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Tanya Siddiqi, Sandra H Thomas, Robert Chen City of Hope, Department of Hematology and Hematopoietic Cell Transplantation, Duarte, CA, USA Abstract: Brentuximab vedotin (BV) is an antibody-drug conjugate that targets CD30-positive malignancies via an anti-CD30 monoclonal antibody linked to monomethyl auristatin E, a microtubule-disrupting agent, by a protease-cleavable linker. BV has received accelerated approval from the US Food and Drug Administration for the treatment of classical Hodgkin lymphoma that has relapsed either after autologous stem cell transplantation (ASCT) or after two lines of combination chemotherapy in patients ineligible for ASCT, and in systemic anaplastic large cell lymphoma after failure of at least one line of multiagent chemotherapy. Phase I studies in CD30-positive lymphomas have determined the maximum tolerated dose to be 1.8 mg/kg intravenously every 21 days. In relapsed/refractory Hodgkin lymphoma, a pivotal Phase II study of single-agent BV showed an overall response rate of 75%, with 34% complete responses and a median remission duration of 20 months for complete responders. BV has a modest toxicity profile, with peripheral neuropathy as one of the most clinically significant side effects, and this is largely reversible. Therefore, BV is the treatment of choice for patients with relapsed/refractory Hodgkin lymphoma after ASCT or two standard regimens. Ongoing trials are evaluating the role of BV as salvage therapy prior to ASCT and for maintenance after ASCT for patients with relapsed/refractory disease. Keywords: Hodgkin lymphoma, brentuximab vedotin, CD 30, antibody-drug conjugate

Despite more than 20 years since the discovery of the first gas giant planet with an anomalously large radius, the mechanism for planet inflation remains unknown. Here, we report the discovery of K2-132b, an inflated gas giant planet found with the NASA K2 Mission, and a revised mass for another inflated planet, K2-97b. These planets orbit on ≈9 day orbits around host stars that recently evolved into red giants. We constrain the irradiation history of these planets using models constrained by asteroseismology and Keck/High Resolution Echelle Spectrometer spectroscopy and radial velocity measurements. We measure planet radii of 1.31 0.11 R J and 1.30 0.07 R J, respectively. These radii are typical for planets receiving the current irradiation, but not the former, zero age main-sequence irradiation of these planets. This suggests that the current sizes of these planets are directly correlated to their current irradiation. Our precise constraints of the masses and radii of the stars and planets in these systems allow us to constrain the planetary heating efficiency of both systems as . These results are consistent with a planet re-inflation scenario, but suggest that the efficiency of planet re-inflation may be lower than previously theorized. Finally, we discuss the agreement within 10% of the stellar masses and radii, and the planet masses, radii, and orbital periods of both systems, and speculate that this may be due to selection bias in searching for planets around evolved stars.

Abstract Introduction The ability to self-assess is a crucial skill in identifying one’s own strengths and weaknesses and in coordinating self-directed learning. The Dunning-Kruger effect occurs when limited knowledge causes individuals to overestimate their competence and underestimate others’, leading to poor self-assessment and unrecognized incompetence. To serve as a foundation for developing strategies to improve self-assessment, the self-assessment abilities of first-semester students were assessed. Methods In the final weeks of the summer 2021, winter 2021/22, and summer 2022 semesters, the academic performance (oral anatomy exam) of first semester students was assessed (0–15 points). Before the exam results were announced, students were asked to self-assess their performance. Results Exam scores (M = 10.64, SD = 2.95) and self-assessed scores (M = 10.38, SD = 2.54) were comparable. The absolute difference between them, as a measure of self-assessment ability ranged from − 9 to + 9 points (M = -0.26, SD = 2.59). Among participants (N = 426), 18.5% assessed themselves accurately, 35.5% overestimated, and 46.0% underestimated their performance. The correlation between actual score and self-assessment was ρ = -0.590 (p

Abstract Traditional anatomical preparations as they are often found in university collections are both historical treasure and moral responsibility of the hosting institutions. These remains not only represent the tradition and history of anatomical science and education, but above all are the remains of human beings and thus should be treated with dignity. While the discussion on public display of historical human remains is ongoing, the responsibility to keep them in an optimal state of preservation is not in question. However, most time-honored anatomical collections do or did not have the financial and/or technical capacity to keep these high standards, underlining the need for exchange of technical know-how between anatomical institutes and the support of restoration/conservation professionals. Here, we present a state-of-the-art conservation and restoration of a fetal natural skeleton from the early twentieth century along with the professional documentation of restoration-measures. Therefore, we used modern photo- and video documentation, including photogrammetry, as well as UV- and x-ray-examinations to record historical and new restoration procedures. We carried out measures to reconstitute the structural stability of the skeleton. Moreover, we replaced lost parts of the left foot skeleton, and critically discuss the legitimacy of body part replacement in historical specimens. We are convinced, that similar cases of insufficiently preserved specimens can be found in most anatomical collections. Therefore, this article is not only intended to document the state-of-the-art conservation and restoration of a natural skeleton, but also serve as an inspiration for similar campaigns in other institutions in the future.

Abstract X-ray amorphous material comprises 15-73 wt.% of sedimentary rocks and eolian sediments in Gale crater. This material is variably siliceous and iron rich but aluminum poor. The presence of volatiles is consistent with the existence of incipient weathering products. To better understand the implications of this material for past aqueous conditions on Mars, here we investigate X-ray amorphous material formation and longevity within terrestrial iron rich soils with varying ages and environmental conditions using bulk and selective dissolution methods, X-ray diffraction, and transmission electron microscopy. Results indicate that in situ aqueous alteration is required to concentrate iron into clay-size fraction material. Cooler climates promote the formation and persistence of X-ray amorphous material whereas warmer climates promote the formation of crystalline secondary phases. Iron rich X-ray amorphous material formation and persistence on Mars are therefore consistent with past cool and relatively wet environments followed by long-term cold and dry conditions.

Essix trays are commonly used within dentistry for the temporary replacement of missing teeth following extraction of dental alveolar trauma. Typically, this procedure is performed easily with the use of an impression of existing arch, denture tooth, and Essix Tray material. This following report is unique due to the complexity of his existing maxillary dentition being restored with a combination of removable and fixed prosthodontics and the location of the fracture occurring within the esthetic zone. Furthermore, the patient's complex medical history and severe gag reflex added additional factors to the rehabilitation of this patient.A 64-year-old Caucasian male presented to the General Practice Residency with fracture of his fixed partial denture (#9-11). Patient's maxillary arch was restored previously using FPD #6-8 and #9-11 with a Kennedy Class I removable partial denture. Opposing dentition was restored with all ceramic zirconia crowns. Secondary caries noted on fractured #11 deemed non-restorable and #9 fractured equigingival with fair prognosis for restoring via NSRCT, post, core and crown. History of Myocardial Infarction within past year and severe gag reflex. Impressions for this patient required the use of intravenous moderate procedural sedation. Consultation with PCP and cardiologist for medical clearance for moderate sedation were obtained and patient was appointed for impressions, records, and extraction of #9 and #11. Patient was offered plans including traditional denture fabrication, implant retained, or implant fixated prosthesis. Patient requested a temporary prosthesis to allow time to make decision on the final plans due to financial considerations.This case report illustrates a unique application of the Essix Appliance for the temporization of this patient. Additionally, this case report shows a proof of concept for using Essix appliances in temporization of patients already restored with removable prosthesis. The final esthetics, function, and retention of the prosthesis were evaluated as adequate and acceptable to the patient. Pt was able to function with this temporary appliance for 3 months and was restored with an immediate maxillary denture. Patient is being seen for follow up to evaluate patient adaptation to the denture.

Synaptic changes are early manifestations of neuronal dysfunction in Huntington's disease (HD). However, the mechanisms by which mutant HTT protein impacts synaptogenesis and function are not well understood. Herein we explored HD pathogenesis in the BACHD mouse model by examining synaptogenesis and function in long term primary cortical cultures. At DIV14 (days in vitro), BACHD cortical neurons showed no difference from WT neurons in synaptogenesis as revealed by colocalization of a pre-synaptic (Synapsin I) and a post-synaptic (PSD95) marker. From DIV21 to DIV35, BACHD neurons showed progressively reduced colocalization of Synapsin I and PSD95 relative to WT neurons. The deficits were effectively rescued by treatment of BACHD neurons with BDNF. The recombinant apical domain of CCT1 (ApiCCT1) yielded a partial rescuing effect. BACHD neurons also showed culture age-related significant functional deficits as revealed by multielectrode arrays (MEAs). These deficits were prevented by BDNF, whereas ApiCCT1 showed a less potent effect. These findings are evidence that deficits in BACHD synapse and function can be replicated in vitro and that BDNF or a TRiC-inspired reagent can potentially be protective against these changes in BACHD neurons. Our findings support the use of cellular models to further explicate HD pathogenesis and potential treatments.

Two traps currently ensnare Heideggerian scholarship: the “language trap” and the “being trap”. To avoid them, the text argues we should follow Heidegger’s important indication that movement (aka ex-sistential becoming or Zeit) determines all forms of meaning (aka the significance of things or Sein). This requires a radical rewriting of the terminology and the structure of Zeitlichkeit in § 65 of Sein und Zeit. The text also argues for moving beyond Heidegger’s early and late formulations of fundamental ontology and into a meta- ontological ethics that would apply to the economic, social, and political worlds in which we live our daily lives.

Direct-acting anti-infective drugs target pathogen-coded gene products and are a highly successful therapeutic paradigm. However, they generally target a single pathogen or family of pathogens, and the targeted organisms can readily evolve resistance. Host-targeted agents can overcome these limitations. One family of host-targeted, anti-infective agents modulate human sirtuin 2 (SIRT2) enzyme activity. SIRT2 is one of seven human sirtuins, a family of NAD+-dependent protein deacylases. It is the only sirtuin that is found predominantly in the cytoplasm. Multiple, structurally distinct SIRT2-targeted, small molecules have been shown to inhibit the replication of both RNA and DNA viruses, as well as intracellular bacterial pathogens, in cell culture and in animal models of disease. Biochemical and X-ray structural studies indicate that most, and probably all, of these compounds act as allosteric modulators. These compounds appear to impact the replication cycles of intracellular pathogens at multiple levels to antagonize their replication and spread. Here, we review SIRT2 modulators reported to exhibit anti-infective activity, exploring their pharmacological action as anti-infectives and identifying questions in need of additional study as this family of anti-infective agents advances to the clinic.

Abstract Nucleation of H2O vapor bubbles in magma requires surpassing a chemical supersaturation threshold via decompression. The threshold is minimized in the presence of a nucleation substrate (heterogeneous nucleation, 100 MPa). The existence of explosively erupted aphyric rhyolite magma staged from shallow (

Abstract We document the presence, composition, and number density (TND) of titanomagnetite nanolites and ultra‐nanolites in aphyric rhyolitic pumice, obsidian, and vesicular obsidian from the 1060 CE Glass Mountain volcanic eruption of Medicine Lake Volcano, California, using magnetic methods. Curie temperatures indicate compositions of Fe2.40Ti0.60O4 to Fe3O4. Rock‐magnetic parameters sensitive to domain state, which is dependent on grain volume, indicate a range of particle sizes spanning superparamagnetic (10 μm) particles. Cylindrical cores drilled from the centers of individual pumice clasts display anisotropy of magnetic susceptibility with prolate fabrics, with the highest degree of anisotropy coinciding with the highest vesicularity. Fabrics within a pumice clast require particle alignment within a fluid, and are interpreted to result from the upward transport of magma driven by vesiculation, ensuing bubble growth, and shearing in the conduit. Titanomagnetite number density (TND) is calculated from titanomagnetite volume fraction, which is determined from ferromagnetic susceptibility. TND estimates for monospecific assemblages of 1,000 nm–10 nm cubes predict 1012 to 1020 m−3 of solid material, respectively. TND estimates derived using a power law distribution of grain sizes predict 1018 to 1019 m−3. These ranges agree well with TND determinations of 1018 to 1020 m−3 made by McCartney et al. (2024), and are several orders of magnitude larger than the number density of bubbles in these materials. These observations are consistent with the hypothesis that titanomagnetite crystals already existed in extremely high number‐abundance at the time of magma ascent and bubble nucleation.

Introduction There is a growing body of research evidencing the detrimental impact of the COVID-19 pandemic on the mental health and well-being of young people. This impact may be worse in low-resource settings, especially those in sub-Saharan Africa, where pandemic impacts may be exacerbated by poverty, limited healthcare access and other health epidemics including HIV. We explored the COVID-19 pandemic impacts on young people living with HIV in Lesotho to understand the experiences of HIV management, well-being, financial stability and education status.Methods Thirty-one semistructured, face-to-face interviews were conducted with young people aged 15–19 years of age living with HIV from eight districts across Lesotho. Interviews were conducted in Sesotho, audio-recorded, later transcribed and translated to English prior to analysis. Analysis consisted of a thematic analysis using principles of constant comparison to explore key and emerging themes.Results Analysis revealed five major themes: ‘financial instability and food insecurity’, ‘challenges to health and well-being’, ‘changing relationship dynamics’, ‘loss of educational opportunities’ and ‘understanding the threat of COVID-19’.Conclusions While participants discussed being able to access antiretroviral therapy, this study highlights the significant impact of the COVID-19 pandemic and associated lockdown measures on the mental health and well-being, financial stability and educational development of young people living with HIV in Lesotho.

Effective pain management is essential for optimal surgical outcomes; however, it can be challenging in patients with a history of opioid use disorder (OUD). Buprenorphine, a partial opioid agonist, is a valuable treatment option for patients with OUD. Initiating buprenorphine treatment in patients concurrently taking opioids can be complex due to potential adverse outcomes like precipitated withdrawal. Evolving guidelines suggest there are benefits to continuing buprenorphine for surgical patients throughout the perioperative period, however situations do arise when buprenorphine has been discontinued. Typically, in this scenario patients would be restarted on buprenorphine after they have fully recovered from post-surgical pain and no longer require opioids for pain control. Unfortunately, holding MOUD may expose the patient to risks such as opioid induced respiratory depression or addiction relapse. In this case series, we discuss a novel method to restart buprenorphine in small incremental doses, known as micro-dosing, while the patient is still taking opioids for pain. We will present two complex clinical cases when this method was used successfully at a tertiary care hospital system.

End-point evaluation of stream health is essential for the quantification of water quality. To this end, many Multi-Metric Indices (MMIs) have been developed to quantify water quality. The most extensive work has occurred in North America and Europe, while other areas of the world are in development. In this study, we compared the use of relevant physical, chemical and biological parameters in MMIs to various other stream health indicators to assess water quality throughout a three-river corridor along the north central Pacific slope of Costa Rica. Analysis of the data suggested MMIs were the best indicators of water quality and, more specifically, insect MMIs were the most predicative. MMIs were also best at pinpointing anthropomorphic impact throughout the corridor. Further, less complex insect MMIs such as compilations of family diversity using Ephemeroptera, Plecoptera and Trichoptera (EPT) orders were equally as predictive as the more complex models. With a need to better understand and use citizen monitors to predict water quality in these tropical environments, less complex insect MMIs show promise as a solution.

The study examines the role of economy, the environment, and the source country’s tourism seasonality in driving the inflow of tourists into Kerala from the top three source countries, viz. the United Kingdom (UK), the United States (US), and France. The methodology employed is the double-log regression technique. It was found that the income of the source countries was merely moderately and selectively related to the predicted variable, while environmental factors, viz. rainfall of the origin countries and the relative temperature, play a decisive role in shaping Kerala’s international tourism. At the same time, relative prices were relevant in explaining Kerala’s international tourism demand. We conclude that Kerala receives more foreign tourists (especially from the advanced economies in Europe and North America) not because the nominal income of the source markets rises but because Kerala’s destinations remain competitive for the tourists from the top three source markets. While climatic factors provide a background for tourism seasonality, it is argued that lower relative prices remain the primary and active force of tourist arrivals.

Background: Breakfast is considered the most important meal of the day, providing essential nutrients and energy needed for daily activities. Skipping breakfast has been associated with various health complications, including impaired cognitive function and increased risk of chronic diseases. Understanding the prevalence and reasons behind breakfast skipping among medical students is crucial for promoting healthy habits and overall well-being. Objectives: This study aimed to determine the proportion of medical students skipping breakfast, assess awareness about the importance of breakfast consumption, and explore associated factors such as gender and academic semester. Methodology: A cross-sectional study was conducted among medical undergraduates at Kasturba Medical College, Mangalore. A semi-structured questionnaire was administered to 285 students from the 2nd, 3rd, and 4th year MBBS classes. Convenience sampling was used, and data were analysed using descriptive statistics and chi-square tests. Results: Of the 285 students surveyed, 53% reported skipping breakfast. Reasons for skipping included waking up late (77.48%), dissatisfaction with available food options (44.37%), and lack of appetite (21.85%). While most students were aware of the negative effects of breakfast skipping on cognitive function and mood, fewer recognized its association with cardiovascular problems and menstrual irregularities. Significant associations were found between breakfast skipping and academic semester, with 6th-semester students exhibiting the highest prevalence. However, no significant gender differences were observed. Conclusion: The study highlights a concerning prevalence of breakfast skipping among medical students, emphasizing the need for targeted interventions to promote healthy breakfast habits.

Abstract Background Armed conflicts impact on the health and well-being of everyone, but its effect on adolescent mental health is a significant, yet under-explored area in global health. Mental health disorders which develop during adolescence often lead to behavioural problems, risky decision-making, under-age substance use and can adversely impact on educational attainment. This study aimed to estimate the prevalence of common mental disorders, substance use and their correlates with social support and resilience among adolescents (age 12–19 years) in Vavuniya; a post-conflict region of Sri Lanka. Methods A population-based cross-sectional study was conducted, with a modified cluster sampling method used for participant selection. Eight culturally adapted instruments were used for data collection. A total of 585 adolescents participated in the study. Analyses were performed using SPSS Version 23 statistical software package. All statistical tests were two-sided (p

Abstract Moving down a hillslope from ridge to valley, soil develops and becomes increasingly weathered. Downslope variation in clay content, organic matter, and porosity should produce concomitant changes in soil strength that influence slope stability and erosion. This has yet to be demonstrated, however, because in situ measurements of soil rheology are challenging and rare. Here we employ a robotic leg as a mechanically sensitive and time‐efficient penetrometer to map soil strength along a canonical temperate hillslope profile. We observe a systematic downslope weakening, and increasing heterogeneity, of soil strength associated with a transition from sand‐rich ridge materials to cohesive valley bottom soil aggregates. Weathering‐induced changes in soil composition lead to physically distinct mechanical behaviors in cohesive soils that depart from the behavior observed for sand. We also demonstrate the promise that legged robots may use their limbs to sense and improve mobility in complex environments, with implications for planetary exploration.

X-ray phase-contrast micro computed tomography using synchrotron radiation (SR PhC-µCT) offers unique 3D imaging capabilities for visualizing microstructure of the human brain. Its applicability for unstained soft tissue is an area of active research. Acquiring images from a tissue block without needing to section it into thin slices, as required in routine histology, allows for investigating the microstructure in its natural 3D space. This paper presents a detailed step-by-step guideline for imaging unstained human brain tissue at resolutions of a few micrometers with SR PhC-µCT implemented at SYRMEP, the hard X-ray imaging beamline of Elettra, the Italian synchrotron facility. We present examples of how blood vessels and neurons appear in the images acquired with isotropic 5 μm and 1 µm voxel sizes. Furthermore, the proposed protocol can be used to investigate important biological substrates such as neuromelanin or corpora amylacea. Their spatial distribution can be studied using specifically tailored segmentation tools that are validated by classical histology methods. In conclusion, SR PhC-µCT using the proposed protocols, including data acquisition and image processing, offers viable means of obtaining information about the anatomy of the human brain at the cellular level in 3D.

BackgroundCutaneous (CL) and mucocutaneous leishmaniasis (MCL) are parasitic diseases caused by parasites of the genus leishmania leading to stigma caused by disfigurations. This study aimed to systematically review the dimensions, measurement methods, implications, and potential interventions done to reduce the CL- and MCL- associated stigma, synthesising the current evidence according to an accepted stigma framework.MethodsThis systematic review followed the PRISMA guidelines and was registered in PROSPERO (ID- CRD42021274925). The eligibility criteria included primary articles discussing stigma associated with CL and MCL published in English, Spanish, or Portuguese up to January 2023. An electronic search was conducted in Medline, Embase, Scopus, PubMed, EBSCO, Web of Science, Global Index Medicus, Trip, and Cochrane Library. The mixed methods appraisal tool (MMAT) was used for quality checking. A narrative synthesis was conducted to summarise the findings.ResultsA total of 16 studies were included. The studies report the cognitive, affective, and behavioural reactions associated with public stigma. Cognitive reactions included misbeliefs about the disease transmission and treatment, and death. Affective reactions encompass emotions like disgust and shame, often triggered by the presence of scars. Behavioural reactions included avoidance, discrimination, rejection, mockery, and disruptions of interpersonal relationships. The review also highlights self-stigma manifestations, including enacted, internalised, and felt stigma. Enacted stigma manifested as barriers to forming proper interpersonal relationships, avoidance, isolation, and perceiving CL lesions/scars as marks of shame. Felt stigma led to experiences of marginalisation, rejection, mockery, disruptions of interpersonal relationships, the anticipation of discrimination, fear of social stigmatisation, and facing disgust. Internalised stigma affected self-identity and caused psychological distress.ConclusionsThere are various manifestations of stigma associated with CL and MCL. This review highlights the lack of knowledge on the structural stigma associated with CL, the lack of stigma interventions and the need for a unique stigma tool to measure stigma associated with CL and MCL.

Due to an increasingly aging population and long-term care available, the number of older adults seeking long-term care facilities is growing. Resident satisfaction indicators have become important measurements of service quality. However, few scoping reviews have investigated the evidence on prevalent resident satisfaction indicators and associated factors. The aim of the study is to summarize the evidence on the types of resident satisfaction indicators utilized in long term care settings in the United States. We searched the PubMed, PsycInfo, AgeLine, MEDLINE, Web of Science for articles that published on resident care satisfaction indicators in long-term care facilities. A total of thirty-three articles provided evidence about the determinants of resident satisfaction in different long-term care settings. The analysis yielded two groups of indicators of resident care satisfaction: multi-factor indicators spanning room, staff, food, care services, activities, laundry, autonomy, finances, overall rating, and those related to single factors of resident satisfaction, including facility factor, resident factors, service program factor, food service factor, and staff factor. Most nursing homes used multi-factor indicators for the benefit of comprehensiveness. Single factor indicators tend to be used in assisted living and other residential aged care communities for getting a clear picture of what specific changes need to be made in certain service area. Combinations of multiple factors and single factor can obtain both a comprehensive satisfaction and detailed information to guide change.Study designA cross sectional survey designThe results indicate that satisfaction with staff care has a moderate and positive effect on all other aspects of resident satisfaction. The relationships among satisfaction components are different for nursing home and hostel residents.

Abstract Background The ShK toxin from Stichodactyla helianthus has established the therapeutic potential of sea anemone venom peptides, but many lineage-specific toxin families in Actiniarians remain uncharacterised. One such peptide family, sea anemone 8 (SA8), is present in all five sea anemone superfamilies. We explored the genomic arrangement and evolution of the SA8 gene family in Actinia tenebrosa and Telmatactis stephensoni, characterised the expression patterns of SA8 sequences, and examined the structure and function of SA8 from the venom of T. stephensoni. Results We identified ten SA8-family genes in two clusters and six SA8-family genes in five clusters for T. stephensoni and A. tenebrosa, respectively. Nine SA8 T. stephensoni genes were found in a single cluster, and an SA8 peptide encoded by an inverted SA8 gene from this cluster was recruited to venom. We show that SA8 genes in both species are expressed in a tissue-specific manner and the inverted SA8 gene has a unique tissue distribution. While the functional activity of the SA8 putative toxin encoded by the inverted gene was inconclusive, its tissue localisation is similar to toxins used for predator deterrence. We demonstrate that, although mature SA8 putative toxins have similar cysteine spacing to ShK, SA8 peptides are distinct from ShK peptides based on structure and disulfide connectivity. Conclusions Our results provide the first demonstration that SA8 is a unique gene family in Actiniarians, evolving through a variety of structural changes including tandem and proximal gene duplication and an inversion event that together allowed SA8 to be recruited into the venom of T. stephensoni.

Objective: To compare the performance of established scoring systems (CURB65, NEWS2, qSOFA, SOFA and REDS) to the newly developed scores (ISARIC 4C, PRIEST and novel COVID-19 severity scores) in mortality prediction for patients with confirmed COVID-19 infection in the emergency department (ED). Method: A retrospective observational cohort study of adult patients attending a teaching hospital ED who fulfilled the criteria for suspected sepsis and tested positive for COVID-19. The scores were calculated for each patient. The primary outcome measure was all-cause in-hospital mortality. Receiver operator characteristic (ROC) curves were generated for each score. The area under the ROC (AUROC) curves were compared to that of the ISARIC 4C score. The cut-off points were determined by the statistical software package. The test characteristics at the cut-off scores were noted. Results: Of the 504 patients studied, 153 (30.5%) died in hospital. The AUROC of the ISARIC 4C score was similar to all of the scores except for the NEWS2 score and qSOFA scores, which were significantly lower. The test characteristics of the different scores were similar. Conclusions: In this single-centre study, the newly developed COVID scores outperformed the NEWS2 and qSOFA scores but did not perform better than the other scores studied.

The BIOFIRE SPOTFIRE Respiratory (R) Panel is a novel, in vitro diagnostic PCR assay with 15 pathogen targets. The runtime is about 15 min which is the shortest among similar panels in the market. We evaluated the performance of the SPOTFIRE R Panel with 151 specimens, including 133 collected from the upper respiratory tract (URT), 13 from the lower respiratory tract (LRT) and 5 external quality assessment program (EQAP) samples. The respiratory specimens were enrolled throughout the first two post-COVID-19 influenza seasons in Hong Kong (March to December 2023). For URT specimens, full concordance was observed between the SPOTFIRE R Panel and the standard-of-care FilmArray Respiratory 2.1 plus Panel (RP2.1plus) for 109 specimens (109/133, 81.95%). After discrepant analysis, the SPOTFIRE R Panel identified more pathogens than the RP2.1plus in 15 specimens and vice versa in 3 specimens. The per-target negative and positive percentage agreement (NPA and PPA) were 92.86–100% except the PPA of adenovirus (88.24%). For LRT and EQAP samples, all results were fully concordant. To conclude, the performance of the SPOTFIRE R Panel was comparable to the RP2.1plus.

Accurately forecasting energy metrics is essential for efficiently managing renewable energy generation. Given the high variability in load and renewable energy power output, this represents a crucial area of research in order to pave the way for increased adoption of low-carbon energy solutions. Whilst the impact of different neural network architectures and algorithmic approaches has been researched extensively, the impact of utilising additional weather variables in forecasts have received far less attention. This article demonstrates that weather variables can have a significant influence on energy forecasting and presents methodologies for using these variables within a long short-term memory (LSTM) architecture to achieve improvements in forecasting accuracy. Moreover, we introduce the use of the seasonal components of the target time series, as exogenous variables, that are also observed to increase accuracy. Load, solar and wind generation time series were forecast one hour ahead using an LSTM architecture. Time series data were collected in five Spanish cities and aggregated for analysis, alongside five exogenous weather variables, also recorded in Spain. A variety of LSTM architectures and hyperparameters were investigated. By tuning exogenous weather variables, a 33% decrease in mean squared error was observed for solar generation forecasting. A 22% decrease in mean absolute squared error (MASE), compared to 24-h ahead forecasts made by the Transmission Service Operator (TSO) in Spain, was also observed for solar generation. Compared to using the target variable in isolation, utilising exogenous weather variables decreased MASE by approximately 10%, 15% and 12% for load, solar and wind generation, respectively. By using the seasonal component of the target variables as an exogenous variable itself, we demonstrated decreases in MASE of 19%, 12% and 8% for load, solar and wind generation, respectively. These results emphasise the significant benefits of incorporating weather and seasonal components into energy-related time series forecasts.

The performance of the Xpert Xpress CoV-2/Flu/RSV plus and Alinity m Resp-4-Plex Assays were evaluated using 167 specimens, including 158 human respiratory specimens and 9 external quality assessment program (EQAP) samples. For respiratory specimens, CoV-2/Flu/RSV plus exhibited perfect agreement with the standard-of-care (SOC) methods (Cohen’s κ: 1, 100% agreement). The overall positive and negative percent agreement (PPA and NPA) were 100%, with 95% confidence intervals of 96.50 to 100% and 85.70 to 100%, respectively. On the other hand, Resp-4-Plex revealed an almost perfect agreement with the SOC methods (Cohen’s κ: 0.92, 97.71% agreement). The overall PPA and NPA were 100% (95.76 to 100%) and 88.46% (70.20 to 96.82%), respectively. For EQAP samples, the results of CoV-2/Flu/RSV plus (9/9) and Resp-4-Plex (4/4) were concordant with the expected results. The experimental limit of detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the lowest (25 copies/mL for both methods), and that of the respiratory syncytial virus was the highest (400 copies/mL for CoV-2/Flu/RSV plus and 100 copies/mL for Resp-4-Plex). Threshold cycle (Ct) value correlation showed a large positive linear association between CoV-2/Flu/RSV plus and Resp-4-Plex, with R-squared values of 0.92–0.97, and on average, the Ct values of CoV-2/Flu/RSV plus were higher than that of Resp-4-Plex by 1.86–2.78, except for Flu A1 target (−0.66). To conclude, the performance of both assay was comparable to the SOC methods for both upper and lower respiratory specimens. Implementation of these rapid assay may reinforce the diagnostic capacity for the post-pandemic co-circulation of SARS-CoV-2 and other respiratory viruses.

Corpora amylacea (CA) are polyglucosan aggregated granules that accumulate in the human body throughout aging. In the cerebrum, CA have been found in proximity to ventricular walls, pial surfaces, and blood vessels. However, studies showing their three-dimensional spatial distribution are sparse. In this study, volumetric images of four human brain stems were obtained with MRI and phase-contrast X-ray microtomography, followed up by Periodic acid Schiff stain for validation. CA appeared as hyperintense spheroid structures with diameters up to 30 μm. An automatic pipeline was developed to segment the CA, and the spatial distribution of over 200,000 individual corpora amylacea could be investigated. A threefold—or higher—density of CA was detected in the dorsomedial column of the periaqueductal gray (860–4,200 CA count/mm3) than in the superior colliculus (150–340 CA count/mm3). We estimated that about 2% of the CA were located in the immediate vicinity of the vessels or in the peri-vascular space. While CA in the ependymal lining of the cerebral aqueduct was rare, the sub-pial tissue of the anterior and posterior midbrain contained several CA. In the sample with the highest CA density, quantitative maps obtained with MRI revealed high R2* values and a diamagnetic shift in a region which spatially coincided with the CA dense region.

Introduction: Preclinical studies have demonstrated the ability of radiation therapy (RT) to augment immune response and tumor control by immune checkpoint inhibitors (ICI). However, numerous clinical trials combining RT and ICI have yielded relatively disappointing results. To improve understanding of optimal use of these therapies, we assessed systemic immune effects of prior RT in patients receiving ICI. Methods and Materials: Pre- and post-ICI blood samples were collected from patients enrolled in a prospective immunotherapy biospecimen protocol. Mutiplex panels of 40 cytokines and 120 autoantibodies (Ab) were analyzed. We identified differences in these parameters according to receipt, timing, and type of prior RT. We calculated P values using the Pearson product-moment correlation coefficient and false discovery rate (FDR) using the Benjamini-Hochberg Procedure. Results: Among 277 total patients, 69 (25%) received RT in the 6 months prior to ICI initiation. Among RT-treated patients, 23 (33%) received stereotactic RT, and 33 (48%) received curative intent RT. There was no significant difference in demographics or type of immunotherapy between patients according to prior RT exposure. Baseline complement C8 Ab and MIP-1d/CCL15 were significantly higher among patients with prior RT. For MIP-1d/CCL15, only prior stereotactic RT was associated with significant differences. Conclusions: Prior RT is associated with few changes in systemic immune parameters in patients receiving ICI. The underlying mechanisms and optimal approach to harnessing the potential synergy of RT and ICI require further prospective clinical investigation.

Summary: Background: Accurate prediction of side-specific extraprostatic extension (ssEPE) is essential for performing nerve-sparing surgery to mitigate treatment-related side-effects such as impotence and incontinence in patients with localised prostate cancer. Artificial intelligence (AI) might provide robust and personalised ssEPE predictions to better inform nerve-sparing strategy during radical prostatectomy. We aimed to develop, externally validate, and perform an algorithmic audit of an AI-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA). Methods: Each prostatic lobe was treated as an individual case such that each patient contributed two cases to the overall cohort. SEPERA was trained on 1022 cases from a community hospital network (Trillium Health Partners; Mississauga, ON, Canada) between 2010 and 2020. Subsequently, SEPERA was externally validated on 3914 cases across three academic centres: Princess Margaret Cancer Centre (Toronto, ON, Canada) from 2008 to 2020; L'Institut Mutualiste Montsouris (Paris, France) from 2010 to 2020; and Jules Bordet Institute (Brussels, Belgium) from 2015 to 2020. Model performance was characterised by area under the receiver operating characteristic curve (AUROC), area under the precision recall curve (AUPRC), calibration, and net benefit. SEPERA was compared against contemporary nomograms (ie, Sayyid nomogram, Soeterik nomogram [non-MRI and MRI]), as well as a separate logistic regression model using the same variables included in SEPERA. An algorithmic audit was performed to assess model bias and identify common patient characteristics among predictive errors. Findings: Overall, 2468 patients comprising 4936 cases (ie, prostatic lobes) were included in this study. SEPERA was well calibrated and had the best performance across all validation cohorts (pooled AUROC of 0·77 [95% CI 0·75–0·78] and pooled AUPRC of 0·61 [0·58–0·63]). In patients with pathological ssEPE despite benign ipsilateral biopsies, SEPERA correctly predicted ssEPE in 72 (68%) of 106 cases compared with the other models (47 [44%] in the logistic regression model, none in the Sayyid model, 13 [12%] in the Soeterik non-MRI model, and five [5%] in the Soeterik MRI model). SEPERA had higher net benefit than the other models to predict ssEPE, enabling more patients to safely undergo nerve-sparing. In the algorithmic audit, no evidence of model bias was observed, with no significant difference in AUROC when stratified by race, biopsy year, age, biopsy type (systematic only vs systematic and MRI-targeted biopsy), biopsy location (academic vs community), and D'Amico risk group. According to the audit, the most common errors were false positives, particularly for older patients with high-risk disease. No aggressive tumours (ie, grade >2 or high-risk disease) were found among false negatives. Interpretation: We demonstrated the accuracy, safety, and generalisability of using SEPERA to personalise nerve-sparing approaches during radical prostatectomy. Funding: None.

Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as opportunistic agents in immunosuppressed patients. We have developed a family of compounds that modulate sirtuin 2, an NAD+-dependent deacylase, and now report the properties of a member of that family, FLS-359. Biochemical and x-ray structural studies show that the drug binds to sirtuin 2 and allosterically inhibits its deacetylase activity. FLS-359 inhibits the growth of RNA and DNA viruses, including members of the coronavirus, orthomyxovirus, flavivirus, hepadnavirus, and herpesvirus families. FLS-359 acts at multiple levels to antagonize cytomegalovirus replication in fibroblasts, causing modest reductions in viral RNAs and DNA, together with a much greater reduction in infectious progeny, and it exhibits antiviral activity in humanized mouse models of infection. Our results highlight the potential of sirtuin 2 inhibitors as broad-spectrum antivirals and set the stage for further understanding of how host epigenetic mechanisms impact the growth and spread of viral pathogens.

Plant defensins are a large family of small cationic proteins with diverse functions and mechanisms of action, most of which assert antifungal activity against a broad spectrum of fungi. The partial mechanism of action has been resolved for a small number of members of plant defensins, and studies have revealed that many act by more than one mechanism. The plant defensin Ppdef1 has a unique sequence and long loop 5 with fungicidal activity against a range of human fungal pathogens, but little is known about its mechanism of action. We screened the S. cerevisiae non-essential gene deletion library and identified the involvement of the mitochondria in the mechanism of action of Ppdef1. Further analysis revealed that the hyperpolarisation of the mitochondrial membrane potential (MMP) activates ROS production, vacuolar fusion and cell death and is an important step in the mechanism of action of Ppdef1, and it is likely that a similar mechanism acts in Trichophyton rubrum.

Plain English Summary All major problems, including complex global problems such as air pollution and pandemics, require reliable data sharing between disciplines in order to respond effectively. Such problems require evidence-informed collaborative methods, multidisciplinary research and interventions in which the people who are affected are involved in every stage. However, there is currently no standardised way to share information about initiatives and problem-solving across and between fields such as health, environment, basic science, manufacturing, education, media and international development. A multi-disciplinary international team of over 100 citizens, experts and data-users has been involved in co-creating STARDIT to help everyone in the world share, find and understand information about collective human actions, which are referred to as ‘initiatives’. STARDIT is an open access data-sharing system to standardise the way that information about initiatives is reported, including information about which tasks were done by different people. Reports can be updated at all stages, from planning to evaluation, and can report impacts in many languages, using Wikidata. STARDIT is free to use, and data can be submitted by anyone. Report authors can be verified to improve trust and transparency, and data checked for quality. STARDIT can help create high-quality standardised information on initiatives trying to solve complex multidisciplinary global problems. Among its main benefits, STARDIT offers those carrying out research and interventions access to standardised information which enables well-founded comparisons of the effectiveness of different methods. This article outlines progress to date; current usage; information about submitting reports; planned next steps and how anyone can become involved.

Abstract Characterizing the microvasculature of the human brain is critical to advance understanding of brain vascular function. Most methods rely on tissue staining and microscopy in two-dimensions, which pose several challenges to visualize the three-dimensional structure of microvessels. In this study, we used an edge-based segmentation method to extract the 3D vasculature from synchrotron radiation phase-contrast microtomography (PC-μCT) of two unstained, paraffin-embedded midbrain region of the human brain stem. Vascular structures identified in PC-μCT were validated with histology of the same specimen. Using the Deriche-Canny edge detector that was sensitive to the boundary between tissue and vascular space, we could segment the vessels independent of signal variations in PC-μCT images. From the segmented volumetric vasculature, we calculated vessel diameter, vessel length and volume fraction of the vasculature in the superior colliculi. From high resolution images, we found the most frequent vessel diameter to be between 8.6–10.2 µm. Our findings are consistent with the known anatomy showing two types of vessels with distinctive morphology: peripheral collicular vessels and central collicular vessels. The proposed method opens up new possibilities for vascular research of the central nervous system using synchrotron radiation PC-μCT of unstained human tissue.

Introduction Sexual health is essential for general health and well-being. Sexual health services for middle-aged and older adults are not prioritised and optimising available services for this population is often overlooked. Not much is known about preferences for accessing sexual health services among middle-aged and older people or level of satisfaction with current services. The aim of this study is to explore preferences for seeking sexual health services among middle-aged and older adults in the UK. This study will use discrete choice experiments (DCEs) including initial qualitative interviews followed by the survey, which have been used as a tool to explore preferences in various health service delivery.Methods and analysis The project will be carried out in two phases. First, we will conduct in-depth semi-structured interviews with 20–30 adults (aged 45+), including disabled people, and those from sexual minority groups resident in the UK. Interviews will explore indications, preferences and factors related to accessing sexual health services. Themes and subthemes emerging from the analysis of the interviews will then be used to design the choice sets and attribute level for the DCEs. For the second phase, for the DCEs, we will design choice sets composed of sexual health service delivery scenarios. The software Ngene will be used to develop the experimental design matrix for the DCE. We will use descriptive statistics to summarise the key sociodemographic characteristics of the study population. Multinomial logit, latent class and mixed logit models will be explored to assess sexual health service preferences and preference heterogeneity.Ethics and dissemination Ethical approval for both parts of this study was granted by the Research and Ethics Committee at the London School of Hygiene & Tropical Medicine. Findings from this study will be disseminated widely to relevant stakeholders via scheduled meetings, webinars, presentations and journal publications.

BackgroundThe recent global outbreak of mpox (monkeypox) has already been declared a public health emergency of international concern by the World Health Organization. Given the health, social, and economic impacts of the COVID-19 pandemic, there is understandable concern and anxiety around the emergence of another infectious disease—especially one about which little is known. ObjectiveWe used Google Trends to explore online health information seeking patterns for mpox in endemic and nonendemic countries and investigated the impact of the publication of the first in-country case on internet search volume. MethodsGoogle Trends is a publicly accessible and free data source that aggregates worldwide Google search data. Google search data were used as a surrogate measure of online health information seeking for 178 days between February 18 and August 18, 2022. Searching data were downloaded across this time period for nonendemic countries with the highest case count (United States, Spain, Germany, United Kingdom, and France) and 5 endemic countries (Democratic Republic of Congo, Nigeria, Ghana, Central African Republic, and Cameroon). Joinpoint regression analysis was used to measure changes in searching trends for mpox preceding and following the announcement of the first human case. ResultsOnline health information seeking significantly increased after the publication of the first case in all the nonendemic countries—United States, Spain, Germany, United Kingdom, and France, as illustrated by significant joinpoint regression models. Joinpoint analysis revealed that models with 3 significant joinpoints were the most appropriate fit for these data, where the first joinpoint represents the initial rise in mpox searching trend, the second joinpoint reflects the start of the decrease in the mpox searching trend, and the third joinpoint represents searching trends’ return to searching levels prior to the first case announcement. Although this model was also found in 2 endemic countries (ie, Ghana and Nigeria), it was not found in Central African Republic, Democratic Republic of Congo, or Cameroon. ConclusionsFindings demonstrate a surge in online heath information seeking relating to mpox after the first in-country case was publicized in all the nonendemic countries and in Ghana and Nigeria among the endemic counties. The observed increases in mpox searching levels are characterized by sharp but short-lived periods of searching before steep declines back to levels observed prior to the publication of the first case. These findings emphasize the importance of the provision of accurate, relevant online public health information during disease outbreaks. However, online health information seeking behaviors only occur for a short time period, and the provision of accurate information needs to be timely in relation to the publication of new case-related information.

ABSTRACT Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.