify compression down at the pontomedullary sulcus. Deeply located compression site can easily be missed with microscopic inspection alone., (© Congress of Neurological Surgeons 2021.)

Post-transplant cytomegalovirus (CMV) infections and increased viral replication are associated with CMV-specific T-cell anergy. In the ATHENA-study, de-novo everolimus (EVR) with reduced-exposure tacrolimus (TAC) or cyclosporine (CyA) showed significant benefit in preventing CMV infections in renal transplant recipients as compared to standard TAC + mycophenolic acid (MPA). However, immunomodulatory mechanisms for this effect remain largely unknown. Ninety patients from the ATHENA-study completing the 12-month visit on-treatment (EVR + TAC n = 28; EVR + CyA n = 19; MPA + TAC n = 43) were included in a posthoc analysis. Total lymphocyte subpopulations were quantified. CMV-specific CD4 T cells were determined after stimulation with CMV-antigen, and cytokine-profiles and various T-cell anergy markers were analyzed using flow cytometry. While 25.6% of MPA + TAC-treated patients had CMV-infections, no such events were reported in EVR-treated patients. Absolute numbers of lymphocyte subpopulations were comparable between arms, whereas the percentage of regulatory T cells was significantly higher with EVR + CyA versus MPA + TAC (p = 0.019). Despite similar percentages of CMV-specific T cells, their median expression of CTLA-4 and PD-1 was lower with EVR + TAC (p < 0.05 for both) or EVR + CyA (p = 0.045 for CTLA-4) compared with MPA + TAC. Moreover, mean percentages of multifunctional CMV-specific T cells were higher with EVR + TAC (27.2%) and EVR + CyA (29.4%) than with MPA + TAC (19.0%). In conclusion, EVR-treated patients retained CMV-specific T-cell functionality, which may contribute to enhanced protection against CMV infections., (© 2020 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Purpose: Ac-225 labeled with prostate-specific membrane antigen (PSMA-617), a transmembrane glycoprotein which is highly expressed in prostate carcinoma cells, is presently being considered a promising agent of targeted alpha therapy for the treatment of patients suffering from metastatic castration-resistant prostate cancer. In the present study, we report an optimized protocol for the preparation of therapeutic dose of Ac-225 PSMA-617 with high yield and radiochemical purity (RCP)., Methods: Ac-225 PSMA-617 was prepared by adding the peptidic precursor-PSMA-617 (molar ratios, Ac-225: PSMA-617 = 30:1) in 1 ml ascorbate buffer to Ac-225 and heating the reaction mixture at 90°C for 25 min to obtain the radiopeptide with high RCP and yield. The radiolabeled peptide was administered in patients who met the eligibility criteria and posttherapy assessment was done., Results: Ten batches of Ac-225 PSMA-617 were prepared following this protocol. The radiopeptide was obtained with an adequate yield of 85%-87% and RCP of 97%-99%., Conclusion: The current protocol allows single-step, successful, routine inhouse radiolabeling of Ac-225 with PSMA-617 with high yield and RCP., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Indian Journal of Nuclear Medicine.)

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets., Competing Interests: Declaration of interests N.D.M., O.A., I.T., A.R., M.L.S., and K.W.W. are co-inventors of a patent application on the CLEC2D-CD161 pathway for the treatment of cancer. K.W.W., M.L.S., and A.R. are co-founders of Immunitas Therapeutics. K.W.W., M.L.S., and I.T. are advisory board members of Immunitas Therapeutics. K.W.W. serves on the scientific advisory board of TCR2 Therapeutics, T-Scan Therapeutics, SQZ Biotech, and Nextechinvest and received sponsored research funding from Bristol-Myers Squibb and Novartis. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics, and until August 31, 2020, was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and Thermo Fisher Scientific. From August 1, 2020, A.R. is an employee of Genentech. N.D.M. serves as a scientific advisor to Immunitas Therapeutics. A.M. is cofounder, member of the Boards of Directors, and member of Scientific Advisory Boards of Spotlight Therapeutics and Arsenal Biosciences. A.M. has served as an advisor to Juno Therapeutics, was a member of the scientific advisory board at PACT Pharma, and an advisor to Trizell. A.M. has received an honorarium from Merck and a consulting fee from AlphaSights and is an investor in and informal advisor to Offline Ventures. A.M. owns stock in Arsenal Biosciences, Spotlight Therapeutics, and PACT Pharma. The Marson lab has received research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead, and Anthem. E.A.C. is currently an advisor to Advantagene Inc., Alcyone Biosciences, Insightec, Inc., Sigilon Therepeutics, and DNAtrix Inc. and has equity interest in DNAtrix; A.M. has advised Oncorus, Merck, Tocagen, Ziopharm, Stemgen, NanoTx., Ziopharm Oncology, Cerebral Therapeutics, Genenta, Merck, Janssen, Karcinolysis, and Shanaghai Biotech and has received research support from Advantagene, NewLink Genetics, and Amgen. A.M. is a named inventor on patents related to oncolytic HSV1. D.A.R. has received research support from Acerta Phamaceuticals, Agenus, Celldex, EMD Serono, Incyte, Inovio, Midatech, Omniox, and Tragara, and he has served as paid consultant for Abbvie, Advantagene, Agenus, Amgen, Bayer, Bristol-Myers Squibb, Celldex, DelMar, EMD Serono, Genentech/Roche, Inovio, Merck, Merck KGaA, Monteris, Novocure, Oncorus, Oxigene, Regeneron, Stemline, and Taiho Oncology, Inc. P.K.B., outside the scope of this work, has consulted for Angiochem, Genentech-Roche, Lilly, Tesaro, ElevateBio, Pfizer (Array), SK Life Sciences, and Dantari and is supported by the Breast Cancer Research Foundation, Damon Runyon Cancer Research Foundation, Ben and Catherine Ivy Foundation, and the National Cancer Institute (5R01CA244975-02, 5R21CA220253-02, and 5R01CA227156-03), BMS, Lilly, and honoraria from Merck, Genentech-Roche, and Lilly. D.P.C. has consulted for Lilly and Boston Pharmaceuticals and has received honoraria and travel reimbursement from Merck. O.R.-R. is an employee of Genentech since October 2020. O.R.-R. is a co-inventor on patent applications filed by the Broad Institute for inventions relating to work in single-cell genomics, such as in PCT/US2018/060860 and US provisional application 62/745,259. E.A.C. is currently an advisor to Advantagene Inc., Alcyone Biosciences, Insightec Inc., DNAtrix, Immunomic Therapeutics, Sangamo Therapeutics, and Seneca Therapeutics, has equity interest in DNAtrix, Immunomic Therapeutics, and Seneca Therapeutics, and has also advised Oncorus, Merck, Tocagen, Ziopharm, Stemgen, NanoTx., Ziopharm Oncology, Cerebral Therapeutics, Genenta. Merck, Janssen, Karcinolysis, and Shanghai Biotech. E.A.C. has received research support from NIH, US Department of Defense, American Brain Tumor Association, National Brain Tumor Society, Alliance for Cancer Gene Therapy, Neurosurgical Research Education Foundation, Advantagene, NewLink Genetics, and Amgen and also is a named inventor on patents related to oncolytic HSV1 and noncoding RNAs. X.S.L. is a cofounder, board member, and consultant of GV20 Oncotherapy and its subsidiaries, SAB of 3DMedCare, a consultant for Genentech, a stockholder of Bristol Myers Squibb (BMY), Thermo Fisher Scientific (TMO), Walgreens Boots Alliance (WBA), Abbott Laboratories (ABT), AbbVie Inc. (ABBV), and Johnson & Johnson (JNJ), and receives research funding from Takeda and Sanofi., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To evaluate changes of anterior and posterior corneal astigmatism after superficial keratectomy in peripheral hypertrophic subepithelial corneal opacification (PHSCO)., Methods: Patients with PHSCO, who had received superficial keratectomy with mitomycin C 0.02%, were included in this retrospective study. Scheimpflug imaging of the cornea (Pentacam®, Oculus, Wetzlar, Germany), best-corrected visual acuity (BCVA) and objective refraction were determined preoperatively and 3 months after superficial keratectomy., Results: Fifteen eyes of 15 patients (age: 55 ± 16 years; range: 36-82 years) were included. The mean preoperative BCVA was logMAR 0.4 ± 0.2 and improved to logMAR 0.21 ± 0.3 ( p < .01) postoperatively. The median preoperative astigmatism of the anterior corneal surface was 4.67 ± 2.4 D (range: 0.9-13.2 D) and decreased to 1.4 ± 0.4 D (range: 0.8-2.3 D) 3 months after surgery. The median astigmatism of the posterior corneal surface was 0.6 ± 0.5 D (range: 0.1-2.2 D) before surgery and decreased to 0.3 ± 0.2 D (range: 0-0.7 D) 3 months after surgery., Conclusion: Superficial keratectomy reduces anterior corneal astigmatism more than posterior corneal astigmatism in patients with PHSCO. Furthermore, a myopic shift and corneal steepening in the peripheral and mid-peripheral cornea was observed after removal of the subepithelial corneal opacification spots.

Transmembrane β-barrel proteins (TMBs) are of great interest for single-molecule analytical technologies because they can spontaneously fold and insert into membranes and form stable pores, but the range of pore properties that can be achieved by repurposing natural TMBs is limited. We leverage the power of de novo computational design coupled with a "hypothesis, design, and test" approach to determine TMB design principles, notably, the importance of negative design to slow β-sheet assembly. We design new eight-stranded TMBs, with no homology to known TMBs, that insert and fold reversibly into synthetic lipid membranes and have nuclear magnetic resonance and x-ray crystal structures very similar to the computational models. These advances should enable the custom design of pores for a wide range of applications., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

As chemists and materials scientists, it is our duty to synthesize and utilize materials for a multitude of applications that promote the development of society and the well-being of its citizens. Since the inception of metal-organic frameworks (MOFs), researchers have proposed a variety of design strategies to rationally synthesize new MOF materials, studied their porosity and gas sorption performances, and integrated MOFs onto supports and into devices. Efforts have explored the relevance of MOFs for applications including, but not limited to, heterogeneous catalysis, guest delivery, water capture, destruction of nerve agents, gas storage, and separation. Recently, several start-up companies have undertaken MOF commercialization within industrial sectors. Herein, we provide a brief overview of the state of the MOF field from their design and synthesis to their potential applications, and finally, to their commercialization.

Partial anterior cruciate ligament (ACL) tears comprise an estimated 10% to 27% of isolated ACL injuries. Partial ACL tears may be challenging to clinically diagnose. We reviewed relevant studies focusing on the anatomy, diagnosis, imaging, and treatment of a partial injury with the goal of providing guidance to clinicians. Although a comprehensive patient history, thorough clinical examination, and imaging studies are helpful in arriving at a diagnosis, the benchmark for diagnosis remains visualization and examination of the ACL at the time of knee arthroscopy. Currently, limited data exist about the long-term outcomes of nonsurgical treatment. Some studies demonstrate that younger, active patients have the risk of progressing to a complete ACL rupture with conservative treatment. The decision to proceed with surgery is based on careful history and physical examination findings that suggest either a "functional" or "nonfunctional" ACL. Surgical treatment consists of augmenting the intact bundle with a selective bundle reconstruction versus a traditional ACL reconstruction. Selective bundle reconstruction has limited data available but is an option. The best evidence supports traditional ACL reconstruction for the surgical management of patients with documented nonfunctional partial tears of the ACL.

Introduction: Although hepatitis C virus (HCV) infection remains a major clinical, economic, and societal burden, the development of curative antiviral therapy may accelerate the path toward elimination. This analysis assessed the progress of United States (US) states towards achieving the World Health Organization's (WHO) 2030 HCV elimination targets for incidence, mortality, diagnosis, and treatment., Methods: A previously published Markov model was used to simulate HCV progression over time to estimate the path to HCV elimination in each state based on prevalence, annual treatment, and diagnosis inputs from two large US laboratory datasets from January 2013 to December 2017. State-specific fibrosis stage restrictions on treatment in 2017 were included. The model estimated the year individual states would meet the WHO targets for diagnosing 90% of the HCV-infected population, treating 80% of the eligible population, reducing new HCV infections by 80%, and reducing HCV-related deaths by 65%. The minimum number of annual treatments needed between 2020 and 2030 to achieve the WHO treatment target was also calculated., Results: Overall, the USA is projected to achieve HCV elimination by 2037, with individual targets related to mortality, diagnosis, treatment, and incidence being achieved by 2020, 2027, 2033, and 2037, respectively. Three states (Connecticut, South Carolina, and Washington) are on track to meet all four elimination targets by 2030, and 18 states are not expected to meet these targets before 2040. The estimated annual number of treatments required during 2020-2030 nationally to reach the WHO treatment target is 173,514., Conclusion: With the exception of three states, the USA is not on target to meet the WHO 2030 elimination targets and 35% are off track by 10 years or more. Strategies must be implemented to reduce overall prevalence by preventing new infections, increasing rates of screening, improving linkage to care, and implementing unfettered access to curative therapy.

Purpose: The primary objective of this study was to evaluate the in vivo pre-lens non-invasive drying-up time of two types of daily disposable contact lenses (DDCLs) after 12 hours of wear., Methods: This prospective, randomized, single-center, cross-over pilot study evaluated 31 subjects aged 18-44 years with normal eyes and good tear film stability who were adapted current soft contact lens wearers. Subjects wore nelfilcon A and stenfilcon A DDCLs for 12 hours each on two different days. Non-invasive video keratography drying-up time (NIK-DUT) videos of each eye were recorded 12 hours after lens insertion for about 25 seconds, with a 5-minute tear film recovery time allowed between video recordings of the right and left eyes to avoid bias. Post-blink time required to reach 15% distortion of the projected rings and the speed of break-up at 15 seconds post-blink were measured at each time point and on-eye wettability was determined by ring mire projection under white light illumination., Results: Mean time to reach 15% ring distortion was similar for nelfilcon A (19.25±3.20 sec) and stenfilcon A (20.24±3.02 sec) DDCLs but varied highly among subjects. The mean speed of break-up at 15 sec post-blink was 0.3±0.38% distortion/sec (95% confidence interval [CI] 0.138-0.365% distortion/sec) for nelfilcon A and 0.2±0.23% distortion/sec (95% CI 0.048-0.279% distortion/sec) for stenfilcon A DDCLs., Conclusion: Multifunctional topography allowed the objective evaluation of in vivo pre-lens tear film stability using ring mire projection. This dynamic method was simple, fast and non-invasive, enabling measurements of NIK-DUT and evaluating wettability over a large area, greater than the optical zone of the contact lens surface, for the entire inter-blink interval., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Marx et al.)

Purpose: Age and etiology play a crucial role in success of endoscopic third ventriculostomy (ETV) as a treatment of obstructive hydrocephalus. Outcome is worse in infants, and controversies still exist whether ETV is superior to shunt placement. We retrospectively analyzed 70 patients below 2 years from 4 different centers treated with ETV and assessed success., Methods: Children < 2 years who received an ETV within 1994-2018 were included. Patients were classified according to age and etiology; < 3, 4-12, and 13-24 months, etiologically; aqueductal stenosis, post-hemorrhagic-hydrocephalus (PHH), tumor-related, fourth ventricle outflow obstruction, with Chiari-type II and following CSF infection. We investigated statistically the predictors for ETV success through computing Kaplan-Meier estimates using patient's follow-up time and time to ETV failure., Results: We collected 70 patients. ETV success rate was 41.4%. The highest rate was in tumor-related hydrocephalus and fourth ventricle outlet obstruction (62.5%, 60%) and the lowest rate was in Chiari-type II and following infection (16.7%, 0%). The below 3 months age group showed relatively lower success rate (33.3%) in comparison to older groups which showed similar results (46.4%, 46.6%). Statistically, a previous VP shunt was a predictor for failure (p value < 0.05)., Conclusion: Factors suggesting a high possibility of failure were age < 3 months and etiology such as Chiari-type II or following infection. Altered CSF dynamics in patients with PHH and under-developed arachnoid villi may play a role in ETV failure. We do not recommend ETV as first line in children < 3 months of age or in case of Chiari II or following infection.

Introduction: Normalisation of macrocirculatory parameters during resuscitation therapy does not guarantee the restoration of microcirculatory perfusion in critical illness due to haemodynamic incoherence. Persistent microcirculatory abnormalities are associated with severity of organ dysfunction and mandate the development of bedside microcirculatory monitoring. A novel hyperspectral imaging (HSI) system can visualise changes in skin perfusion, oxygenation and water content at the bedside. We aim to evaluate the effectiveness of HSI for bedside monitoring of skin microcirculation and the association of HSI parameters with organ dysfunction in patients with sepsis and major abdominal surgery., Methods and Analysis: Three independent groups will be assessed and separately analysed within a clinical prospective observational study: (1) 25 patients with sepsis or septic shock (according to sepsis-3 criteria), (2) 25 patients undergoing pancreatic surgery and (3) 25 healthy controls. Patients with sepsis and patients undergoing pancreatic surgery will receive standard therapy according to local protocols derived from international guidelines. In addition, cardiac output of perioperative patients and patients with sepsis will be measured. Healthy controls undergo one standardised evaluation. The TIVITA Tissue System is a novel HSI system that uses the visible and near-infrared spectral light region to determine tissue microcirculatory parameters. HSI analysis (hand/knee) will be done in parallel to haemodynamic monitoring within defined intervals during a 72-hour observation period. HSI data will be correlated with the Sequential Organ Failure Assessment score, global haemodynamics, inflammation and glycocalyx markers, surgical complications and 30-day outcome., Ethics and Dissemination: The protocol has been approved by the local ethics committee of the University of Heidelberg (S-148/2019). Study results will be submitted to peer-reviewed journals and medical conferences., Trial Registration Number: DRKS00017313; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neuroendoscopic resection of colloid cysts has gained tremendous popularity over the last 2 decades because of good clinical outcomes and a low complication profile. However, in comparison to microsurgical resections, endoscopic resection has a lower rate of gross-total resection, which leaves the patient at risk for cyst recurrence. At present, there is still ongoing debate as to the best surgical approach for colloid cysts. Endoscopic resection as a technique has to compete with the good outcomes of microsurgical resections with respect to a long-term recurrence-free outcome. It is the authors' belief that gross-total resection should be the aim of endoscopic cyst resection. In this technical note, they describe their surgical technique for achieving safe gross-total resection of colloid cysts by using a ventriculoscopic system. The surgical technique includes a far anterolateral entry point, navigational guidance, bimanual sharp dissection, use of the endoscopic sheath as a retractor, the small-chamber irrigation technique, and the dry-field technique for hemostasis.