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Abstract Objective: Patients on dialysis are at high risk for severe COVID-19 and associated morbidity and mortality. We examined the humoral response to SARS-CoV-2 mRNA vaccine BNT162b2 in a maintenance dialysis population. Design: Single-center cohort study. Setting and participants: Adult maintenance dialysis patients at 3 outpatient dialysis units of a large academic center. Methods: Participants were vaccinated with 2 doses of BNT162b2, 3 weeks apart. We assessed anti–SARS-CoV-2 spike antibodies (anti-S) ∼4–7 weeks after the second dose and evaluated risk factors associated with insufficient response. Definitions of antibody response are as follows: nonresponse (anti-S level,

Animal models have been extensively used as a gold standard in various biological research, including immunological studies. Despite high availability and ease of handling procedure, they inadequately represent complex interactions and unique cellular properties in humans due to inter-species genetic and microenvironmental differences which have resulted in clinical-stage failures. Organoid technology has gained enormous attention as they provide sophisticated insights about tissue architecture and functionality in miniaturized organs. In this review, we describe the use of organoid system to overcome limitations in animal-based investigations, such as physiological mismatch with humans, costly, time-consuming, and low throughput screening. Immune organoids are one of the specific advancements in organogenesis ex vivo, which can reflect human adaptive immunity with more physiologically relevant aspects. We discuss how immune organoids are established from patient-derived lymphoid tissues, as well as their characteristics and functional features to understand immune mechanisms and responses. Also, some bioengineering perspectives are considered for any potential progress of immuno-engineered organoids.

OBJECTIVES: The primary objective of this investigation was to determine the types and frequency of PIMs prescribed to geriatric patients at the Dental College of Georgia at Augusta University (DCG) while considering patients’ age groups and American Society of Anesthesiologists (ASA) physical status. The secondary objective was to determine the source of PIMs prescriptions based on the prescribers’ specialty and professional status. METHODS: The most recent Beers List and STOPP/START criteria were studied, and PIMs identified. A retrospective electronic chart review of patients at DCG aged 65 and above was performed for calendar years 2018, 2019, 2020, 2021 and 2022. Search queries were also generated for the patients’ medical history, along with PIMs prescribers’ specialty and professional status. RESULTS: Of 10675 geriatric patients identified, 6.2% (n=662) received PIMs prescriptions. Of those, 73.7% had an ASA III status. 77% received one PIM prescription, while others received between two to six. NSAIDs were the most commonly prescribed PIM (60.1% of patients), followed by opioids (32.5% of patients). A dramatic drop in prescribing NSAIDs was detected in recent years. Surprisingly, a similar pattern was not observed with opioids. Both NSAIDs and opioids were largely provided by oral-maxillofacial surgery (OMFS) followed by restorative dentistry and periodontics. Benzodiazepines were mostly prescribed by endodontics, while tricyclic antidepressants (TCAs), muscle relaxants and anticonvulsants were most commonly prescribed by oral medicine. Residents prescribed opioids at similar rates to faculty (p=0.78), but exceeded faculty in prescribing benzodiazepines (p

Intravascular Lithotripsy (IVL) is a relatively modern endovascular tool accepted for use to address vascular calcification in the iliac arterial system and below. This case study shows evidence of successful application of IVL followed by stent placement to calcific disease present within the aorta as well. A 78-year-old female with numerous comorbidities and a history of an aorto right femoral left iliac bypass graft in 1998 presented with severe lifestyle limiting claudication secondary to high-grade atherosclerotic stenosis of her infrarenal abdominal aorta at the level of the proximal anastomosis of her bypass graft. Initial ABIs were 0.54 and 0.55 on the right and left respectively. Initially the operative plan was to conduct a retroperitoneal aortic endarterectomy. However, after the surgical optimization center deemed the patient intermediate risk and her pulmonary function decreased prior to the procedure, the decision was made to proceed with IVL followed by angioplasty and aortic stent placement. The patient tolerated the procedure well without complication and she was discharged home the following day. At follow up appointment 6 weeks later, the patient's repeat ABIs were significantly improved to 0.77 in the right and 0.86 in the left with a coinciding improvement in symptoms. In conclusion, IVL is safe and effective in calcific aortic disease and should be considered in patients who are not optimal open surgical candidates.

Pulmonary hypertension (PH) is a progressive disease marked by pulmonary vascular remodeling and right ventricular failure. Inflammation and oxidative stress are critical in PH pathogenesis, with early pulmonary vascular inflammation preceding vascular remodeling. Extracellular superoxide dismutase (EC-SOD), a key vascular antioxidant enzyme, mitigates oxidative stress and protects against inflammation and fibrosis in diverse lung and vascular disease models. This study utilizes a murine hypobaric hypoxia model to investigate the role of lung EC-SOD on hypoxia-induced platelet activation and platelet lung accumulation, a critical factor in PH-related inflammation. We found that lung EC-SOD overexpression blocked hypoxia-induced platelet activation and platelet accumulation in the lung. Though lung EC-SOD overexpression increased lung EC-SOD content, it did not impact plasma extracellular SOD activity. However, ex vivo, exogenous extracellular SOD treatment specifically blunted convulxin-induced platelet activation but did not blunt platelet activation with thrombin or ADP. Our data identify platelets as a novel target of EC-SOD in response to hypoxia, providing a foundation to advance the understanding of dysregulated redox signaling and platelet activation in PH and other chronic hypoxic lung diseases.

Introduction: Imaging surveillance of contrast-enhancing lesions after the treatment of malignant brain tumors with radiation is plagued by an inability to reliably distinguish between tumor recurrence and treatment effects. Magnetic resonance perfusion-weighted imaging (PWI)—among other advanced brain tumor imaging modalities—is a useful adjunctive tool for distinguishing between these two entities but can be clinically unreliable, leading to the need for tissue sampling to confirm diagnosis. This may be partially because clinical PWI interpretation is non-standardized and no grading criteria are used for assessment, leading to interpretation discrepancies. This variance in the interpretation of PWI and its subsequent effect on the predictive value has not been studied. Our objective is to propose structured perfusion scoring criteria and determine their effect on the clinical value of PWI. Methods: Patients treated at a single institution between 2012 and 2022 who had prior irradiated malignant brain tumors and subsequent progression of contrast-enhancing lesions determined by PWI were retrospectively studied from CTORE (CNS Tumor Outcomes Registry at Emory). PWI was given two separate qualitative scores (high, intermediate, or low perfusion). The first (control) was assigned by a neuroradiologist in the radiology report in the course of interpretation with no additional instruction. The second (experimental) was assigned by a neuroradiologist with additional experience in brain tumor interpretation using a novel perfusion scoring rubric. The perfusion assessments were divided into three categories, each directly corresponding to the pathology-reported classification of residual tumor content. The interpretation accuracy in predicting the true tumor percentage, our primary outcome, was assessed through Chi-squared analysis, and inter-rater reliability was assessed using Cohen’s Kappa. Results: Our 55-patient cohort had a mean age of 53.5 ± 12.2 years. The percentage agreement between the two scores was 57.4% (κ: 0.271). Upon conducting the Chi-squared analysis, we found an association with the experimental group reads (p-value: 0.014) but no association with the control group reads (p-value: 0.734) in predicting tumor recurrence versus treatment effects. Conclusions: With our study, we showed that having an objective perfusion scoring rubric aids in improved PWI interpretation. Although PWI is a powerful tool for CNS lesion diagnosis, methodological radiology evaluation greatly improves the accurate assessment and characterization of tumor recurrence versus treatment effects by all neuroradiologists. Further work should focus on standardizing and validating scoring rubrics for PWI evaluation in tumor patients to improve diagnostic accuracy.

The progress and development of science and technology that humans sometimes achieve cannot be separated from human exploration of the universe and its contents. The reason is that science and technology seek sources of knowledge from nature. And Islam, the religion sent down by Allah, which calls on humans to explore and experiment with nature, was one of the factors in this progress. Through the integration of faith and science and technology, it is hoped that various weaknesses and setbacks of Muslims can be corrected, so that they can again feel the progress and glory achieved by Muslims in classical times. This will also affect Islamic education which is expected to survive the rapid development of science and technology in this century. This research uses the library method or library research. The collection of data from this research comes from reading sources related to this discussion. The results of the research is synthesis or a combination of religion and science is the unification of human understanding, both of which are a unity of truth. Both come from the Almighty, namely Allah SWT. Both work side by side to fill human life.

We propose a multiphase modeling approach to describe glioma pseudopalisade patterning under the influence of acidosis. The phases considered at the model onset are glioma, normal tissue, necrotic matter, and interstitial fluid in a void-free volume with acidity represented by proton concentration. We start from mass and momentum balance to characterize the respective volume fractions and deduce reaction-cross diffusion equations for the space-time evolution of glioma, normal tissue, and necrosis. These are supplemented with a reaction-diffusion equation for the acidity dynamics and lead to formation of patterns which are typical for high grade gliomas. Unlike previous works, our deduction also works in higher dimensions and involves less restrictions. We also investigate the existence of weak solutions to the obtained system of equations and perform numerical simulations to illustrate the solution behavior and the pattern occurrence.

The use of nanoparticle systems for the controlled release of growth factors is a promising approach to mimicking of the biochemical environment of native tissues in tissue engineering. However, sustaining growth factor release inside an appropriate therapeutic window is a challenge, particularly in bioprinted scaffolds. In this study, a chitosan-coated alginate-based nanoparticle system loaded with hepatocyte growth factor was developed and then incorporated into bioprinted scaffolds. The release kinetics were investigated with a focus on identifying the impact of the chitosan coating and culture conditions. Our results demonstrated that the chitosan coating decreased the release rate and lessened the initial burst release, while culturing in dynamic conditions had no significant impact compared to static conditions. The nanoparticles were then incorporated into bioinks at various concentrations, and scaffolds with a three-dimensional (3D) structure were bioprinted from the bioinks containing human pulmonary fibroblasts and bronchial epithelial cells to investigate the potential use of a controlled release system in respiratory tissue engineering. It was found that the bioink loaded with a concentration of 4 µg/mL of nanoparticles had better printability compared to other concentrations, while the mechanical stability of the scaffolds was maintained over a 14-day culture period. The examination of the incorporated cells demonstrated a high degree of viability and proliferation with visualization of the beginning of an epithelial barrier layer. Taken together, this study demonstrates that a chitosan-coated alginate-based nanoparticle system allows the sustained release of growth factors in bioprinted respiratory tissue scaffolds.

Electronic nicotine delivery systems (ENDSs) are designed as a non-combustible alternative to cigarettes, aiming to deliver nicotine without the harmful byproducts of tobacco combustion. As the category evolves and new ENDS products emerge, it is important to continually assess the levels of toxicologically relevant chemicals in the aerosols and characterize any related toxicology. Herein, we present a proposed framework for characterizing novel ENDS products (i.e., devices and formulations) and determining the reduced risk potential utilizing analytical chemistry and in vitro toxicological studies with a qualitative risk assessment. To demonstrate this proposed framework, long-term stability studies (12 months) analyzing relevant toxicant emissions from six formulations of a next-generation product, JUUL2, were conducted and compared to reference combustible cigarette (CC) smoke under both non-intense and intense puffing regimes. In addition, in vitro cytotoxicity, mutagenicity, and genotoxicity assays were conducted on aerosol and smoke condensates. In all samples, relevant toxicants under both non-intense and intense puffing regimes were substantially lower than those observed in reference CC smoke. Furthermore, neither cytotoxicity, mutagenicity, nor genotoxicity was observed in aerosol condensates generated under both intense and non-intense puffing regimes, in contrast to results observed for reference cigarettes. Following the proposed framework, the results demonstrate that the ENDS products studied in this work generate significantly lower levels of toxicants relative to reference cigarettes and were not cytotoxic, mutagenic, or genotoxic under these in vitro assay conditions.

Abstract Acute respiratory distress syndrome is a heterogeneous pathophysiological process responsible for significant morbidity and mortality in pediatric intensive care patients. Diagnosis is defined by clinical characteristics that identify the syndrome after development. Subphenotyping patients at risk of progression to ARDS could provide the opportunity for therapeutic intervention. microRNAs, non-coding RNAs stable in circulation, are a promising biomarker candidate. We conducted a single-center prospective cohort study to evaluate random forest classification of microarray-quantified circulating microRNAs in critically ill pediatric patients. We additionally selected a sub-cohort for parallel metabolomics profiling as a pilot study for concurrent use of miRNAs and metabolites as circulating biomarkers. In 35 patients (n = 21 acute respiratory distress, n = 14 control) 15 microRNAs were differentially expressed. Unsupervised random forest classification accurately grouped ARDS and control patients with an area under the curve of 0.762, which was improved to 0.839 when subset to only patients with bacterial infection. Nine metabolites were differentially abundant between acute respiratory distress and control patients (n = 4, both groups) and abundance was highly correlated with miRNA expression. Random forest classification of microRNAs differentiated critically ill pediatric patients who developed acute respiratory distress relative to those who do not. The differential expression of microRNAs and metabolites provides a strong foundation for further work to validate their use as a prognostic biomarker.

UMKM memiliki keunggulan yakni cepat beradaptasi karena struktur organisasi dan pengelolaannya secara sederhana. Akan tetapi, UMKM seringkali terkendala dengan keterbatasan modal dan pengetahuan. Salah satu sentra kuliner yang cukup berkembang di Surabaya adalah Sentra Wisata Kuliner Wiyung yang berlokasi di Jalan Wiyung Pondok Indah masih banyak permasalahan yang dihadapi oleh para pedagang UMKM di Sentra Wisata Kuliner Wiyung. Akar masalah yang diidentifikasi adalah lambatnya adopsi digitalisasi di kalangan pedagang UMKM di Sentra Wisata Kuliner Wiyung. Berdasarkan akar permasalahan tersebut kami mengidentifikasi adanya dua masalah utama yakni masalah kemampuan digitalisasi pemasaran dan digitalisasi di bidang keuangan. Guna mengatasi permasalahan ini maka melalui program insentif Pengabdian masyarakat Terintegrasi dengan mbkm Berbasis kinerja IKU bagi PTS Tahun 2022 maka dibuat kegiatan akselerasi digitalisasi yang dibagi kedalam tiga kegiatan utama. Pertama, dengan kegiatan talk show dari para narasumber pelaku digital marketing dan content creator youtube di bidang kuliner untuk memberikan insight tentang bagaimana dalam mengemas produk dan jasa pada usaha kuliner agar menarik bagi calon konsumen dan mempertahankan standar mutu. Kedua, workshop tentang pelatihan Google Business dan QRIS untuk membantu digitalisasi dalam marketing dan keuangan.

More than 3 million Australians are estimated to have migraine disorders, and over a quarter of a million Australians are estimated to have medication overuse headache (MOH). The personal, societal and economic burden of MOH is high. MOH impacts an individual’s ability to work or study, care for family or themselves, culminating in poor quality of life. Accurate and timely diagnosis and treatment of MOH are imperative. Withdrawal failures and relapse rates are high in MOH.Treatment of MOH is aimed at ceasing medication overuse and reducing monthly migraine days with the aim of achieving a pattern of well-controlled episodic migraine. Current treatment approaches in routine practice include withdrawal with preventive treatment, withdrawal with optional preventive treatment in the subsequent weeks and preventive treatment without withdrawal. This viewpoint article provides an overview of managing MOH in Australian clinical practice, with a focus on the importance of patient education and the role of preventive treatment in supporting patients as they withdraw from acute migraine medication(s).

Abstract Rosai‐Dorfman disease (RDD) is a proliferative disorder of histiocytes typically found in nodal sites and commonly observed in females. Patients often present with systemic symptoms such as fever, lymphadenopathy, and weight loss. However, extra‐nodal disease has been identified in locations including the skin and subcutaneous tissue. We present a case of a 59‐year‐old female presenting with abnormal bilateral findings on screening mammography, who was found to have a rare presentation of Rosai‐Dorfman disease.

Glioblastoma (GBM) is one of the most common primary brain tumours in adults, with a dismal prognosis despite aggressive multimodality treatment by a combination of surgery and adjuvant radiochemotherapy. A detailed knowledge of the spreading of glioma cells in the brain might allow for more targeted escalated radiotherapy, aiming to reduce locoregional relapse. Recent years have seen the development of a large variety of mathematical modelling approaches to predict glioma migration.The aim of this study is hence to evaluate the clinical applicability of a detailed micro- and meso-scale mathematical model in radiotherapy. First and foremost, a clinical workflow is established, in which the tumour is automatically segmented as input data and then followed in time mathematically based on the diffusion tensor imaging data. The influence of several free model parameters is individually evaluated, then the full model is retrospectively validated for a collective of 3 GBM patients treated at our institution by varying the most important model parameters to achieve optimum agreement with the tumour development during follow-up. Agreement of the model predictions with the real tumour growth as defined by manual contouring based on the follow-up MRI images is analyzed using the dice coefficient.The tumour evolution over 103-212 days follow-up could be predicted by the model with a dice coefficient better than 60% for all three patients. In all cases, the final tumour volume was overestimated by the model by a factor between 1.05 and 1.47.To evaluate the quality of the agreement between the model predictions and the ground truth, we must keep in mind that our gold standard relies on a single observer's (CB) manually-delineated tumour contours. We therefore decided to add a short validation of the stability and reliability of these contours by an inter-observer analysis including three other experienced radiation oncologists from our department. In total, a dice coefficient between 63% and 89% is achieved between the four different observers. Compared with this value, the model predictions (62-66%) perform reasonably well, given the fact that these tumour volumes were created based on the pre-operative segmentation and DTI.

Acute lung injury (ALI) is a severe form of lung inflammation causing acute respiratory distress syndrome in patients. ALI pathogenesis is closely linked to uncontrolled alveolar inflammation. We hypothesize that specific enzymes of the glycolytic pathway could function as key regulators of alveolar inflammation. Therefore, we screened isolated alveolar epithelia from mice exposed to ALI induced by injurious ventilation to assess their metabolic responses. These studies pointed us toward a selective role for isoform 3 of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). Pharmacologic inhibition or genetic deletion of Pfkfb3 in alveolar epithelia (Pfkfb3loxP/loxP SPC-ER-Cre+ mice) was associated with profound increases in ALI during injurious mechanical ventilation or acid instillation. Studies in genetic models linked Pfkfb3 expression and function to Hif1a. Not only did intratracheal pyruvate instillation reconstitute Pfkfb3loxP/loxP or Hif1aloxP/loxP SPC-ER-Cre+ mice, but pyruvate was also effective in ALI treatment of wild-type mice. Finally, proof-of-principle studies in human lung biopsies demonstrated increased PFKFB3 staining in injured lungs and colocalized PFKFB3 to alveolar epithelia. These studies reveal a specific role for PFKFB3 in counterbalancing alveolar inflammation and lay the groundwork for novel metabolic therapeutic approaches during ALI.

Acute respiratory distress syndrome (ARDS) has approximately 40% in-hospital mortality, and treatment is limited to supportive care. Pneumonia is the underlying etiology in many cases with unrestrained inflammation central to the pathophysiology. We have previously shown that CNP-miR146a, a radical scavenging cerium oxide nanoparticle (CNP) conjugated to the anti-inflammatory microRNA(miR)-146a, reduces bleomycin- and endotoxin-induced acute lung injury (ALI) by decreasing inflammation. We therefore hypothesized that CNP-miR146a would decrease inflammation in murine infectious ALI. Mice were injured with intratracheal (IT) MRSA or saline followed by treatment with IT CNP-miR146a or saline control. Twenty-four hours post-infection, bronchoalveolar lavage fluid (BALF) and whole lungs were analyzed for various markers of inflammation. Compared to controls, MRSA infection significantly increased proinflammatory gene expression (IL-6, IL-8, TNFα, IL-1β; p < 0.05), BALF proinflammatory cytokines (IL-6, IL-8, TNFα, IL-1β; p < 0.01), and inflammatory cell infiltrate (p = 0.03). CNP-miR146a treatment significantly decreased proinflammatory gene expression (IL-6, IL-8, TNFα, IL-1β; p < 0.05), bronchoalveolar proinflammatory protein leak (IL-6, IL-8, TNFα; p < 0.05), and inflammatory infiltrate (p = 0.01). CNP-miR146a decreases inflammation and improves alveolar–capillary barrier integrity in the MRSA-infected lung and has significant promise as a potential therapeutic for ARDS.

The aim of this work was to scrutinize the physiochemical properties of a new pyridazin-3(2H)-one derivative with potential pharmaceutical effectiveness via density functional theory (DFT) and molecular docking analysis. The compound 2-(2-(4-fluorophenyl)-2-oxoethyl)-6-methyl-5-(4-methylbenzyl)pyridazin-3(2H)-one (FOMMP) was synthesized and characterized by FT-IR, UV-Vis, 1H-NMR, 13C-NMR, ESI-MS, and single-crystal XRD analysis. In addition, the geometrical structure of the molecule was analyzed. Frontier molecular orbital (FMO) analysis showed a low energy gap that suggests the chemical reactivity of the title compound. The electrophilicity index (ω) points towards the probable biological activity of FOMMP. The molecular electrostatic potential (MEP) was used to assess the local reactivity properties and suggests that the nitrogen atom sites are electronegative. Computational and experimental UV-spectral analyses were performed to attain the bandgap associated with electronic transitions while the charge transfer length helped us determine that the excitation mode associated with the electronic transitions is long-ranged. Natural hybrid orbital (NHO) and natural bond orbital (NBO) analyses depicted the prominent acceptor-donor interactions in terms of the stabilization energies. Hirshfeld surface analysis was performed to analyze the intermolecular interactions in the crystal structure. In addition, a molecular docking study was executed to evaluate the potential of the protease inhibitors (PIs) against SARS-CoV-2.

ABSTRACT Background Colorectal cancer (CRC) treatment and patient survival improved greatly. Consequently an increased incidence of non‐cancer‐related deaths is observed. This study analyzed the causes of non‐cancer death for people suffering from CRC based on the year of diagnosis, follow‐up time, and patient's age. Methods The data from patients diagnosed with CRC in the years 2000–2016 were taken from the Surveillance, Epidemiology, and End Results 18 database. Patients were categorized according to: death from CRC, non‐CRC cancer, and non‐cancer. Constituent ratios and standardized mortality ratios (SMRs) were calculated to describe the death causes distribution and relative death risks. Results Between 2000 and 2016, a stable and rapid drop for the original diagnosis as death cause for CRC patients was observed (70.19% to 49.35%). This was coupled to an increase in non‐cancer‐associated death reasons (23.38% to 40.00%). The most common non‐cancer death cause was heart disease, especially for elderly patients. However, deaths from accidents and adverse effects were frequent in younger CRC patients. Patients died from septicemia more often within the first follow‐up year; however, a 6‐fold increase in death from Alzheimer's disease was found for after at least 180 months follow‐up time. The SMRs of all 25 non‐cancer death causes initially decreased in all CRC subgroups, followed by an increase with follow‐up times. Gradually decreasing SMR values were observed with increasing age of CRC patients. Conclusions These findings could help modify and sharpen preventive measures and clinical management and raise physician's awareness to potential non‐CRC death risk factors for CRC patients.

Abstract Background End-stage renal disease (ESRD) patients receiving haemodialysis (HD) are a vulnerable group of patients with increased mortality from COVID-19. Despite improved understanding, the duration of host immunity following COVID-19 infection and role of serological testing alone or in addition to real-time reverse transcription polymerase chain reaction (rRT-PCR) testing in the HD population is not fully understood, which this study aimed to investigate. Methods There were two parts to this study. Between 15th March 2020 to 15th July 2020, patients receiving HD who tested positive on rRT-PCR for SARS-CoV-2 were recruited into the COVID-19 arm, whilst asymptomatic patients without a previous diagnosis of COVID-19 were recruited to the epidemiological arm of the Salford Kidney Study (SKS). All patients underwent monthly testing for anti-SARS-CoV-2 antibodies as per routine clinical practice since August 2020. The aims were twofold: firstly, to determine seroprevalence and COVID-19 exposure in the epidemiological arm; secondly, to assess duration of the antibody response in the COVID-19 arm. Baseline characteristics were reviewed between groups. Statistical analysis was performed using SPSS. Mann-Whitney U and Chi-squared tests were used for testing significance of difference between groups. Results In our total HD population of 411 patients, 32 were PCR-positive for COVID-19. Of the remaining patients, 237 were recruited into the SKS study, of whom 12 (5.1%) had detectable anti-SARS-CoV-2 antibodies. Of the 32 PCR-positive patients, 27 (84.4%) were symptomatic and 25 patients admitted to hospital due to their symptoms. Of the 22 patients in COVID-19 arm that underwent testing for anti-SARS-CoV-2 IgG antibodies beyond 7 months, all had detectable antibodies. A higher proportion of the patients with COVID-19 were frail compared to patients without a diagnosis of COVID-19 (64.3% vs 34.1%, p = 0.003). Other characteristics were similar between the groups. Over a median follow up of 7 months, a higher number of deaths were recorded in patients with a diagnosis of COVID-19 compared to those without (18.7% vs 5.9%, p = 0.003). Conclusions Serological testing in the HD population is a valuable tool to determine seroprevalence, monitor exposure, and guide improvements for infection prevention and control (IPC) measures to help prevent local outbreaks. This study revealed HD patients mount a humoral response detectable until at least 7 months after COVID-19 infection and provides hope of similar protection with the vaccines recently approved.

Abstract Background Migraine affects 80.8 million people in Western Europe and is the first cause of disability among people between ages 15 and 49 worldwide. Despite being a highly prevalent and disabling condition, migraine remains under-diagnosed and poorly managed. Methods An international, online survey was conducted among 201 general practitioners (GPs) from 5 European countries (France, Germany, Italy, Spain and the UK) who are experienced in the management of headache disorders. Results The majority of GPs (82%) did not refer patients with chronic migraine (CM) to migraine specialists. Among those patients, the participants estimated that around 55% received preventive medication. Some differences between countries were observed regarding referral rate and prescription of preventive treatment. Most GPs (87%) reported a lack of training or the need to be updated on CM management. Accordingly, 95% of GPs considered that a migraine anamnesis guide could be of use. Overall, more than 95% of GPs favoured the use of a patient diary, a validated diagnostic tool and a validated scale to assess impact of migraine on patients’ daily life. Similarly, 96% of the GPs considered that the inclusion of warning features (red flags) in an anamnesis guide would be useful and 90% favoured inclusion of referral recommendations. Conclusions The results from this survey indicate that more education on diagnosis and management of CM is needed in primary care. Better knowledge on the recognition and management of migraine in primary care would improve both prognosis and diagnosis and reduce impact of migraine on patients’ lives, healthcare utilization and societal burden.

Abstract Background Migraine is a prevalent and disabling headache disorder that affects more than 1.04 billion individuals world-wide. It can result in reduction in quality of life, increased disability, and high socio-economic burden. Nevertheless, and despite the availability of evidence-based national and international guidelines, the management of migraine patients often remains suboptimal, especially for chronic migraine (CM) patients. Methods My-LIFE anamnesis project surveyed 201 General practitioners (GPs) from 5 European countries (France, Germany, Italy, Spain, and the UK) with the aim of understanding chronic migraine (CM) patients’ management in the primary care setting. Results In our survey, GPs diagnosed episodic migraine (EM) more often than CM (87% vs 61%, p

Recent increases in SARS-CoV-2 infections have led to questions about duration and quality of vaccine-induced immune protection. While numerous studies have been published on immune responses triggered by vaccination, these often focus on studying the impact of one or two immunisation schemes within subpopulations such as immunocompromised individuals or healthcare workers. To provide information on the duration and quality of vaccine-induced immune responses against SARS-CoV-2, we analyzed antibody titres against various SARS-CoV-2 antigens and ACE2 binding inhibition against SARS-CoV-2 wild-type and variants of concern in samples from a large German population-based seroprevalence study (MuSPAD) who had received all currently available immunisation schemes. We found that homologous mRNA-based or heterologous prime-boost vaccination produced significantly higher antibody responses than vector-based homologous vaccination. Ad26.CoV2S.2 performance was particularly concerning with reduced titres and 91.7% of samples classified as non-responsive for ACE2 binding inhibition, suggesting that recipients require a booster mRNA vaccination. While mRNA vaccination induced a higher ratio of RBD- and S1-targeting antibodies, vector-based vaccines resulted in an increased proportion of S2-targeting antibodies. Given the role of RBD- and S1-specific antibodies in neutralizing SARS-CoV-2, their relative over-representation after mRNA vaccination may explain why these vaccines have increased efficacy compared to vector-based formulations. Previously infected individuals had a robust immune response once vaccinated, regardless of which vaccine they received, which could aid future dose allocation should shortages arise for certain manufacturers. Overall, both titres and ACE2 binding inhibition peaked approximately 28 days post-second vaccination and then decreased.

CONTEXT Little research exists to determine if medical students experience symptoms of depression after examinations and if symptoms vary by gender. OBJECTIVES Determine if is there a difference between male and female medical students in the number of symptoms of major depressive disorder (MDD) experienced after exams, as well as which coping strategies are used by students to alleviate depression symptoms. METHODS An anonymous and secure survey was sent via university email to first, second, and third-year medical students after exams for 2 consecutive exam periods. Surveys that were not fully completed were excluded from the analysis. RESULTS A total of 162 out of 550 students completed the survey for a response rate of 30%. Overall, a greater proportion of female students experienced more symptoms of depression compared to males. This was statistically significant for the Diagnostic and Statistical Manual of Mental Disorders 5th Edition symptoms of MDD: depressed mood, anhedonia, changes in sleep, fatigue, and difficulty with concentration after exams compared to their male counterparts. Male first-year medical students experienced higher rates of depression compared to their third-year counterparts. Most students exhibited coping strategies that helped them feel less depressed. The 3 most common coping strategies reported were: reaching out to social support networks, physical activity/exercise, and engaging in hobbies. CONCLUSIONS Both gender and year in a medical school play a role in the number of symptoms of depression experienced after medical school exams. Recognizing that examinations can be a trigger of depressive symptoms in medical students, particularly female and first-year students, has important implications on student mental health. Helping students recognize these symptoms and employ healthy coping strategies may further help alleviate these symptoms. Long-term consequences of experiencing symptoms of depression after recurrent exams in medical school are unknown and require further research.

Objective Current research indicates that weakness of glucose metabolism plays an important role in silencing of invasiveness and growth of hypoxic tumors such as GBM. Moreover, there are indications that DXM, frequently used in treatment, may support GBM energy metabolism and provoke its recurrence. Methods We carried out in vitro experiments on the commercial T98G cell line and two primary GBM lines (HROG02, HROG17) treated with TMZ and/or DXM in physiological oxygen conditions for GBM (2.5% oxygen) and for comparison, in standard laboratory conditions (20% oxygen). The influence of different glucose levels on selected malignancy features of GBM cells-cellular viability and division, dynamic of cell culture changes, colony formation and concentration of InsR have been elevated. Results Under 2.5% oxygen and high glucose concentration, an attenuated cytotoxic effect of TMZ and intensification of malignancy features in all glioblastoma cell lines exposed to DXM was seen. Furthermore, preliminary retrospective analysis to assess the correlation between serum glucose levels and Ki-67 expression in surgical specimens derived from patients with GBM (IV) treated with radio-chemotherapy and prophylactic DXM therapy was performed. Conclusion The data suggest a link between the in vitro study results and clinical data. High glucose can influence on GBM progression through the promotion of the following parameters: cell viability, dispersal, InsR expression and cell proliferation (Ki-67). However, this problem needs more studies and explain the mechanism of action studied drugs.

Recent recession of the Larsen Ice Shelf C has revealed that microbial alteration of illite can occur within marine sediments, a process previously thought to only occur abiotically during low-grade metamorphism. Here, the authors show that such microbial alteration of illite could provide a potential source of Fe release to Southern Ocean waters during Holocene glacial cycles.

Background: In rural Tanzania, women and girls disproportionately bear the burden of water scarcity. Gendered social norms on the acceptability of women’s participation in the public sphere limit their decision-making power within local water governance structures. The UPWARD (Uplifting Women’s Participation in Water-Related Decision-Making) intervention sought to understand how a community-based gendered social norms approach using organized diffusion can lead to changes in the gendered social norms impacting women's participation in water-related governance structures.Methods: As part of WARIDI, a 5-years integrated water resource management (IWRM) program, a gendered-social norms change (GSNC) activity (UPWARD: Uplifting Women’s Participation in Water-Related Decision-Making) was implemented in two villages in Iringa and Kilombero districts. Encouraging organized diffusion, UPWARD promoted gender-equitable norms among a critical mass of community members. WARIDI identified and trained a Community Facilitation Team (CFT) of three women and men to lead a series of education and empowerment sessions in two communities. The intervention reached >300 individuals directly (∼10% of total village population). Changes in social norms were assessed through social norms analysis plots (SNAP) delivered in focus group discussions (FGDs) of 8–12 participants.Results: At baseline, most participants reported that women’s involvement in water-related decision-making was restricted to household decisions. Men viewed themselves as primary decision-makers in water governance. Women who spoke in village meetings experienced sanctions for disrespect and outspokenness; their husbands were teased for being “controlled.” At endline, participants reported fewer instances of ridicule towards women’s participation. Women expressed a greater sense of solidarity with each other; men reported greater respect for men whose wives contribute. The intervention’s effects appeared more pronounced in areas with greater cultural heterogeneity, suggesting norm change may be harder to affect where norms are tighter.Conclusion: UPWARD provides evidence that gendered social norms change programs can have identifiable impacts on women’s participation in water-related decision-making over a short time. While other interventions have used larger, multi-level strategies to affect gender norms, UPWARD has shown that community mobilization with brief (∼4 months) but concentrated engagement with communities can promote changes in social norms that persist at least 6 months after intervention’s end.

Abstract Signatory countries to the Convention on Biological Diversity (CBD) are formulating goals and indicators through 2050 under the post‐2020 Global Biodiversity Framework (GBF). Among the goals is increasing the integrity of ecosystems. The CBD is now seeking input toward a quantifiable definition of integrity and methods to track it globally. Here, we offer a schema for using Earth observations (EO) to monitor and evaluate global forest ecosystem integrity (EI). Our approach builds on three topics: the concept of EI, the use of satellite‐based EO, and the use of “essential biodiversity variables” to monitor and report on it. Within this schema, EI is a measure of the structure, function, and composition of an ecosystem relative to the range of variation determined by climatic–geophysical environment. We use evaluation criteria to recommend eight potential indicators of EI that can be monitored around the globe using Earth Observations to support the efforts of nations to monitor and report progress to implement the post‐2020 GBF. If operationalized, this schema should help Parties to the CBD take action and report progress on achieving ecosystem commitments during this decade.

Background: If the diagnosis of neuroendocrine neoplasm (NEN) increases the risk of patients to commit suicide has not been investigated so far. Identifying NEN patients at risk to commit suicide is important to increase their life quality and life expectancy.Methods and findings: Cancer cases were extracted from the Surveillance, Epidemiology, and End Results program and were divided into the NEN and the non-NEN cohorts. Subsequently, the NEN patients were randomly split into a training data set and a validation data set. Analyzing the training data set, we developed a score for assessing the risk to commit suicide for patients with NEN. In addition, we validated the score using the validation data set and evaluated, if this score could also be applied to other cancer entities by using the test data set, a non-NEN cohort. The odds ratio (OR) of suicide between NEN and non-NEN patients was determined. Moreover, the performance of a score was evaluated by the receiver operating characteristic curve and the area under the curve (AUC). Compared to non-NEN, NEN significantly increased the risk of suicide to 1.8-fold (NEN vs. non-NEN; OR, 1.832; P < 0.001). In addition, we observed that age, gender, race, marital status, tumor stage, histologic grade, surgery, and chemotherapy were associated with suicide among NEN patients; and a synthesized score based on these factors could significantly distinguish suicide individuals from non-suicide individuals in the training data set (AUC, 0.829; P < 0.001) and in the validation data set (AUC, 0.735; P < 0.001). This score also had a good performance when it was assessed by the test data set (AUC, 0.690; P < 0.001). This demonstrates that the score might also be applicable to other cancer entities.Conclusions: This population-based study suggests that NEN patients have a higher risk of suicide than non-NEN patients. In addition, this study provided a score, which can identify NEN patients at high-risk of committing suicide. Thus, this score in combination with current screening and prevention strategies for suicide may improve life quality and life expectancy of NEN patients.

Exudative epidermitis (EE), also known as greasy pig disease, is one of the most frequent skin diseases affecting piglets. Zoonotic infections in human occur. EE is primarily caused by virulent strains of Staphylococcus (S.) hyicus. Generally, antibiotic treatment of this pathogen is prone to decreasing success, due to the incremental development of multiple resistances of bacteria against antibiotics. Once approved, bacteriophages might offer interesting alternatives for environmental sanitation or individualized treatment, subject to the absence of virulence and antimicrobial resistance genes. However, genetic characterization of bacteriophages for S. hyicus has, so far, been missing. Therefore, we investigated a piglet raising farm with a stock problem due to EE. We isolated eleven phages from the environment and wash water of piglets diagnosed with the causative agent of EE, i.e., S. hyicus. The phages were morphologically characterized by electron microscopy, where they appeared Siphoviridae-like. The genomes of two phages were sequenced on a MiSeq instrument (Illumina), resulting in the identification of a new virulent phage, PITT-1 (PMBT8), and a temperate phage, PITT-5 (PMBT9). Sequencing of three host bacteria (S. hyicus) from one single farm revealed the presence of two different strains with genes coding for two different exfoliative toxin genes, i.e., exhA (2 strains) and exhC (1 strain). The exhC-positive S. hyicus strain was only weakly lysed by most lytic phages. The occurrence of different virulent S. hyicus strains in the same outbreak limits the prospects for successful phage treatment and argues for the simultaneous use of multiple and different phages attacking the same host.

Abstract Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern. The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms. Median survival is less than 10 years. Recently, pathogenic mutations in CSF1R were reported in a clinically and histologically similar leukoencephalopathy segregating in several families. Still, the cause of HDLS-S remained elusive since its initial description in 1984, with no CSF1R mutations identified in the family. Here we update the original findings associated with HDLS-S after a systematic and recent assessment of several family members. We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease. The variant affects an amino acid located in the aminoacylation domain of the protein and does not cause differences in splicing or expression in the brain. Brain pathology in one case after 10 years of disease duration showed the end stage of the disease to be characterized by widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front. These results point to AARS as a candidate gene for rapidly progressing adult-onset CSF1R-negative leukoencephalopathies.

The most aggressive tumor cells, which often reside in a hypoxic environment, can release vast amounts of lactate and protons via monocarboxylate transporters (MCTs). This additional proton efflux exacerbates extracellular acidification and supports the formation of a hostile environment. In the present study we propose a novel, data-based model for this proton-coupled lactate transport in cancer cells. The mathematical settings involve systems coupling nonlinear ordinary and stochastic differential equations describing the dynamics of intra- and extracellular proton and lactate concentrations. The data involve time series of intracellular proton concentrations of normoxic and hypoxic MCF-7 breast cancer cells. The good agreement of our final model with the data suggests the existence of proton pools near the cell membrane, which can be controlled by intracellular and extracellular carbonic anhydrases to drive proton-coupled lactate transport across the plasma membrane of hypoxic cancer cells.

Commonly used intestinal in vitro models are limited in their potential to predict oral drug absorption. They either lack the capability to form a tight cellular monolayer mimicking the intestinal epithelial barrier or the expression of cytochrome P450 3A4 (CYP3A4). The aim of this study was to establish a platform of colorectal cancer patient-derived cell lines for evaluation of human intestinal drug absorption and metabolism. We characterized ten 2D cell lines out of our collection with confluent outgrowth and long-lasting barrier forming potential as well as suitability for high throughput applications with special emphasis on expression and inducibility of CYP3A4. By assessment of the transepithelial electrical resistance (TEER) the cells barrier function capacity can be quantified. Very high TEER levels were detected for HROC60. A high basal CYP3A4 expression and function was found for HROC32. Eight cell lines showed higher CYP3A4 induction by stimulation via the vitamin D receptor compared to Caco-2 cells (5.1- to 16.8-fold change). Stimulation of the pregnane X receptor led to higher CYP3A4 induction in two cell lines. In sum, we identified the two cell lines HROC183 T0 M2 and HROC217 T1 M2 as useful tools for in vitro drug absorption studies. Due to their high TEER values and inducibility by drug receptor ligands, they may be superior to Caco-2 cells to analyze oral drug absorption and intestinal drug–drug interactions. Significance statement: Selecting appropriate candidates is important in preclinical drug development. Therefore, cell models to predict absorption from the human intestine are of the utmost importance. This study revealed that the human cell lines HROC183 T0 M2 and HROC217 T1 M2 may be better suited models and possess higher predictive power of pregnane X receptor- and vitamin D-mediated drug metabolism than Caco-2 cells. Consequently, they represent useful tools for predicting intestinal absorption and simultaneously enable assessment of membrane permeability and first-pass metabolism.

In-system clinical laboratories have proven themselves to be a fundamentally important resource to their institutions during the COVID-19 pandemic of the past year. The ability to provide SARS-CoV-2 molecular testing to our hospital system allowed us to offer the best possible care to our patients, and to support neighboring hospitals and nursing homes. In-house testing led to significant revenue enhancement to the laboratory and institution, and attracted new patients to the system. Timely testing of inpatients allowed the majority who did not have COVID-19 infection to be removed from respiratory and contact isolation, conserving valuable personal protective equipment and staff resources at a time that both were in short supply. As 2020 evolved and our institution restarted delivery of routine care, the availability of in-system laboratory testing to deliver both accurate and timely results was absolutely critical. In this article, we attempt to demonstrate the value and impact of an in-system laboratory during the COVID-19 pandemic. A strong in-house laboratory service was absolutely critical to institutional operational and financial success during 2020, and will ensure resiliency in the future as well.

“Aspirin resistance” (AR) is associated with increased risk of vascular events. We aimed to compare different platelet function tests used in identifying AR and assess their implications on clinical outcome. We performed platelet aggregation studies on non-cardioembolic ischaemic stroke patients taking aspirin 100 mg/day and 30 non-stroke controls. Data were collected on demographics, vascular risk factors, and concomitant medications. Cut-offs for AR were (1) light transmission aggregometry (LTA) of ≥20% using arachidonic acid (AA), ≥70% using ADP, or ≥60% using collagen; and (2) VerifyNow® assay ≥ 550 ARU. Telephone follow-ups were conducted by study staff blinded to AR status to ascertain the occurrence of vascular outcomes (stroke, myocardial infarction, amputation, death). A total of 113 patients were recruited, mean age 65 ± 8 years, 47% women, 45 ± 15 days from index stroke. 50 (44.3%, 95% CI 34.9–53.9) had AR on at least 1 test. Frequency of AR varied from 0% to 39% depending on method used and first vs. recurrent stroke. There were strong correlations between LTA AA, VerifyNow® and Multiplate® ASPItest (r = 0.7457–0.8893), but fair to poor correlation between LTA collagen and Multiplate® COLtest (r = 0.5887) and between LTA ADP and Multiplate® ADPtest (r = 0.0899). Of 103 patients with a mean follow up of 801 ± 249 days, 10 (9.7%) had vascular outcomes, of which six had AR by LTA-ADP. AR by LTA-ADP is associated with increased risk of vascular outcome (p = 0.034). Identification of AR is not consistent across different platelet function tests. LTA of ≥70% using 10 µM ADP in post-stroke patients taking aspirin is associated with increased risk of vascular outcome.

Adults with type 2 diabetes mellitus tend to exhibit an increased level of central adiposity, augmenting their risk of further non-communicable diseases (NCDs). Importantly, consistent evidence demonstrates a significant, negative association between cardiorespiratory fitness (CRF) and waist circumference (WC). However, no previous studies have investigated differences in these CRF-related reductions in WC between adults with and without diabetes.This study used data from the Aerobic Center for Longitudinal Studies, conducted between 1970 and 2006 among predominately Non-Hispanic White, middle-to-upper class adults in Texas. Quantile regression models were used to estimate CRF-related differences in WC between persons with and without diabetes. Age, height, smoking status and birth cohort served as covariates. The analytic sample included 45901 adults.Significantly larger reductions in WC were observed among adults with diabetes as compared to without diabetes across all WC percentiles. Among males, high CRF levels were associated with significant reductions, as compared to their low-fit counterparts, in WC as large as 21.9 cm for adults without diabetes and as large as 27 cm for adults with diabetes. Among females, high CRF levels were associated with significant reductions, as compared to their low-fit counterparts, in WC as large as 22.3 and 30.0 cm for adults without and with diabetes, respectively.This study demonstrated that higher CRF is associated with significant reductions in WC, with greater magnitudes found among adults with diabetes, especially among the most centrally obese, highlighting the necessity of exercise prescription in this clinical population potentially leading to lower risks of future NCDs.