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Abstract Background End-stage renal disease is a growing global health issue, disproportionately impacting low- and middle-income countries. While kidney transplantation remains the best treatment for end-stage renal disease, access to this treatment modality is limited by chronic donor organ shortages. To address this critical need, we are developing transplantable bioengineered kidney grafts. Methods Podocyte differentiation was achieved in adherent monoculture through Wnt and TGF-β inhibition with IWR-1 and SB431542, respectively. Podocytes along with endothelial cells were then used to recapitulate glomeruli within decellularized porcine kidney scaffolds to generate bioengineered kidneys grafts. These bioengineered kidney grafts were functionally assessed via normothermic perfusion which compared kidney grafts recellularized with only endothelial cells as a control to bi-culture kidney grafts comprised of endothelial cells and podocytes. Heterotopic implantation further tested bi-culture kidney graft function over 3 successive implant sessions with 1–2 grafts per session. Results We demonstrate the ability to source primary human podocytes at scale. Decellularized porcine kidney grafts repopulated with podocytes and endothelial cells exhibit native glomerular structure and display blood filtration capabilities during normothermic perfusion testing. Extending these findings to a clinically relevant model, bioengineered kidneys produce urine with indices of filtration when heterotopically implanted in pigs. Conclusions Our results showcase a human-scale, transplantable bioengineered kidney capable of performing requisite filtration function. This study reinforces the possibility for the bioengineering of transplantable human kidneys, which could someday provide increased and more equitable access to kidney grafts for the treatment of end-stage renal disease.

ABSTRACT Objective Ultrasound (US) is a well‐established imaging modality for the evaluation of head and neck anatomy. The Butterfly iQ is a handheld ultrasound device that uses a semiconductor silicon chip array (capacitive micromachined ultrasound transducers, CMUT) instead of piezoelectric crystals used by traditional ultrasounds (TUS), but its accuracy has not been investigated with respect to salivary gland imaging and associated transcutaneous procedures. We aimed to perform a pilot cadaver study to determine the utility and fidelity of the CMUT‐US for parotid and submandibular gland imaging and guiding transcutaneous gland injection. Methods One otolaryngologist injected 0.5 mL of dye into three distinct salivary gland sites (two intraparotid sites and one submandibular gland site) bilaterally on 20 cadavers (n = 120 glands), using either CMUT‐US or TUS to guide injection. The cadavers were dissected to identify whether the dye was accurately injected into each site. Results The accuracies of CMUT‐US and TUS‐guided injections in the parotid gland were 95.0% (n = 40) and 90.0% (n = 40), respectively (p = 0.69). In the submandibular gland, the accuracies for the CMUT‐US (n = 20) and TUS (n = 20) were both 75.0% (p = 0.72). Across all salivary gland sites, injection accuracy was 88.3% (n = 60) using TUS versus 85.0% (n = 60) using CMUT‐US (p = 0.79). No significant differences between modalities were seen in the accuracy of injection based on injection subsite, laterality, cadaver sex, or age. Conclusion This pilot study demonstrates that CMUT‐US‐guided salivary gland injection offers similar high accuracy and reproducibility to TUS‐guided injection. Level of Evidence V.

This paper presents a first connectedness analysis using the novel Climate Policy Uncertainty Index (CUI) proposed by Gavriilidis (2021), Green equity and bonds (GE and GB – Green investments), and Dirty equity and bonds (DE and DB – dirty investments). Using data covering the years from 2007 to 2021, we show that the effect of climate policy uncertainty as measured by the CUI is far from constant through time. While static analysis indicates that green investments are isolated from fluctuations in the CUI, an inspection from a dynamic perspective shows that CUI is mostly a transmitter of shocks. This role as a transmitter is evident primarily in two crises since 2008: the subprime crisis and the European debt crisis. Interestingly, during recent years, the influence of climate change policy uncertainty as measured by the CUI has weakened, and it has even become a net recipient of shocks.

Background Adequate venous drainage of brain parenchyma is essential to maintain cerebral perfusion and clearance of cerebrospinal fluid. The cortical vein opacification score (COVES) is a radiographic metric calculated from a computed tomography angiogram that provides a measure of venous drainage using 3 cortical veins in each hemisphere. Emerging evidence indicates that longitudinal declines in COVES correlates with poor outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), but the clinical factors associated with a low COVES, and the relationship between COVES and other outcomes remains poorly understood. Methods We performed a single‐center retrospective analysis of 54 patients with aSAH to characterize the relationship between the COVES score and radiographic vasospasm. Results We found that patients with high‐grade aSAH (Hunt and Hess 4–5) had worse cortical venous drainage (mean total COVES±SEM, 10.2±0.2, n = 21) compared with patients with lower grade aSAH (Hunt and Hess 2–3, n = 33, 9.5±0.3, P

Summary: Perineural invasion (PNI) is a significant risk factor for cancer recurrence and metastasis; however, its mechanisms relating to cancer aggressiveness remain poorly understood. Here, we present a protocol for a non-surgical model of PNI in mice using a neurotropic melanoma cell line that migrates from the skin to the sciatic nerve. We describe the steps for cell culture and injection, tumor burden measurements, mouse euthanasia, and tissue dissection. We then detail procedures for sample cross-section and confocal imaging. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Cover cropping has the potential to generate private economic benefits to farm operations as well as larger-scale environmental benefits to the broader community. However, cover crop adoption remains limited in the United States (US) (i.e., 4.7 % in 2022 (USDA-NASS, 2024)), primarily due to uncertainty in economic outcomes, with several studies showing potentially negative net returns from cover crop use in the short-term (1–3 years). This study investigates the medium-term (5–7 years) economic impact of cover crop adoption using plot-level data from field experiments in the state of Maryland. The empirical analysis employs ordinary least squares (OLS) statistical models and partial budgeting techniques to achieve the study objective. Our results show that cover crops do not have a statistically significant effect on crop yield, fertilizer costs, or pesticide costs, but we find that cover crop use statistically increases field operation and seed expenses. As a result, the private net return from cover crop adoption in the medium term is generally negative based on the Maryland field trial data used in the analysis. Specifically, the average net return per acre with cover crops is approximately $60-$90 lower for corn and around $60 lower for soybeans compared to fields without cover crops. This empirical finding suggests that public support through incentive payments may help further incentivize cover crop adoption in the US, which can then provide environmental and ecosystem services that are of benefit to the general public.

Background: Provisional Tic Disorder (PTD) is common in childhood. The received wisdom among clinicians is that PTD is short-lived and mild, with at most a few tics, and rarely includes complex tics, premonitory phenomena or comorbid illnesses. However, such conclusions come from clinical experience, with biased ascertainment and limited follow-up. Methods: Prospective study of 89 children with tics starting 0–9 months ago (median 4 months), fewer than half from clinical sources. Follow-up at 12 (± 24, 36, 48) months after the first tic. Results: At study entry, many children had ADHD (39), an anxiety disorder (27), OCD (9) or enuresis (17). All had at least two current tics, with a mean total since onset of 6.9 motor and 2.0 phonic tics. Forty-one had experienced a complex tic, and 69 could suppress some tics. Tics were clinically meaningful: 64 had tics severe enough for a clinical trial, and 76 families sought medical attention for the tics.At 12 months, 79 returned, and 78 still had tics. Of these, 29 manifested no tics during history and extended examination, but only via audio-visual monitoring when the child was seated alone. Only 12/70 now had plans to see a doctor for tics. Most who returned at 2–4 years still had tics known to the child and family, but medical impact was low. Conclusions: Our results do not contradict previous data, but overturn clinical lore. The data strongly argue against the longstanding but arbitrary tradition of separating tic disorders into recent-onset versus chronic.

Intermittent fasting (IF), a dietary pattern alternating between eating and fasting periods within a 24-hour cycle, has garnered recognition for its potential to enhance both healthspan and lifespan in animal models and humans. It also shows promise in alleviating age-related diseases, including neurodegeneration. Vascular cognitive impairment (VCI) spans a severity range from mild cognitive deficits to severe cognitive deficits and loss of function in vascular dementia. Chronic cerebral hypoperfusion has emerged as a significant contributor to VCI, instigating vascular pathologies such as microbleeds, blood-brain barrier dysfunction, neuronal loss, and white matter lesions. Preclinical studies in rodents strongly suggest that IF has the potential to attenuate pathological mechanisms, including excitotoxicity, oxidative stress, inflammation, and cell death pathways in VCI models. Hence, this supports evaluating IF in clinical trials for both existing and at-risk VCI patients. This review compiles existing data supporting IF’s potential in treating VCI-related vascular and neuronal pathologies, emphasizing the mechanisms by which IF may mitigate these issues. Hence providing a comprehensive overview of the available data supporting IF’s potential in treating VCI by emphasizing the underlying mechanisms that make IF a promising intervention for VCI.

Abstract People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.

Abstract Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we perform single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Helicobacter pylori is a class I carcinogen that infects more than 100 million individuals in the United States. Antimicrobial therapy for H. pylori has typically been prescribed empirically rather than based on susceptibility testing. Until recently, therapeutic recommendations have generally ignored the principles of antibiotic stewardship. A combination of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin (triple therapy) remains popular despite increasing clarithromycin resistance and poor cure rates. Concomitant therapy (a PPI, amoxicillin, clarithromycin, and metronidazole) is recommended and widely used despite all patients receiving at least one unneeded antibiotic. In 2020, the Food and Drug Administration approved vonoprazan, amoxicillin, and clarithromycin triple therapy, which administers unneeded clarithromycin to >90% of patients (i.e., ~6 tons of unneeded clarithromycin/million treatments). In the late 1980s, the infectious disease community functionally transferred responsibility for the management of H. pylori to gastroenterology, which has managed the infection as another common gastrointestinal disease such as constipation. In 2022, both traditional and noninvasive molecular-based susceptibility testing for H. pylori became available in the United States. In order to reduce and prevent antibiotic misuse, the infectious disease community should reclaim responsibility for the management of this important infectious disease.

This article examines how Reformed pastors’ understanding and exercise of their office shaped their response to Anabaptists living in rural parishes of the Swiss Confederation in the seventeenth century. In the wake of Swiss reformations, illicit Anabaptist communities continued to represent a threat to territorial religious unity and the Reformed clergy’s spiritual leadership, but the precise contours of their activity and social influence at a village level remained obscure. In the absence of a clear picture of dissent, Reformed churchmen endeavored to make Anabaptism visible, employing tools of information management, into which their training had initiated them. A series of cases from rural jurisdictions (the counties (Landvogteien) of Kyburg and Grüningen) and a seat of ecclesiastical power (Zurich) illustrate how documentary production, organization, and activation consistently drove this project forward. These means rendered Anabaptist life perceptible, facilitating and justifying its elimination by Reformed governments.

Abstract Corona ionizers are used to enhance the effectiveness of indoor air cleaners, remove odors, and to promote inactivation of viruses attached to airborne particles. However, there is limited experimental evidence of the effectiveness of ions in indoor air quality, and many commercial products have ambiguous or misleading performance statements. This study measured the effect of corona generated ions on particle wall deposition and on the performance of air cleaning systems. The experiments measured the indoor particle concentration decay of a polydisperse NaCl aerosol as a function of time for a variety of indoor room conditions including: (1) zero ventilation in the room, (2) HVAC system (100% outdoor air) at fixed flow rate, (3) Indoor air cleaners at different flow settings. For the zero-ventilation case, unipolar ions enhance wall particle deposition by a factor of 2, while bipolar ions do not enhance particle wall deposition. For the HVAC system and indoor air cleaners, the aerosol decay rates in the room increased by 10 to 30%, depending on the operating conditions. Ion and ozone concentrations were also measured in the room. This work demonstrates that unipolar ions can help improve indoor air quality, particularly in poorly ventilated environments, and have a measurable modest enhancement of the performance of air cleaning systems.

Purpose: Peer mentorship provides professional and personal support between physicians with similar experiences and levels of training. While peer mentorship has shown to benefit academic success and professional growth, little data has examined contextual factors, such as curricular change, that may affect the quality of these relationships. This study aims to explore the impact of a new, nationwide radiation oncology (RO) residency curriculum, known as competence by design (CBD), on peer mentorship experiences between Canadian RO residents. Methods and Materials: A qualitative study, with a social constructivist approach, was conducted with 2 groups of Canadian RO residents. The first were those in the academic year before CBD implementation (non-CBD cohort), and the second were those in the inaugural year of CBD (CBD cohort). Semistructured 1-on-1 interviews were conducted to explore experiences of peer mentorship as it related to curriculum change. Interviews were transcribed and analyzed with deductive and inductive methods until data saturation. Results: Between April and December 2021, 14 participants (6 non-CBD and 8 CBD residents) from 8 out of 10 eligible English-speaking RO training programs across Canada participated. Three major themes were identified: (1) the CBD cohort identified fewer opportunities for peer mentorship, with specific concerns regarding new evaluation processes and uncertainty about the later stages of training; (2) there was minimal impact on specialty-specific learning; and (3) peer mentorship thrived when occurring as spontaneous in-person interactions. Conclusions: Inaugural residents of a CBD curriculum perceived fewer opportunities for peer mentorship. There were specific concerns about new evaluative processes, though this did not affect specialty-specific learning. Peer mentorship was most impactful as informal and in-person interactions. Our findings suggest that unintended consequences of curriculum change may be mitigated by improving communication about new training objectives and increasing opportunities for informal interactions between residents.

Background Many cardiomyopathy‐associated FLNC pathogenic variants are heterozygous truncations, and FLNC pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood. Methods and Results We describe an individual with biallelic FLNC pathogenic variants, p.Arg650X and c.970‐4A>G, with peripartum cardiomyopathy and ventricular arrhythmias. We also describe clinical findings in probands with FLNC variants including Val2715fs87X, Glu2458Serfs71X, Phe106Leu, and c.970‐4A>G with hypertrophic and dilated cardiomyopathy, atrial fibrillation, and ventricular tachycardia. Induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) were generated. The FLNC truncation, Arg650X/c.970‐4A>G, showed a marked reduction in filamin C protein consistent with biallelic loss of function mutations. To assess loss of filamin C, gene editing of a healthy control iPSC line was used to generate a homozygous FLNC disruption in the actin binding domain. Because filamin C has been linked to protein quality control, we assessed the necessity of filamin C in iPSC‐CMs for response to the proteasome inhibitor bortezomib. After exposure to low‐dose bortezomib, FLNC‐null iPSC‐CMs showed an increase in the chaperone proteins BAG3, HSP70 (heat shock protein 70), and HSPB8 (small heat shock protein B8) and in the autophagy marker LC3I/II. FLNC null iPSC‐CMs had prolonged electric field potential, which was further prolonged in the presence of low‐dose bortezomib. FLNC null engineered heart tissues had impaired function after low‐dose bortezomib. Conclusions FLNC pathogenic variants associate with a predisposition to arrhythmias, which can be modeled in iPSC‐CMs. Reduction of filamin C prolonged field potential, a surrogate for action potential, and with bortezomib‐induced proteasome inhibition, reduced filamin C led to greater arrhythmia potential and impaired function.

Background Colitis caused by checkpoint inhibitors (CPI) is frequent and is treated with empiric steroids, but CPI colitis mechanisms in steroid-experienced or refractory disease are unclear.Methods Using colon biopsies and blood from predominantly steroid-experienced CPI colitis patients, we performed multiplexed single-cell transcriptomics and proteomics to nominate contributing populations.Results CPI colitis biopsies showed enrichment of CD4+resident memory (RM) T cells in addition to CD8+ RM and cytotoxic CD8+ T cells. Matching T cell receptor (TCR) clonotypes suggested that both RMs are progenitors that yield cytotoxic effectors. Activated, CD38+ HLA-DR+ CD4+ RM and cytotoxic CD8+ T cells were enriched in steroid-experienced and a validation data set of steroid-naïve CPI colitis, underscoring their pathogenic potential across steroid exposure. Distinct from ulcerative colitis, CPI colitis exhibited perturbed stromal metabolism (NAD+, tryptophan) impacting epithelial survival and inflammation. Endothelial cells in CPI colitis after anti-TNF and anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) upregulated the integrin α4β7 ligand molecular vascular addressin cell adhesion molecule 1 (MAdCAM-1), which may preferentially respond to vedolizumab (anti-α4β7).Conclusions These findings nominate CD4+ RM and MAdCAM-1+ endothelial cells for targeting in specific subsets of CPI colitis patients.

Abstract Background Tissue environment is critical in determining tumour metabolic vulnerability. However, in vivo drug testing is slow and waiting for tumour growth delay may not be the most appropriate endpoint for metabolic treatments. An in vivo method for measuring energy stress would rapidly determine tumour targeting in a physiologically relevant environment. The sodium-iodide symporter (NIS) is an imaging reporter gene whose protein product co-transports sodium and iodide, and positron emission tomography (PET) radiolabelled anions into the cell. Here, we show that PET imaging of NIS-mediated radiotracer uptake can rapidly visualise tumour energy stress within minutes following in vivo treatment. Methods We modified HEK293T human embryonic kidney cells, and A549 and H358 lung cancer cells to express transgenic NIS. Next, we subjected these cells and implanted tumours to drugs known to induce metabolic stress to observe the impact on NIS activity and energy charge. We used [18F]tetrafluoroborate positron emission tomography (PET) imaging to non-invasively image NIS activity in vivo. Results NIS activity was ablated by treating HEK293T cells in vitro, with the Na+/K+ ATPase inhibitor digoxin, confirming that radiotracer uptake was dependent on the sodium–potassium concentration gradient. NIS-mediated radiotracer uptake was significantly reduced (− 58.2%) following disruptions to ATP re-synthesis by combined glycolysis and oxidative phosphorylation inhibition in HEK293T cells and by oxidative phosphorylation inhibition (− 16.6%) in A549 cells in vitro. PET signal was significantly decreased (− 56.5%) within 90 min from the onset of treatment with IACS-010759, an oxidative phosphorylation inhibitor, in subcutaneous transgenic A549 tumours in vivo, showing that NIS could rapidly and sensitively detect energy stress non-invasively, before more widespread changes to phosphorylated AMP-activated protein kinase, phosphorylated pyruvate dehydrogenase, and GLUT1 were detectable. Conclusions NIS acts as a rapid metabolic sensor for drugs that lead to ATP depletion. PET imaging of NIS could facilitate in vivo testing of treatments targeting energetic pathways, determine drug potency, and expedite metabolic drug development.

Non-invasive imaging of tumors expressing reporter transgenes is a popular preclinical method for studying tumor development and response to therapy in vivo due to its ability to distinguish signal from tumors over background noise. However, the utilized transgenes, such as firefly luciferase, are immunogenic and, therefore, impact results when expressed in immune-competent hosts. This represents an important limitation, given that cancer immunology and immunotherapy are currently among the most impactful areas of research and therapeutic development. Here we present a non-immunogenic preclinical tumor imaging approach. Based on the expression of murine sodium iodide symporter (mNIS), it facilitates sensitive, non-invasive detection of syngeneic tumor cells in immune-competent tumor models without additional immunogenicity arising from exogenous transgenic protein or selection marker expression. NIS-expressing tumor cells internalize the gamma-emitting [99mTc]pertechnetate ion and so can be detected by SPECT (single photon emission computed to-mography). Using a mouse model of pancreatic ductal adenocarcinoma hepatic metastases in immune-competent C57BL/6 mice, we demonstrate that the technique enables the detection of very early metastatic lesions and longitudinal assessment of immunotherapy responses using precise and quantifiable whole-body SPECT/CT imaging.

Abstract Activation of endogenous neural stem cells (NSCs) is greatly significant for the adult neurogenesis; however, it is extremely limited in the spinal cord after injury. Recent evidence suggests that accumulation of protein aggregates impairs the ability of quiescent NSCs to activate. Ubiquitin c-terminal hydrolase l-1 (UCHL1), an important deubiquitinating enzyme, plays critical roles in protein aggregations clearance, but its effects on NSC activation remains unknown. Here, we show that UCHL1 promotes NSC activation by clearing protein aggregates through ubiquitin-proteasome approach. Upregulation of UCHL1 facilitated the proliferation of spinal cord NSCs after spinal cord injury (SCI). Based on protein microarray analysis of SCI cerebrospinal fluid, it is further revealed that C3+ neurotoxic reactive astrocytes negatively regulated UCHL1 and proteasome activity via C3/C3aR signaling, led to increased abundances of protein aggregations and decreased NSC proliferation. Furthermore, blockade of reactive astrocytes or C3/C3aR pathway enhanced NSC activation post-SCI by reserving UCHL1 and proteasome functions. Together, this study elucidated a mechanism regulating NSC activation in the adult spinal cord involving the UCHL1-proteasome approach, which may provide potential molecular targets and new insights for NSC fate regulation.

This study, conducted between 4 October 2013, and 30 November 2018, tested the hypothesis that triple antimicrobial therapy, targeting Mycobacterium avium subspecies paratuberculosis (MAP), long considered a putative cause, would favorably affect Crohn’s disease. A double-blind multicenter study of adults with active Crohn’s disease, (i.e., Crohn’s Disease Activity Index [CDAI] 220–450 plus C-reactive protein ≥ 1.0 mg/dL, fecal calprotectin (FCP) >162.9 µg/g stool, or recent endoscopic or radiographic confirmation of active disease) receiving concomitant standard-of-care Crohn’s disease treatment (Clinicaltrials.gov: NCT01951326) were stratified by anti-tumor necrosis factor use and randomized (1:1) to anti-MAP RHB-104 (clarithromycin 95 mg, rifabutin 45 mg, and clofazimine 10 mg per capsule) (n = 166), resulting in clarithromycin 950 mg/day, rifabutin 450 mg/day, and clofazimine 100 mg/day, or placebo (n = 165) for up to 52 weeks. A greater proportion of RHB-104 versus placebo-treated patients met the primary endpoint—remission (i.e., CDAI < 150)—at week 26 (36.7% [61/166] vs. 22.4% [37/165], respectively; 95% CI for difference: 4.6, 24.0, p = 0.0048; chi-square test). Clinical response (reduction of CDAI by ≥100 points from baseline) at week 26 (first secondary endpoint) was also higher among the patients treated with RHB-104 (73/166 [44.0%]) compared with placebo (50/165 [30.3%]; 95% CI for difference: 3.4, 24.0, p = 0.0116), and it remained higher at week 52 among the patients treated with RHB-104 (59/166 [35.5%] vs. (35/165 [21.2%] for placebo; 95% CI for difference: 4.7, 23.9, p = 0.0042). A statistically significantly greater decline in FCP (another prospective efficacy endpoint) was also observed in RHB-104-treated patients, compared with placebo, at weeks 12, 26, and 52. The rates of serious adverse events were similar between groups (RHB-104: 18.7%; placebo: 18.8%). No patient died during the study. Antimicrobial therapy directed against MAP resulted in significantly greater improvement in clinical and laboratory (FCP) measures of active Crohn’s disease.

Summary:. Intraoperative anaphylaxis can be life threatening. Anaphylaxis to gelatin-based topical hemostatic agents is an underrecognized hypersensitivity. To date, only 21 cases of intraoperative anaphylaxis have been reported for gelatin-based hemostatic agents. In this article, we report the case of a 10-year-old male patient who sustained anaphylaxis after the use of Gelfoam during harvest of a bone graft. Rapid diagnosis and treatment of intraoperative anaphylaxis is imperative to prevent adverse outcomes. Referral to an allergist for identification of the allergen and appropriate notation in the medical record are paramount to avoid future anaphylactic events. Surgeons should avoid gelatin-based hemostatic agents, such as Gelfoam, in patients with reported intolerance of gelatin-based foods and medicines.

Abstract Vascular cognitive impairment (VCI) describes a wide spectrum of cognitive deficits related to cerebrovascular diseases. Although the loss of blood flow to cortical regions critically involved in cognitive processes must feature as the main driver of VCI, the underlying mechanisms and interactions with related disease processes remain to be fully elucidated. Recent clinical studies of cerebral blood flow measurements have supported the role of chronic cerebral hypoperfusion (CCH) as a major driver of the vascular pathology and clinical manifestations of VCI. Here we review the pathophysiological mechanisms as well as neuropathological changes of CCH. Potential interventional strategies for VCI are also reviewed. A deeper understanding of how CCH can lead to accumulation of VCI-associated pathology could potentially pave the way for early detection and development of disease-modifying therapies, thus allowing preventive interventions instead of symptomatic treatments.

Abstract Sources of neurotoxic mercury in forests are dominated by atmospheric gaseous elemental mercury (GEM) deposition, but a dearth of direct GEM exchange measurements causes major uncertainties about processes that determine GEM sinks. Here we present three years of forest-level GEM deposition measurements in a coniferous forest and a deciduous forest in northeastern USA, along with flux partitioning into canopy and forest floor contributions. Annual GEM deposition is 13.4 ± 0.80 μg m−2 (coniferous forest) and 25.1 ± 2.4 μg m−2 (deciduous forest) dominating mercury inputs (62 and 76% of total deposition). GEM uptake dominates in daytime during active vegetation periods and correlates with CO2 assimilation, attributable to plant stomatal uptake of mercury. Non-stomatal GEM deposition occurs in the coniferous canopy during nights and to the forest floor in the deciduous forest and accounts for 24 and 39% of GEM deposition, respectively. Our study shows that GEM deposition includes various pathways and is highly ecosystem-specific, which complicates global constraints of terrestrial GEM sinks.

Abstract This study reviews the air pollution control strategy at an advanced semiconductor fab focusing on its continuous improvements and future challenges. A wide range of air pollutants is emitted from various sources classified as organic solvents, corrosive, toxic and combustible gases. This effective strategy employs a two-stage treatment method to comply with national emission regulations. Eight different types of local scrubbers (typ. gas flow rate: 0.3–2.0 CMM for the dry type or 60–83.3 CMM for the wet type) are used as pre-treatment devices at the first stage to remove specific target pollutants with high concentrations emitted from process chambers. Exhaust gases from local scrubbers are then grouped and further treated by central control facilities at the second stage, including the dual zeolite rotor-concentrator plus the thermal oxidizer for VOCs (typ. gas flow rate: 2500 CMM), the dual-central wet scrubbers (CWS) and alkaline CWS (typ. gas flow rate: 2000 CMM) for acid and alkaline gases, respectively. After the two-stage treatment, the removal efficiency of the VOCs can reach higher than 98.4%, surpassing the emission standard of 90%. The design parameters and operating conditions of the CWSs meet the criteria set in the emission standard for the semiconductor industry. In the future, CWS performance can further be improved by using advanced structured packing materials with larger specific surface areas to shorten the residence time and lower the chemical dosing amount and pressure drop while achieving higher removal efficiency for acid and alkaline gases at a reduced operating cost. The challenges to removing derived fine PM and white smoke still remain which can be resolved by using efficient control devices in the pre- and post-treatment stages, such as wet electrostatic precipitators. Finally, the by-product NOx can be minimized by using low-NOx burners or de-NOx control technologies in the future.

Abstract Background Early-onset renal cell carcinoma (eoRCC) is typically associated with pathogenic germline variants (PGVs) in RCC familial syndrome genes. However, most eoRCC patients lack PGVs in familial RCC genes and their genetic risk remains undefined. Methods Here, we analyzed biospecimens from 22 eoRCC patients that were seen at our institution for genetic counseling and tested negative for PGVs in RCC familial syndrome genes. Results Analysis of whole-exome sequencing (WES) data found enrichment of candidate pathogenic germline variants in DNA repair and replication genes, including multiple DNA polymerases. Induction of DNA damage in peripheral blood monocytes (PBMCs) significantly elevated numbers of $$\gamma$$ γ H2AX foci, a marker of double-stranded breaks, in PBMCs from eoRCC patients versus PBMCs from matched cancer-free controls. Knockdown of candidate variant genes in Caki RCC cells increased $$\gamma$$ γ H2AX foci. Immortalized patient-derived B cell lines bearing the candidate variants in DNA polymerase genes (POLD1, POLH, POLE, POLK) had DNA replication defects compared to control cells. Renal tumors carrying these DNA polymerase variants were microsatellite stable but had a high mutational burden. Direct biochemical analysis of the variant Pol δ and Pol η polymerases revealed defective enzymatic activities. Conclusions Together, these results suggest that constitutional defects in DNA repair underlie a subset of eoRCC cases. Screening patient lymphocytes to identify these defects may provide insight into mechanisms of carcinogenesis in a subset of genetically undefined eoRCCs. Evaluation of DNA repair defects may also provide insight into the cancer initiation mechanisms for subsets of eoRCCs and lay the foundation for targeting DNA repair vulnerabilities in eoRCC.

Abstract Air filters are widely used in residential and industrial applications. It is designed to remove particulate pollutants in the air to supply cleaner air to either occupants or industrial equipment. Without air filters, the occupants might suffer from polluted air, and expensive industrial equipment could be damaged by contaminants. However, air filters are installed and operated with a limited performance monitoring system, and the efficacy of air filters is unknown after replacement. Here, we propose and prototype a smart filter performance monitoring system that costs less than 200 U.S. dollars and can report filtration efficiency, differential pressure, temperature, and RH (relative humidity) in real time. Three case studies are presented: an air purifier, a teaching building HVAC (heating, ventilation, and air conditioning) system, and a large-scale air cleaning system. Applications of the proposed system cover from household to industrial, which not only verified the concept of the system but also proved its feasibility and advantages of the system. With the proposed system, residential customers can rest assured with their air purifiers or HVAC furnace filter; industrial customers can monitor the filtered air cleanness that will enter their internal combustion engines or gas turbines. Moreover, filter monitoring data can establish a database for researchers to validate the filter models or train a machine learning model for filter performance prediction. Filter or air-cleaning device manufacturers can improve their products or recommend suitable products to their customers based on big data contributed by this filter monitoring system.

Abstract Wearing respirators and face masks is effective for protecting the public from COVID-19 infection. Thus, there is a need to evaluate the performance of the commonly used respirators and face masks. Two experimental systems were developed to investigate seven different mask materials, which have a fiber size range from 0.1 µm (100 nm) to 20 µm (20,000 nm). One of the systems is a computer-controlled setup for measuring the filtration performance, including size-dependent filtration efficiency and pressure drop, while the other system is for testing the fiber shedding behavior of the materials. The technique of scanning electron microscope (SEM) was applied to observe the dimensions and structures of those materials, which are made of nonwoven-fabrics electret-treated media, cotton woven fabrics, or nanofiber media. The study indicated that the 3M N95 respirator has the best overall filtration performance with over 95% efficiency and low pressure drop of 74.1 Pa. The two commercial cotton face masks have the worst filtration performance in general, with a filtration efficiency of around 25%. No broken fibers from by the seven tested respirator and face mask materials were discovered; however, dendrite structures likely shed by the SHEMA97 face mask with a size comparable to its nanoscale fibers were identified. The reason for this phenomena is presented.

Abstract In the present study, water and saliva droplet evaporation rates are experimentally evaluated in various environmental conditions: temperature and relative humidity. We found that the ratio of saliva residue size to saliva initial droplet size is 0.216. We also found that the saliva correction factor which is defined as a ratio of water evaporation coefficient to saliva evaporation coefficient was not affected by environmental conditions and was determined as 0.857. By considering the evaporation and gravitational settling effects, the saliva airborne lifetime, i.e., the evaporation-falling curve is numerically calculated and characterized. In addition to this numerical calculation results, we present the simple correlation equation for obtaining the evaporation-falling curve under different temperatures and relative humidity.

Introduction: Ehlers–Danlos syndrome (EDS) is a connective tissue disorder that has been linked to several neurological problems including Chiari malformations, atlantoaxial instability (AAI), craniocervical instability (CCI), and tethered cord syndrome. However, neurosurgical management strategies for this unique population have not been well-explored to date. The purpose of this study is to explore cases of EDS patients who required neurosurgical intervention to better characterize the neurological conditions they face and to better understand how neurosurgeons should approach the management of these patients. Methods: A retrospective review was done on all patients with a diagnosis of EDS who underwent a neurosurgical operation with the senior author (FAS) between January 2014 and December 2020. Demographic, clinical, operative, and outcome data were collected, with additional radiographic data collected on patients chosen as case illustrations. Results: Sixty-seven patients were identified who met the criteria for this study. The patients experienced a wide array of preoperative diagnoses, with Chiari malformation, AAI, CCI, and tethered cord syndrome representing the majority. The patients underwent a heterogeneous group of operations with the majority including a combination of the following procedures– suboccipital craniectomy, occipitocervical fusion, cervical fusion, odontoidectomy, and tethered cord release. The vast majority of patients experienced subjective symptomatic relief from their series of procedures. Conclusions: EDS patients are prone to instability, especially in the occipital-cervical region, which may predispose these patients to require a higher rate of revision procedures and may require modifications in neurosurgical management that should be further explored.

Abstract High concentrations of ambient particulate matter (PM) have caused millions of premature deaths annually worldwide. The source control strategy was normally implemented to bring the PM pollution down to meet the standards. However, it took more than 50 years for UK and US. As PM pollution is hurting people’s health on daily basis in many countries, a fast and inexpensive control technology should be developed to remedy the slow pace of source control. It should be applied in highly polluted areas, e.g., cities and industrial parks, where people are spending a considerable time outdoors. In this study, a medium-scale filter-based blower-driven cleaning system was designed based on a computational fluid dynamic (CFD) simulation and experiments. We found the system with a dimension of 20 m (L) × 20 m (W) × 23 m (H) using 40 sets of 40-HP blowers can output ~1000 m3 s−1 (CMS) of cleaned air. In PM removal, the design of the system, including the filter specifications, filter bank arrangement, and filter quantity, is crucial which results in the PM filtration efficiency, filter service life, and energy consumption. The clean air delivery rate (CADR), the product of the system flow rate (1000 CMS) and filtration efficiency (> 80%), is expected to be more than 800 CMS or ~70,000,000 m3 day−1 (CMD). The experiments showed that the filter service life is expected to be 2 and 6 months for the prefilter and final filter, respectively, under total suspended particulate and PM2.5 concentrations of 600 and 300 (µg m−3, respectively. The CFD simulations showed the area of the effective PM2.5 reduction zone (> 50% PM2.5 concentration reduction) is as large as ~300 m in diameter by this system. The CFD model also shows deploying 400 cleaning systems with 1 km apart, the PM2.5 reduced zone can cover an area of 400 km2.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

BackgroundElectronic health record (EHR)–integrated digital personal health records (PHRs) via Fast Healthcare Interoperability Resources (FHIR) are promising digital health tools to support care coordination (CC) for children and youth with special health care needs but remain widely unadopted; as their adoption grows, mixed methods and implementation research could guide real-world implementation and evaluation. ObjectiveThis study (1) evaluates the feasibility of an FHIR-enabled digital PHR app for CC for children and youth with special health care needs, (2) characterizes determinants of implementation, and (3) explores associations between adoption and patient- or family-reported outcomes. MethodsThis nonrandomized, single-arm, prospective feasibility trial will test an FHIR-enabled digital PHR app’s use among families of children and youth with special health care needs in primary care settings. Key app features are FHIR-enabled access to structured data from the child’s medical record, families’ abilities to longitudinally track patient- or family-centered care goals, and sharing progress toward care goals with the child’s primary care provider via a clinician dashboard. We shall enroll 40 parents or caregivers of children and youth with special health care needs to use the app for 6 months. Inclusion criteria for children and youth with special health care needs are age 0-16 years; primary care at a participating site; complex needs benefiting from CC; high hospitalization risk in the next 6 months; English speaking; having requisite technology at home (internet access, Apple iOS mobile device); and an active web-based EHR patient portal account to which a parent or caregiver has full proxy access. Digital prescriptions will be used to disseminate study recruitment materials directly to eligible participants via their existing EHR patient portal accounts. We will apply an intervention mixed methods design to link quantitative and qualitative (semistructured interviews and family engagement panels with parents of children and youth with special health care needs) data and characterize implementation determinants. Two CC frameworks (Pediatric Care Coordination Framework; Patient-Centered Medical Home) and 2 evaluation frameworks (Consolidated Framework for Implementation Research; Technology Acceptance Model) provide theoretical foundations for this study. ResultsParticipant recruitment began in fall 2022, before which we identified >300 potentially eligible patients in EHR data. A family engagement panel in fall 2021 generated formative feedback from family partners. Integrated analysis of pretrial quantitative and qualitative data informed family-centered enhancements to study procedures. ConclusionsOur findings will inform how to integrate an FHIR-enabled digital PHR app for children and youth with special health care needs into clinical care. Mixed methods and implementation research will help strengthen implementation in diverse clinical settings. The study is positioned to advance knowledge of how to use digital health innovations for improving care and outcomes for children and youth with special health care needs and their families. Trial RegistrationClinicalTrials.gov NCT05513235; https://clinicaltrials.gov/study/NCT05513235 International Registered Report Identifier (IRRID)DERR1-10.2196/46847

BackgroundExcessive neutrophil extracellular traps (NETs) is involved in the progression of acute pancreatitis (AP) but the mechanisms controlling NETs formation in AP are not fully understood. Therefore, our study sought to investigate the mechanism of the highly expressed P-selectin stimulating the formation of NETs in AP.MethodsNETs formation was detected by flow cytometry, immunofluorescence staining, and cf-DNA and MPO-DNA complexes were measured as biomarkers of NETs formation. Neutrophils treated with P-selectin and pharmacological inhibitors were examined by western blot, immunofluorescence staining and flow cytometry. Mouse model of AP was established by caerulein and the effect of inhibiting P-selectin by PSI-697 on the level of NETs and PAD4 in pancreatic tissue was observed. The severity of AP was evaluated by histopathological score and the detection of serum amylase and lipase.ResultsPatients with AP had elevated levels of NETs and P-selectin compared with healthy volunteers. Stimulation of P-selectin up-regulated the expression of PSGL-1, increased the phosphorylation of Syk, mediated intracellular calcium signal and led to the activation and expression of PAD4, which modulated NETs formation in neutrophils. Pretreament with PSI-697 blunted NETs formation and PAD4 expression in the pancreatic tissue, and ameliorated the severity of AP in mice.ConclusionTaken together, these results suggest that P-selectin induces NETs through PSGL-1 and its downstream Syk/Ca2+/PAD4 signaling pathway, and that targeting this pathway might be a promising strategy for the treatment of AP.

The clinical management of wounds is known to be a significant challenge: not only does the dressing need to ensure and provide the appropriate barrier and healing characteristics, but consideration of patient compliance concerning comfort, functionality, and practicality also needs to be included. The poly(3-hydroxybutyrate-co-4-hydroxubutyrate) (P(3HB-co-4HB)) copolymer, isolated from Cupriavidus malaysiensis USM1020 (C. malaysiensis USM1020), was produced in the presence of excess carbon sources (1,4-butanediol and 1,6-hexanediol) using either a shake flask cultivation process or a bioreactor fermentation system. P(3HB-co-4HB) is widely known to be biodegradable and highly biocompatible and contains a tuneable 4HB monomer molar fraction, which is known to affect the final physicochemical properties of the intracellular copolymer. In this paper, we describe not only the fabrication of the polymeric gel but also its optimised profiling using a range of physical and mechanical techniques, i.e., SEM, FTIR, DMA, DSC, and WCA. The further enhancement of the gel through additional functionalisation with sol-gel-derived bioactive glass and liquid-exfoliated graphene was also investigated. The biocompatibility and biological characterisation of the substrates was assessed using murine osteoblasts (MC3T3), human primary dermal fibroblasts (HDFs), human fibroblast (BJ) cells, and standard cell culture assays (i.e., metabolic activity, LDH release, and live/dead staining). In short, P(3HB-co-4HB) was successfully isolated from the bacteria, with the defined physico-chemical profiles dependent on the culture substrate and culturing platform used. The additional enhancement of the copolymer with bioactive glass and/or graphene was also demonstrated by varying the combination loading of the materials, i.e., graphene resulted in an increase in tensile strength (~11 MPa) and the wettability increased following the incorporation of bioactive glass and 0.01 wt% graphene (WCA ~46.3°). No detrimental effects in terms of biocompatibility were noticed during the 7 days of culture in the primary and established cell lines. This study demonstrates the importance of optimising each of the individual components within the biocomposite and their relationship concerning the fine-tuning of the material’s properties, thus targeting and impacting the endpoint application.

Mutations in the chloride channel CFTR that impair plasma membrane insertion and ion transport are the cause of cystic fibrosis. Here, the authors identify a macrocycle that stabilizes the interaction of mutant CFTR with the chaperone-like protein 14-3-3 and rescues its biological function.

Abstract Background The effects of bone marrow mesenchymal stem cells (BMSCs) during the treatment of cartilage damage have been proven to be attributed to paracrine mechanisms, particularly the effect of exosomes. Exosomes from different batches are inhomogeneous, and different treatment effects are observed between samples. The purpose of this research was to find more effective and homogeneous exosomes for the repair of chondrocytes in osteoarthritis (OA). We observed the potential effects and possible mechanisms of exosomes derived from parathyroid hormone (PTH) (1-34)-preconditioned BMSCs (ExoPTH) in the alleviation of OA. Materials and methods Exosomes derived from BMSCs (ExoBMSC) and ExoPTH were isolated by differential centrifugation. Primary rat chondrocytes were used to establish the OA model by interleukin 1 beta (IL-1β) in vitro. The effects of these two types of exosomes on OA chondrocyte proliferation, migration, apoptosis, and extracellular matrix formation were measured and compared. We observed changes in IL-2, TNF-α, and IL-6 levels via Western blotting (WB), and quantitative real-time PCR (qRT–PCR). Results We successfully extracted ExoBMSC and ExoPTH and established an IL-1β-induced OA model in primary chondrocytes from rats. Our study showed that IL-2, TNF-α, and IL-6 levels increased significantly in OA chondrocytes; however, both ExoBMSC and ExoPTH reduced the levels of IL-2, TNF-α, and IL-6. In addition, ExoPTH exhibited stronger anti-inflammatory effects. ExoPTH had a more marked effect on proliferation, migration, and production of the extracellular matrix (Col-II) in OA chondrocytes than ExoBMSC at 24 h. Conclusion ExoPTH increased the migration, proliferation, and chondral matrix formation of OA chondrocytes in vitro. In OA chondrocyte therapy, the potential mechanism of ExoPTH might involve the inhibition of production of proinflammatory cytokines. Although the two types of exosomes had some similar effects, most effects of ExoPTH were better than those of ExoBMSC, so ExoPTH may have a better ability to alleviate OA.

Abstract Properly responding to DNA damage is vital for eukaryotic cells, including the induction of DNA repair, growth arrest and, as a last resort to prevent neoplastic transformation, cell death. Besides being crucial for ensuring homeostasis, the same pathways and mechanisms are at the basis of chemoradiotherapy in cancer treatment, which involves therapeutic induction of DNA damage by chemical or physical (radiological) measures. Apart from typical DNA damage response mediators, the relevance of cell-intrinsic antiviral signaling pathways in response to DNA breaks has recently emerged. Originally known for combatting viruses via expression of antiviral factors including interferons (IFNs) and establishing of an antiviral state, RIG-I-like receptors (RLRs) were found to be critical for adequate induction of cell death upon the introduction of DNA double-strand breaks. We here show that presence of IRF3 is crucial in this process, most likely through direct activation of pro-apoptotic factors rather than transcriptional induction of canonical downstream components, such as IFNs. Investigating genes reported to be involved in both DNA damage response and antiviral signaling, we demonstrate that IRF1 is an obligatory factor for DNA damage-induced cell death. Interestingly, its regulation does not require activation of RLR signaling, but rather sensing of DNA double-strand breaks by ATM and ATR. Hence, even though independently regulated, both RLR signaling and IRF1 are essential for full-fledged induction/execution of DNA damage-mediated cell death programs. Our results not only support more broadly developing IRF1 as a biomarker predictive for the effectiveness of chemoradiotherapy, but also suggest investigating a combined pharmacological stimulation of RLR and IRF1 signaling as a potential adjuvant regimen in tumor therapy.

Background: Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the morbidity and mortality of individuals with breast cancer, the use of these agents is limited by adverse cardiotoxic side effects. Both the nutraceutical agent flaxseed (FLX) and the pharmaceutical drug perindopril (PER) have been studied individually in the prevention of chemotherapy-mediated cardiac dysfunction. The objective of this study was to determine whether the prophylactic administration of FLX is comparable and/or synergistic with PER in preventing DOX + TRZ-induced cardiotoxicity. Methods: Over a six-week period, 81 wild-type C57Bl/6 female mice (8–12 weeks old) were randomized to receive regular chow (RC) or 10% FLX-supplemented diets with or without PER (3 mg/kg/week; oral gavage). Starting at week 4, mice were randomized to receive a weekly injection of saline or DOX (8 mg/kg) + TRZ (3 mg/kg). Serial echocardiography was conducted weekly and histological and biochemical analyses were performed at the end of the study. Results: In mice treated with RC + DOX + TRZ, left ventricular ejection (LVEF) decreased from 75 ± 2% at baseline to 37 ± 3% at week 6. However, prophylactic treatment with either FLX, PER, or FLX + PER partially preserved left ventricular systolic function with LVEF values of 61 ± 2%, 62 ± 2%, and 64 ± 2%, respectively. The administration of FLX, PER, or FLX + PER was also partially cardioprotective in preserving cardiomyocyte integrity and attenuating the expression of the inflammatory biomarker NF-κB due to DOX + TRZ administration. Conclusion: FLX was equivalent to PER at preventing DOX + TRZ-induced cardiotoxicity in a chronic in vivo murine model.

Abstract Background Traditional fishing communities are strongholds of ethnobiological knowledge but establishing to what degree they harbor cultural consensus about different aspects of this knowledge has been a challenge in many ethnobiological studies. Methods We conducted an ethnobiological study in an artisanal fishing community in northeast Brazil, where we interviewed 91 community members (49 men and 42 women) with different type of activities (fishers and non-fishers), in order to obtain free lists and salience indices of the fish they know. To establish whether there is cultural consensus in their traditional knowledge on fish, we engaged a smaller subset of 45 participants in triad tasks where they chose the most different fish out of 30 triads. We used the similarity matrices generated from the task results to detect if there is cultural consensus in the way fish were classified by them. Results The findings show how large is the community’s knowledge of fish, with 197 ethnospecies registered, of which 33 species were detected as salient or important to the community. In general, men cited more fish than women. We also found that there was no cultural consensus in the ways fish were classified. Conclusions Both free-listing and triad task methods revealed little cultural consensus in the way knowledge is structured and how fish were classified by community members. Our results suggest that it is prudent not to make assumptions that a given local community has a single cultural consensus model in classifying the organisms in their environment.

Abstract Most cases of cystic fibrosis (CF) are caused by class 2 mutations in the cystic fibrosis transmembrane regulator (CFTR). These proteins preserve some channel function but are retained in the endoplasmic reticulum (ER). Partial rescue of the most common CFTR class 2 mutant, F508del-CFTR, has been achieved through the development of pharmacological chaperones (Tezacaftor and Elexacaftor) that bind CFTR directly. However, it is not clear whether these drugs will rescue all class 2 CFTR mutants to a medically relevant level. We have previously shown that the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen can correct F508del-CFTR trafficking. Here, we utilized RNAi and pharmacological inhibitors to determine the mechanism of action of the NSAID glafenine. Using cellular thermal stability assays (CETSAs), we show that it is a proteostasis modulator. Using medicinal chemistry, we identified a derivative with a fourfold increase in CFTR corrector potency. Furthermore, we show that these novel arachidonic acid pathway inhibitors can rescue difficult-to-correct class 2 mutants, such as G85E-CFTR > 13%, that of non-CF cells in well-differentiated HBE cells. Thus, the results suggest that targeting the arachidonic acid pathway may be a profitable way of developing correctors of certain previously hard-to-correct class 2 CFTR mutations.

Neufeldt et al. evaluate transcriptional and cytokine secretion profiles of cells and patient sera following SARS-CoV-2 infection and detect distinct upregulation of inflammatory cytokines. They also demonstrate that this upregulation is mediated by cGAS-STING and NF-κB signalling, which could provide a potential avenue for the development of future therapies against SARS-CoV-2.

Abstract There is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset and progression. However, there is a limited understanding of the underlying pathophysiology of VCI, especially in relation to CCH. Neuroinflammation is a significant contributor in the progression of VCI as increased systemic levels of the proinflammatory cytokine interleukin-1β (IL-1β) has been extensively reported in VCI patients. Recently it has been established that CCH can activate the inflammasome signaling pathways, involving NLRP3 and AIM2 inflammasomes that critically regulate IL-1β production. Given that neuroinflammation is an early event in VCI, it is important that we understand its molecular and cellular mechanisms to enable development of disease-modifying treatments to reduce the structural brain damage and cognitive deficits that are observed clinically in the elderly. Hence, this review aims to provide a comprehensive insight into the molecular and cellular mechanisms involved in the pathogenesis of CCH-induced inflammasome signaling in VCI.

Abstract Neuroimaging is crucial for assessing mass effect in brain-injured patients. Transport to an imaging suite, however, is challenging for critically ill patients. We evaluated the use of a low magnetic field, portable MRI (pMRI) for assessing midline shift (MLS). In this observational study, 0.064 T pMRI exams were performed on stroke patients admitted to the neuroscience intensive care unit at Yale New Haven Hospital. Dichotomous (present or absent) and continuous MLS measurements were obtained on pMRI exams and locally available and accessible standard-of-care imaging exams (CT or MRI). We evaluated the agreement between pMRI and standard-of-care measurements. Additionally, we assessed the relationship between pMRI-based MLS and functional outcome (modified Rankin Scale). A total of 102 patients were included in the final study (48 ischemic stroke; 54 intracranial hemorrhage). There was significant concordance between pMRI and standard-of-care measurements (dichotomous, κ = 0.87; continuous, ICC = 0.94). Low-field pMRI identified MLS with a sensitivity of 0.93 and specificity of 0.96. Moreover, pMRI MLS assessments predicted poor clinical outcome at discharge (dichotomous: adjusted OR 7.98, 95% CI 2.07–40.04, p = 0.005; continuous: adjusted OR 1.59, 95% CI 1.11–2.49, p = 0.021). Low-field pMRI may serve as a valuable bedside tool for detecting mass effect.