Seasonal environmental transitions and metabolic plasticity in a sea-ice alga from an individual cell perspective.

Sea-ice microalgae are a key source of energy and nutrient supply to polar marine food webs, particularly during spring, prior to open-water phytoplankton blooms. The nutritional quality of microalgae as a food source depends on their biomolecular (lipid:protein:carbohydrate) composition. In this study, we used synchrotron-based Fourier transform infra-red microspectroscopy (s-FTIR) to measure the biomolecular content of a dominant sea-ice taxa, Nitzschia frigida, from natural land-fast ice communities throughout the Arctic spring season. Repeated sampling over six weeks from an inner (relatively stable) and an outer (relatively dynamic) fjord site revealed high intra-specific variability in biomolecular content, elucidating the plasticity of N. frigida to adjust to the dynamic sea ice and water conditions. Environmental triggers indicating the end of productivity in the ice and onset of ice melt, including nitrogen limitation and increased water temperature, drove an increase in lipid and fatty acids stores, and a decline in protein and carbohydrate content. In the context of climate change and the predicted Atlantification of the Arctic, dynamic mixing and abrupt warmer water advection could truncate these important end-of-season environmental shifts, causing the algae to be released from the ice prior to adequate lipid storage, influencing carbon transfer through the polar marine system.

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.

Definition and Epidemiology of Sepsis.

Here we review the epidemiology of sepsis, focusing on its definition, incidence, and mortality, as well as the demographic insights and risk factors that influence its occurrence and outcomes. We address how age, sex, and racial/ethnic disparities impact upon incidence and mortality rates. Sepsis is more frequent and severe among the elderly, males, and certain racial and ethnic groups. Poor socioeconomic status, geographic location, and pre-existing comorbidities also elevate the risk of developing and dying from sepsis. Seasonal variations, with an increased incidence during winter months, is also apparent. We delve into the predictive value of disease severity scores such as the Sequential Organ Failure Assessment score. We also highlight issues relating to coding and administrative data that can generate erroneous and misleading information, and the need for greater consistency. The Sepsis-3 definitions, offering more precise clinical criteria, are a step in the right direction. This overview will, we hope, facilitate understanding of the multi-faceted epidemiological characteristics of sepsis and current challenges.

Identification of unique cell type responses in pancreatic islets to stress.

Diabetes involves the death or dysfunction of pancreatic ß-cells. Analysis of bulk sequencing from human samples and studies using in vitro and in vivo models suggest that endoplasmic reticulum and inflammatory signaling play an important role in diabetes progression. To better characterize cell type-specific stress response, we perform multiplexed single-cell RNA sequencing to define the transcriptional signature of primary human islet cells exposed to endoplasmic reticulum and inflammatory stress. Through comprehensive pair-wise analysis of stress responses across pancreatic endocrine and exocrine cell types, we define changes in gene expression for each cell type under different diabetes-associated stressors. We find that ß-, α-, and ductal cells have the greatest transcriptional response. We utilize stem cell-derived islets to study islet health through the candidate gene CIB1, which was upregulated under stress in primary human islets. Our findings provide insights into cell type-specific responses to diabetes-associated stress and establish a resource to identify targets for diabetes therapeutics.

Rapamycin-encapsulated nanoparticle delivery in polycystic kidney disease mice.

Rapamycin slows cystogenesis in murine models of polycystic kidney disease (PKD) but failed in clinical trials, potentially due to insufficient drug dosing. To improve drug efficiency without increasing dose, kidney-specific drug delivery may be used. Mesoscale nanoparticles (MNP) selectively target the proximal tubules in rodents. We explored whether MNPs can target cystic kidney tubules and whether rapamycin-encapsulated-MNPs (RapaMNPs) can slow cyst growth in Pkd1 knockout (KO) mice. MNP was intravenously administered in adult Pkd1KO mice. Serum and organs were harvested after 8, 24, 48 or 72 h to measure MNP localization, mTOR levels, and rapamycin concentration. Pkd1KO mice were then injected bi-weekly for 6 weeks with RapaMNP, rapamycin, or vehicle to determine drug efficacy on kidney cyst growth. Single MNP injections lead to kidney-preferential accumulation over other organs, specifically in tubules and cysts. Likewise, one RapaMNP injection resulted in higher drug delivery to the kidney compared to the liver, and displayed sustained mTOR inhibition. Bi-weekly injections with RapaMNP, rapamycin or vehicle for 6 weeks resulted in inconsistent mTOR inhibition and little change in cyst index, however. MNPs serve as an effective short-term, kidney-specific delivery system, but long-term RapaMNP failed to slow cyst progression in Pkd1KO mice.

Influence of the agrochemical benomyl on Cryptococcus gattii-plant interaction in vitro and in vivo.

Cryptococcus gattii, an environmental fungus, is one of the agents of cryptococcosis. The influence of agrochemicals on fungal resistance to antifungals is widely discussed. However, the effects of benomyl (BEN) on fungal interaction with different hosts is still to be understood. Here we studied the influence of adaptation to BEN in the interaction with a plant model, phagocytes and with Tenebrio molitor. First, the strain C. gattii L24/01 non-adapted (NA), adapted (A) to BEN, and adapted with further culture on drug-free media (10p) interact with Nicotiana benthamiana, with a peak in the yeast burden on the 7th day post-inoculation. C. gattii L24/01 A and 10p provided lower fungal burden, but these strains increased cell diameter and capsular thickness after the interaction, together with decreased fungal growth. The strains NA and A showed reduced ergosterol levels, while 10p exhibited increased activity of laccase and urease. L24/01 A recovered from N. benthamiana was less engulfed by murine macrophages, with lower production of reactive oxygen species. This phenotype was accompanied by increased ability of this strain to grow inside macrophages. Otherwise, L24/01 A showed reduced virulence in the T. molitor larvae model. Here, we demonstrate that the exposure to BEN, and interaction with plants interfere in the morphophysiology and virulence of the C. gattii.

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.

Trabecular Metal Augments During Complex Primary Total Hip Arthroplasty.

Background: Trabecular metal augments (TMAs) have been extensively used in revision total hip arthroplasty (THA) to address acetabular bone defects. However, limited data exists regarding TMA utilization during primary THA. This study aims to assess the clinical and radiographic outcomes of TMAs used during primary THA. Methods: A single-institution retrospective case series of primary THA patients treated with TMA between 2010 and 2019 was performed. Patient demographics, complications, and revisions were recorded. Cup position, center of rotation, leg length, and radiolucent lines were assessed radiographically. The Kaplan-Meier method was used to compute implant survivorship. Results: Twenty-six patients (30 hips) were included with average age of 52.6 ± 15.3 years (range: 22-78) and mean follow-up of 4.1 ± 2.1 years (range: 2.0-8.9). Most TMAs were indicated for developmental dysplasia of the hip (n = 18; 60.0%). On average, hip center of rotation was lowered 1.5 ± 1.3 cm and lateralized 1.2 ± 1.5 cm, while leg length and global offset were increased by 2.4 ± 1.2 cm and 0.4 ± 1.0 cm, respectively. At final follow-up, 3 hips (10.0%) required revision: one (3.3%) for aseptic loosening and 2 (6.7%) for instability. No patients had progressive radiolucent lines at final follow-up. Five-year survival with aseptic loosening and all-cause revision as endpoints was 100% (95% confidence interval: 90.0%-100.0%) and 92.1% (95% confidence interval: 81.3%-100.0%), respectively. One patient required revision for aseptic loosening after the 5-year mark. Conclusions: Trabecular metal augmentation during primary THA demonstrates satisfactory early to mid-term outcomes. TMA is a viable option for complex primary THA when bone loss is encountered or secondary support is required. Level of Evidence: Level IV.

Correction: Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

[This corrects the article DOI: 10.1371/journal.pone.0140310.].

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.

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.

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.

Perifollicular Melanocyte Regeneration in Bullous Pemphigoid.

Bullous pemphigoid (BP) is an autoimmune skin disorder that causes fluid-filled blisters to appear on various body parts, often preceded by urticaria and pruritis. This case report describes the perifollicular melanocyte regeneration within diseased areas in a skin of color patient with BP. By reviewing the various pathologies that can result in melanocyte destruction and the basic science of melanocyte regeneration, we can better identify and explain this phenomenon to patients and lead to earlier diagnoses. Furthermore, due to the lack of published information on skin conditions in skin of color patients, this report can assist in raising awareness of an atypical BP presentation in the dermatological community.

SigmaR1 shapes rough endoplasmic reticulum membrane sheets.

Rough endoplasmic reticulum (ER) sheets are a fundamental domain of the ER and the gateway into the secretory pathway. Although reticulon proteins stabilize high-curvature ER tubules, it is unclear whether other proteins scaffold the flat membranes of rough ER sheets. Through a proteomics screen using ER sheet-localized RNA-binding proteins as bait, we identify the sigma-1 receptor (SigmaR1) as an ER sheet-shaping factor. High-resolution live cell imaging and electron tomography assign SigmaR1 as an ER sheet-localized factor whose levels determine the amount of rough ER sheets in cells. Structure-guided mutagenesis and in vitro reconstitution on giant unilamellar vesicles further support a mechanism whereby SigmaR1 oligomers use their extended arrays of amphipathic helices to bind and flatten the lumenal leaflet of ER membranes to oppose membrane curvature and stabilize rough ER sheets.

Spontaneous cerebrovascular reactivity at rest in older adults with and without mild cognitive impairment and memory deficits.

Background: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment. Methods: 161 older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's biomarkers, and brain MRI. Spontaneous CVR was quantified during 5 minutes of rest. Results: Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for Alzheimer's biomarkers and vascular risk factors. Conclusion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, indicating medial temporal microvascular dysfunction's role in cognitive decline.

A standardized approach to evaluate effectiveness of aerobic exercise training interventions in cardiovascular disease at the individual level.

BACKGROUND: Reliable change indices can determine pre-post intervention changes at an individual level that are greater than chance or practice effect. We applied previously developed minimal meaningful change (MMCRCI) scores for oxygen uptake (V̇O2) values associated with estimated lactate threshold (θLT), respiratory compensation point (RCP), and peak oxygen uptake (V̇O2peak) to evaluate the effectiveness of exercise training in cardiovascular disease patients. METHODS: 303 patients (65 ± 11 yrs.; 27% female) that completed a symptom-limited cardiopulmonary exercise test (CPET) before and after 6-months of guideline-recommended exercise training were assessed to determine absolute and relative V̇O2 at θLT, RCP, and V̇O2peak. Using MMCRCI ∆V̇O2 scores of ±3.9 mL·kg-1·min-1, ±4.0 mL·kg-1·min-1, and ± 3.6 mL·kg-1·min-1 for θLT, RCP, and V̇O2peak, respectively, patients were classified as "positive" (ΔθLT, ΔRCP, and/or ΔV̇O2peak ≥ +MMCRCI), "non-" (between ±MMCRCI), or "negative" responders (≤ -MMCRCI). RESULTS: Mean RCP (n = 86) and V̇O2peak (n = 303) increased (p < 0.05) from 19.4 ± 3.6 mL·kg-1·min-1 and 18.0 ± 6.3 mL·kg-1·min-1 to 20.1 ± 3.8 mL·kg-1·min-1 and 19.2 ± 7.0 mL·kg-1·min-1 at exit, respectively, whereas θLT (n = 140) did not change (15.5 ± 3.4 mL·kg-1·min-1 versus 15.7 ± 3.8 mL·kg-1·min-1, p = 0.324). For changes in θLT, 6% were classified as "positive" responders, 90% as "non-responders", and 4% as "negative" responders. For RCP, 10% exhibited "positive" changes, 87% were "non-responders", and 2% were "negative" responders. For ΔV̇O2peak, 57 patients (19%) were classified as "positive" responders, 229 (76%) as "non-responders", and 17 (6%) as "negative" responders. CONCLUSION: Most patients that completed the exercise training program did not achieve reliable improvements greater than that of chance or practice at an individual level in θLT, RCP and V̇O2peak.

Bronchoscopy with and without needle-based confocal laser endomicroscopy for peripheral lung nodule diagnosis: protocol for a multicentre randomised controlled trial (CLEVER trial).

INTRODUCTION: Despite many technological advances, the diagnostic yield of bronchoscopic peripheral lung nodule analysis remains limited due to frequent mispositioning. Needle-based confocal laser endomicroscopy (nCLE) enables real-time microscopic feedback on needle positioning, potentially improving the sampling location and diagnostic yield. Previous studies have defined and validated nCLE criteria for malignancy, airway and lung parenchyma. Larger studies demonstrating the effect of nCLE on diagnostic yield are lacking. We aim to investigate if nCLE-imaging integrated with conventional bronchoscopy results in a higher diagnostic yield compared with conventional bronchoscopy without nCLE. METHODS AND ANALYSIS: This is a parallel-group randomised controlled trial. Recruitment is performed at pulmonology outpatient clinics in universities and general hospitals in six different European countries and one hospital in the USA. Consecutive patients with a for malignancy suspected peripheral lung nodule (10-30 mm) with an indication for diagnostic bronchoscopy will be screened, and 208 patients will be included. Web-based randomisation (1:1) between the two procedures will be performed. The primary outcome is diagnostic yield. Secondary outcomes include diagnostic sensitivity for malignancy, needle repositionings, procedure and fluoroscopy duration, and complications. Pathologists will be blinded to procedure type; patients and endoscopists will not. ETHICS AND DISSEMINATION: Primary approval by the Ethics Committee of the Amsterdam University Medical Center. Dissemination involves publication in a peer-reviewed journal. SUPPORT: Financial and material support from Mauna Kea Technologies. TRIAL REGISTRATION NUMBER: NCT06079970.

Motivating parents to protect their children from wildfire smoke: the impact of air quality index infographics.

Background. Wildfire smoke events are increasing in frequency and intensity due to climate change. Children are especially vulnerable to health effects even at moderate smoke levels. However, it is unclear how parents respond to Air Quality Indices (AQIs) frequently used by agencies to communicate air pollution health risks. Methods. In an experiment (3 × 2 × 2 factorial design), 2,100 parents were randomly assigned to view one of twelve adapted AQI infographics that varied by visual (table, line, gauge), index type (AQI [0-500], AQHI [1-11+]), and risk level (moderate, high). Participants were told to imagine encountering the infographic in a short-term exposure scenario. They reported worry about wildfire smoke, intentions to take risk-mitigating actions (e.g., air purifier use), and support for various exposure reduction policies. Subsequently, participants were told to imagine encountering the same infographic daily during a school week in a long-term exposure scenario and again reported worry, action intentions, and policy support. Results. Parents' responses significantly differentiated between risk levels that both pose a threat to children's health; worry and action intentions were much higher in the high-risk group than the moderate-risk group in both short-exposure (F = 748.68 p<.001; F = 411.59, p<.001) and long-exposure scenarios (F = 470.51, p<.001; F = 212.01, p<.001). However, in the short-exposure scenario, when shown the AQHI [1-11+] with either the line or gauge visuals, parents' action intentions were more similar between moderate- and high-risk level groups (3-way interaction, F = 6.03, p = .002). Conclusions. These results suggest some index formats such as the AQHI-rather than the AQI-may better attune parents to moderate levels of wildfire smoke being dangerous to children's health. Our research offers insights for agencies and officials seeking to improve current public education efforts during wildfire smoke events and speaks to the critical need to educate parents and help them act short-term and long-term to protect children's health.