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ABSTRACT Tuberous sclerosis complex (TSC) is a variable multisystem disorder. The “no mutations identified” (NMI) group are reportedly phenotypically milder than those with an identified molecular cause, and often have mosaic or intronic variants not detected by standard sequencing methods. Methods We describe the phenotypes in an Australian TSC NMI group (n = 18) and a molecular testing strategy implementable in a diagnostic laboratory. Massively parallel sequencing (MPS) of the whole genomic regions of TSC1 and TSC2 was performed using DNA extracted from multiple tissue samples per participant. Results Our study showed that the phenotype in TSC NMI individuals can be similar to those with heterozygous, particularly TSC1, variants. Although neurodevelopmental outcomes can be less severe, the number of organ systems involved was similar to the non‐mosaic groups. A diagnostic yield of 72% (13/18) was achieved, with the majority (10/13) being mosaic variants and the remainder heterozygous variants missed on previous testing. Conclusion Testing DNA from multiple tissue samples allowed for validation of otherwise discarded low‐level mosaic variants and detection of mosaic variants by MPS without excessive cost or the need for specialised techniques. Implementing this approach in a diagnostic setting is viable and allows optimal clinical care of patients with NMI TSC.

ObjectivesThis study aimed to evaluate the agreement between explosive detection dog (EDD) handlers and a team of veterinarians in assessing body condition score (BCS) and muscle condition score (MCS), hypothesizing significant BCS differences between handlers and veterinarians, and no significant MCS differences in healthy active duty EDDs.MethodsThis prospective study analyzed variance and inter-rater intraclass correlation coefficients (ICC) of agreement within BCS and MCS assessments collected from the 43 EDDs by four blinded graders; the EDDs’ respective handler and three veterinarians with varying levels of veterinary expertise.ResultsThe results of the study showed that 74.4% of the EDD population was graded as ideal BCS (4 or 5 out of 9) by the handlers compared to 67.44% by the members of the veterinary team; however, the graders scored different subsets of individual EDDs as ideal. Normal MCS (3 out of 3) was assessed in 86.05% (n = 37) of EDDs by the handlers versus in 70.54% by the veterinary team.ConclusionThis study highlights the importance of standardized training and guidelines for BCS and MCS assessments in working dogs to improve agreement between all members of the healthcare team.

Abstract Episomal AMA1‐based plasmids are increasingly used for expressing biosynthetic pathways and CRISPR/Cas systems in filamentous fungi cell factories due to their high transformation efficiency and multicopy nature. However, the gene expression from AMA1 plasmids has been observed to be highly heterogeneous in growing mycelia. To overcome this limitation, here we developed next‐generation AMA1‐based plasmids that ensure homogeneous and strong expression. We achieved this by evaluating various degradation tags fused to the auxotrophic marker gene on the AMA1 plasmid, which introduces a more stringent selection pressure throughout multicellular fungal growth. With these improved plasmids, we observed in Aspergillus nidulans a 5‐fold increase in the expression of a fluorescent reporter, a doubling in the efficiency of a CRISPRa system for genome mining, and a up to a 10‐fold increase in the production of heterologous natural product metabolites. This strategy has the potential to be applied to diverse filamentous fungi.

This thematic issue brings together a set of articles that empirically map the state of the ongoing geoeconomic turn in the global political economy from an international political economy (IPE) perspective. Changes in the modus operandi of the global political economy urge the development of new conceptual and theoretical tools to grasp the new geoeconomic reality of world affairs. At the same time, the contemporary study of geoeconomics remains theory-centred and focused on its security dimension, thereby underplaying the empirical nuances and variegated aspects of these developments. We therefore make the case for an empirically grounded study of concrete cases and instances of the geoeconomic turn, which can then deliver insights for further theory-building. Likewise, many aspects of the geoeconomic turn cannot be explained by security logics only, but have political economy roots that need to be brought to the foreground. Our thematic issue excavates these dynamics across four key challenges for the global economy: the role of states and firms in a geoeconomic world; global technological competition; the green transition; and implications of the geoeconomic turn for the non-Western world. Collectively, the contributions demonstrate that the geoeconomic turn is only starting to concretely (and partially) materialize and that these transformations, in many cases, tend to replicate existing power structures that prioritize capital(ist) interests related to profit-maximisation over societal interests, ecological sustainability, or social equity. We close by delineating prospects for further IPE research into the ongoing geoeconomic turn in the global political economy.

Introduction: Cardiac amyloidosis (CA) poses significant diagnostic and therapeutic challenges. In this case report, we detail a patient with CA due to a rare transthyretin (CA-TTR) mutation, manifesting with negative myocardial scintigraphy and requiring genetic testing for diagnosis. The patient also had severe aortic stenosis (AS), necessitating discussion with a heart team to determine the optimal treatment strategy. Case report: A 70-year-old male with a family history of sudden death was previously diagnosed with third-degree atrioventricular block and treated with a pacemaker. He presented with worsening exertional dyspnoea, and examination revealed a third heart sound, a systolic murmur indicative of AS and bilateral muscular atrophy in the thenar region. Transthoracic echocardiography indicated severe AS and moderate left ventricular dysfunction, with images suggesting infiltrative disease. Pyrophosphate scintigraphy revealed no abnormal cardiac tracer uptake. Cardiac magnetic resonance imaging (MRI) revealed extensive, heterogeneous, subendocardial late gadolinium enhancement in both the atria and ventricles, which was consistent with CA. Genetic testing identified the Phe84Leu mutation in the TTR gene. Following heart team discussions, the patient underwent successful transcatheter aortic valve implantation (TAVI) and remained asymptomatic in follow-up, being monitored at an outpatient clinic specializing in CA and using tafamidis. Discussion: CA-TTR can be an autosomal dominant disease with variable penetrance involving abnormal amyloid protein deposition in tissues and can often be diagnosed noninvasively via myocardial scintigraphy. However, some TTR mutations do not affect scintigraphy results, necessitating genetic testing when clinical suspicion is high, potentially avoiding endomyocardial biopsy. Moreover, AS occurs in up to 16 % of TTR amyloidosis patients, with the conditions mutually exacerbating each other. Recent consensus suggests that TAVI reduces mortality in patients with severe AS and amyloidosis. Conclusions: Various diagnostic algorithms emphasize the use of myocardial scintigraphy for suspected CA-TTR. Genetic testing is crucial when scintigraphy results are negative, but clinical suspicion remains high, potentially circumventing invasive procedures. Compared with medical management alone, TAVI has been shown to improve quality of life and survival in patients with concurrent severe AS and CA.

Abstract Ethylenediaminetetraacetic acid (EDTA), a classically used chelating agent of decalcification, maintains good morphological details, but its slow decalcification limits its wider applications. Many procedures have been reported to accelerate EDTA-based decalcification, involving temperature, concentration, sonication, agitation, vacuum, microwave, or combination. However, these procedures, concentrating on purely tissue-outside physical factors to increase the chemical diffusion, do not enable EDTA to exert its full capacity due to tissue intrinsic chemical resistances around the diffusion passage. The resistances, such as tissue inner lipids and electric charges, impede the penetration of EDTA. We hypothesized that delipidation and shielding electric charges would accelerate EDTA-based penetration and the subsequent decalcification. The hypothesis was verified by the observation of speedy penetration of EDTA with additives of detergents and hypertonic saline, testing on tissue-mimicking gels of collagen and adult mouse bones. Using a 26% EDTA mixture with the additives at 45°C, a conventional 7-day decalcification of adult mouse ankle joints could be completed within 24 h while the tissue morphological structure, antigenicity, enzymes, and DNA were well preserved, and mRNA better retained compared to using 15% EDTA at room temperature. The addition of hypertonic saline and detergents to EDTA decalcification is a simple, rapid, and inexpensive method that doesn't disrupt the current histological workflow. This method is equally or even more effective than the currently most used decalcification methods in preserving the morphological details of tissues. It can be highly beneficial for the related community.

Since December 2019, a new form of Severe Acute Respiratory Syndrome (SARS) has emerged worldwide, caused by SARS coronavirus 2 (SARS-CoV-2). This disease was called COVID-19 and was declared a pandemic by the World Health Organization in March 2020. Symptoms can vary from a common cold to severe pneumonia, hypoxemia, respiratory distress, and death. During this period of world stress, the medical and scientific community were able to acquire information and generate scientific data at unprecedented speed, to better understand the disease and facilitate vaccines and therapeutics development. Notably, bioinformatics tools were instrumental in decoding the viral genome and identifying critical targets for COVID-19 diagnosis and therapeutics. Through the integration of omics data, bioinformatics has also improved our understanding of disease pathogenesis and virus-host interactions, facilitating the development of targeted treatments and vaccines. Furthermore, molecular biology techniques have accelerated the design of sensitive diagnostic tests and the characterization of immune responses, paving the way for precision medicine approaches in treating COVID-19. Our analysis highlights the indispensable contributions of bioinformatics and molecular biology to the global effort against COVID-19. In this review, we aim to revise the COVID-19 features, diagnostic, prevention, treatment options, and how molecular biology, modern bioinformatic tools, and collaborations have helped combat this pandemic. An integrative literature review was performed, searching articles on several sites, including PUBMED and Google Scholar indexed in referenced databases, prioritizing articles from the last 3 years. The lessons learned from this COVID-19 pandemic will place the world in a much better position to respond to future pandemics.

The so-called geoeconomic turn in global trade policy-making has changed the context in which the European Union positions itself as a trade actor. However, there is little scholarly attention paid to how the geoeconomic turn affects the EU’s relations with developing countries. This article analyses the potential implications of new EU autonomous trade and investment instruments for developing countries, and how the EU has taken these consequences into account when designing them. We rely on a combination of desk research of official documents, trade data, and secondary literature complemented with expert interviews. We find that a trade-off between geoeconomic and development objectives is more pertinent in sustainability-related than in competitiveness- and security-oriented instruments. In these sustainability instruments, differential treatment of developing countries rarely features in the design—despite some proposals having been made. The geoeconomic turn has thus made it more difficult to align the different objectives in the EU’s trade and investment policies, and development concerns are sometimes relegated to the background.

Abstract Here, four MOFs, namely Sc-TBAPy, Al-TBAPy, Y-TBAPy, and Fe-TBAPy (TBAPy: 1,3,6,8-tetrakis(p-benzoic acid)pyrene), were characterized and evaluated for their ability to remediate glyphosate (GP) from water. Among these materials, Sc-TBAPy demonstrates superior performance in both the adsorption and degradation of GP. Upon light irradiation for 5 min, Sc-TBAPy completely degrades 100% of GP in a 1.5 mM aqueous solution. Femtosecond transient absorption spectroscopy reveals that Sc-TBAPy exhibits enhanced charge transfer character compared to the other MOFs, as well as suppressed formation of emissive excimers that could impede photocatalysis. This finding was further supported by hydrogen evolution half-reaction (HER) experiments, which demonstrated Sc-TBAPy’s superior catalytic activity for water splitting. In addition to its faster adsorption and more efficient photodegradation of GP, Sc-TBAPy also followed a selective pathway towards the oxidation of GP, avoiding the formation of toxic aminomethylphosphonic acid observed with the other M3+-TBAPy MOFs. To investigate the selectivity observed with Sc-TBAPy, electron spin resonance, depleted oxygen conditions, and solvent exchange with D2O were employed to elucidate the role of different reactive oxygen species on GP photodegradation. The findings indicate that singlet oxygen (1O2) plays a critical role in the selective photodegradation pathway achieved by Sc-TBAPy.

Abstract Type 2 innate lymphoid cells (ILC2s) perform vital functions in orchestrating humoral immune responses, facilitating tissue remodelling, and ensuring tissue homeostasis. Additionally, in a role that has garnered considerably less attention, ILC2s can also enhance Th1-related cytolytic T lymphocyte immune responses against tumours. Studies have thus far generally failed to address the mystery of how one ILC2 cell-type can participate in a multiplicity of functions. Here we utilized single cell RNA sequencing analysis to create the first comprehensive atlas of naïve and tumour-associated lung ILC2s and discover multiple unique subtypes of ILC2s equipped with developmental gene programs that become skewed during tumour expansion favouring inflammation, antigen processing, immunological memory and Th1-related anti-tumour CTL responses. The discovery of these new subtypes of ILC2s challenges current paradigms of ILC2 biology and provides an explanation for their diversity of function.

Communication technologies offer new opportunities for building and maintaining social connections at university. However, these technologies need to be better understood for their influence on student experiences in hybrid-style classrooms and guided more effectively. This study identified qualities of social connection to understand how students built/maintained social connection. The study was conducted over two autumn semesters in three hybrid-style classes in Switzerland and Norway. Qualitative methods included observations, interviews, and auto-photography. Approximately 150 h of observational data were gained, including auto-photography of 17 students’ physical online learning spaces, and four interviews with class lecturers. The findings indicated that informal/private spaces, crucial for building/maintaining social connection, were hard to access in hybrid-style learning environments. Communication cultures and social structures offered limited support for accessing these spaces for building/maintaining social connection. Addressing this issue required a processual effort across user-levels to support social connection within a hybrid-style university culture. This effort involved opening access to informal/private spaces by applying the concept of affective atmospheres within placemaking and interaction-design theories. A dimensions of affect framework is developed to help curate learning environments towards social connection. For university campus development, addressing these people–place relations with communication technology could foster technology more effectively to support connection.

IntroductionUreteropelvic junction obstruction (UPJO) syndrome is one of the most common causes of neonatal hydronephrosis. Management varies from simple monitoring to surgical intervention, with indications differing between institutions. A consensus of 8 societies recently described a new Urinary Tract Dilation (UTD) classification which aims to standardize ultrasound description of hydronephrosis, but which is also supposed to have predictive value in children with hydronephrosis. Our aim was to compare, in a monocentric prospective cohort of children with UPJO, the ability of UTD to predict the occurrence of a clinically significant event within the first year of life, as compared to anteroposterior diameter of the renal pelvis (APD).Study designWe used a preexisting cohort of children followed in a prospective study on UPJO. A pediatric radiologist, blinded to the children's outcome, classified the last antenatal ultrasound and postnatal ultrasound according to the UTD-A and UTD-P classification. He also confirmed the APD-A and APD-P measures. We defined a clinically significant event as being: increased pelvic dilation (>5 mm) and/or the presence of a febrile urinary tract infection (fUTI) and/or impaired renal function on initial nuclear scan (5 mm in dilation, 6 presented an episode of fUTI and 9 had impaired function of the affected kidney. APD-A was the most effective individual criterion for predicting the occurrence of a significant clinical event (AUC = 0.867).ConclusionIn our series, for children with UPJO, the most significant marker was prenatal APD >15 mm to predict an increase in dilation >5 mm.

Cell-based cancer immunotherapy has achieved significant advancements, providing a source of hope for cancer patients. Notwithstanding the considerable progress in cell-based immunotherapy, the persistently low response rates and the exorbitant costs associated with their implementation still present a formidable challenge in clinical settings. In the landscape of cell-based cancer immunotherapies, an uncharted territory involves Type 2 innate lymphoid cells (ILC2s) and interleukin-33 (IL-33) which promotes ILC2 functionality, recognized for their inherent ability to enhance immune responses. Recent discoveries regarding their role in actuating cytolytic T lymphocyte responses, including curbing tumor growth rates and hindering metastasis, have added a new dimension to our understanding of the IL-33/ILC2 axis. These recent insights may hold significant promise for ILC2 cell-based immunotherapy. Nevertheless, the prospect of adoptively transferring ILC2s to confer immune protection against tumors has yet to be investigated. The present study addresses this hypothesis, revealing that ILC2s isolated from the lungs of tumor-bearing mice, and tumor infiltrating ILC2s when adoptively transferred after tumor establishment at a ratio of one ILC2 per sixty tumor cells, leads to an influx of tumor infiltrating CD4+ and CD8+ T lymphocytes as well as tumor infiltrating eosinophils resulting in a remarkable reduction in tumor growth. Moreover, we find that post-adoptive transfer of ILC2s, the number of tumor infiltrating ILC2s is inversely proportional to tumor size. Finally, we find corollaries of the IL-33/ILC2 axis enhancing the infiltration of eosinophils in human prostate carcinomas patients' expressing high levels of IL-33 versus those expressing low levels of IL-33. Our results underscore the heightened efficacy of adoptively transferred ILC2s compared to alternative approaches, revealing an approximately one hundred fifty-fold superiority on a cell-per-cell basis over CAR T-cells in the specific targeting and elimination of tumors within the same experimental model. Overall, this study demonstrates the functional significance of ILC2s in cancer immunosurveillance and provides the proof of concept of the potential utility of ILC2 cell-based cancer immunotherapies.

Molnupiravir (MOV) was introduced in Israel in January 2022 during the SARS-CoV-2 Omicron surge for high-risk patients contraindicated for nirmatrelvir/ritonavir. This retrospective cohort study aimed to describe characteristics of patients offered COVID-19 antiviral treatment in Maccabi Healthcare Services (antiviral treatment-eligible cohort; n = 5596) between 12 January and 28 February 2022, and the subset of these who were dispensed MOV (MOV-treated cohort; n = 1147), as well as outcomes following MOV dispensation. Median (interquartile range) age in the antiviral treatment-eligible and MOV-treated cohorts were 70.5 (61.1, 77.3) and 74.1 (64.3, 81.7) years, respectively. The MOV-treated cohort (male: 53.2%) had high rates of COVID-19 vaccination (91.4%) and comorbidities, including immunosuppression (40.0%) and chronic kidney disease (67.0%; eGFR < 30 mL/min/1.73 m2: 28.8%), and most used comedications either contraindicated or with major potential for drug–drug interactions with nirmatrelvir/ritonavir (87.3%). At 28 days post-MOV dispensation, the cumulative incidence (95% CI) of COVID-19-related hospitalization and/or all-cause mortality was 3.6% (2.5%, 4.6%), with similar rates across sexes and age groups (18–64 vs. ≥65 years), and lower rates among recently vaccinated and/or recently SARS-CoV-2-infected patients. These data describe the characteristics and outcomes for MOV-treated patients in Israel, whose clinical characteristics may preclude the use of nirmatrelvir/ritonavir to treat their COVID-19 infection.

Abstract The anterior ilioinguinal and the posterior Kocher-Langenbeck approach have long been the standard surgical approaches to the acetabulum. The last decade has witnessed the development of so-called intrapelvic approaches for anterior pathologies because they provide better exposure of the quadrilateral plate. Currently, the modified Stoppa approach and the pararectus approach are frequently used by surgeons for the treatment of acetabular fractures. We investigated an even more direct access to the entire anterior column and the quadrilateral plate via the abdominal wall muscles, between the incisions for the ilioinguinal and the pararectus approach. After intensive study of anatomic specimens, a cadaver dissection was performed prior to clinical application. The approach was then used in 20 patients who were assessed retrospectively. Postoperative CT scans showed that, according to the Matta scoring system, the quality of fracture reduction was “anatomical” (≤ 1 mm) in 12 (60%), “imperfect” (2–3 mm) in four (20%), and “poor” (> 3 mm) in four (20%) patients. Numerous minor complications were observed; the majority of these had resolved at the time of discharge. In conclusion, the anterior transmuscular intrapelvic approach (ATI) is a safe and effective alternative to the ilioinguinal and pararectal approaches, and may be regarded as an evolutionary advancement of traditional procedures.

Abstract Background Myasthenia gravis (MG) is a rare neuromuscular disorder. Symptoms can range from ptosis only to life threatening myasthenic crisis. Thymectomy is recommended for anti-acetylcholine receptor-antibody positive patients with early-onset MG. Here, we investigated prognostic factors shaping therapeutic outcomes of thymectomy to improve patient stratification. Methods We retrospectively collected single-center data from a specialized center for MG from all consecutive adult patients that underwent thymectomy from 01/2012 to 12/2020. We selected patients with thymoma-associated and non-thymomatous MG for further investigations. We analyzed the patient collective regarding perioperative parameters in relation to the surgical approach. Furthermore, we investigated the dynamics of the anti-acetylcholine receptor-antibody titers and concurrent immunosuppressive therapies, as well as the therapeutic outcomes in dependence of clinical classifications. Results Of 137 patients 94 were included for further analysis. We used a minimally invasive approach in 73 patients, whereas 21 patients underwent sternotomy. A total of 45 patients were classified as early-onset MG (EOMG), 28 as late-onset MG (LOMG) and 21 as thymoma-associated MG (TAMG). The groups differed in terms of age at diagnosis (EOMG: 31.1 ± 12.2 years; LOMG: 59.8 ± 13.7 years; TAMG: 58.6 ± 16.7 years; p

IntroductionThe study investigated the utilization of odor detection dogs to identify the odor profile of Staphylococcus aureus (S. aureus) biofilms in pure in vitro samples and in in vivo biosamples from animals and humans with S. aureus periprosthetic joint infection (PJI). Biofilms form when bacterial communities aggregate on orthopedic implants leading to recalcitrant infections that are difficult to treat. Identifying PJI biofilm infections is challenging, and traditional microbiological cultures may yield negative results even in the presence of clinical signs.MethodsDogs were trained on pure in vitro S. aureus biofilms and tested on lacrimal fluid samples from an in vivo animal model (rabbits) and human patients with confirmed S. aureus PJI.ResultsThe results demonstrated that dogs achieved a high degree of sensitivity and specificity in detecting the odor profile associated with S. aureus biofilms in rabbit samples. Preliminary results suggest that dogs can recognize S. aureus volatile organic compounds (VOCs) in human lacrimal fluid samples.DiscussionTraining odor detection dogs on in vitro S. aureus, may provide an alternative to obtaining clinical samples for training and mitigates biosecurity hazards. The findings hold promise for culture-independent diagnostics, enabling early disease detection, and improved antimicrobial stewardship. In conclusion, this research demonstrates that dogs trained on in vitro S. aureus samples can identify the consistent VOC profile of PJI S. aureus biofilm infections. The study opens avenues for further investigations into a retained VOC profile of S. aureus biofilm infection. These advancements could revolutionize infectious disease diagnosis and treatment, leading to better patient outcomes and addressing the global challenge of antimicrobial resistance.

Abstract Background Adherence is key to the treatment success of multi-drug resistant tuberculosis (MDR-TB) and prevention of community transmission. Directly observed therapy (DOT) is the recommended approach for the management of patients with MDR-TB. Uganda implements a health facility-based DOT approach where all patients diagnosed with MDR-TB report to the nearest private or public health facility for daily observation of ingesting their medicines by a health care provider. Directly observed therapy is very costly for both the patient and health care system. It follows the assumption that MDR TB patients have a history of poor adherence to TB treatment. But only 21% of MDR-TB patients notified globally and 1.4–12% notified in Uganda had been previously treated for TB. The shift to all oral treatment regimen for MDR-TB provides an opportunity for the exploration of self-administered therapy for this group of patients even with use of remotely operated adherence technology. We are conducting a non-inferiority open-label randomized controlled trial to compare adherence to MDR-TB treatment among patients on self-administered therapy (measured by Medication Events Monitoring System (MEMS) technology) with a control group on DOT. Methods We plan to enrol 164 newly diagnosed MDR-TB patients aged ≥ 8 years from three regional hospitals based in rural and urban Uganda. Patients with conditions that affect their dexterity and ability to operate the MEMS-operated medicine equipment will not be eligible to participate in the trial. Patients are randomized to either of the two study arms: self-administered therapy with adherence being monitored using MEMS technology (intervention arm) or health facility-based DOT (control arm) and will be followed up monthly. Adherence is measured by the number of days the medicine bottle is open to access medication as recorded by the MEMS software in the intervention arm and treatment complaint days as recorded in the TB treatment card in the control arm. The primary outcome is the comparison of adherence rates between the two study arms. Discussion The evaluation of self-administered therapy for patients with MDR-TB is important to inform cost-effective management strategies for these patients. The approval of all oral regimens for the treatment of MDR-TB provides an opportunity for innovations such as MEMS technology to support sustainable options for MDR-TB treatment adherence support in low-resource settings. Trial registration Pan African Clinical Trials Registry, Cochrane #PACTR202205876377808. Retrospectively registered on 13 May 2022

Abstract Gene expression profiling has helped tremendously in the understanding of biological processes and diseases. However, interpreting processed data to gain insights into biological mechanisms remain challenging, especially to the non-bioinformaticians, as many of these data visualization and pathway analysis tools require extensive data formatting. To circumvent these challenges, we developed STAGEs (Static and Temporal Analysis of Gene Expression studies) that provides an interactive visualisation of omics analysis outputs. Users can directly upload data created from Excel spreadsheets and use STAGEs to render volcano plots, differentially expressed genes stacked bar charts, pathway enrichment analysis by Enrichr and Gene Set Enrichment Analysis (GSEA) against established pathway databases or customized gene sets, clustergrams and correlation matrices. Moreover, STAGEs takes care of Excel gene to date misconversions, ensuring that every gene is considered for pathway analysis. Output data tables and graphs can be exported, and users can easily customize individual graphs using widgets such as sliders, drop-down menus, text boxes and radio buttons. Collectively, STAGEs is an integrative platform for data analysis, data visualisation and pathway analysis, and is freely available at https://kuanrongchan-stages-stages-vpgh46.streamlitapp.com/ . In addition, developers can customise or modify the web tool locally based on our existing codes, which is publicly available at https://github.com/kuanrongchan/STAGES .

Introdução: Eventos neurológicos em pacientes com endocardite infecciosa (EI) são frequentes e impactam manejo e desfechos. Objetivo: Descrever eventos neurológicos em pacientes com EI e compará-lo com outros casos de EI na coorte. Métodos: Pacientes adultos com EI definitiva de acordo com os critérios de Duke modificados foram incluídos, prospectiva e consecutivamente, de 2006 a 2021. EI com eventos neurológicos (EIEN) foram evento isquêmico cerebral, evento isquêmico com transformação hemorrágica e hemorragia intracraniana, identificados por tomografia computadorizada de crânio realizada sistematicamente na EI esquerda. EIEN foi comparada aos demais pacientes com EI da coorte por teste de proporções. Análise estatística foi realizada com o software Jamovi e R Resultados: Eventos neurológicos ocorreram em 26,1% das EI. Não foi observado diferença entre sexo e idade entre os dois grupos, tampouco em relação ao local de aquisição ou tipo de válvula afetada. A valvopatia reumática (37,8% vs 28.3%, p = 0,046) foi a única predisposição que ocorreu com maior frequência nos EIEN. Não houve diferença na proporção de comorbidades (insuficiência cardíaca, insuficiência renal crônica e diabetes) dentre os grupos. Dentre as complicações, esplenomegalia (30,2% vs 15,3%, p < 0,001), aneurisma micótico (28,8% vs 2,7%, p < 0,001) e eventos vasculares embólicos para outros sítios (83,2% vs 31,3%, p < 0,001) foram os mais prevalentes na EIEN. Dos eventos embólicos, o local mais acometido além do sistema nervoso central (SNC) foi o baço, (60,3% vs 26,3%, p < 0,001). Pacientes transferidos apresentaram com maior frequência eventos embólicos para o SNC (59,5% vs 49,3%, p = 0,044). Pacientes com EIEN foram indicados para cirurgia cardíaca em uma proporção similar ao restante da coorte (82,4% vs 83,7%), no entanto, foram menos frequentemente operados (62,7% vs 79,1%, p < 0,001). A taxa de mortalidade dos pacientes na EIEN foi similar ao restante da coorte (23,4% vs 26,9%). Conclusão: Eventos neurológicos ocorreram em cerca de 1/4 dos pacientes da coorte, sendo mais associado a pacientes transferidos de outros hospitais e com EI por viridans, possivelmente pelo quadro arrastado de EI. O número de eventos embólicos (além dos neurológicos) e a incidência de aneurisma micótico foi maior nos pacientes com EIEN. Por fim, é importante ressaltar que os eventos neurológicos interferem diretamente na realização ou não da cirurgia, no entanto, a taxa de mortalidade foi similar ao restante da coorte.

Introdução: O uso de dispositivos cardíacos eletrônicos implantáveis (DCEI) tem crescido nos últimos anos. Nosso objetivo foi avaliar as características clínicas da endocardite infecciosa (EI) envolvendo dispositivos cardíacos (EIDCEI) em uma série de EI nos últimos 17 anos. Métodos: De janeiro de 2006 a maio de 2023, 502 casos definitivos de EI, pelos critérios de Duke modificados, em adultos, foram diagnosticados em nosso centro, e incluídos consecutiva e prospectivamente. As EIDCEI foram buscadas e descritas. Resultados: EIDCEI ocorreu em 37/502 (7,4%) casos de EI. A idade média ± desvio padrão foi de 54,6±19,0 anos, sendo 64,8% do sexo masculino. Aquisição comunitária de EI ocorreu em 11 (29,7%), nosocomial em 19 (51,3%) e associada a assistência à saúde não nosocomial em 7(18,9%). Na história pregressa, 17 (45,9%) tinham feito cirurgia cardíaca, 18 (48,6%) tinham insuficiência cardíaca congestiva (ICC), 12 (32,4%) tinham doença arterial coronariana, 9 (24,3%) insuficiência renal crônica e 24 (64,8%) hipertensão arterial. Ecocardiograma transesofágico foi realizado em 32/37(86.5%) dos pacientes e acometimento concomitante de valva tricúspide, mitral e aórtica foi encontrado em 7/37(18.9%),513.5%) e 1(2,7%) casos respectivamente. Febre foi observada em 89,2%, novo sopro regurgitante em 16,2%, evento vascular embólico em 27%. Proteína C reativa estava elevada em 30/37(81%) e velocidade de hemossedimentação em 5/22(22,7%). Todos os pacientes colheram hemoculturas, das quais, 73% foram positivas. Os microrganismos causadores foram predominantemente Staphylococcus aureus (35%), Gram negativos não HACEK (10,8%) e fungos (10,8%). As principais complicações foram bacteremia persistente em 7(18.9%), IC aguda em 8 (21,6%), insuficiência renal aguda em 14 (37,8%) e embolização para pulmões em 10/35 (28,5%). A cirurgia foi indicada para 33 (89,2%) pacientes e efetivamente realizada em 30 (81%). A mortalidade intra-hospitalar foi de 15/37 (40,5%). Conclusão: A endocardite infecciosa em DCEI tem apresentado incidência crescente na literatura, em função do maior número de dispositivos inseridos, do envelhecimento da população e das comorbidades, e em nosso centro representou quase 10% de todas as EI nos últimos 17 anos. Os agentes etiológicos podem ser não usuais na EI em geral, como bastonetes Gram negativos e fungos. Trata-se de uma doença grave, com alto índice de complicações e óbitos, que requer a retirada do dispositivo.

Introdução: A endocardite infecciosa (EI) é uma doença grave, com alta mortalidade. Nosso objetivo é descrever uma série de pacientes adultos com EI atendidos em um centro de referência cardiológico, destacando suas especificidades. Métodos: Pacientes adultos com EI definitiva de acordo com os critérios de Duke modificados foram incluídos de 2006 a 2023 prospectiva e consecutivamente. Análise estatística foi realizada nos softwares Jamovi 1.6 e R 4.0.1. Resultados: Houve 502 episódios de EI no período do estudo. A média de idade ± DP foi de 48,4±17,2 anos; 327(65,1%) eram homens. Aquisição comunitária ocorreu em 324(64,7%), e nosocomial em 128(25,5%). A EI precoce de prótese valvar foi responsável por 59/502(11,7%) casos e a EI tardia de prótese por 99(19,7%). Na história pregressa, 203(40,4%) tinham feito cirurgia cardíaca, 196(39,0%) tinham insuficiência cardíaca congestiva (ICC), 107(21,4%) insuficiência renal crônica. As principais predisposições para EI foram valvopatia reumática (VP) em 151(30,7%), prótese valvar em 31,5%, cardiopatia congênita em 73(14,5%), EI prévia em 64(12,7%). Vegetações foram observadas na valva mitral em 235(46,8%), aórtica em 207(41,2%), e em dispositivos intracardíacos, em 37(7,4%). Febre ocorreu em 90,4%, novos sopros regurgitantes em 50,7%, embolia em 45%, esplenomegalia em 19,2%; Nódulos de Osler, lesões de Janeway, hemorragias subconjuntivais e hemorragias subungueais foram vistos em menos de 5% cada. Proteína C reativa estava elevada em 72,3% e VHS em 20,7%. Hemoculturas foram colhidas em 98,6%, sendo positivas em apenas 67,7%. Patógenos mais frequentemente isolados foram estreptococos do grupo viridans, EGV (19,3%), S.aureus(10,4%) e enterococos(12,2%). As principais complicações foram IC aguda, em 291(58%), insuficiência renal aguda (32,8%), abscesso miocárdico (21,6%), evento neurológico central (26,1%) e embolização esplênica (35,2%). A cirurgia foi indicada para 418(83,4%) e efetivamente realizada em 352(74,7%). A mortalidade intra-hospitalar foi de 125/502(25%). Conclusões: Em nosso centro, predominou a EI esquerda, com hemoculturas negativas. EGV foram os patógenos mais frequentemente encontrados nas hemoculturas positivas. A VR foi a principal predisposição. Esses achados diferem daqueles descritos em séries de países em desenvolvimento. A indicação cirúrgica foi frequente, devido ao viés de referenciamento, e a mortalidade geral foi alta, mas semelhante à literatura de centros cardiológicos brasileiros.

Introdução: A endocardite infecciosa (EI) está associada a complicações graves e alta mortalidade. A avaliação da mortalidade e fatores associados é importante para identificar fatores modificáveis e melhorar desfechos. Objetivos: Avaliar os desfechos clínicos de pacientes com EI e determinar fatores associados a mortalidade hospitalar. Materiais e Métodos: Estudo retrospectivo de centro único, incluindo pacientes com EI definitiva de acordo com os critérios de Duke modificados, de 2006-2023, usando ficha de coleta de dados padronizada. Foram avaliados comorbidades, apresentação clínica, microbiologia e desfechos durante a internação, e comparados os pacientes que foram a óbito aos que não foram. A análise estatística foi realizada com o software Jamovi e R; p < 0,05 foi considerado significativo. Resultados: Foram incluídos 502 pacientes com EI (65,1% do sexo masculino, média de idade de 48,4 ± 17,2 anos) e 123 vieram a óbito, com uma mortalidade hospitalar de 24,9%. Cerca de 80% dos pacientes tinha EI esquerda. Tinham indicação cirúrgica 347; dos que operaram, a mortalidade foi 74/347 (21,3%); 68 tinham indicação cirúrgica e não operaram; destes, 39/68 morreram (mortalidade 57,4%); 51 não tiveram indicação cirúrgica e não operaram; destes, 9/51 morreram (mortalidade 17,6%). Na história pregressa, apresentavam insuficiência cardíaca congestiva (ICC) 50,4% dos que foram a óbito, vs 34,9% (p = 0,002), diabetes mellitus (DM) 23,2% vs 12,9% (p = 0,004) e insuficiência renal crônica (IRC) 37,6% vs 16,1% (p < 0,001). EI de prótese tardia ocorreu em 29,6% vs 16,5% (p = 0,001). Hemocultura positiva foi detectada em 75,2% dos que morreram vs 65,2%, (p = 0,039). Estreptococos do grupo viridans ocorreram em 12% dos que foram a óbito vs 21,6% (p = 0,018) e fungos em 7,2% vs 1,6% (p = 0,001). Dentre os que foram a óbito, a EI foi de aquisição nosocomial mais frequentemente (32,8% vs 23,3%, p = 0,035) e relacionada a assistência à saúde não-nosocomial (15,2% vs 8,1%; p = 0,021). Abscessos, insuficiência renal nova e necessidade de hemodiálise foram as complicações mais frequentes no grupo que foi a óbito, representando 21,8% vs 12,8% (p = 0,015), 47,9% vs 27,5% (p < 0,001) e 33,3% vs 11,7% (p < 0,001), respectivamente. Conclusão: Os fatores associados à mortalidade hospitalar na EI foram comorbidades pregressas (ICC, DM e IRC), endocardite tardia de prótese, etiologia fúngica e associada a assistência à saúde O tratamento cirúrgico diminuiu significativamente o risco de morte.

A Endocardite Infecciosa (E.I.) é uma séria complicação do implante Transcatéter de Valva Aórtica (TAVI). A incidência pós TAVI é similar à pós troca valvar cirúrgica. Há expectativa que o número de TAVI cresça nos próximos anos. A EI de TAVI possui maior incidência nos primeiros meses após procedimento, e seu manejo é complicado pelo alto risco cirúrgico dos pacientes. Caso 1: mulher, 71 anos, hipertensa, diabética, coronariopata, com Doença Renal Crônica (DRC) em Tratamento Conservador (TCon), submetida a TAVI por estenose aórtica grave há 10 meses. Dá entrada em emergência com hemiparesia esquerda. Ao exame força grau 3 em dimídio esquerdo e discreta alteração da sensibilidade. Tomografia Computadorizada (TC) de crânio sem alterações agudas. Leucocitose de 19.900 mL, PCR-T: 26,8 mg/mL. Coletadas hemoculturas, com crescimento de Enterococcus faecalis. Iniciado ceftriaxone e ampicilina. Ecocardiograma transesofágico (ECOTE) demonstrou prótese aórtica de implante percutâneo normofuncionante, sem imagens aditivas. TC de abdome: áreas sugestivas de isquemia em baço e artéria mesentérica superior com falha de enchimento sugerindo infarto da gordura mesentérica. Ressonância Magnética de crânio mostrou injúria vascular isquêmica recente. PET-CT com FDG após 2 semanas de antibióticos foi normal. Colonoscopia sem alterações. Paciente sem possibilidade cirúrgica, sendo realizados 42 dias de antibiótico, com boa evolução clínica. Caso 2: homem, 84 anos, hipertenso, diabético, ex-tabagista, portador de DRC em TCon, coronariopata, submetido a TAVI há 3 meses. Procura emergência após febre e astenia há 1 semana. Coletadas hemoculturas, realizadas TCs de crânio e abdome sem alterações agudas, além de ECOTE. Este demonstrou prótese aórtica tipo TAVI com regurgitação periprotética moderada, sem imagens aditivas. Hemoculturas colhidas. Prescrito ampicilina e gentamicina. Identificação de E. faecalis, resistente à gentamicina, substituída por ceftriaxona. Cintilografia com leucócitos marcados demonstrou captação no sítio da TAVI. Sem condições cirúrgicas, tratado com 42 dias de ceftriaxona e ampicilina com boa evolução. Descrevemos dois casos de EI em TAVI, ambas em pacientes idosos com comorbidades e com alto risco cirúrgico, que foram tratadas conservadoramente com sucesso. E. faecalis foi o agente isolado em ambos os casos, cuja porta de entrada foi provavelmente o acesso femoral para a TAVI. É fundamental rever a profilaxia antimicrobiana e antissepsia para a TAVI.

Introdução: Endocardite Infecciosa (EI) por Estafilococos Coagulase Negativos (ECN) está associada a alta taxa de mortalidade, principalmente em pacientes hospitalizados, sendo seu estudo de grande relevância. Nosso objetivo foi descrever casos de EI por ECN (EIECN) num centro cardiológico e compará-lo com outros casos de EI na coorte. Métodos: Pacientes adultos com EI definitiva pelos critérios de Duke modificados foram incluídos, prospectiva e consecutivamente, de 2006 a 2021. EIECN foi comparada aos demais pacientes com EI da coorte por teste de proporções. Análise estatística foi realizada com o software Jamovi e R. Resultados: ECN foi responsável por 39/435(9%) episódios de EI. A EIECN foi encontrada com maior frequência em pacientes mais velhos (mediana 55 vs. 47, p

Abstract Background Canadians endured unprecedented mental health (MH) and support access challenges during the first COVID-19 wave. Identifying groups of individuals who remain at risk beyond the acute pandemic phase is key to guiding systemic intervention efforts and policy. We hypothesized that determinants of three complementary, clinically actionable psychiatric outcomes would differ across Canadian age groups. Methods The Personal Impacts of COVID-19 Survey (PICS) was iteratively developed with stakeholder feedback, incorporating validated, age-appropriate measures. Baseline, cross-sectional online data collected between November 2020-July 2021 was used in analyses. Age group-specific determinants were sought for three key baseline MH outcomes: (1) current probable depression, generalized anxiety disorder, obsessive–compulsive disorder and/or suicide attempt during COVID-19, (2) increased severity of any lifetime psychiatric diagnosis, and (3) inadequate MH support access during COVID-19. Multivariable logistic regression models were constructed for children, youth (self- and parent-report), young adults (19–29 years) and adults over 29 years, using survey type as a covariate. Statistical significance was defined by 95% confidence interval excluding an odds ratio of one. Results Data from 3140 baseline surveys were analyzed. Late adolescence and early adulthood were identified as life phases with the worst MH outcomes. Poverty, limited education, home maker/caregiver roles, female and non-binary gender, LGBTQ2S + status and special educational, psychiatric and medical conditions were differentially identified as determinants across age groups. Interpretation Negative psychiatric impacts of COVID-19 on Canadians that include poor access to MH support clearly persisted beyond the first wave, widening pre-existing inequity gaps. This should guide policy makers and clinicians in current and future prioritization efforts.

Abstract Background Patient-reported outcome measures (PROMs) are recommended for assessing patient-centered outcomes in inflammatory bowel disease (IBD). The main aims were to assess the level of participation in an electronic PROM (ePROM) data collection system among patients with IBD, and evaluate reliability and validity of the resulting scores. Methods Patients included in the IBD registry of Maccabi Healthcare Services, a state-mandated healthcare provider for over 2.6 million people in Israel, were invited to complete the IBD-Control measure and a general health item, with follow-up ePROMs at 3 and 6 months including a global rating of change item. Descriptive statistics were used to compare patient characteristics by participation rate, and assess survey completion time. Initial scores were assessed for internal consistency reliability using Cronbach's alpha. Test–retest reliability was assessed using the intraclass correlation coefficient from paired scores of patients identified as unchanged between the initial and first follow-up. Construct validity was assessed by the ability of IBD-control scores to discriminate between patient sub-groups in expected ways. Empirical validity was assessed using ePROM score correlations with laboratory markers of disease activity. Score coverage was also assessed. Results A total of 13,588 patients were invited to participate [Mean age = 49 years (SD = 17); females = 51%]. Participation rate was 31.5%. Participants compared to non-participants were slightly older, were more likely to be female, to have a history of biologic treatment, to have higher socio-economic status, and to be more experienced in the usage of the digital patient portal. Median survey completion time was approximately 1:30 min. Internal consistency and test–retest reliability were 0.86 and 0.98, respectively. Scores discriminated between patient sub-groups in clinically expected ways, with expected correlations to laboratory markers of disease activity. A notable ceiling effect was observed (> 15%) for IBD-Control scores. Conclusions Feasibility, reliability, and validity of the ePROM system was supported for measuring the level of perceived disease control in patients diagnosed with IBD in Israel. Additional research is needed to identify ways to increase patient participation, assess clinical implications of the identified measurement ceiling of the IBD-control, and evaluate the added value of the derived scores in support of clinical decision making.

Le répertoire actuel de la chanson enfantine au Japon s’est constitué entre les années 1880 et 1920, période durant laquelle se sont développés l’un après l’autre une éducation musicale obligatoire, qui introduisit la pratique vocale et les chants scolaires dans les écoles, et un mouvement poétique et littéraire qui mena à la constitution de chants dits artistiques à destination des enfants. Mais les comptines populaires issues du patrimoine culturel enfantin de transmission orale, qui avaient précédé l’apparition de ces deux types de chants sur l’archipel, représentent aussi une part significative de ce répertoire. Les berceuses japonaises, les komori uta, sont un cas particulier de chansons de l’enfance qu’il est difficile de classer de manière absolue dans l’une ou l’autre des catégories qui composent ce répertoire. Parfois chants d’endormissement, parfois chants de labeur, elles furent tour à tour récupérées par la chanson populaire et la musique classique, selon des processus compositionnels qui estompèrent peu à peu l’origine de leur création : les gardes d’enfants. Envoyées loin de chez elles, ces jeunes filles qui pouvaient avoir à peine huit ou neuf ans passaient leurs journées à prendre soin des bébés de la famille pour qui elles travaillaient. Cet article s’attachera à présenter l’évolution particulière des komori uta au début du xxe siècle, une évolution qui révèle plusieurs des changements majeurs que connut la société japonaise à l’époque.

Chronic wasting disease (CWD) is a highly infectious, fatal prion disease that affects cervid species. One promising method for CWD surveillance is the use of detection dog–handler teams wherein dogs are trained on the volatile organic compound signature of CWD fecal matter. However, using fecal matter from CWD-positive deer poses a biohazard risk; CWD prions can bind to soil particles and remain infectious in contaminated areas for extended periods of time, and it is very difficult to decontaminate the affected areas. One solution is to use noninfectious training aids that can replicate the odor of fecal matter from CWD-positive and CWD-negative deer and are safe to use in the environment. Trained CWD detection dogs’ sensitivity and specificity for different training aid materials (cotton, GetXent tubes, and polydimethylsiloxane, or PDMS) incubated with fecal matter from CWD-positive and CWD-negative deer at two different temperatures (21 °C and 37 °C) for three different lengths of time (6 h, 24 h, and 48 h) were evaluated. Cotton incubated at 21 °C for 24 h was identified as the best aid for CWD based on the dogs’ performance and practical needs for training aid creation. Implications for CWD detection training and for training aid selection in general are discussed.

Severe COVID-19 is a major cause of morbidity and mortality worldwide, especially among those with co-morbidities, the elderly, and the immunocompromised. However, the molecular determinants critical for severe COVID-19 progression remain to be fully elucidated. Meta-analyses of transcriptomic RNAseq and single-cell sequencing datasets comparing severe and mild COVID-19 patients have demonstrated that the early expansion of myeloid-derived suppressor cells (MDSCs) could be a key feature of severe COVID-19 progression. Besides serving as potential early prognostic biomarkers for severe COVID-19 progression, several studies have also indicated the functional roles of MDSCs in severe COVID-19 pathogenesis and possibly even long COVID. Given the potential links between MDSCs and severe COVID-19, we examine the existing literature summarizing the characteristics of MDSCs, provide evidence of MDSCs in facilitating severe COVID-19 pathogenesis, and discuss the potential therapeutic avenues that can be explored to reduce the risk and burden of severe COVID-19. We also provide a web app where users can visualize the temporal changes in specific genes or MDSC-related gene sets during severe COVID-19 progression and disease resolution, based on our previous study.

The National Center for Children’s Literature (CNLJ) keeps an important collection of the Japanese publisher Fukuinkan shoten, which celebrates in 2022 its 70 years anniversary. This collection was initially acquired from la Joie par les livres and the publisher himself regularly sends some of its collections to the National Library of France. Often compared to L’école des loisirs in France, Fukuinkan shoten is a major publisher in Japan that contributed greatly to the development of children’s literature in the archipelago but also to the recognition of Japanese children’s literature in the world. This article aims to present the publisher and some collections available at the National Library of France and to define some directions for further research.

BackgroundDuring national lockdowns in response to the COVID-19 pandemic, previously office-based workers who transitioned to home-based teleworking faced additional demands (e.g., childcare, inadequate homeworking spaces) likely resulting in poor work privacy fit. Previous office research suggests poor work privacy fit is associated with lower wellbeing and higher work fatigue. Emerging evidence suggests a relationship between childcare duties during pandemic teleworking and work fatigue. In addition to psychosocial working conditions (job demand, job control, and job change management), which are acknowledged predictors of work fatigue, this poses a significant threat to occupational health during pandemic teleworking. However, the relative effects of aspects of the psychosocial environment (job demands and resources), the home office environment (including privacy fit), and the social environment (childcare) on work fatigue as well as their interactions are under-explored.ObjectiveThis study examined the relationships between the psychosocial, environmental, and social working conditions of teleworking during the first COVID-19 lockdown and work fatigue. Specifically, the study examined teleworkers’ physical work environment (e.g., if and how home office space is shared, crowding, and noise perceptions) as predictors of privacy fit and the relationship between privacy fit, childcare, psychosocial working conditions (job demand, job control, and job change management), and work fatigue. Work privacy fit was hypothesized to mediate the relationship between childcare and work fatigue.MethodsAn online cross-sectional survey was conducted with teleworkers (n = 300) during the first COVID-19 lockdown in April and May 2020; most participants were in Germany, Switzerland, and the United Kingdom.ResultsPath analysis was used to examine the hypothesized relationships. Privacy fit was lower for those reporting greater levels of noise in home-working spaces and those feeling crowded at home. Work fatigue was lower amongst those with greater privacy fit and higher amongst those with high levels of job demand. An indirect relationship was observed between childcare and work fatigue with privacy fit mediating this relationship.ConclusionThe influence of privacy fit has so far been largely neglected in research on teleworking, especially during the pandemic. However, its contribution to workers’ wellbeing should be acknowledged in occupational health strategies.

Abstract Background This study sought to identify cognitive and behavioral predictors of COVID‐19 vaccine hesitancy. Specifically, this study examined the effect of anxiety about developing COVID‐19 and proactive coping behavior on the likelihood of reporting COVID‐19 vaccine hesitancy in a sample of adults living in the United States. Methods An online survey of proactive coping strategies, anxiety related to developing COVID‐19, and vaccine hesitancy was administered in October 2020 to 534 adults aged 21–79‐years old. Age, gender, race, self‐rated health, years of education, COVID‐19 knowledge, and perceived constraints were included as covariates. Results Over half of the study participants (56.7%) were COVID‐19 vaccine hesitant. People who were less anxious about developing COVID‐19 were more likely to be vaccine hesitant. A statistically significant COVID‐19 anxiety × proactive coping interaction showed the odds of vaccine hesitancy was highest among individuals with low anxiety about developing COVID‐19 and high proactive coping, whereas vaccine hesitancy was lowest among individuals with high COVID‐19 anxiety and high proactive coping. Conclusion Results support a future‐oriented approach to public health outreach efforts regarding COVID‐19 vaccines. Improvement of proactive coping skills and emphasis on the likelihood of contracting COVID‐19 may be more effective in increasing vaccine uptake than simply restating scientific facts regarding safety or efficacy.

Summary: Background: Mass vaccination has dramatically reduced the incidence of severe COVID-19, with most cases now presenting as self-limiting upper respiratory tract infections. However, those with co-morbidities, the elderly and immunocompromised, as well as the unvaccinated, remain disproportionately vulnerable to severe COVID-19 and its sequelae. Furthermore, as the effectiveness of vaccination wanes with time, immune escape SARS-CoV-2 variants could emerge to cause severe COVID-19. Reliable prognostic biomarkers for severe disease could be used as early indicator of re-emergence of severe COVID-19 as well as for triaging of patients for antiviral therapy. Methods: We performed a systematic review and re-analysis of 7 publicly available datasets, analysing a total of 140 severe and 181 mild COVID-19 patients, to determine the most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients. In addition, we included an independent cohort where blood transcriptomics of COVID-19 patients were prospectively and longitudinally monitored previously, to track the time in which these gene expression changes occur before nadir of respiratory function. Single cell RNA-sequencing of peripheral blood mononuclear cells from publicly available datasets was then used to determine the immune cell subsets involved. Findings: The most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients were MCEMP1, HLA-DRA and ETS1 across the 7 transcriptomics datasets. Moreover, we found significantly heightened MCEMP1 and reduced HLA-DRA expression as early as four days before the nadir of respiratory function, and the differential expression of MCEMP1 and HLA-DRA occurred predominantly in CD14+ cells. The online platform which we developed is publicly available at https://kuanrongchan-covid19-severity-app-t7l38g.streamlitapp.com/, for users to query gene expression differences between severe and mild COVID-19 patients in these datasets. Interpretation: Elevated MCEMP1 and reduced HLA-DRA gene expression in CD14+ cells during the early phase of disease are prognostic of severe COVID-19. Funding: K.R.C is funded by the National Medical Research Council (NMRC) of Singapore under the Open Fund Individual Research Grant (MOH-000610). E.E.O. is funded by the NMRC Senior Clinician-Scientist Award (MOH-000135-00). J.G.H.L. is funded by the NMRC under the Clinician-Scientist Award (NMRC/CSAINV/013/2016-01). S.K. is funded by the NMRC under the Transition Award. This study was sponsored in part by a generous gift from The Hour Glass.

Adenomyosis is a uterine form of endometriosis that poses unique challenges in the management of infertility. Severe pelvic pain and menorrhagia associated with these conditions are commonly managed with intramuscular injections of a gonadotropin-releasing hormone agonist (leuprolide acetate). Since receiving approval by the US Food and Drug Administration in 2018, a novel oral gonadotropin-releasing hormone antagonist, elagolix, has also been increasingly used to manage endometriosis-associated pain. However, the efficacy of elagolix in the treatment of adenomyosis and infertility remains uncertain. In this clinical case of an infertile patient with endometriosis and diminished ovarian reserve, treatment with elagolix effectively controlled her severe endometriosis-related pelvic pain but, surprisingly, failed to prevent concurrent progression of adenomyosis. Subsequently, elagolix was changed to treatment with leuprolide acetate, which led to improvement of adenomyosis in preparation for an embryo transfer during an in vitro fertilization cycle. Women's health providers should be aware that elagolix may not as effectively suppress adenomyosis as leuprolide acetate, particularly in infertility patients undergoing treatment with assisted reproductive technologies.

Abstract Smith‐Lemli‐Opitz syndrome (SLOS) is a relatively common genetic cause of developmental delay and may only present in conjunction with 2,3 toe syndactyly. This case series illustrates a milder phenotype of SLOS, where the predominant findings are neurocognitive in the presence of 2,3 toe syndactyly.

Traditional histological stains, such as hematoxylin-eosin (HE), special stains, and immunofluorescence (IF), have defined myriads of cellular phenotypes and tissue structures in a separate stained section. However, the precise connection of information conveyed by the various stains in the same section, which may be important for diagnosis, is absent. Here, we present a new staining modality-Flow chamber stain, which complies with the current staining workflow but possesses newly additional features non-seen in conventional stains, allowing for (1) quickly switching staining modes between destain and restain for multiplex staining in one single section from routinely histological preparation, (2) real-time inspecting and digitally capturing each specific stained phenotype, and (3) efficiently synthesizing graphs containing the tissue multiple-stained components at site-specific regions. Comparisons of its stains with those by the conventional staining fashions using the microscopic images of mouse tissues (lung, heart, liver, kidney, esophagus, and brain), involving stains of HE, Periodic acid-Schiff, Sirius red, and IF for Human IgG, and mouse CD45, hemoglobin, and CD31, showed no major discordance. Repetitive experiments testing on targeted areas of stained sections confirmed the method is reliable with accuracy and high reproducibility. Using the technique, the targets of IF were easily localized and seen structurally in HE- or special-stained sections, and the unknown or suspected components or structures in HE-stained sections were further determined in histological special stains or IF. By the technique, staining processing was videoed and made a backup for off-site pathologists, which facilitates tele-consultation or -education in current digital pathology. Mistakes, which might occur during the staining process, can be immediately found and amended accordingly. With the technique, a single section can provide much more information than the traditional stained counterpart. The staining mode bears great potential to become a common supplementary tool for traditional histopathology.

A large literature has demonstrated the link between poverty and mental ill-health. Yet, the potential causal effects of poverty alleviation measures on mental disorders are not well-understood. In this systematic review, we summarize the evidence of the effects of a particular kind of poverty alleviation mechanism on mental health: the provision of cash transfers in low- and middle-income countries. We searched eleven databases and websites and assessed over 4,000 studies for eligibility. Randomized controlled trials evaluating the effects of cash transfers on depression, anxiety, and stress were included. All programs targeted adults or adolescents living in poverty. Overall, 17 studies, comprising 26,794 participants in Sub-Saharan Africa, Latin America, and South Asia, met the inclusion criteria of this review. Studies were critically appraised using Cochrane’s Risk of Bias tool and publication bias was tested using funnel plots, egger’s regression, and sensitivity analyses. The review was registered in PROSPERO (CRD42020186955). Meta-analysis showed that cash transfers significantly reduced depression and anxiety of recipients (dpooled = -0.10; 95%-CI: -0.15, -0.05; p

Introduction. The evaluation of the patterns of liver injury, derived from liver chemistry panels, often may narrow on probable causes of the liver insult especially when coupled with clinical history, examination, and other diagnostic tests. Methods. Among people living with and without HIV and attending care, we used the R ratio to evaluate for liver injury patterns. Liver injury patterns were defined as cholestatic (R5). Results. Overall, the proportions of participants with cholestatic liver injury, mixed liver injury, and hepatocellular liver injury were 55%, 34%, and 4%, respectively, with similar distribution when stratified by HIV status. Alcohol use among participants without HIV was associated with all patterns of liver injury (cholestatic liver injury (OR=4.9 CI (1.0-24.2); p=0.054), mixed liver injury (OR=5.3 CI (1.1-27.3); p=0.043), and hepatocellular liver injury (OR=13.2 CI (1.0-167.3); p=0.046)). Increasing age was associated with cholestatic liver injury among participants with HIV (OR=2.3 CI (1.0-5.3); p=0.038). Despite a high hepatitis B prevalence among participants with HIV, there was no association with liver injury. Conclusions. Liver injury is prevalent among both people living with and without HIV in care, and cholestatic liver injury is the most common pattern. Alcohol is associated with all patterns of liver injury and increasing age associated with cholestatic liver injury among people living without HIV and people living with HIV, respectively.

The European Union In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR) introduces companion diagnostics (CDx) as a new legal term. CDx are applied in combination with a medicinal product to identify patient subgroups most likely to benefit from a treatment or who are at increased risk. This new regulation came into full effect on 26 May 2022 and represents the current development in personalized medicine. The implementation of IVDR and CDx is a regulatory challenge in the EU, requiring re-assessment of in vitro diagnostic medical devices (IVD) in terms of their CDx designation. To retrospectively identify IVD biomarker testing applied in clinical trials, a systematic search in the German PharmNet Clinical Trials database was developed. In total 3643 clinical trials conducted between 2004 and 2022 were identified. The results were analyzed in terms of medicinal products, biomarkers, and IVDs. Patient stratification based on biomarker testing mainly takes place in oncology-related trials, and the biomarkers most frequently tested are PD-L1 and HER2. Furthermore, there is a significant overlap between the collected data and non-European national authorities that have already implemented the CDx concept. This analysis could be indicatory of the medicinal products and corresponding IVD tests that could be CDx candidates under the IVDR.

BackgroundThe use of telemedicine has increased dramatically through the COVID-19 pandemic. Although data are available about patient satisfaction with telemedicine, little is known about immigrant patients’ experience. ObjectiveWe sought to investigate patients’ experiences with telehealth compared to in- person visits between immigrants and nonimmigrants. We wanted to identify and describe next visit preferences within the Farmington University of Connecticut Internal Medicine practice to ultimately guide suggestions for more equitable use and accessibility of visit options. MethodsA total of 270 patients including 122 immigrants and 148 nonimmigrants were seen by 4 Internal Medicine providers in an in-person (n=132) or telemedicine (n=138) university practice setting. Patients were queried between February and April 2021, using an adaptation of a previously validated patient satisfaction survey that contained standard questions developed by the Consumer Assessment of Healthcare Providers and Systems Program. Patients seen via in-person visits completed a paper copy of the survey. The same survey was administered by a follow-up phone call for telemedicine visits. Patients surveyed spoke English, Spanish, or Arabic and were surveyed in their preferred language. For televisits, the same survey was read to the patient by a certified translator. The survey consisted of 10 questions on a Likert scale of 1-5. Of them, 9 questions assessed patient satisfaction under the categories of access to care, interpersonal interaction, and quality of care. An additional question asked patients to describe and explain the reasons behind next visit preferences. Survey question responses were compared by paired t tests. ResultsAcross both immigrant and nonimmigrant patient populations, satisfaction with perceived quality of care was high, regardless of visit type (P=.80, P=.60 for televisits and P=.76, P=.37 for in-person visits). During televisits, immigrants were more likely to feel providers spent sufficient time with them (P

Background: Non-HACEK Gram-negative bacilli (NGNB) infective endocarditis (IE) has a growing frequency. We aimed to describe cases of NGNB IE and find associated risk factors. Methods: We conducted a prospective observational study of consecutive patients with definitive IE according to the modified Duke criteria in four institutions in Brazil. Results: Of 1154 adult patients enrolled, 38 (3.29%) had IE due to NGNB. Median age was 57 years, males predominated, accounting for 25/38 (65.8%). Most common etiologies were Pseudomonas aeruginosa and Klebsiella spp. (8 episodes, 21% each). Worsening heart failure occurred in 18/38 (47.4%). Higher prevalence of embolic events was found (55,3%), mostly to the central nervous system 7/38 (18.4%). Vegetations were most commonly on aortic valves 17/38 (44.7%). Recent healthcare exposure was found in 52.6% and a central venous catheter (CVC) in 13/38 (34.2%). Overall mortality was 19/38 (50%). Indwelling CVC (OR 5.93; 95% CI, 1.29 to 27.3; p = 0.017), hemodialysis (OR 16.2; 95% CI, 1.78 to 147; p = 0.008) and chronic kidney disease (OR 4.8; 95% IC, 1.2 to 19.1, p = 0.049) were identified as risk factors for mortality. Conclusions: The rate of IE due to NGNB was similar to that in previous studies. Enterobacterales and P. aeruginosa were the most common etiologies. NGNB IE was associated with central venous catheters, prosthetic valves, intracardiac devices and hemodialysis and had a high mortality rate.

Student social connectedness is indicated to be changing with the increasing digitalisation of universities. This narrative literature review aims to bring new meanings to the hybrid university learning environment (HULE), and to develop a framework for the benefit of student social connectedness by using placemaking theories. It searches through the academic literature for evidence of experience with three attributes of social connectedness: socialising, social support, and sense of belonging, in relation to individuals’ sense of place, bringing a range of outcomes, such as identity development, which might contribute to improved social connectedness. This is then expanded in the HULE by looking at the physical and online spaces, with a focus on liminal space and co-design. The findings show that an overly rigid structure of the HULE can cause negative student social connectedness, with co-design being proposed as a way of creating a tailored and connected learning experience. However, this is underdeveloped for learning environment needs and could be enhanced by applying placemaking theories to map levels of student social connectedness in the physical location and in the more-than-real ‘non-places’. This provides an innovative perspective of the HULE based on student social connectedness, impacting the existing pedagogical approach for university courses.

Apoptosis or programmed cell death is important for multicellular organisms to keep cell homeostasis and for the clearance of mutated or infected cells. Apoptosis can be induced by intrinsic or extrinsic stimuli. The first event in extrinsic apoptosis is the formation of the Death-Inducing Signalling Complex (DISC), where the initiator caspases-8 and -10 are fully activated by several proteolytic cleavage steps and induce the caspase cascade leading to apoptotic cell death. Analysing the processing of procaspases-8 and -10 by Western blot is a commonly used method to study the induction of apoptosis by death receptor stimulation. To analyse procaspase-8 and -10 cleavage, cells are stimulated with a death ligand for different time intervals, lysed and subjected to Western blot analysis using anti-caspase-8 and anti-caspase-10 antibodies. This allows monitoring the caspase cleavage products and thereby induction of apoptosis.