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The switch/sucrose-non-fermenting (SWI/SNF) complex is an ATP-dependent chromatin remodeling complex that plays important roles in DNA repair, transcription and cell differentiation. This complex consists of multiple subunits and is of particular interest in thoracic malignancies due to frequent subunit alteration of SMARCA4 (BRG1). Much less is known about SMARCB1 (INI1) deficient intrathoracic neoplasms, which are rare, often misclassified and understudied. In a retrospective analysis of 1479 intrathoracic malignant neoplasms using immunohistochemistry for INI1 (SMARCB1) on tissue micro arrays (TMA) and a search through our hospital sarcoma database, we identified in total nine intrathoracic, INI1 deficient cases (n = 9). We characterized these cases further by additional immunohistochemistry, broad targeted genomic analysis, methylation profiling and correlated them with clinical and radiological data. This showed that genomic SMARCB1 together with tumor suppressor alterations drive tumorigenesis in some of these cases, rather than epigenetic changes such as DNA methylation. A proper diagnostic classification, however, remains challenging. Intrathoracic tumors with loss or alteration of SMARCB1 (INI1) are highly aggressive and remain often underdiagnosed due to their rarity, which leads to false diagnostic interpretations. A better understanding of these tumors and proper diagnosis is important for better patient care as clinical trials and more targeted therapeutic options are emerging.

Neurosurgery (NS) is among the most selective specialties in the United States. As the United States Medical Licensing Examination (USMLE) Step 1 transitions to a binary pass/fail score, residency programs face unclear challenges in screening and evaluating applicants. The aim of this study is to provide insights into the perceived impact of changes to the USMLE Step 1 grading in the applicant selection process.We created a survey using questions regarding NS program demographics, the perceived predictive abilities of Step 1 and Step 2 clinical knowledge (CK), and several factors that programs consider when assessing applicants. We queried program directors (PDs), program coordinators (PCs), and assistant PDs at 117 NS residency programs. Respondents were asked to rank these factors in order of importance for selection at their respective training program. We used descriptive statistics and a Wilcoxon matched-pairs signed-rank test to evaluate the effects of these changes using STATA 17.A total of 35 (30%) residency programs responded with 26 (74%) completing the factor ranking questions. 86% (95% confidence interval, 71.5%-94.3%) disagreed that the changes will better prepare students clinically. USMLE Step 2 CK scores, class rank, and away rotations saw significant increases in priority in the absence of a graded Step 1, whereas letters of recommendation and surrogates for research productivity saw notable, but not significant, changes after adjusting for multiple testing.Reporting binary Step 1 grades marks a significant shift in assessing applicants for NS residency by emphasizing Step 2 CK, class rank, and research productivity.

Establishing tolerance remains a central, if elusive, goal of transplantation. In solid-organ transplantation, one strategy for inducing tolerance has been cotransplantation of various forms of thymic tissue along with another organ. As one of the biological foundations of central tolerance, thymic tissue carries with it the ability to induce tolerance to any other organ or tissue from the same donor (or another donor tissue-matched to the thymic tissue) if successfully transplanted. In this review, we outline the history of this approach as well as work to date on its application in organ transplantation, concluding with future directions. We also review our experience with allogeneic processed thymus tissue for the treatment of congenital athymia, encompassing complete DiGeorge syndrome and other rare genetic disorders, and consider whether allogeneic processed thymic tissue implantation may offer a novel method for future experimentation with tolerance induction in organ transplantation.

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.

Purpose: Previously, clinical trials of experimental virotherapy for recurrent glioblastoma multiforme (GBM) demonstrated that inoculation with a conditionally replication–competent Δγ134.5 oncolytic herpes simplex virus (oHSV), G207, was safe. Following the initial safety study, a phase Ib trial enrolled 6 adult patients diagnosed with GBM recurrence from which tumor tissue was banked for future studies. Patients and Methods: Here, we analyzed tumor RNA sequencing (RNA-seq) data obtained from pre- and posttreatment (collected 2 or 5 days after G207 injection) biopsies from the phase Ib study patients. Results: Using a Spearman rank-order correlation analysis, we identified approximately 500 genes whose expression pattern correlated with survival duration. Many of these genes were enriched for the intrinsic IFN-mediated antiviral and adaptive immune functional responses, including immune cell chemotaxis and antigen presentation to T-cells. Furthermore, we show that the expression of several T-cell–related genes was highest in the patient with the longest survival after G207 inoculation. Conclusions: Our data support that the oHSV-induced type I IFN production and the subsequent recruitment of an adaptive immune response differed between enrolled patients and showed association with survival duration in patients with recurrent malignant glioma after treatment with an early generation oHSV.

The physical connection of mother and offspring during pregnancy allows the bi-directional exchange of a small number of cells through the placenta. These cells, which can persist long-term in the recipient individual are genetically foreign to it and therefore fulfill the principle of microchimerism. Over the last years, pioneer research on microchimeric cells revealed their role in immune adaptation during pregnancy and priming of tolerogenic responses in the progeny. However, the mechanisms involved in cell transfer across the placenta barrier remain poorly investigated. In this review, we summarize the evidence of fetomaternal microchimerism, propose a mechanism for cell trafficking through the placenta and discuss the different models and techniques available for its analysis. Likewise, we aim to generate interest in the use of ex vivo placenta perfusion to investigate microchimerism in physiological and pathological settings.

Objectives: Assistive reproductive therapies can help those who have difficulty conceiving but different forms of assistive reproductive therapies are associated with different treatment characteristics. We undertook a large, multinational discrete choice experiment to understand patient preferences for assistive reproductive therapies. Methods: We administered an online discrete choice experiment with persons who had experience with subfertility or assistive reproductive therapies in the USA, UK, the Nordic region (Denmark, Norway, Sweden, Finland), Spain, and China. Attributes encouraged trade-offs between effectiveness, risk of adverse effects, treatment (dis)comfort, (in)convenience, cost per cycle and shared decision making. We used multinomial logit and mixed-logit models to estimate preferences and attribute importance by country/region, and estimated willingness to pay for changes in attribute levels. Results: A total of 7565 respondents participated. Mixed logit had a better fit than multinomial logit across all samples. Preferences moved in expected directions across all samples, but the relative importance of attributes differed between countries. Willingness to pay was greatest for improvements in effectiveness and a greater degree of shared decision making, and we observe a substantial ‘option value’ independent of treatment characteristics. Unexpectedly, preferences over cost were insignificant in the Chinese sample, limiting the use of willingness to pay in this sample. Conclusions: Respondents balanced concerns for effectiveness with other considerations, including the cost and (dis)comfort of treatment, and the degree of shared decision making, but there is also substantial option value independent of treatment characteristics, demonstrating value of assistive reproductive therapies to individuals with experience of subfertility. We hypothesise that price insensitivity in the Chinese sample may reflect a degree of social desirability bias.

The pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFβ signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFβ signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC’s with born to be bad traits.

22q11.2 deletion syndrome (22q11.2DS) is the most common human chromosomal microdeletion, causing developmentally linked congenital malformations, thymic hypoplasia, hypoparathyroidism, and/or cardiac defects. Thymic hypoplasia leads to T cell lymphopenia, which most often results in mild SCID. Despite decades of research, the molecular underpinnings leading to thymic hypoplasia in 22q11.2DS remain unknown. Comparison of embryonic thymuses from mouse models of 22q11.2DS (Tbx1neo2/neo2) revealed proportions of mesenchymal, epithelial, and hematopoietic cell types similar to those of control thymuses. Yet, the small thymuses were growth restricted in fetal organ cultures. Replacement of Tbx1neo2/neo2 thymic mesenchymal cells with normal ones restored tissue growth. Comparative single-cell RNA-Seq of embryonic thymuses uncovered 17 distinct cell subsets, with transcriptome differences predominant in the 5 mesenchymal subsets from the Tbx1neo2/neo2 cell line. The transcripts affected included those for extracellular matrix proteins, consistent with the increased collagen deposition we observed in the small thymuses. Attenuating collagen cross-links with minoxidil restored thymic tissue expansion for hypoplastic lobes. In colony-forming assays, the Tbx1neo2/neo2-derived mesenchymal cells had reduced expansion potential, in contrast to the normal growth of thymic epithelial cells. These findings suggest that mesenchymal cells were causal to the small embryonic thymuses in the 22q11.2DS mouse models, which was correctable by substitution with normal mesenchyme.

Species differences are among the main reasons for the high failure rate of preclinical studies. A better awareness and understanding of these differences might help to improve the outcome of preclinical research. In reproduction, the placenta is the central organ regulating fetal exposure to a substance circulating in the maternal organism. Exact information about placental transfer can help to better estimate the toxic potential of a substance. From an evolutionary point of view, the chorioallantoic placenta is the organ with the highest anatomical diversity among species. Moreover, frequently used animal models in reproduction belong to rodents and lagomorphs, two groups that are characterized by the generation of an additional type of placenta, which is crucial for fetal development, but absent from humans: the inverted yolk sac placenta. Taken together, the translatability of placental transfer studies from laboratory animals to humans is challenging, which is supported by the fact that numerous species-dependent toxic effects are described in literature. Thus, reliable human-relevant data are frequently lacking and the toxic potential of chemicals and pharmaceuticals for humans can hardly be estimated, often resulting in recommendations that medical treatments or exposure to chemicals should be avoided for safety reasons. Although species differences of placental anatomy have been described frequently and the need for human-relevant research models has been emphasized, analyses of substances with species-dependent placental transfer have been performed only sporadically. Here, we present examples for species-specific placental transfer, including that of nanoparticles and pharmaceuticals, and discuss potential underlying mechanisms. With respect to the COVID 19-pandemic it might be of interest that some antiviral drugs are reported to feature species-specific placental transfer. Further, differences in placental structure and antibody transfer may affect placental transfer of ZIKA virus.

European spine journal 31(4), 1013-1021 (2021). doi:10.1007/s00586-021-07035-4, Published by Springer, Berlin ; Heidelberg ; New York

Deficiency or mutation of von Willebrand factor (VWF) leads to a coagulation disorder (von Willebrand disease; VWD) which requires a lifelong therapy. For avoiding maternal complications treatment may be necessary also in pregnancy, but placental transfer to the fetus might impact its coagulation system and evoke undesired side effects. As VWF is a very large molecule it may be assumed that it does not pass the placental barrier. To prove this hypothesis the materno-fetal transfer of recombinant VWF (rVWF) has been analyzed ex vivo in a total of 21 valid dual side placenta perfusions. Three groups of five placentas each have been perfused with physiological and up to ten-fold increased concentrations of rVWF for 2 h. Six placentas have been used for control perfusions. A series of different control parameters has been assessed for documentation of intactness and functionality of the placenta and the perfusion system. In not a single analysis, independent of time and concentration, rVWF was detected in the fetal circuit. In the maternal circuit VWF concentration decreased slightly during perfusion. These results demonstrate that recombinant VWF does not pass the human placenta.

Determination of treatment response to immunotherapy in glioblastoma multiforme (GBM) is a process which can take months. Detection of CD8+ T cell recruitment to the tumor with a noninvasive imaging modality such as positron emission tomography (PET) may allow for tumor characterization and early evaluation of therapeutic response to immunotherapy. In this study, we utilized 89Zr-labeled anti-CD8 cys-diabody-PET to provide proof-of-concept to detect CD8+ T cell immune response to oncolytic herpes simplex virus (oHSV) M002 immunotherapy in a syngeneic GBM model. Immunocompetent mice (n = 16) were implanted intracranially with GSC005 GBM tumors, and treated with intratumoral injection of oHSV M002 or saline control. An additional non-tumor bearing cohort (n = 4) receiving oHSV M002 treatment was also evaluated. Mice were injected with 89Zr-labeled anti-CD8 cys-diabody seven days post oHSV administration and imaged with a preclinical PET scanner. Standardized uptake value (SUV) was quantified. Ex vivo tissue analyses included autoradiography and immunohistochemistry. PET imaging showed significantly higher SUV in tumors which had been treated with M002 compared to those without M002 treatment (p = 0.0207) and the non-tumor bearing M002 treated group (p = 0.0021). Accumulation in target areas, especially the spleen, was significantly reduced by blocking with the non-labeled diabody (p + cell trafficking patterns after oHSV treatment. This PET imaging strategy could aid in distinguishing responders from non-responders during immunotherapy of GBM.

Introduction Safe and effective vaccines against severe acute respiratory syndrome-associated coronavirus 2 are essential tools in the fight against the coronavirus disease 2019 (COVID-19) pandemic. However, hesitancy to vaccination is a major barrier to achieving herd immunity, particularly among a population working on a military base. To better understand the perceptions and concerns of these individuals, a voluntary survey was conducted. Materials and Methods An interactive, online survey was constructed and disseminated to individuals associated with Wright-Patterson Air Force Base (WPAFB) in Dayton, OH. Survey participation was voluntary with responses collected over the initial weeks in which WPAFB began to distribute COVID-19 vaccines in a series of phases. Although initially designed to collect demographic data and identify reasons for potential vaccine hesitancy among WPAFB 88th Medical Group personnel, the study population was expanded to include all WPAFB-affiliated personnel at the direction of base leadership. The chi-squared test was used to examine the relationships between categorical variables, while multivariable logistic regression was used to assess age and occupation as independent risk factors for vaccine hesitancy. Results A total of 816 individuals completed the survey, of whom 22.7% (n = 185) self-identified as vaccine hesitant (VH). The VH group had a lower mean age than the not vaccine hesitant (NVH) group (39.3 ± 14.2 vs. 45.9 ± 13.4, P Conclusions Younger age and medical occupation were independent risk factors for vaccine hesitancy and these individuals were less likely to recommend vaccination to a friend or family member. We also identified several key concerns related to vaccination hesitancy, in particular those related to short- and long-term side effects, and the spread of misinformation. Among military personnel, these findings carry important implications that may negatively impact mission readiness, a matter that merits further investigation. Our COVID-19 vaccination hesitancy findings can be used to guide targeted interventions at future vaccination campaigns in a military population.

Vancomycin plus piperacillin–tazobactam (VPT) is a commonly used antimicrobial regimen for septic patients. VPT is more nephrotoxic than other regimens such as vancomycin plus cefepime (VC) when given over several days. This risk of nephrotoxicity is less clear when VPT is given for initial empiric therapy in sepsis and de-escalated quickly based on evolving clinical information. The objective of this study was to assess nephrotoxicity among septic patients empirically treated with either VPT or VC at initial clinical presentation. We conducted a retrospective study of septic patients who received VPT or VC within 12 h of presentation to the emergency department. The primary outcomes were acute kidney injury (AKI) and renal recovery 72 h after presentation. For the total of 418 patients, 306 received VPT and 112 received VC. Rates of AKI at 72 h were 15.2% for VPT patients and 11.0% for VC patients [p = 0.44]. Among patients with AKI at presentation, 16.3% of VPT patients had AKI at 72 h compared to 8.9% of VC patients [p = 0.19]. Among those without AKI at presentation, 14.2% VPT patients and 16.7% VC patients had AKI at 72 h [p = 0.71]. Renal recovery rates for patients with AKI at presentation were 42.3% for VPT patients versus 40.3% for VC patients [p = 0.78]. In-hospital renal replacement therapy occurred in 6.2% VPT patients and 0.9% VC patients [p = 0.024]. Therefore, initial empiric therapy with VPT in sepsis may not confer increased risk of AKI when de-escalated appropriately.

With the ever-increasing demand for lithium (Li) for portable energy storage devices, there is a global concern associated with environmental contamination of Li, via the production, use, and disposal of Li-containing products, including mobile phones and mood-stabilizing drugs. While geogenic Li is sparingly soluble, Li added to soil is one of the most mobile cations in soil, which can leach to groundwater and reach surface water through runoff. Lithium is readily taken up by plants and has relatively high plant accumulation coefficient, albeit the underlying mechanisms have not been well described. Therefore, soil contamination with Li could reach the food chain due to its mobility in surface- and ground-waters and uptake into plants. High environmental Li levels adversely affect the health of humans, animals, and plants. Lithium toxicity can be considerably managed through various remediation approaches such as immobilization using clay-like amendments and/or chelate-enhanced phytoremediation. This review integrates fundamental aspects of Li distribution and behaviour in terrestrial and aquatic environments in an effort to efficiently remediate Li-contaminated ecosystems. As research to date has not provided a clear picture of how the increased production and disposal of Li-based products adversely impact human and ecosystem health, there is an urgent need for further studies on this field. Refereed/Peer-reviewed

Covid-19 has been a global concern since 2019, crippling the world economy and health. Biological diagnostic tools have since been developed to identify the virus from bodily fluids and since the virus causes pneumonia, which results in lung inflammation, the presence of the virus can also be detected using medical imaging by expert radiologists. The success of each diagnostic method is measured by the hit rate for identifying Covid infections. However, the access for people to each diagnosis tool can be limited, depending on the geographic region and, since Covid treatment denotes a race against time, the diagnosis duration plays an important role. Hospitals with X-ray opportunities are widely distributed all over the world, so a method investigating lung X-ray images for possible Covid-19 infections would offer itself. Promising results have been achieved in the literature in automatically detecting the virus using medical images like CT scans and X-rays using supervised artificial neural network algorithms. One of the major drawbacks of supervised learning models is that they require enormous amounts of data to train, and generalize on new data. In this study, we develop a Swish activated, Instance and Batch normalized Residual U-Net GAN with dense blocks and skip connections to create synthetic and augmented data for training. The proposed GAN architecture, due to the presence of instance normalization and swish activation, can deal with the randomness of luminosity, that arises due to different sources of X-ray images better than the classical architecture and generate realistic-looking synthetic data. Also, the radiology equipment is not generally computationally efficient. They cannot efficiently run state-of-the-art deep neural networks such as DenseNet and ResNet effectively. Hence, we propose a novel CNN architecture that is 40% lighter and more accurate than state-of-the-art CNN networks. Multi-class classification of the three classes of chest X-rays (CXR), ie Covid-19, healthy and Pneumonia, is performed using the proposed model which had an extremely high test accuracy of 99.2% which has not been achieved in any previous studies in the literature. Based on the mentioned criteria for developing Corona infection diagnosis, in the present study, an Artificial Intelligence based method is proposed, resulting in a rapid diagnostic tool for Covid infections based on generative adversarial and convolutional neural networks. The benefit will be a high accuracy of lung infection identification with 99% accuracy. This could lead to a support tool that helps in rapid diagnosis, and an accessible Covid identification method using CXR images.

BACKGROUND Pneumoscrotum is a rare clinical occurrence in which air accumulates in the scrotum. The origin of air is primarily from trauma, but spontaneous pneumoscrotum can develop from gastrointestinal or pulmonary sources. Physical examination of pneumoscrotum typically includes crepitus of the perineal region and scrotal swelling and associated findings depending on the origin of the free air. However, pneumoscrotum in the setting of a scrotal wound, which allows air to pass freely outside the body, has not been previously documented in the literature. CASE REPORT A 72-year-old man who recently underwent a scrotal incision and drainage for recurrent epididymitis presented to a local emergency room with chief concerns of "whistling scrotum" and dyspnea. The chest CT revealed bilateral pneumothoraces, pneumomediastinum, and excessive subcutaneous emphysema throughout his abdomen, perineum, and scrotum. His scrotum had a dehiscent wound without any gross edema or air trapping contained within the scrotum. He received bilateral chest tubes and subcutaneous air drains with complete resolution of his pneumothoraces. The pneumoscrotum and associated subcutaneous emphysema of the perineum and thighs resolved after a prolonged period, and necessitated additional scrotal surgery. CONCLUSIONS Prompt evaluation for source control is necessary with pneumoscrotum, as the source likely requires immediate stabilization or surgical intervention. This case report describes a unique presentation of a common entity (pneumothorax) within pulmonology/critical care in a patient with an open scrotal wound from a recent scrotal procedure, which allowed the air to escape from his abdominal compartment, and resulted in his "scrotal whistling." It is unclear how the air passing through the scrotum affected the patient's presentation, such as allowing more air to build up in the subcutaneous tissues versus developing critical illness.

Background Prolonged mechanical ventilation in post Coronary Artery Bypass Graft Surgery (CABG) is associated with deleterious effects including, increased ICU and hospital length of stay (LOS), infectious complications, and mortality. Standardized ventilator weaning protocols and the utilization of critical care physicians in post CABG patient care vary substantially among institutions. The purpose of this study was to evaluate if intensivist consultation in conjunction with a multidisciplinary, standardized ventilator weaning protocol improves outcomes in CABG patients. Materials and Methods We performed a single-center, retrospective, before-after cohort analysis at Miami Valley Hospital in Dayton, OH, a 970-bed community hospital. Patients were divided into two arms: the before cohort or delayed-consult group (critical care consult after six hours on ventilator) and after cohort or immediate-consult group (immediate critical care consult). All patients were weaned from ventilator using a standardized weaning protocol. Results A total of 764 patients were enrolled, 411 in the delayed-consult group and 353 in the immediate-consult group. The immediate-consult group had less time on initial mechanical ventilation than the delayed-consult group (5.86 ± 4.75 h vs. 6.00 ± 6.64 h, P = 0.038). The small advantages to immediate critical care consultation for higher percent of early extubations, fewer re-intubations, shorter ICU LOS, and lower rate of ICU readmission were not statistically significant. The two groups had similar ventilator free days, prolonged mechanical ventilation, hospital LOS, and in-hospital mortality. Conclusion Our study suggests that intensivist-driven ventilator management in conjunction with a multidisciplinary standardized weaning protocol shortens duration of mechanical ventilation in coronary artery bypass graft surgery patients.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in 2019 in Wuhan, China, and has rapidly spread across the world. As of April 2021, SARS-CoV-2 has infected more than 140,000,000 and caused more than 3,000,000 deaths globally. In November 2020, the monoclonal antibody bamlanivimab was approved by the FDA for non-hospitalized patients with SARS-CoV-2 (COVID-19) who possessed risk factors for progression to severe COVID-19. This provided a treatment option that may help prevent hospitalization. Methods Patients who regularly received ambulatory care at a military treatment facility and who were diagnosed with mild-to-moderate COVID-19 and possessed risk factors for progression to severe COVID-19 were treated with a single, intravenous infusion (700 mg) of the virus-neutralizing monoclonal antibody bamlanivimab. The primary outcome was improvement of self-reported symptoms within 24 to 72 hours of receiving the infusion. The secondary outcome was prevention of disease progression requiring emergency department (ED) utilization or hospitalization related to COVID-19 within 30 days of infusion. Bamlanivimab was administered in accordance with the FDA’s approval and Defense Health Agency’s guidance, including follow-up within 72 hours of administration. Institutional Review Board (IRB) approval was obtained. Results Of the COVID-19 patients who were given the option of a bamlanivimab infusion, 40 accepted and 6 did not (40/46, 86.9%). Thirty-six of 40 patients in the treatment group were contacted within 72 hours. ED/hospitalization information was available for all 46 patients. In the treatment group, 94.4% (34/36) reported global improvement. Three of 40 (7.5%) patients in the treatment group required inpatient admission, and 2 of 40 patients (5%) required ED evaluation within 30 days of infusion. Therefore, 5 of 40 (12.5%) patients required evaluation shortly after infusion, while 2 of 6 (33.3%) patients who declined treatment required hospital evaluation or admission related to COVID-19 within 30 days of infusion (P = .15). Conclusions Global improvement of symptoms within 24 to 72 hours of infusion was reported by 94.4% of patients receiving bamlanivimab; however, statistical significance could not be determined due to the small sample size and lack of placebo group due to study design. Furthermore, ED visits and hospital admissions were analyzed, but with only six patients in the comparison group, the relative risk was not statistically significant and could not be precisely estimated. In the future, this study can be replicated with both larger control/treatment arms to validate the initial results of this small, retrospective, cohort study.

Introduction Research on human placental development and function lacks a conclusive in vivo model. To investigate the intracellular molecular mechanisms in trophoblast cells, different cell lines have been established during the last decades. So far, none of these accomplishes all features of primary trophoblast, thus their suitability as well as the transferability of the results has been discussed. The aim of this study is to assess molecular markers and features matching different trophoblast subpopulations in trophoblastic cell lines to provide orientation on their suitability and relevance for distinct research questions. Methods The commonly used trophoblastic cell lines, BeWo, JEG-3, HTR-8/SVneo, AC1-M59, AC1-M32, ACH-3P and Swan71 were selected. qPCR and immunoblotting were used to determine expression of characteristic molecular markers. C14MC, C19MC and miR-371-3 miRNA expression were investigated by real time PCR. Proliferation, migration and network stabilization assays were performed. Hormone secretion was determined by chemiluminescent-immunoassays. DNA profiles were obtained by Short Tandem Repeat (STR)-genotyping. Results Immortalized cell lines differ from choriocarcinoma-derived ones in the expression of HLA-G, E-cadherin, N-cadherin, VE-cadherin, cadherin-11, cytokeratin 7, vimentin, ADAM12 and PRG2. Compared to choriocarcinoma-derived cell lines, expression of C19MC and hormone secretion were almost absent in immortalized cell lines. Conversely, they express C14MC and exhibit higher migration and network stabilization. Discussion The data presented will help justify the use of a cell line to evaluate distinct features of trophoblast biology and pathology. In general, characteristics and markers of choriocarcinoma derived cell lines seem to be more similar to in vivo trophoblast than immortalized cell lines and thus might be regarded as more suitable models.

Properly planned single isocenter volumetric modulated arc therapy (VMAT) radiosurgery plans exhibit high quality and efficiency. We report here the largest clinical experience to date, to our knowledge, comparing manual planning with a new automated platform designed to standardize and simplify radiosurgery planning and delivery processes.We treated 693 patients with single isocenter VMAT radiosurgical plans generated by either our conventional manual (mVMAT) or a recently implemented automated (HyperArcThe median Radiation Therapy Oncology Group (RTOG) conformity index was 1.14 and was not different between the 2 techniques. The median Paddick gradient index was 5.42 for HyperArc versus 7.09 for mVMAT (P.001). The median mean brain doses were 4.6% and 5.1% for HyperArc and mVMAT, respectively (P = .04). The PSQA for both techniques met clinical criteria, but 97% of the HyperArc plans satisfied the gamma tolerance limit recommended by the American Association of Physicists in Medicine Task Group No. 218, compared with 94% of the mVMAT plans (P = .02). The median treatment-planning times were not significantly different. The median treatment times were 10.5 and 11.4 minutes for HyperArc and mVMAT, respectively (P.001). The Kaplan-Meier estimate of local control was 90.1% at 1 year.HyperArc produces high-quality radiosurgical plans that are at least as good as mVMAT plans created by an expert manual planner with easier planning and more efficient delivery workflow. A less experienced planner can produce very high-quality radiosurgical plans even for patients with more than 10 targets. The use of a single-isocenter technique for multiple targets with no PTV margin did not compromise clinical outcomes, and 1-year local control for treated targets remained congruent with historical series.

Purpose Several roles are attributed to the myometrium including sperm and embryo transport, menstrual discharge, control of uterine blood flow, and labor. Although being a target of diabetes complications, the influence of high glucose on this compartment has been poorly investigated. Both miRNAs and IGF1R are associated with diabetic complications in different tissues. Herein, we examined the effects of high glucose on the expression of miRNAs and IGF1R signaling pathway in the human myometrium. Methods Human myometrial explants were cultivated for 48 h under either high or low glucose conditions. Thereafter, the conditioned medium was collected for biochemical analyses and the myometrial samples were processed for histological examination as well as miRNA and mRNA expression profiling by qPCR. Results Myometrial structure and morphology were well preserved after 48 h of cultivation in both high and low glucose conditions. Levels of lactate, creatinine, LDH and estrogen in the supernatant were similar between groups. An explorative screening by qPCR arrays revealed that 6 out of 754 investigated miRNAs were differentially expressed in the high glucose group. Data validation by single qPCR assays confirmed diminished expression of miR-215-5p and miR-296-5p, and also revealed reduced miR-497-3p levels. Accordingly, mRNA levels of IGF1R and its downstream mediators FOXO3 and PDCD4, which are potentially targeted by miR-497-3p, were elevated under high glucose conditions. In contrast, mRNA expression of IGF1, PTEN, and GLUT1 was unchanged. Conclusions The human myometrium responds to short-term exposure (48 h) to high glucose concentrations by regulating the expression of miRNAs, IGF1R and its downstream targets.

Background Utilization of primary-care and specialist physicians seems to be associated differently with socioeconomic status (SES). This review aims to summarize and compare the evidence on socioeconomic inequalities in consulting primary-care or specialist physicians in the general adult population in high-income countries. Methods We carried out a systematic search across the most relevant databases (Web of Science, Medline) and included all studies, published since 2004, reporting associations between SES and utilization of primary-care and/or specialist physicians. In total, 57 studies fulfilled the eligibility criteria. Results Many studies found socioeconomic inequalities in physician utilization, but inequalities were more pronounced in visiting specialists than primary-care physicians. The results of the studies varied strongly according to the operationalization of utilization, namely whether a physician was visited (probability) or how often a physician was visited (frequency). For probabilities of visiting primary-care physicians predominantly no association with SES was found, but frequencies of visits were higher in the most disadvantaged. The most disadvantaged often had lower probabilities of visiting specialists, but in many studies no link was found between the number of visits and SES. Conclusion This systematic review emphasizes that inequalities to the detriment of the most deprived is primarily a problem in the probability of visiting specialist physicians. Healthcare policy should focus first off on effective access to specialist physicians in order to tackle inequalities in healthcare. PROSPERO registration number CRD42019123222. Supplementary Information The online version contains supplementary material available at 10.1186/s12939-020-01375-1.

OBJECTIVES The amount of colorectal cancer (CRC) screening using the noninvasive fecal immunochemical test (FIT) at a federally qualified health center, Five Rivers Health Clinic (Dayton, Ohio), has been low historically. Our quality improvement (QI) project aimed to improve CRC screening adherence in eligible patients who opted for FIT. METHODS Three hundred ninety-two patients with FIT orders for CRC were screened during an 11-month period. The preintervention group (pre-I) was enrolled from December 1, 2018 to May 31, 2019, and the postintervention group (post-I) from June 1, 2019 to October 31, 2019. Three interventions were used: resident physicians trained during clinic meetings regarding FIT education for patients, posters displayed in patient rooms outlining the benefits of CRC screening, and standardized US mail reminder letters sent to FIT patients. Patient demographics and clinical variables were collected along with return rate. RESULTS The return rate for post-I was twice that of pre-I (74.4%, 95% confidence interval 64.6-82.3 vs 31.1, 95% confidence interval 26.2-36.6; P < 0.001). The pre-I/post-I groups did not differ on demographic and clinical characteristics, and, except for race, none of these variables was associated with returning the FIT screening card. CONCLUSIONS The compliance rate for FIT completion and return more than doubled among our clinic patients after using a three-component QI intervention. Except for a difference in race, the lack of association between demographic and clinical characteristics with either pre-I/post-I group or return/no return of the FIT card leads us to conclude that our QI program for increasing FIT compliance is effective. Other settings where CRC screening is a prominent component of preventive care may benefit from adopting a similar QI intervention.

The “Blechschmidt Collection of Human Embryos” housed at the Anatomical Institute of Göttingen University (Germany) is an important historical collection of human embryo specimens whose history dates back up to the mid-1940s. It is named after its founder Prof. Erich Blechschmidt (1904–1992). A 2-year research project was conducted from 2017 to 2019 with the aim of clarifying the provenience of the human embryo specimens collected by Blechschmidt. This project not only has provided information on the origin of the specimens but, additionally, led to the discovery of photographic documents illustrating the process by which Blechschmidt built the enlarged 3-dimensional replicas of human embryos that are shown in a dedicated exhibition hall in the basement of the Anatomical Institute. Here, we report on an embryo from the Blechschmidt collection whose biography as a microscopical specimen as well as a source for objects of Blechschmidt’s collection of 3-dimensional replicas of human embryos is documented by letters, lab-books, and photographs. Our report is complemented by a short historical review on the production and usage of enlarged 3-dimensional replicas in research on the anatomy of human embryo.

A complex network composed of at least 1900 microRNA (miRNA) species orchestrates the development and function of the human placenta. These molecules regulate genes and pathways operating major functional processes in trophoblast cells such as proliferation, invasion, differentiation, and metabolism. Nevertheless, the cellular localization and role of most placental miRNAs remain to be determined. The existence of eutherian- (C14MC) and primate-specific miRNA clusters (C19MC), together with human placenta-specific miRNAs, indicate the relevance of these molecules in evolution and diversification of the placenta, including the acquisition of its unique features in humans. They may be related also to diseases that are exclusively present in primates, such as preeclampsia. Changes in the miRNA expression profile have been reported in several placental pathologies. Which miRNAs are involved in the pathomechanism of these diseases or act to maintain placental homeostasis is uncertain. Placenta-derived miRNAs are packed into extracellular vesicles (EVs) and distributed through the maternal circulation to distant organs, where they contribute to adaptations required during pregnancy. Similarly, the placenta also receives molecular information from other tissues to adapt fetoplacental metabolic demands to the maternal energetic supply. These processes can be impaired in pathologic conditions. Therefore, the collection of circulating placental miRNAs constitutes potentially a minimally-invasive approach to assess the fetoplacental status and to diagnose pregnancy diseases. Future therapies may include manipulation of miRNA levels for prevention and treatment of placental complications to protect maternal health and fetal development.

The standard camera- and force plate-based set-up for motion analysis suffers from the disadvantage of being limited to laboratory settings. Since adaptive algorithms are able to learn the connection between known inputs and outputs and generalise this knowledge to unknown data, these algorithms can be used to leverage motion analysis outside the laboratory. In most biomechanical applications, feedforward neural networks are used, although these networks can only work on time normalised data, while recurrent neural networks can be used for real time applications. Therefore, this study compares the performance of these two kinds of neural networks on the prediction of ground reaction force and joint moments of the lower limbs during gait based on joint angles determined by optical motion capture as input data. The accuracy of both networks when generalising to new data was assessed using the normalised root-mean-squared error, the root-mean-squared error and the correlation coefficient as evaluation metrics. Both neural networks demonstrated a high performance and good capabilities to generalise to new data. The mean prediction accuracy over all parameters applying a feedforward network was higher (r = 0.963) than using a recurrent long short-term memory network (r = 0.935).

Non-coding RNAs (ncRNAs) play a central and regulatory role in almost all cells, organs, and species, which has been broadly recognized since the human ENCODE project and several other genome projects. Nevertheless, a small fraction of ncRNAs have been identified, and in the placenta they have been investigated very marginally. To date, most examples of ncRNAs which have been identified to be specific for fetal tissues, including placenta, are members of the group of microRNAs (miRNAs). Due to their quantity, it can be expected that the fairly larger group of other ncRNAs exerts far stronger effects than miRNAs. The syncytiotrophoblast of fetal origin forms the interface between fetus and mother, and releases permanently extracellular vesicles (EVs) into the maternal circulation which contain fetal proteins and RNA, including ncRNA, for communication with neighboring and distant maternal cells. Disorders of ncRNA in placental tissue, especially in trophoblast cells, and in EVs seem to be involved in pregnancy disorders, potentially as a cause or consequence. This review summarizes the current knowledge on placental ncRNA, their transport in EVs, and their involvement and pregnancy pathologies, as well as their potential for novel diagnostic tools.

Objective: Chronic pain is common in the military, and over a quarter of active-duty military members have received a prescription for opioids. This study reviewed the initial opioid prescription among those who became future long-term users at an Air Force base in the United States and reports the characteristics of the provider and patient.Methods: Our single-center retrospective study evaluated initial opioid prescriptions leading to long-term use within the military’s electronic medical record at a large military medical treatment facility including active-duty patients and veterans. Of the 3,701 charts reviewed, 348 patients met the inclusion criteria for the long-term opioid use.Results: Older patient groups received a higher initial amount of opioids than younger groups (p = 0.007). Primary care outpatient clinics started 43 percent of initial long-term opioid users, while surgical specialties contributed to 34 percent of the sample. In our study, 35.9 percent of the long-term opioid users were given their first opioid prescription within 30 days of an operation. Veterans or those separated from the military were less likely to have a behavioral disorder than active duty or family members.Conclusions: Our sample mirrored the civilian population in terms of age, gender, and most common pain diagnosis. We found that older patients initially received a higher dispensed amount compared to our younger patients. There was a concerning trend for surgical patients to develop into chronic opioid users.

Humans harbor numerous species of colonic bacteria that digest fiber polysaccharides in commonly consumed terrestrial plants. More recently in history, regional populations have consumed edible macroalgae seaweeds containing unique polysaccharides. It remains unclear how extensively gut bacteria have adapted to digest these nutrients. Here, we show that the ability of gut bacteria to digest seaweed polysaccharides is more pervasive than previously appreciated. Enrichment-cultured Bacteroides harbor previously discovered genes for seaweed degradation, which have mobilized into several members of this genus. Additionally, other examples of marine bacteria-derived genes, and their mobile DNA elements, are involved in gut microbial degradation of seaweed polysaccharides, including genes in gut-resident Firmicutes. Collectively, these results uncover multiple separate events that have mobilized the genes encoding seaweed degrading-enzymes into gut bacteria. This work further underscores the metabolic plasticity of the human gut microbiome and global exchange of genes in the context of dietary selective pressures.

Introduction Current electroencephalography (EEG) practice relies on interpretation by expert neurologists, which introduces diagnostic and therapeutic delays that can impact patients’ clinical outcomes. As EEG practice expands, these experts are becoming increasingly limited resources. A highly sensitive and specific automated seizure detection system would streamline practice and expedite appropriate management for patients with possible nonconvulsive seizures. We aimed to test the performance of a recently FDA-cleared machine learning method (Claritγ, Ceribell Inc.) that measures the burden of seizure activity in real time and generates bedside alerts for possible status epilepticus (SE). Methods We retrospectively identified adult patients (n = 353) who underwent evaluation of possible seizures with Rapid Response EEG system (Rapid-EEG, Ceribell Inc.). Automated detection of seizure activity and seizure burden throughout a recording (calculated as the percentage of ten-second epochs with seizure activity in any 5-min EEG segment) was performed with Claritγ, and various thresholds of seizure burden were tested (≥ 10% indicating ≥ 30 s of seizure activity in the last 5 min, ≥ 50% indicating ≥ 2.5 min of seizure activity, and ≥ 90% indicating ≥ 4.5 min of seizure activity and triggering a SE alert). The sensitivity and specificity of Claritγ’s real-time seizure burden measurements and SE alerts were compared to the majority consensus of at least two expert neurologists. Results Majority consensus of neurologists labeled the 353 EEGs as normal or slow activity (n = 249), highly epileptiform patterns (HEP, n = 87), or seizures [n = 17, nine longer than 5 min (e.g., SE), and eight shorter than 5 min]. The algorithm generated a SE alert (≥ 90% seizure burden) with 100% sensitivity and 93% specificity. The sensitivity and specificity of various thresholds for seizure burden during EEG recordings for detecting patients with seizures were 100% and 82% for ≥ 50% seizure burden and 88% and 60% for ≥ 10% seizure burden. Of the 179 EEG recordings in which the algorithm detected no seizures, seizures were identified by the expert reviewers in only two cases, indicating a negative predictive value of 99%. Discussion Claritγ detected SE events with high sensitivity and specificity, and it demonstrated a high negative predictive value for distinguishing nonepileptiform activity from seizure and highly epileptiform activity. Conclusions Ruling out seizures accurately in a large proportion of cases can help prevent unnecessary or aggressive over-treatment in critical care settings, where empiric treatment with antiseizure medications is currently prevalent. Claritγ’s high sensitivity for SE and high negative predictive value for cases without epileptiform activity make it a useful tool for triaging treatment and the need for urgent neurological consultation.

Brain tumors represent the most common pediatric solid neoplasms and leading cause of childhood cancer-related morbidity and mortality. Although most adult brain tumors are supratentorial and arise in the cerebrum, the majority of pediatric brain tumors are infratentorial and arise in the posterior fossa, specifically the cerebellum. Outcomes from malignant cerebellar tumors are unacceptable despite aggressive treatments (surgery, radiation, and/or chemotherapy) that are harmful to the developing brain. Novel treatments/approaches such as oncolytic virotherapy are urgently needed. Preclinical and prior clinical studies suggest that genetically engineered oncolytic herpes simplex virus (HSV-1) G207 can safely target cerebellar malignancies and has potential to induce an antitumor immune response at local and distant sites of disease, including spinal metastases and leptomeningeal disease. Herein, we outline the rationale, design, and significance of a first-in-human immunotherapy Phase 1 clinical trial targeting recurrent cerebellar malignancies with HSV G207 combined with a single low-dose of radiation (5 Gy), designed to enhance virus replication and innate and adaptive immune responses. We discuss the unique challenges of inoculating virus through intratumoral catheters into cerebellar tumors. The trial utilizes a single arm open-label traditional 3 + 3 design with four dose cohorts. The primary objective is to assess safety and tolerability of G207 with radiation in recurrent/progressive malignant pediatric cerebellar tumors. After biopsy to prove recurrence/progression, one to four intratumoral catheters will be placed followed by a controlled-rate infusion of G207 for 6 h followed by the removal of catheters at the bedside. Radiation will be given within 24 h of virus inoculation. Patients will be monitored closely for toxicity and virus shedding. Efficacy will be assessed by measuring radiographic response, performance score, progression-free and overall survival, and quality of life. The data obtained will be invaluable in our efforts to produce more effective and less toxic therapies for children with high-grade brain tumors.

ZusammenfassungDie Humanembryologische Dokumentationssammlung Blechschmidt, entstanden an der Universität Göttingen im Zeitraum von 1942 bis etwa 1970, stellt eine einmalige Kombination histologischer Schnittserien menschlicher Embryonen und darauf aufbauender, großformatiger und öffentlich zugänglicher Modelle dar. Nicht nur erfolgte diese Sammlungsgründung für die Disziplin der Humanembryologie erstaunlich spät, sondern ist auch in einer zweiten Hinsicht bemerkenswert: Während an anderen Standorten Modelle primär als Forschungsobjekte verstanden wurden und mit einem Lehreinsatz eine Umnutzung stattfand, war für den Göttinger Embryologen Erich Blechschmidt (1904–1992) von Beginn an ein pädagogischer Impetus maßgeblich. Im Beitrag werden die eigenwilligen Merkmale der Blechschmidt’schen Unternehmung vor ihrem disziplinären Hintergrund herausgearbeitet. Der Schwerpunkt liegt dabei auf den beiden für die Humanembryologie zentralen Praktiken des Sammelns und Modellierens und den dadurch in Göttingen geschaffenen Objektbeständen. Diese waren schon im Entstehungsprozess von einem besonderen Spannungsverhältnis von Individualität und Universalität geprägt, das sich auch in der späteren Nutzung der Sammlung spiegelt. Diese führt durch eine spezifische Individualisierung zuvor anonym gemachter Präparate weit aus der ursprünglichen fachwissenschaftlich-anatomischen Bestimmung in die breite gesellschaftliche Debatte um den ethischen Status menschlicher Embryonen und den Schwangerschaftsabbruch.

Doxorubicin (DOX) is one of the most commonly used drugs for the treatment of childhood cancers, including leukemia and lymphomas. Despite the high survival rate, female leukemia survivors are at higher risk of ovarian failure and infertility later in life. Treatment with chemotherapeutic drugs like DOX is associated with damage in ovarian follicles, but the affectation grade of granulosa cells remains unclear. To assess and avoid the possible side-effects of DOX, early biomarkers of ovarian injury and chemotherapy-induced ovarian toxicity should be identified. MicroRNAs (miRNAs) have emerged in recent years as a promising new class of biomarkers for drug-induced tissue toxicity. In this study, the effects of DOX on cell viability, steroidogenesis, and miRNA expression were studied in primary granulosa cells (GCs) and in two cellular models (COV434 and KGN cells). We report that compared to other chemotherapeutic drugs, DOX treatment is more detrimental to granulosa cells as observed by decrease of cell viability. Treatment with DOX changes the expression of the aromatase gene (CYP19A1) and the secretion of 17β-estradiol (E2) in a cell-specific manner. miR-132-3p is dose-dependently increased by DOX in all cellular models. In absence of DOX, miR-132-3p overexpression in COV434 cells has no effect on E2 secretion or CYP19A1 expression. Altogether, these findings contribute to understanding the hormonal disbalance caused by DOX in human ovarian cells and suggest miR-132 as a putative sensor to predict DOX-induced ovarian toxicity.

Distress in oncology patients (pts) has a negative impact on quality of life, survival, and healthcare satisfaction. Higher distress leads to lower compliance with treatment and follow-up [1–8]. The 2012 American College of Surgeons Commission on Cancer (CoC) standard of care for oncology pts included an assessment for distress [1]. A screening process for distress allows the healthcare team to address these issues early and refer to appropriate resources [2–9]. This project was initiated to meet National Comprehensive Cancer Network (NCCN) and CoC standard of care, identify distress in veterans with cancer, and address these concerns. Patients who attended the Tuesday oncology clinic at the Dayton VAMC were given the NCCN Distress Thermometer (DT) during triage. The treating physician addressed problems identified. The Wilcoxon signed rank test and the Friedman test were used. DTs were completed by 296 pts from March to December 2016. Mean age was 68, 93% male, 83% white, 55% married, and 93% without PTSD. The distress level was not different from T1 through T3. Number of problems decreased over three time periods. Referrals to nutrition, mental health, and social work services increased over time. Although over time periods we found no decrease in distress scores, there was a decline in number of problems. The mean distress score at all but time 4 was

OBJECTIVE Recent studies have shown an increase of C-reactive-protein (CRP) after exposure to zinc- and copper-containing welding fumes. The objective of this study was to determine the effects of exposure to zinc- and copper-containing welding fumes on leukocytes, their subtypes, and myeloperoxidase (MPO). METHODS Serum samples of male volunteers were examined after exposures to welding fumes in two settings: repeated exposure on 4 consecutive days for 6 hours and single exposures for different times (3, 4, 5 hours). RESULTS Neutrophil granulocyte and MPO levels showed increases 24 hours after single and repeated exposures for 6 hours similar to CRP increases reported in literature. Overall leukocyte levels and levels of monocytes and lymphocytes were not significantly affected. CONCLUSIONS This study indicates the involvement of neutrophil granulocytes in welding fume fever additional to mediator related effects.

The Colloid Cyst Risk Score (CCRS) was devised to identify patients with symptomatic colloid cyst and stratify risk of hydrocephalus. The CCRS considers patient age, presence of headache, colloid cyst diameter, fluid-attenuated inversion recovery hyperintensity, and location within the third ventricle.The purpose of this study was to independently evaluate the validity of the CCRS.Patients with a colloid cyst of the third ventricle were identified retrospectively from institutional billing records and radiology report archives. Patients without a confirmed diagnosis of colloid cyst of the third ventricle or magnetic resonance imaging of the brain were excluded. Data were collected via retrospective chart review.One hundred and fifty-six patients met inclusion and exclusion criteria. In our cohort, the CCRS stratified symptomatic patients and patients with hydrocephalus across all scores (P0.001). From CCRS 2 to 5, the percentage of symptomatic patients increased from 13% to 100%, whereas the percentage of patients with hydrocephalus increased from 8% to 83%. Simple logistic regression showed that total CCRS, headache, axial diameter, fluid-attenuated inversion recovery hyperintensity, and risk zone were all highly predictive of symptomatic status and hydrocephalus (P0.001). Logistic regression with receiver operating curves for the CCRS showed an area under the curve of 0.914 for symptomatic colloid cysts and an area under the curve of 0.892 for colloid cysts with hydrocephalus.Our data analysis validates the predictive value of the CCRS for both symptomatic status and hydrocephalus and supports the use of the CCRS in risk stratification and clinical decision making.

Background In critical care settings, electroencephalography (EEG) with reduced number of electrodes (reduced montage EEG, rm-EEG) might be a timely alternative to the conventional full montage EEG (fm-EEG). However, past studies have reported variable accuracies for detecting seizures using rm-EEG. We hypothesized that the past studies did not distinguish between differences in sensitivity from differences in classification of EEG patterns by different readers. The goal of the present study was to revisit the diagnostic value of rm-EEG when confounding issues are accounted for. Methods We retrospectively collected 212 adult EEGs recorded at Massachusetts General Hospital and reviewed by two epileptologists with access to clinical, trending, and video information. In Phase I of the study, we re-configured the first 4 h of the EEGs in lateral circumferential montage with ten electrodes and asked new readers to interpret the EEGs without access to any other ancillary information. We compared their rating to the reading of hospital clinicians with access to ancillary information. In Phase II, we measured the accuracy of the same raters reading representative samples of the discordant EEGs in full and reduced configurations presented randomly by comparing their performance to majority consensus as the gold standard. Results Of the 95 EEGs without seizures in the selected fm-EEG, readers of rm-EEG identified 92 cases (97%) as having no seizure activity. Of 117 EEGs with “seizures” identified in the selected fm-EEG, none of the cases was labeled as normal on rm-EEG. Readers of rm-EEG reported pathological activity in 100% of cases, but labeled them as seizures (N = 77), rhythmic or periodic patterns (N = 24), epileptiform spikes (N = 7), or burst suppression (N = 6). When the same raters read representative epochs of the discordant EEG cases (N = 43) in both fm-EEG and rm-EEG configurations, we found high concordance (95%) and intra-rater agreement (93%) between fm-EEG and rm-EEG diagnoses. Conclusions Reduced EEG with ten electrodes in circumferential configuration preserves key features of the traditional EEG system. Discrepancies between rm-EEG and fm-EEG as reported in some of the past studies can be in part due to methodological factors such as choice of gold standard diagnosis, asymmetric access to ancillary clinical information, and inter-rater variability rather than detection failure of rm-EEG as a result of electrode reduction per se.

Currently, stem cell donor registries include more than 35 million potential donors worldwide to provide HLA‐matched stem cell products for patients in need of an unrelated donor transplant. DKMS is a leading stem cell donor registry with more than 9 million donors from Germany, Poland, the United States, the United Kingdom, India and Chile. DKMS donors have donated hematopoietic stem cells more than 80,000 times. Many aspects of donor registry work are closely related to topics from immunogenetics or population genetics. In this two‐part review article, we describe, analyse and discuss these areas of donor registry work by using the example of DKMS. Part 1 of the review gives a general overview on DKMS and includes typical donor registry activities with special focus on the HLA system: high‐throughput HLA typing of potential stem cell donors, HLA haplotype frequencies and resulting matching probabilities, and donor file optimization with regard to HLA diversity.

Human body donation and tissue collections are nowadays grounded on a legal framework centered around the concept of informed consent in most countries. Comparable regulations did not exist prior to the second half of the 20th century, when several of the most important collections of human embryos were established. As a particularly prominent example, the Human Embryology Collection (“Blechschmidt Collection”) at the Center of Anatomy, University Medical Center Göttingen, Germany, is described here with regard to how to approach a human specimen collection from the perspective of both collection ethics and the history of science. The methods and concepts used as well as the outcome in terms of historical and ethical knowledge will be discussed as a model for future projects of similar scope at other collection sites. It it also shown that general ethical recommendations published by museum and collection experts are of value only if they are related to profound knowledge about the history of the particular collection in focus.

BACKGROUND/PURPOSE: Metastatic hepatoblastoma continues to pose a significant treatment challenge, primarily because the precise mechanisms involved in metastasis are not fully understood, making cell lines and preclinical models that depict the progression of disease and metastasis-related biology paramount. We aimed to generate and characterize a metastatic hepatoblastoma cell line to create a model for investigation of the molecular mechanisms associated with metastasis. MATERIALS/METHODS: Using a murine model of serial tail vein injections of the human hepatoblastoma HuH6 cell line, non-invasive bioluminescence imaging, and dissociation of metastatic pulmonary lesions, we successfully established and characterized the metastatic human hepatoblastoma cell line, HLM_3. RESULTS: The HLM_3 cells exhibited enhanced tumorigenicity and invasiveness, both in vitro and in vivo compared to the parent HuH6 cell line. Moreover, HLM_3 metastatic hepatoblastoma cells exhibited a stem cell-like phenotype and were more resistant to the standard chemotherapeutic cisplatin. CONCLUSION: This newly described metastatic hepatoblastoma cell line offers a novel tool to study mechanisms of tumor metastasis and evaluate new therapeutic strategies for metastatic hepatoblastoma.

Background and aims Problematic pornography use can be conceptualized as an impulse control disorder or alternatively as a behavioral addiction. Stress is an important trigger in addiction, but less is known about the neural effect of stress in problematic pornography use. Therefore, we aimed at investigating the effect of stress during the anticipation and viewing of sexually explicit material while considering person characteristics related to potentially being at risk for developing problematic pornography use. Methods In an fMRI study (n = 157 men, age: mean = 25.46, SD = 4.11) we used a sexual incentive delay task. A social stress test was used to induce stress in half of the participants. Salivary cortisol was repeatedly measured and person characteristics were considered moderating the effects of cortisol response. Results We found no group differences in the neural responses during the anticipation phase, but a higher reactivity to sexual stimuli in the dACC in the stress group. Acute stress activated a pronounced cortisol response, which positively correlated with neural activations in the reward system (NAcc, dACC) to sexual cues. Further, the individual time spent on pornography use moderated the effect of cortisol in some regions of the reward system (dACC, mOFC). Discussion and conclusions Our results suggest that acute stress related increases in cortisol can enhance the incentive value of cues announcing sexual stimuli. This might explain why acute stress is considered a trigger of pornography use and relapse and why individual stress response might be a risk factor for developing a problematic pornography use.

Primary Central Nervous System Lymphoma (PCNSL) is an aggressive tumor that is confined to the CNS. Although the provision of high-dose methotrexate (HD-MTX) has remarkably improved outcomes in PCNSL patients, the optimal treatment regimens and standard MTX dose for induction therapy have been largely controversial. Herein, we sought to explore the impact of adjuvant rituximab and different dosages of induction HD-MTX on survival outcomes of immunocompetent patients with PCNSL.In this study, we examined patients with PCNSL treated at a single NCI-designated comprehensive cancer center to evaluate their survival outcomes. We conducted a retrospective analysis of 51 immunocompetent patients with PCNSL who received their induction chemotherapy at the University of Alabama at Birmingham (UAB) between 2001 and 2019. Only adult patients with a confirmed diagnosis of PCNSL who had either HD-MTX alone or in combination with rituximab were included. Patients' demographics, clinical characteristics, and survival data were collected and analyzed.There is no significant difference in survival among patients who received MTX alone versus MTX plus rituximab (HR = 0.996 (95% CI: 0.398-2.493), p = 0.994). Lower doses of MTX were associated with worse survival outcomes (HR = 0.680 (95% CI: 0.530-0.872), p = 0.002); however, this difference in survival was not significant when adjusted to age (HR = 0.797 (95% CI: 0.584-1.088), p = 0.153).Our experience challenges the role of rituximab in PCNSL during induction therapy. Our study also highlights the shorter survival in elderly patients with PCNSL which can be related, to some extent, to the relatively lower doses of HD-MTX. There is an unmet need to establish a consensus on the most effective upfront regimen in PCNSL through prospective studies.