Evaluation of fear, willingness to seek care, and healthcare delivery preferences for patients with nephrolithiasis during the COVID-19 pandemic.

Background: Although minimal is known about coronavirus disease 2019 (COVID-19)'s impact on patient healthcare perceptions, improved understanding can guide healthcare providers to adequately address patient concerns. This cross-sectional study investigated how fear induced by COVID-19 impacted nephrolithiasis patients' perceptions, decision-making, and preferences for care delivery. Methods: Utilizing the validated Fear of COVID-19 Scale (FCV-19S), patients were surveyed at a single stone clinic during part of the COVID-19 pandemic, 03/2021-04/2022. One-way analysis of variance (ANOVA), Chi-square tests, and multinomial logistic regression evaluated the effect of sociodemographics on responses. Results: Two hundred and four surveys were completed. Mean age was 58±16 years, and 112 (54.9%) were women. Mean FCV-19S was 14.8±5.8 points (range, 7-33). Women and non-Caucasian races were associated with higher fear scores (P<0.01 and P=0.01 respectively). Stone prevention effort was not associated with fear (P=0.38). Poorer self-assessed health status was associated with increased stone prevention efforts (P=0.04). Preference for in-person care was reported in 89% of patients. Willingness to seek care varied by age and education, with decreased likelihood to seek care for middle-aged patients (P=0.04) and increased education (P=0.01). Conclusions: Perceived fear during the COVID-19 pandemic was highly variable in nephrolithiasis patients, with higher fear scores in women and non-Caucasians. Willingness to seek care during the pandemic varied with age, education level, symptom severity, COVID-19 fear, current stone status, and health status. Stone patients greatly preferred in-person medical care over telemedicine during COVID-19. Future studies are needed to further evaluate these health disparities, discrepancies in fear, and comfort in seeking stone-related healthcare to help us better inform health policymakers and provide patient-centered care.

Updating and profiling the natural product-likeness of Latin American compound libraries.

Compound databases of natural products play a crucial role in drug discovery and development projects and have implications in other areas, such as food chemical research, ecology and metabolomics. Recently, we put together the first version of the Latin American Natural Product database (LANaPDB) as a collective effort of researchers from six countries to ensemble a public and representative library of natural products in a geographical region with a large biodiversity. The present work aims to conduct a comparative and extensive profiling of the natural product-likeness of an updated version of LANaPDB and the individual ten compound databases that form part of LANaPDB. The natural product-likeness profile of the Latin American compound databases is contrasted with the profile of other major natural product databases in the public domain and a set of small-molecule drugs approved for clinical use. As part of the extensive characterization, we employed several chemoinformatics metrics of natural product likeness. The results of this study will capture the attention of the global community engaged in natural product databases, not only in Latin America but across the world.

Synthesis and in vitro assessment of the reactivation profile of clinically available oximes on the acetylcholinesterase model inhibited by A-230 nerve agent surrogate.

The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed.

A modified step-ramp-step protocol to prescribe constant-speed exercise in treadmill running.

PURPOSE: This study investigated whether a running-adapted version of the cycling-based "step-ramp-step" (SRS) protocol would improve prediction of V ˙ O2 in treadmill exercise compared to the traditional prescriptive approach. METHODS: Fourteen healthy individuals (6 females; 25 ± 6 years; 66.1 ± 12.7 kg) performed a treadmill-based SRS protocol including a ramp-incremental test to task failure followed by two constant-speed bouts within the moderate-(MODstep-below estimated lactate threshold; θLT), and heavy-intensity domains (HVYstep-between θLT and respiratory compensation point; RCP). Using the uncorrected V ˙ O2-to-speed relationship from the ramp exercise, three constant-speed bouts were performed at 40-50% between: baseline and θLT (CSEMOD); θLT and RCP (CSEHVY); and RCP and peak (CSESEV). For CSEMOD, CSEHVY, and CSESEV measured end-exercise V ˙ O2 was compared to predicted V ˙ O2 based on the: (i) "SRS-corrected" V ˙ O2-to-speed relationship (where MODstep and HVYstep were used to adjust the V ˙ O2 relative to speed); and (ii) linear "uncorrected" data. RESULTS: Average treadmill speeds for CSEMOD and CSEHVY were 7.8 ± 0.8 and 11.0 ± 1.4 km·h-1, respectively, eliciting end-exercise V ˙ O2 of 1979 ± 390 and 2574 ± 540 mL·min-1. End-exercise V ˙ O2 values were not different compared to SRS-predicted V ˙ O2 at CSEMOD (mean difference: 5 ± 166 mL·min-1; p = 0.912) and CSEHVY (20 ± 128 mL·min-1; p = 0.568). The linear "uncorrected" estimates were not different for CSEMOD (- 91 ± 172 mL·min-1; p = 0.068) but lower for CSEHVY (- 195 ± 146 mL·min-1; p < 0.001). For CSESEV (running speed: 13.8 ± 1.7 km·h-1), the end-exercise V ˙ O2 was not different from peak V ˙ O2 achieved during the ramp (3027 ± 682 vs. 2979 ± 655 mL·min-1; p = 0.231). CONCLUSION: In healthy individuals, the SRS protocol more accurately predicts speeds for a target V ˙ O2 compared to traditional approaches.

Neural Stem Cell Relay from B1 to B2 cells in the adult mouse Ventricular-Subventricular Zone.

Neurogenesis and gliogenesis continue in the Ventricular-Subventricular Zone (V-SVZ) of the adult rodent brain. B1 cells are astroglial cells derived from radial glia that function as primary progenitors or neural stem cells (NSCs) in the V-SVZ. B1 cells, which have a small apical contact with the ventricle, decline in numbers during early postnatal life, yet neurogenesis continues into adulthood. Here we found that a second population of V-SVZ astroglial cells (B2 cells), that do not contact the ventricle, function as NSCs in the adult brain. B2 cell numbers increase postnatally, remain constant in 12-month-old mice and decrease by 18 months. Transcriptomic analysis of ventricular-contacting and non-contacting B cells revealed key molecular differences to distinguish B1 from B2 cells. Transplantation and lineage tracing of B2 cells demonstrate their function as primary progenitors for adult neurogenesis. This study reveals how NSC function is relayed from B1 to B2 progenitors to maintain adult neurogenesis.

Co-option of mitochondrial nucleic acid sensing pathways by HSV-1 UL12.5 for reactivation from latent Infection.

Although viruses subvert innate immune pathways for their replication, there is evidence they can also co-opt anti-viral responses for their benefit. The ubiquitous human pathogen, Herpes Simplex Virus-1 (HSV-1), encodes a protein (UL12.5) that induces the release of mitochondrial nucleic acid into the cytosol, which activates immune sensing pathways and reduces productive replication in non-neuronal cells. HSV-1 establishes latency in neurons and can reactivate to cause disease. We found that UL12.5 is required for HSV-1 reactivation in neurons and acts to directly promote viral lytic gene expression during initial exit from latency. Further, the direct activation of innate immune sensing pathways triggered HSV reactivation and compensated for a lack of UL12.5. Finally, we found that the induction of HSV-1 lytic genes during reactivation required intact RNA and DNA sensing pathways, demonstrating that HSV-1 can both respond to and active antiviral nucleic acid sensing pathways to reactivate from a latent infection.

Pan-cortical cellular imaging in freely behaving mice using a miniaturized micro-camera array microscope (mini-MCAM).

Understanding how circuits in the brain simultaneously coordinate their activity to mediate complex ethnologically relevant behaviors requires recording neural activities from distributed populations of neurons in freely behaving animals. Current miniaturized imaging microscopes are typically limited to imaging a relatively small field of view, precluding the measurement of neural activities across multiple brain regions. Here we present a miniaturized micro-camera array microscope (mini-MCAM) that consists of four fluorescence imaging micro-cameras, each capable of capturing neural activity across a 4.5 mm x 2.55 mm field of view (FOV). Cumulatively, the mini-MCAM images over 30 mm 2 area of sparsely expressed GCaMP6s neurons distributed throughout the dorsal cortex, in regions including the primary and secondary motor, somatosensory, visual, retrosplenial, and association cortices across both hemispheres. We demonstrate cortex-wide cellular resolution in vivo Calcium (Ca 2+ ) imaging using the mini-MCAM in both head-fixed and freely behaving mice.

Network ecology: Tie fitness in social context(s).

Social relations are embedded in material, cultural, and institutional settings that affect network dynamics and the resulting topologies. For example, romantic entanglements are subject to social and cultural norms, interfirm alliances are constrained by country-specific legislation, and adolescent friendships are conditioned by classroom settings and neighborhood effects. In short, social contexts shape social relations and the networks they give rise to. However, how and when they do so remain to be established. This paper presents network ecology as a general framework for identifying how the proximal environment shapes social networks by focusing interactions and social relations, and how these interactions and relations in turn shape the environment in which social networks form. Tie fitness is introduced as a metric that quantifies how well particular dyadic social relations would align with the setting. Using longitudinal networks collected on two cohorts each in 18 North American schools, i.e., 36 settings, we develop five generalizable observations about the time-varying fitness of adolescent friendship. Across all 252 analyzed networks, tie fitness predicted new tie formation, tie longevity, and tie survival. Dormant fit ties cluster in relational niches, thereby establishing a resource base for social identities competing for increased representation in the relational system.

Diethyl phthalate and dibutyl phthalate disrupt sirtuins expression in the HepG2 cells.

Background: Phthalates are additives used as plasticizers among other uses, classified as endocrine disruptors and may contribute to some metabolic disorders. The aim of this work was to determine the effect of the exposure of diethyl phthalate (DEP) and dibutyl phthalate (DBP) on cell viability and reactive oxygen species (ROS) production, as well as the regulation of sirloins in HepG2 cells. Methods: HepG2 cells were exposed to DEP or DBP at 0.1, 1, 10 and 100 µg/mL, and after 48 or 72 h the gene and protein expression of sirtuins was quantified by qRT-PCR and Western-Blot, respectively. Results: Results showed that even at a low concentration of 0.1 µg/mL DEP affected the expression of Sirt3 and Sirt4, whereas DBP at 0.1 µg/mL affected Sirt3 and Sirt5 gene expression. Protein analysis showed a reduction in Sirt1 levels at a DEP concentration of 1 µg/mL and higher, while DBP at higher dose (100 µg/mL) decreased Sirt3 protein levels. Cell viability decreased by 20% only at higher dose (100 µg/mL) and ROS production increased at 10 and 100 µg/mL for both phthalates. Conclusion: These findings indicate that exposure to low concentrations (0.1 µg/mL) of DEP or DBP can negatively influence the expression of some sirtuins.

The hydrophobicity of the CARD8 N-terminus tunes inflammasome activation.

Mounting evidence indicates that proteotoxic stress is a primary activator of the CARD8 inflammasome, but the complete array of signals that control this inflammasome have not yet been established. Notably, we recently discovered that several hydrophobic radical-trapping antioxidants (RTAs), including JSH-23, potentiate CARD8 inflammasome activation through an unknown mechanism. Here, we report that these RTAs directly alkylate several cysteine residues in the N-terminal disordered region of CARD8. These hydrophobic modifications destabilize the repressive CARD8 N-terminal fragment and accelerate its proteasome-mediated degradation, thereby releasing the inflammatory CARD8 C-terminal fragment from autoinhibition. Consistently, we also found that unrelated (non-RTA) hydrophobic electrophiles as well as genetic mutation of the CARD8 cysteine residues to isoleucines similarly potentiate inflammasome activation. Overall, our results not only provide further evidence that protein folding stress is a key CARD8 inflammasome-activating signal, but also indicate that the N-terminal cysteines can play key roles in tuning the response to this stress.

Sports and Recreation-Related Wrist Fractures: An Epidemiological Study.

Background Wrist fractures have increased over the past several decades. The objective of this study was to identify all-cause and sports-related incidence rates of wrist fractures presenting to emergency departments (EDs) in the United States (U.S.) from 2013 to 2022. A secondary aim of the study was to identify if wrist fractures significantly decreased during 2020. Methodology The National Electronic Injury Surveillance System database was queried to identify the number of wrist fractures presenting to U.S. EDs from 2013 to 2022. Incidence rates in 100,000 person-years were calculated by sport, age, sex, and year. Results From 2013 to 2022, there were 2,027,131 wrist fractures evaluated at U.S. EDs. Injuries peaked in the 10-14-year-old age group, followed by the 5-9 and 85+-year-old age groups. In total, 1,096,598 were sustained during sports and recreation. Cycling, playgrounds, and skateboarding were the leading sports and recreation-related activities. Sports-related wrist fractures followed a unimodal distribution peaking in the 10-14-year-old age group. Females sustained 52% of wrist fractures overall but only 39% of sports-related wrist fractures. All-terrain vehicle and skateboarding-related wrist fractures significantly increased over the study period. Playground and soccer-related wrist fractures significantly decreased in 2020. Conclusions All-cause wrist fractures presenting to U.S. EDs significantly increased from 2013 to 2022 though sports-related wrist fractures did not. Pediatric males and elderly females are most at risk for wrist fractures overall while sports-related wrist fractures predominate in the pediatric population. Youth sports and recreation officials should be aware of the risks to mitigate the incidence of sports-related wrist fractures.

SARS-CoV-2 transmission in a highly vulnerable population of Brazil: a household cohort study.

Background: Household transmission studies seek to understand the transmission dynamics of a pathogen by estimating the risk of infection from household contacts and community exposures. We estimated within/extra-household SARS-CoV-2 infection risk and associated factors in a household cohort study in one of the most vulnerable neighbourhoods in Rio de Janeiro city. Methods: Individuals ≥1 years-old with suspected or confirmed COVID-19 in the past 30 days (index cases) and household members aged ≥1 year were enrolled and followed at 14 and 28 days (study period November/2020-December/2021). RT-PCR testing, COVID-19 symptoms, and SARS-CoV-2 serologies were ascertained in all visits. Chain binomial household transmission models were fitted using data from 2024 individuals (593 households). Findings: Extra-household infection risk was 74.2% (95% credible interval [CrI] 70.3-77.8), while within-household infection risk was 11.4% (95% CrI 5.7-17.2). Participants reporting having received two doses of a COVID-19 vaccine had lower extra-household (68.9%, 95% CrI 57.3-77.6) and within-household (4.1%, 95% CrI 0.4-16.6) infection risk. Within-household infection risk was higher among participants aged 10-19 years, from overcrowded households, and with low family income. Contrastingly, extra-household infection risk was higher among participants aged 20-29 years, unemployed, and public transportation users. Interpretation: Our study provides important insights into COVID-19 household/community transmission in a vulnerable population that resided in overcrowded households and who struggled to adhere to lockdown policies and social distancing measures. The high extra-household infection risk highlights the extreme social vulnerability of this population. Prioritising vaccination of the most socially vulnerable could protect these individuals and reduce widespread community transmission. Funding: Fundação Oswaldo Cruz, CNPq, FAPERJ, Royal Society, Instituto Serrapilheira, FAPESP.

Radiographic Findings Associated With Mild Hip Dysplasia in 3869 Patients Using a Deep Learning Measurement Tool.

Background: Hip dysplasia is considered one of the leading etiologies contributing to hip degeneration and the eventual need for total hip arthroplasty (THA). We validated a deep learning (DL) algorithm to measure angles relevant to hip dysplasia and applied this algorithm to determine the prevalence of dysplasia in a large population based on incremental radiographic cutoffs. Methods: Patients from the Osteoarthritis Initiative with anteroposterior pelvis radiographs and without previous THAs were included. A DL algorithm automated 3 angles associated with hip dysplasia: modified lateral center-edge angle (LCEA), Tönnis angle, and modified Sharp angle. The algorithm was validated against manual measurements, and all angles were measured in a cohort of 3869 patients (61.2 ± 9.2 years, 57.1% female). The percentile distributions and prevalence of dysplastic hips were analyzed using each angle. Results: The algorithm had no significant difference (P > .05) in measurements (paired difference: 0.3°-0.7°) against readers and had excellent agreement for dysplasia classification (kappa = 0.78-0.88). In 140 minutes, 23,214 measurements were automated for 3869 patients. LCEA and Sharp angles were higher and the Tönnis angle was lower (P < .01) in females. The dysplastic hip prevalence varied from 2.5% to 20% utilizing the following cutoffs: 17.3°-25.5° (LCEA), 9.4°-15.6° (Tönnis), and 41.3°-45.9° (Sharp). Conclusions: A DL algorithm was developed to measure and classify hips with mild hip dysplasia. The reported prevalence of dysplasia in a large patient cohort was dependent on both the measurement and threshold, with 12.4% of patients having dysplasia radiographic indices indicative of higher THA risk.

Multiplexed spatial profiling of Hodgkin Reed-Sternberg cell neighborhoods in classic Hodgkin lymphoma.

PURPOSE: Classic Hodgkin lymphoma (cHL) is a B cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the exceptional scarcity (1-5%) of the malignant Hodgkin Reed-Sternberg (HRS) cells within a network of non-malignant immune cells. Molecular determinants governing the relationship between HRS cells and their proximal microenvironment remain largely unknown. EXPERIMENTAL DESIGN: We performed spatially resolved multiplexed protein imaging and transcriptomic sequencing to characterize HRS cell states, cellular neighborhoods, and gene expression signatures of 23.6 million cells from 36 newly diagnosed Epstein-Barr virus (EBV) positive and EBV-negative cHL tumors. RESULTS: We show that MHC-I expression on HRS cells is associated with immune inflamed neighborhoods containing CD8+ T cells, MHC-II+ macrophages, and immune checkpoint expression (i.e., PD-1 and VISTA). We identified spatial clustering of HRS cells, consistent with the syncytial variant of cHL, and its association with T cell excluded neighborhoods in a subset of EBV-negative tumors. Finally, a subset of both EBV-positive and EBV-negative tumors contained regulatory T cells high neighborhoods harboring HRS cells with augmented proliferative capacity. CONCLUSIONS: Our study links HRS cell properties with distinct immunophenotypes and potential immune escape mechanisms in cHL.

In adults with COVID-19 and severe hypoxemia, lower vs. higher oxygenation targets increased days alive without life support.

SOURCE CITATION: Nielsen FM, Klitgaard TL, Siegemund M, et al; HOT-COVID Trial Group. Lower vs higher oxygenation target and days alive without life support in COVID-19: the HOT-COVID randomized clinical trial. JAMA. 2024;331:1185-1194. 38501214.

Quantitative reagent monitoring in paper-based electrochemical rapid diagnostic tests.

Paper-based rapid diagnostic tests (RDTs) are an essential component of modern healthcare, particularly for the management of infectious diseases. Despite their utility, these capillary-driven RDTs are compromised by high failure rates, primarily caused by user error. This limits their utility in complex assays that require multiple user operations. Here, we demonstrate how this issue can be directly addressed through continuous electrochemical monitoring of reagent flow inside an RDT using embedded graphenized electrodes. Our method relies on applying short voltage pulses and measuring variations in capacitive discharge currents to precisely determine the flow times of injected samples and reagents. This information is reported to the user, guiding them through the testing process, highlighting failure cases and ultimately decreasing errors. Significantly, the same electrodes can be used to quantify electrochemical signals from immunoassays, providing an integrated solution for both monitoring assays and reporting results. We demonstrate the applicability of this approach in a serology test for the detection of anti-SARS-CoV-2 IgG in clinical serum samples. This method paves the way towards "smart" RDTs able to continuously monitor the testing process and improve the robustness of point-of-care diagnostics.

METABOLIC SYNDROME-ASSOCIATED MURINE AORTIC WALL STIFFENING IS ASSOCIATED WITH PREMATURE ELASTIC FIBERS AGING.

Type 2 diabetes (T2D) constitutes a major public health problem, and despite prevention efforts, this pandemic disease is 'one of the deadliest diseases in the world. In 2022, 6.7 million T2D patients died prematurely from vascular complications. Indeed, diabetes increases the risk of myocardial infarction or stroke eightfold. The identification of the molecular actors involved in the occurrence of cardiovascular complications and their prevention are therefore major axes. Our hypothesis is that factors brought into play during physiological aging appear prematurely with diabetes progression. Our study focused on the aging of the extracellular matrix (ECM), a major element in the maintenance of vascular homeostasis. We characterized the morphological and functional aspects of aorta, with a focus on the collagen and elastic fibers of diabetic mice aged from 6 months to non-diabetic mice aged 6 months and 20 months. The comparison with the two non-diabetic models (young and old) highlighted an exacerbated activity of proteases, which could explain a disturbance in the collagen accumulation and an excessive degradation of elastic fibers. Moreover, the generation of circulating elastin-derived peptides reflects premature aging of the ECM. These extracellular elements contribute to the appearance of vascular rigidity, often the origin of pathologies such as hypertension and atherosclerosis. In conclusion, we show that diabetic mice aged 6 months present the same characteristics of ECM wear as those observed in mice aged 20 months. This accelerated aortic wall remodeling could then explain the early onset of cardiovascular diseases and, therefore, the premature death of DT2 patients.

Key Issues in Surgical Residency Education: Recommendations of the Blue Ribbon II Committee Residency Education Subcommittee.

In September 2022, a summit was convened by the American Board of Surgery (ABS) to discuss competency-based reform in surgical education. A key output of that summit was the recommendation that the prior work of the Blue Ribbon I Committee convened 20 years earlier be revived. With leadership from the American College of Surgeons (ACS) and the American Surgical Association (ASA) , the Blue Ribbon Committee (BRC) II was subsequently convened. This paper describes the output of the Residency Education Subcommittee of the BRC II Committee. The Subcommittee organized its work around prioritized themes including curriculum, assessment, and transition to practice. Top recommendations, time-based action steps, potential barriers, and required resources were detailed and vetted through group discussion, broader Committee review and critique, and subsequent refinement. Primary concluding emphases included transitioning to a competency-based training model, facilitating dynamically capable curricular reform emphasizing the digital transformation of surgical care, using predictive analytic assessment strategies to optimize training effectiveness and efficiency, and creating mentorship strategies to govern the transition from training to independent practice in an outcomes-accountable fashion. It was recognized that coordinated efforts across existing organizational structures will be required, informed by dataset integration strategies that meaningfully measure educational and related patient outcomes.

Atypical hemolytic uremic syndrome during induction chemotherapy in neuroblastoma, a rare phenomenon or common congenital predisposition?

Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy sometimes associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury arise due to aberrant complement protein activation in the circulation. A 13-month-old boy with metastatic neuroblastoma (NB) developed aHUS during his first cycle of induction chemotherapy with germline testing revealing a complement factor H (CFH) gene mutation, currently classified as a variant of uncertain significance (VUS). Now he is in disease remission after successful complement blockade therapy, thus highlighting a unique presentation of aHUS in a patient with newly diagnosed NB.